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Use eyedropper tool to select colors from the expanded color palette: Nuvalent Overview February 26, 2026
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes CAUTIONARY NOTE REGARDING FORWARD -LOOKING STATEMENTS 2 This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding Nuvalent's strategy, business plans, and focus; Nuvalent’s estimated cash runway; the expected timing of potential new product candidate announcements, clinical trial initiations, FDA submissions, product approvals and commercial launch, including the projections in our OnTarget 2026 operating plan; the clinical development programs for zidesamtinib, neladalkib and NVL-330; the potential clinical effects of Nuvalent's product development candidates; the design, timing and enrollment of Nuvalent’s clinical trials, including for the ARROS-1, ALKOVE-1 and ALKAZAR trials their intended pivotal registration-directed design; the potential of Nuvalent's pipeline programs, including zidesamtinib, neladalkib and NVL-330 and expectations regarding Nuvalent’s discovery pipeline; Nuvalent's potential commercialization of its product candidates, if approved; the implications of data readouts and presentations; timing and content of potential discussions with FDA; Nuvalent's research and development programs for the treatment of cancer; and risks and uncertainties associated with drug development. The words "may," "might," "will," "could," "would," "should," "expect," "plan," "anticipate," "aim," "goal," "intend," "believe," "expect," "estimate," "seek," "predict," "future," "project," "potential," "continue," "target" or the negative of these terms and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. You should not place undue reliance on these statements or the scientific data presented. Any forward-looking statements in this presentation are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties, and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this presentation, including, without limitation: risks that Nuvalent may not fully enroll its clinical trials or that enrollment will take longer than expected; unexpected concerns that may arise from additional data, analysis, or results obtained during preclinical studies or clinical trials; the risk that results of earlier clinical trials may not be predictive of the results of later-stage clinical trials; the risk that data from our clinical trials may not be sufficient to support registration and that Nuvalent may be required to conduct one or more additional studies or trials prior to seeking registration of zidesamtinib and neladalkib; risks that Nuvalent may not achieve the goals and milestones set forth in its OnTarget 2026 operating plan; the occurrence of adverse safety events; risks that the FDA may not approve our potential products on the timelines we expect, or at all; risks of unexpected costs, delays, or other unexpected hurdles; risks that Nuvalent may not be able to nominate drug candidates from its discovery programs; the direct or indirect impact of public health emergencies or global geopolitical circumstances on the timing and anticipated timing and results of Nuvalent’s clinical trials, strategy, and future operations, including the ARROS-1, ALKOVE-1, ALKAZAR and HEROEX-1 trials; the timing and outcome of Nuvalent’s planned interactions with regulatory authorities; and risks related to obtaining, maintaining, and protecting Nuvalent’s intellectual property. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Nuvalent’s Annual Report on Form 10-K for the period ended December 31, 2025, as well as any prior and subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Nuvalent’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Nuvalent explicitly disclaims any obligation to update any forward-looking statements.
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxesPlease do not move the page number or footer boxes • Parallel lead programs for ROS1+ and ALK+ NSCLC: Global clinical development ongoing with potential for first U.S. commercial launch in 2026 • Proven discovery capabilities: Third program for HER2-altered NSCLC in Phase 1 investigation & active research pipeline Nasdaq listed Growing team (200+ FTEs) NUVL 3 Hybrid operations with offices in Cambridge, MA Cash runway expected into 2029
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxesPlease do not move the page number or footer boxes 4 GOAL: Maximize Patient Impact Deep Expertise in Chemistry and Structure-based Drug Design Aim to “thread the needle” between kinase resistance and selectivity Aim to Compete in 1st Line with Best-in-Class Profiles Design of Target Product Profiles in Collaboration with Physician-Scientists THE NUVALENT APPROACH
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Meet the 5 Significant experience in drug discovery, development and company building B O A R D O F D I R E C TO R S Grant Bogle Independent Michael Meyers, MD, PhD CMO, Flare Therapeutics Christy Oliger Independent Joseph Pearlberg, MD, PhD Deerfield Management Anna Protopapas Independent James Porter, PhD CEO, Nuvalent Ron Squarer Independent Sapna Srivastava, PhD Independent Cameron Wheeler, PhD Deerfield Management S C I E N T I F I C A D V I S O RS Ross Camidge, MD, PhD Clinical Advisor University of Colorado Alexander Drilon, MD Clinical Advisor Memorial Sloan Kettering Cancer Center Gary Gilliland, MD, PhD Scientific Advisor Independent Consultant Aaron Hata, MD, PhD Translational Research Advisor Mass General Cancer Center Pasi Jänne, MD, PhD Clinical Advisor Dana Farber Cancer Institute Nancy Kohl, PhD Translational Research Advisor Independent Consultant Alice Shaw, MD, PhD Clinical Advisor Dana Farber Cancer Institute L E A D E R S H I P T E A M 12 Prior FDA Approvals* * Experience prior to joining Nuvalent James Porter, PhD Chief Executive Officer Deborah Miller, PhD, JD Chief Legal Officer Josh Horan, PhD SVP, Chemistry Matthew Metivier SVP, Human Resources Alex Balcom, MBA, CPA Chief Financial Officer Darlene Noci, ALM Chief Development Officer Benjamin Lane, PhD SVP, Technical Operations Henry Pelish, PhD Chief Scientific Officer Christopher Turner, MD Chief Medical Officer John Soglia, PhD SVP, Translational Development Jessie Lin SVP, Corporate Strategy & Portfolio Management Ruth Adams SVP, Clinical Operations Jason Waters SVP, Commercial
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 6 Advancing a portfolio of potentially best-in-class products, with complementary initial indications in NSCLC PIPELINE CLINICAL TRIAL ZIDESAMTINIB (NVL-520) NELADALKIB (NVL-655) NVL-330 TKI pre-treated advanced ROS1+ NSCLC TKI-naïve advanced ROS1+ NSCLC Other advanced ROS1+ solid tumors TKI pre-treated advanced ALK+ NSCLC Other advanced ALK+ solid tumors TKI-naïve advanced ALK+ NSCLC (vs. alectinib) Advanced HER2-altered NSCLC PH 1 PH 2 PH 3 STATUS TKI Pre-Treated ALK+ NSCLC: Topline data reported November 2025 Other ALK+ Solid Tumors: Preliminary data reported, enrollment ongoing NDA, new drug application; NSCLC, non-small cell lung cancer; PDUFA, prescription drug user fee act; TKI, tyrosine kinase inhibitor. Registration-directed trial for TKI-naïve ALK+ NSCLC: Enrollment ongoing Enrollment Ongoing NDA for TKI Pre-Treated ROS1+ NSCLC: PDUFA target action date of September 18, 2026 TKI-Naïve ROS1+ NSCLC: Preliminary data reported, enrollment ongoing Additional Discovery Research Programs Ongoing
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes MISSION: Bringing new, potential best-in-class medicines to patients with cancer 7 US commercial launch of zidesamtinib in TKI pre-treated ROS1+ NSCLC in 2H, pending FDA review Submit data to FDA for potential label expansion of zidesamtinib in TKI-naïve ROS1+ NSCLC in 2H Submit NDA for neladalkib in TKI pre-treated ALK+ NSCLC in 1H Progress ALKAZAR Phase 3 trial for TKI-naïve ALK+ NSCLC Progress HEROEX-1 Phase 1a/1b trial for HER2-altered NSCLC Disclose new development candidate by year-end Anticipated 2026 Milestones: 2024 EXECUTE ON GLOBAL REGISTRATIONAL STRATEGIES 2025 FIRST PIVOTAL DATA 2026 FIRST APPROVED PRODUCT GOAL:
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxesPlease do not move the page number or footer boxes 8 Reimagine what is possible Realize the full potential ROS1+ NSCLC ALK+ NSCLC Growing team (200+ FTEs) building integrated US commercial capabilities Well-positioned to unlock the potential for Patient Impact within ROS1+ and ALK+ NSCLC Well capitalized, with cash runway expected into 2029 Pivotal data demonstrates potential to deliver meaningful durability and tolerability
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxesPlease do not move the page number or footer boxes 9 Jim B, patient living with advanced ROS1+ NSCLC Reimagine what is possible ROS1+ NSCLC “ROS1 lung cancer can happen to anyone. I’m a never smoker and considered myself an endurance athlete. While leading a cycling team on a 100-mile ride, I became short of breath. Never could I have imagined this would lead to a diagnosis of lung cancer at age 47.”
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes S T A N D A R D O F C A R E K E Y L I M I T A T I O N S Crizotinib ($374M WW sales, 2023) 4 NCCN guidelines recognize that other ROS1 TKIs may be better for patients with brain metastasis at diagnosis 5 Single ROS1 resistance mutations ROS1 G2032R mutation observed in ~40% of patients progressing on crizotinib 6 Brain penetrance • ~20 – 40% present with brain metastases at diagnosis 7,8 • ~30 – 55% have brain metastases at 1L progression 6,7 ❖ Improve 1L durability of response, while also avoiding CNS adverse events Crizotinib mDOR: 18.3 months 11 Crizotinib mPFS: 19.3 months 12 Evolving standard of care Patients may consider other approved ROS1 TKIs, clinical trials, or chemotherapy/I-O 5 Treatment-limiting off-target adverse events CNS adverse events associated with TRK inhibition observed in 77% of patients receiving the dual TRK/ROS1 inhibitor, repotrectinib 9 Dose reductions due to adverse reactions occurred in 29 – 38% of patients receiving repotrectinib or taletrectinib 9,10 ❖ Improve durability of response after crizotinib or entrectinib, while also avoiding CNS adverse events: USPIs for repotrectinib and taletrectinib*: mDOR: 13.2 – 14.8 months 9, 10 No clear standard of care Patients may consider clinical trials or chemotherapy/I-O 5 Activity No approved therapies have demonstrated activity after the recently approved dual TRK/ROS1 TKIs, repotrectinib or taletrectinib 5 ❖ Demonstrate activity after 2+ prior ROS1 TKIs, including in patients who are repotrectinib and/or taletrectinib experienced ~1 – 3 % of NSCLC 1,2 | Majority are advanced/metastatic at diagnosis 3 ROS1+ NSCLC Treatment Paradigm * Most patients received prior crizotinib only (82% of patients receiving repotrectinib, 79 – 100% of patients receiving taletrectinib). CNS, central nervous system; DOR, duration of response; m, median; ORR, objective response rate; TKI, tyrosine kinase inhibitor; USPI, US prescribing information. Sources: [1] Drilon A. et al., Nat Rev Clin Oncol. 2021. [2] Jordan E.J. et al., Cancer Discovery 2017. [3] Chia P.L. et al., Clin Epidemiol. 2014. [4] Pfizer 2023 Year-end Earnings Report. [5] NCCN Guidelines for NSCLC (version 2.2026). [6] Gainor J et al. JCO Precis Oncol. 2017. [7] Ou S.I. and Zhu V.W., Lung Cancer 2019. [8] Patil T. et al., J Thorac Oncol. 2018. [9] AUGTYRO FDA prescribing information, revised 06/2024. [10] IBTROZI FDA prescribing information, revised 06/2025. [11] XALKORI FDA prescribing information, revised 09/2023. [12] Shaw A. et al., Ann Oncol. 2019. 2L 1L 3L+ POTENTIAL OPPORTUNITY for PATIENT IMPACT 10
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Reimagine what is possible with a ROS1 TKI 11 Sources: [1] Shaw A. et al., Ann Oncol. 2019. [2] Cortellis, product sales accessed 01/2026. [3] Drilon A. et al., JTO 2022. [4] Solomon B.J. et al., J Clin Oncol. 2024. [5] Crizotinib is FDA approved for ROS1+ NSCLC and ALK+ NSCLC, ALCL, and IMT, but sales are not reported by indication and are no longer separately reported as of 2024; Assumes the large majority of crizotinib sales are for ROS1 following alectinib 1L ALK approval in 2017. [6] Year-end Earnings Reports for Pfizer (2023), Roche (2025), and BMS (2024). [7] Sales of repotrectinib are no longer separately reported as of 2025. [8] AUGTYRO FDA prescribing information, revised 06/2024. [9] Desilets et al., Cancer. 2025. NUVALENT VISION Transform the expectation for patient outcomes Deliver transformative durability and tolerability, across lines of therapy, with the first ROS1-selective TKI Unlock the market potential of ROS1+ NSCLC Build a prevalent population of patients living long-term with ROS1+ NSCLC Market Opportunity BACKGROUND: ROS1 is a proven oncogenic driver, but outcomes today may not be as durable compared to other known targets 1,3,4 BACKGROUND: Global sales reflect the continued primary use of 1st generation TKIs INSIGHT: Next generation TKIs that address key drivers of disease progression, including brain penetrance and resistance mutations, are transforming durability for other known targets Lorlatinib for ALK+ NSCLC (3rd Generation TKI) 1L mPFS = Not Reached at 60 months 4 Patient Outcomes & NUVALENT VISION Crizotinib for ROS1+ NSCLC 1L mPFS = 19.3 months 1 1st Generation TKI & Global Market Leader 2 Entrectinib for ROS1+ NSCLC 1L mPFS = 15.7 months 3 1st Generation TKI & 1L Alternative Crizotinib WW sales (2023): $374M 5,6 Entrectinib WW sales (2025): $176M 6 Repotrectinib WW sales (2024): $38M 6,7 INSIGHT: Other available TKIs such as repotrectinib are dual TRK/ROS1 inhibitors associated with risk of CNS adverse events 8 For this patient population that is often diagnosed at a younger age, new options are needed to offer both durability and tolerability 9
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Zidesamtinib A Rationally Designed ROS1-selective, TRK-sparing Inhibitor Zidesamtinib is an investigational candidate and has not been approved by FDA or any other regulatory authority. CNS, central nervous system; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor; TRK, proteins encoded for by the neurotrophic tyrosine receptor kinase (NTRK) family of genes. Sources: [1] Drilon A. et al., Nat Rev Clin Oncol. 2021. [2] Jordan E.J. et al., Cancer Discovery 2017. [3] Gainor J et al. JCO Precis Oncol. 2017. [4] Ou S.I. and Zhu V.W., Lung Cancer 2019. [5] Patil T. et al., J Thorac Oncol. 2018. [6] AUGTYRO FDA prescribing information, revised 06/2024. Potential Best-in-Class Target Product Profile designed in collaboration with physician-scientists to address the limitations of existing agents for ROS1+ NSCLC ROS1 Activity • Primary oncogenic driver in ~1 – 3% of NSCLC 1,2 ROS1 Mutant Activity • ~40% ROS1 G2032R mutation after 1L standard of care, crizotinib 3 CNS Activity • ~20 – 40% CNS disease at diagnosis 4,5 • ~30 – 55% CNS disease after 1L standard of care, crizotinib 3,4 Avoiding TRK • Treatment-limiting neurological adverse events observed with brain-penetrant, dual TRK/ROS1 inhibitors 6 N VL-520 + + + D ES I G N G OAL for Z I D ESA MT I N I B 12
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 13 Preclinical Characterization Demonstrates Desired Target Product Profile Head-to-head clinical studies comparing zidesamtinib (NVL-520) with currently approved or investigational therapies have not been conducted. Above data from preclinical studies and no clinical conclusions can be drawn. BID, twice daily; IC50, half-maximal inhibitory concentration; PDC, patient-derived cell line; PO, orally; pTRK, BDNF-stimulated TRKB phosphorylation. Sources: Drilon A. et al., Cancer Discov 2023; Tangpeerachaikul, A. et al., AACR 2022; Deshpande, A. et al., EORTC-NCI-AACR 2021; Pelish, H.E. et al., AACR 2021. Z I D E S A M T I N I B ( N V L - 520) In Vitro Activity, ROS1 Wild-type & Mutant Sub-10nM activity in 3-day cell viability assays Crizotinib Entrectinib Lorlatinib Taletrectinib Repotrectinib NVL-520 10 -2 10 -1 10 0 10 1 10 2 10 3 10 4 IC50 (nM) Wild-type G2032R F2004C S1986F F2004V L2026M D2033N Ba/F3 expressing WT or mutant CD74-ROS1 fusion: More active for TRKB More active for ROS1 Avoiding TRK Inhibition Selectivity for ROS1 and ROS1 G2032R over TRK 0.01 1 100 10000 Selectivity Index ROS1 vs TRKB ROS1 G2032R vs TRKB 670x 240x 7.7x 0.3x 3.4x 0.07x 0.2x 0.03x NVL-520 Crizotinib Entrectinib Repotrectinib IC50 (pTRKB) IC50 (Ba/F3 CD74-ROS1) Selectivity Index = Taletrectinib 5.8x 1.4x Zidesamtinib
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Crizotinib Entrectinib Lorlatinib Repotrectinib Taletrectinib Zidesamtinib 0.00 0.05 0.10 0.15 0.20 Unbound brain:plasma ratio (Kp,uu) C O N F I D E N T I A L14 Preclinical Characterization Demonstrates Desired Target Product Profile Head-to-head clinical studies comparing zidesamtinib (NVL-520) with currently approved or investigational therapies have not been conducted. Above data from preclinical studies and no clinical conclusions can be drawn. BID, twice daily; QD, once daily. Sources: Tangpeerachaikul et al., Mol Cancer Ther 2025.; Internal data on file. Z I D E S A M T I N I B ( N V L - 520) 0 7 14 21 0 50 100 150 500 1500 2500 Days on treatment Brain bioluminescence (106 photons/s) -100 -50 0 50 2500 5000 Brain bioluminescence (%) * * 0 7 14 21 0 50 100 150 500 1500 2500 Days on treatment Brain BLI (×106 photons/s) Vehicle BID Taletrectinib 100 mg/kg QD ** 2 of 6 mice did not survive to endpoint Repotrectinib 75 mg/kg BID Zidesamtinib 3 mg/kg BID Brain Penetrance Pharmacokinetic data similar to preclinical observations for lorlatinib Wistar Han rats 10 mg/kg, single dose PO 1 hour timepoint Preclinical Intracranial Efficacy Durable inhibition of intracranially implanted Ba/F3 CD74-ROS1 G2032R luciferase cells Taletrectinib Repotrectinib Zidesamtinib Brain Tumor Burden Brain Tumor Burden Change, 23 days
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Zidesamtinib | Global Development Strategy 15 Opportunity for single-arm registration path for line-agnostic expansion: • No prior ROS1 TKI, ≤ 1 prior line of chemo/I-O ❖ n = 104 enrolled as of June 16, 2025 Topline data supports opportunity for broad TKI pre-treated label: • TKI pre-treated ROS1+ NSCLC receiving zidesamtinib at RP2D (N = 117) Phase 2: TKI Pre-treated Cohorts Global enrollment complete Phase 2: TKI-naïve Cohort Global enrollment ongoing 2 L + 1L Parallel development paths ongoing to establish zidesamtinib as a best-in-class drug for all patients with ROS1+ NSCLC NDA accepted for filing by FDA with PDUFA target action date of September 18, 2026 NDA, new drug application; NSCLC, non-small cell lung cancer; RP2D, recommended phase 2 dose (100 mg QD); RTOR, real-time oncology review; TKI, tyrosine kinase inhibitor. Enrollment ongoing for adult and pediatric patients with other ROS1+ solid tumors Submission of data to FDA planned for 2H’26 for potential label expansion in TKI-naïve ROS1+ NSCLC
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes P H A SE 2 I N I T I ATE D SE P T E M BE R 2023 (R P 2D : 100 m g Q D ) Global open-label, multi-cohort design with registrational intent for both TKI pre-treated and TKI-naïve ROS1+ NSCLC 16 A Global First-in-Human Phase 1/2 Clinical Trial of Zidesamtinib in Advanced ROS1-Positive NSCLC and Other Solid Tumors (NCT05118789) CBR, clinical benefit rate; DOR, duration of response; ORR, objective response rate; OS, overall survival; PFS, progression free survival; PK, pharmacokinetics; PRO, patient reported outcomes; QD, once daily; RP2D, recommended phase 2 dose; TKI, tyrosine kinase inhibitor; TTR, time to response. a Either crizotinib or entrectinib; b Platinum-based chemotherapy with or without immunotherapy; c With initial TKI of either crizotinib or entrectinib; d Includes NSCLC who do not qualify for any of the other cohorts. A R R O S- 1 C O H O R T T U M O R T Y P E T R E A T M E N T S T A T U S P R I O R R O S 1 T K I P R I O R C H E M O / I- O D E T A I L 2a ROS1-positive NSCLC ROS1 TKI Naive None ≤ 1 Registrational Intent 2b ROS1-positive NSCLC ROS1 TKI Pre-treated 1a None 2c 1a 1b 2d ≥ 2c ≤ 1 2e Any ROS1-positive Solid Tumor d Any Prior Therapy Any Any Exploratory Cohort • Primary Objective: ORR by blinded independent central review • Secondary Objectives: Additional efficacy measures (DOR, TTR, CBR, PFS, OS), intracranial activity, overall safety and tolerability, confirmation of PK profile, PROs P H A SE 1 I N I T I ATE D JA N UA RY 2022 First-in-human dose-escalation in heavily pre-treated ROS1+ NSCLC & other solid tumors Preliminary data demonstrated clinical proof-of- concept for zidesamtinib’s target product profile: OCTOBER 2024 Updated Phase 1 Data: Durable responses in heavily pre-treated population Besse et al., ESMO 2024 SEPTEMBER 2022 Preliminary Phase 1 Data: Clinical proof-of concept in heavily pre-treated population Drilon et al., EORTC-NCI-AACR 2022
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Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines. Use eyedropper tool to select colors from the expanded color palette: Please try to avoid covering the logo Please do not move the page number or footer boxes 17 0 100 200 300 400 500 600 700 Jan-22 Jan-23 Jan-24 Dec-24 Phase 1 SEPTEMBER 2022 35 Phase 1 MAY 2023 87 Phase 1 Initiation JANUARY 2022 JUNE 16, 2025 539 104 Phase 1 + 435 Phase 2 Transition to Phase 2 SEPTEMBER 2023 104 Phase 1 + Phase 2 SEPTEMBER 2024 331 PHASE 1 + PHASE 2 PATIENT ENROLLMENT Strong enrollment momentum demonstrates enthusiasm for zidesamtinib & clear medical need for TKI pre-treated patients Phase 1 + Phase 2 DECEMBER 31, 2024 430 Phase 1 + Phase 2 MARCH 21, 2025 514
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Use eyedropper tool to select colors from the expanded color palette: Keep content within provided margin guidelines: 12” width – It is ok to adjust width of title vs content boxes as needed. Keep content within provided margin guidelines. It is ok to adjust height of title vs. content boxes as needed. Please try to avoid covering the logoPlease do not move the page number or footer boxes Pivotal Data Populations 18 BICR, blinded independent central review; DOR, duration of response; NSCLC, non-small cell lung cancer; RP2D, recommended phase 2 dose (100 mg QD); TKI, tyrosine kinase inhibitor. a Includes 4 patients with other oncogenic driver(s) in addition to ROS1. b Includes 1 patient with other oncogenic driver(s) in addition to ROS1. ROS1+ NSCLC Pivotal Safety Population 432 Treated at RP2D as of March 21, 2025 Total Enrolled as of March 21, 2025: Phase 1 + Phase 2 514 Any ROS1+ solid tumor, any dose TKI Pre-treated ROS1+ NSCLC a Pivotal Primary Analysis Population 117 Treated at RP2D by May 31, 2024 to allow for at least 6 months DOR follow up for nearly all responders by March 21, 2025 TKI-Naïve ROS1+ NSCLC b Preliminary Data 35 Treated by August 31, 2024 ROS1+ NSCLC treated at RP2D with measurable disease by BICR • Pivotal ROS1+ NSCLC safety population (n = 432) and TKI pre-treated efficacy population (n = 117) • Preliminary data available from 35 TKI-naïve patients with ROS1+ NSCLC ❖ Enrollment continues in TKI-naïve ROS1+ NSCLC and ROS1+ solid tumor cohorts
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Pre-treated ROS1+ NSCLC Population at RP2D 19 Data cut-off: March 21, 2025. All data shown as n (%) unless otherwise specified. BICR, blinded independent central review; CNS, central nervous system; NSCLC, non-small cell lung cancer; RP2D, recommended phase 2 dose (100 mg QD); TKI, tyrosine kinase inhibitor. a Includes 4 patients with other oncogenic driver(s) in addition to ROS1. b By BICR; includes patients with untreated CNS lesions and patients with prior disease progression on the brain-penetrant TKIs entrectinib, lorlatinib, repotrectinib, and/or taletrectinib. c ROS1 mutations as per local or central testing of blood (ctDNA) or tissue. TKI Pre-treated Pivotal Data Z I D E S A M T I N I B ( N V L - 520) Patient Characteristic ROS1 TKI Pre-Treated a Pivotal Efficacy Population N = 117 Age, median (range) 57 (31 – 83) Female 66 (56%) Never smoker 80 (68%) Geographic Region Asia Pacific 30 (26%) Europe 38 (32%) North America 49 (42%) ECOG PS 0 45 (38%) 1 72 (62%) Active CNS disease b 57 (49%) Secondary ROS1 mutation c 42 (36%) G2032R 26 (22%) Treatment History ROS1 TKI Pre-Treated a Pivotal Efficacy Population N = 117 Prior anticancer therapy, median (range) 2 (1 – 11) Prior chemotherapy 62 (53%) Prior ROS1 TKIs ± chemotherapy 1 prior (crizotinib or entrectinib) 55 (47%) Crizotinib 28/55 (51%) Entrectinib 27/55 (49%) 1 prior (repotrectinib or taletrectinib) 4 (3%) ≥2 prior 58 (50%) Lorlatinib, repotrectinib, or taletrectinib 54/58 (93%) Lorlatinib 43/58 (74%) Repotrectinib 15/58 (26%) Taletrectinib 5/58 (9%) Ability to evaluate activity broadly across TKI pre-treated patients and against key drivers of disease progression:
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Topline Efficacy: TKI Pre-treated ROS1+ NSCLC 20 TKI Pre-treated Pivotal Data Z I D E S A M T I N I B ( N V L - 520) Responses were also observed in patients previously treated with: • ≥2 prior ROS1 TKIs ± chemotherapy: ORR = 38% (22/58; 95% CI: [26, 52]) • Prior repotrectinib: ORR = 47% (8/17), DOR range 3.5 to 17.2 months • Prior taletrectinib: ORR = 43% (3/7), DOR range 5.2 to 7.0+ months Encouraging overall activity in TKI pre-treated ROS1-positive NSCLC population, and second-line activity following the most commonly used front-line ROS1 TKIs: ROS1 ACTIVITY ROS1 MT ACTIVITY CNS ACTIVITY AVOIDING TRK + + + PD PD SD SD PD SD SD SD SD SD SD SD SD PD SD SD SD SD SD SD SD SD PR SD PR PR PR PR PR PR PR PR PR SD PR PR SD PR PR PR PR PR PR SD PR PR PR PR PR PR PR PR PR CR 1 Prior ROS1 TKI (crizotinib or entrectinib) ± chemotherapy Prior crizotinib Prior entrectinib + Prior chemotherapy Data pooled for patients treated by May 31, 2024 at RP2D in the Phase 1 or Phase 2 portion of ARROS-1 with a data cut-off of March 21, 2025, allowing for 6 months of follow-up for nearly all responders. Responses were confirmed per RECIST 1.1 as assessed by blinded independent central review (BICR). CI, confidence interval; DOR, duration of response; m, median; NE, not estimable; NSCLC, non-small cell lung cancer; ORR, objective response rate; RP2D, recommended phase 2 dose (100 mg QD); TKI, tyrosine kinase inhibitor. Advanced ROS1+ NSCLC RECIST 1.1 by BICR Any prior ROS1 TKI (range 1 – 4) ± chemotherapy 1 prior ROS1 TKI (crizotinib or entrectinib) ± chemotherapy ORR, % (n/N) [95% CI] 44% (51/117) [34, 53] 51% (28/55) a [37, 65] CR, % (n/N) 1% (1/117) 2% (1/55) a Prior crizotinib only ± chemotherapy: ORR = 68% (19/28). Prior entrectinib only ± chemotherapy: ORR = 33% (9/27).
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes ROS1 ACTIVITY ROS1 MT ACTIVITY CNS ACTIVITY AVOIDING TRK + + + Topline Efficacy: TKI Pre-treated ROS1+ NSCLC 21 TKI Pre-treated Pivotal Data Z I D E S A M T I N I B ( N V L - 520) 0 6 12 18 24 0 25 50 75 100 Patients in Response (%) Months Duration of Response Progression-Free Survival Advanced ROS1+ NSCLC Kaplan-Meier Estimate Any prior ROS1 TKIs (range 1-4) ± chemotherapy a 1 prior ROS1 TKI (crizotinib or entrectinib) ± chemotherapy b Any prior ROS1 TKIs (range 1-4) ± chemotherapy a 1 prior ROS1 TKI (crizotinib or entrectinib) ± chemotherapy b % ≥ 6 months [95% CI] 84% [71, 92] 93% [74, 98] 57% [47, 66] 70% [56, 81] % ≥ 12 months [95% CI] 78% [62, 88] 93% [74, 98] 48% [38, 57] 68% [53, 79] % ≥ 18 months [95% CI] 62% [28, 84] 93% [74, 98] 40% [24, 55] 68% [53, 79] Any prior ROS1 TKIs 51 40 10 3 0 Prior C/E only 28 26 6 3 0 # At Risk # At Risk Any prior ROS1 TKIs 117 64 27 5 0 Prior C/E only 55 37 14 4 0 84% 78% 62% 93% 93% 93% 57% 48% 40% 70% 68% 68% Data cut-off: March 21, 2025 a Any prior ROS1 TKI: Emerging median DOR of 22 months [95% CI: 17, NE] continues to mature. Median PFS was 9.7 [95% CI: 5.5, NE] months with median follow-up of 11.1 months (range 0.2-25.6). b 1 prior ROS1 TKI (crizotinib [C] or entrectinib [E]): Emerging median DOR of 22 months [95% CI: 22, NE] and median PFS of 23.8 months [95% CI: 23.8, NE] continue to mature; median follow-up was 11.8 months (range 1.2-25.6). • In patients that received prior crizotinib only, there were no progression events among responders (DOR range: 7.3+ to 23.2+ months). PFS rate was 89% (95% CI: 70, 96) at 6, 12, and 18 months with median not reached. • In patients that received ≥2 prior ROS1 TKIs ± chemotherapy, DOR rate was 71% (95% CI: 46, 86) at 6 months and 56% (95% CI: 29, 76) at 12 months. 0 6 12 18 24 0 25 50 75 100 Patients in Response (%) Months 0 6 12 18 24 0 25 50 75 100 Patients in Response (%) Months 0 6 12 18 24 0 25 50 75 100 Progression-Free Survival (%) Months
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes ROS1 ACTIVITY ROS1 MT ACTIVITY CNS ACTIVITY AVOIDING TRK + + + Demonstrated Ability To Address Key Drivers of Disease Progression 22 TKI Pre-treated Pivotal Data Z I D E S A M T I N I B ( N V L - 520) 0 3 6 9 12 15 18 0 50 100 Event-Free Probability Months Data pooled for patients treated by May 31, 2024 at RP2D in the Phase 1 or Phase 2 portion of ARROS-1 with a data cut-off of March 21, 2025, allowing for 6 months of follow-up for nearly all responders. Responses were confirmed per RECIST 1.1 as assessed by blinded independent central review (BICR). C, crizotinib, CI, confidence interval; DOR, duration of response; E, entrectinib; NE, not estimable; ORR, objective response rate; RP2D, recommended phase 2 dose (100 mg QD); TKI, tyrosine kinase inhibitor. a Analyses of DOR based on Kaplan-Meier estimates. Kaplan-Meier Plot of DOR ROS1 G2032R Responses were also observed in patients with: • ROS1 G2032R mutation following ≥2 prior ROS1 TKIs ± chemotherapy, including lorlatinib or repotrectinib • Other ROS1 resistance mutations, including G1957A, L1982V, S1986F, F2004C/V, G2032K, and D2033N # At Risk Any prior TKI: 14 13 11 6 3 1 0 1 prior TKI (C/E): 5 4 4 4 1 0 Prior crizotinib or entrectinib only ± chemo Any prior ROS1 TKI ± chemo60% (95% CI: 28, 81) 80% (95% CI: 20, 97) 79% (95% CI: 47, 93) 80% (95% CI: 20, 97) Zidesamtinib achieved responses in the presence of the ROS1 G2032R resistance mutation ǂ Any prior ROS1 TKI ± chemotherapy Prior crizotinib or entrectinib only* ± chemotherapy ORR, % (n/N) 54% (14/26) 83% (5/6) % DOR ≥ 6 months a (95% CI) 79% (47, 93) 80% ** (20, 97) % DOR ≥ 12 months a (95% CI) 60% (28, 81) 80% ** (20, 97) * Patients received zidesamtinib as their first TKI designed with activity against ROS1 G2032R ** One progression event among responders ǂ Emerging mDOR of 17.2 months (95% CI: 3.7, NE) continues to mature
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 0 3 6 9 12 15 0 50 100 Event-Free Probability Months Demonstrated Ability To Address Key Drivers of Disease Progression 23 Data pooled for patients treated by May 31, 2024 at RP2D in the Phase 1 or Phase 2 portion of ARROS-1 with a data cut-off of March 21, 2025, allowing for 6 months of follow-up for nearly all responders. Responses were confirmed per RECIST 1.1 as assessed by blinded independent central review (BICR). CI, confidence interval; CNS, central nervous system; CR, complete response; DOR, duration of response; IC, intracranial; ORR, objective response rate; RP2D, recommended phase 2 dose (100 mg QD); TKI, tyrosine kinase inhibitor. a Includes 2 unconfirmed intracranial partial responses (PR). b Analyses of DOR based on Kaplan-Meier estimates. Z I D E S A M T I N I B ( N V L - 520) TKI Pre-treated Pivotal Data Kaplan-Meier Plot of IC-DOR Measurable CNS Lesions at Baseline # At Risk Any prior TKI: 25 23 17 7 2 0 Prior crizotinib: 11 11 10 5 2 0 Prior crizotinib only ± chemo Any prior ROS1 TKI ± chemo • CNS responses also observed in patients who had received ≥1 prior brain-penetrant TKI, including prior entrectinib, lorlatinib, repotrectinib, or taletrectinib: IC-ORR: 37% (16/43 a; [95% CI 23, 53]), including 4 IC -CRs • No CNS progression was observed among patients who entered the study without brain metastases at baseline per BICR Zidesamtinib demonstrated CNS activity 91% (95% CI: 51, 99) 91% (95% CI: 51, 99) 79% (95% CI: 56, 91) 71% (95% CI: 46, 87) Any prior ROS1 TKI ± chemotherapy Prior crizotinib only* ± chemotherapy IC-ORR, % (n/N) 48% (27/56) a 85% (11/13) CR, % (n/N) 20% (11/56) 54% (7/13) % IC-DOR ≥ 6 months b (95% CI) 79% (56, 91) 91% ** (51, 99) % IC-DOR ≥ 12 months b (95% CI) 71% (46, 87) 91% ** (51, 99) * Limited brain penetrance ** One CNS progression event among CNS responders ROS1 ACTIVITY ROS1 MT ACTIVITY CNS ACTIVITY AVOIDING TRK + + +
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Topline Safety Profile 24 Data pooled for patients in the Phase 1 or Phase 2 portion of ARROS-1 with a data cut-off of March 21, 2025. Patients received at least 1 dose of zidesamtinib at RP2D with median duration of exposure of 5 months (range: 0, 32) NSCLC, non-small cell lung cancer; RP2D, recommended phase 2 dose (100 mg QD); TEAE, treatment emergent adverse event; TRK, proteins encoded for by the neurotrophic tyrosine receptor kinase (NTRK) family of genes. Treatment-Emergent Adverse Events (TEAEs) in ≥ 15% of Patients ROS1-positive NSCLC Treated at RP2D (N = 432) Preferred or Grouped Term Any Grade Grade ≥3 Peripheral edema a 36% 0.7% Constipation 17% 0 Blood CPK increased 16% 3.5% Fatigue b 16% 0.7% Dyspnea c 15% 3.0% a Includes terms oedema peripheral, peripheral swelling, oedema, generalized oedema b Includes terms fatigue, asthenia, malaise c Includes terms dyspnea, dyspnoea extertional, orthopnoea TKI Pre-treated Pivotal Data Z I D E S A M T I N I B ( N V L - 520) • Dose reduction due to TEAE: 10% (43/432) o Most common (>2 patients): peripheral edema (n=8), blood CPK increased (n=4), peripheral sensory neuropathy (n=4), arthralgia (n=3), paresthesia (n=3) • Discontinuation due to TEAE: 2% (10/432) o Most common (>2 patients): pneumonia (n=3) • The only treatment-related adverse event in ≥15% of patients was peripheral edema b (29%) Safety profile of zidesamtinib was generally safe, well tolerated and consistent with its ROS1-selective, TRK-sparing design ROS1 ACTIVITY ROS1 MT ACTIVITY CNS ACTIVITY AVOIDING TRK + + +
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Encouraging Preliminary Data for TKI-naïve Population 25 Data for patients treated by August 31, 2024 at RP2D in the Phase 2 portion of ARROS-1 with a data cut-off of March 21, 2025. Responses were confirmed per RECIST 1.1 as assessed by blinded independent central review (BICR). CR, complete response; DOR, duration of response; IC, intracranial; NSCLC, non-small cell lung cancer; ORR, objective response rate; RP2D, recommended phase 2 dose (100 mg QD); TKI, tyrosine kinase inhibitor. a Includes 1 unconfirmed CR following confirmed partial response (PR). b Analyses of DOR based on Kaplan-Meier estimates. Preliminary TKI-Naive Insights Z I D E S A M T I N I B ( N V L - 520) TKI-naïve advanced ROS1+ NSCLC Analysis by BICR Response-evaluable n = 35 ORR, % (n/N) 89% (31/35) CR, % (n/N) 9% (3/35) a % DOR ≥ 6 months [95% CI] b 96% [76, 99] % DOR ≥ 12 months [95% CI] b 96% [76, 99] DOR range 1.9+ to 13.9+ months a Includes 1 unconfirmed CR following confirmed partial response (PR). b Analyses of DOR based on Kaplan-Meier estimates. TKI-naïve advanced ROS1+ NSCLC Analysis by BICR Measurable intracranial lesions n = 6 IC-ORR, % (n/N) 83% (5/6) IC-CR, % (n/N) 67% (4/6) IC-DOR No CNS progression events among intracranial responders IC-DOR range 4.6+ to 11.1+ months SD PD SD PR PR PR PR PR PR PR PR PR PR PR PR PR PR CR PR PR PR PR PR PR PR PR PR uCR PR PR PR PR PR CR -100 -80 -60 -40 -20 0 20 40 Best % change in target lesions No prior chemotherapy 1 prior line of chemotherapy ROS1 TKI-naïve
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes PRELIMINARY Zidesamtinib: Designed for all patients with ROS1+ NSCLC 26 TOPLINE ROS1 Activity Intracranial Activity Sustain Target Therapeutic Doses Overall Duration of Response (Kaplan-Meier Estimate) Emerging Medians (Kaplan-Meier Estimate) [95% CI] 6 months 12 months 18 months TKI-naïve ± chemo (n = 35) ORR = 89% IC-ORR = 83% (67% IC-CR) Low discontinuation rate due to TEAE (2%) Low dose reduction rate due to TEAE (10%) Single TRAE ≥15%: Peripheral edema (29%) Once daily oral pill (n = 432) 1 Prior TKI crizotinib or entrectinib ± chemo (n = 55) ORR = 51% ROS1 G2032R: ORR = 83% Prior crizotinib only IC-ORR = 85% (54% IC-CR) mDOR: 22 months [22, NE] mPFS: 23.8 months [23.8, NE] Any Prior TKI 1 – 4 TKIs ± chemo (n = 117) ORR = 44% ROS1 G2032R: ORR = 54% IC-ORR = 48% (20% IC-CR) mDOR: 22 months [17, NE] mPFS: 9.7 months [5.5, NE] 96% 96% 93% 93% 93% 84% 78% 62% + + Source: Data at recommended Phase 2 dose of 100 mg QD reported in Drilon et al., WCLC 2025 (Data cut-off: March 21, 2025). Enrollment and follow-up ongoing in registration-directed TKI-naive cohort of ARROS-1
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Reimagine what is possible with a ROS1 TKI 27 Illustrative projections are based on management assumptions as of January 2026 and are subject to change. m, median; NSCLC, non-small cell lung cancer; PFS, progression-free survival. [a] Sales not reported by ALK vs. ROS1 indication; Assumes the large majority of crizotinib sales are for ROS1 following alectinib 1L ALK approval in 2017. [b] “Peak” estimated in 2019 due to share erosion following FDA approval of 2nd ROS1 TKI (entrectinib) in August 2019. [c] “Peak” for adv/met indication estimated in 2023 due to FDA approval for adjuvant ALK+ NSCLC indication in April 2024. [d] Single-arm studies, which lack a comparator arm, may be inadequate to sufficiently evaluate time-to-event endpoints, such as mPFS. The clinical significance of these mPFS data is not known and the observed effect may be attributable to the drug or to other factors. [e] 2023 - 2024 reference: alectinib US = 30 - 34% of global net revenue, lorlatinib US = 42% of global net revenue. Sources: [1] Year-end earnings reports for Pfizer (2019) and Roche (2023); [2] Shaw A. et al., Ann Oncol. 2019. [3] ALECENSA FDA prescribing information, revised 04/2024. [4] Drilon et al., WCLC 2025. [5] NAVLIN, accessed January 2026. The ROS1+ NSCLC market has the potential to match or exceed today’s opportunity in advanced/metastatic ALK+ NSCLC Illustrative ROS1+ NSCLC “Peak” Sales Opportunity (US) US “Peak” Sales Benchmark for ROS1+ NSCLC ~$150M (Crizotinib, 2019) [a,b] x Potential Durability Increase (i.e., “Time on therapy”) ~2 - 3x mPFS [c] Crizotinib 1L mPFS: 19.3 months 2 Zidesamtinib 1L mPFS: Not reached Zidesamtinib 2L mPFS: 23.8 months 4 x Illustrative 2026 Price/Month ~1.9x ~$17,000 (Crizotinib, 2019) 5 → ~$32,000 (Repotrectinib, 2026) 5 Illustrative Potential US “Peak” Sales Opportunity ~$570M - 855M Illustrative Potential WW “Peak” Sales Opportunity ~$1.4B - 2.1B Illustrative if US = 40% of global [e] $0 $200 $400 $600 Crizotinib ROS1 US "Peak" Sales Advanced NSCLC (2019 [b]) Illustrative ROS1 US Opportunity (2026 Pricing) Alectinib ALK US "Peak" Sales Advanced NSCLC (US, 2023 [c]) ~$150M [a],1 ~$570M $519M 1 ILLUSTRATIVE: 2x mPFS + 2025 pricing Millions, USD mPFS: 19.3 months 2 mPFS: 25.7 months 3
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxesPlease do not move the page number or footer boxes 28 Realize the full potential ALK+ NSCLC “We encourage the continued innovation and development of new therapeutic options for patients, with the hope that one day, advanced ALK- positive NSCLC could be managed as a chronic condition more often than as a life- threatening disease.” Kirk S, patient living with advanced ALK+ NSCLC President of the Board, ALKPositive
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes S T A N D A R D O F C A R E K E Y L I M I T A T I O N S Alectinib ($1.9B WW sales, 2025) 3 Single ALK resistance mutations Observed in ~50% of patients progressing on 2G TKIs (i.e., alectinib, brigatinib, ceritinib) 7, 8 Brain penetrance • 30 – 40% present with brain metastases at diagnosis 9, 10, 11 • ~50% will develop brain metastases overall 11 ❖ Demonstrate superiority to alectinib in 1L head-to-head study, while also avoiding CNS adverse events Alectinib ORR: 79% 17 Alectinib mPFS: 25.7 months 17 Lorlatinib ($1.0B WW sales, 2025) 4 3G TKI, designed to address single ALK mutations and improve brain penetrance 5 Single & Compound ALK resistance mutations ALK mutations observed in ~75% of patients progressing on sequential 2G to 3G TKIs, including ~25 – 50% with compound mutations 7, 12 Treatment-limiting off-target adverse events CNS adverse events associated with TRK inhibition observed in >50% of patients receiving lorlatinib 13, 14, 15 ❖ Improve durability of response after ≥ 1 2G ALK TKI: Lorlatinib ORR: 31 – 40% 13, 18, 19 Lorlatinib mDOR: 7.1 – 9.6 months 18, 19 No clear standard of care Patients may consider clinical trials or chemotherapy/I-O 6 Activity No approved therapies have demonstrated activity after sequential 2G to 3G TKIs 16 ❖ Demonstrate activity after 2+ prior ALK TKIs, including in patients who are lorlatinib experienced ~3 – 5% of NSCLC 1 | Majority are advanced/metastatic at diagnosis 2 ALK+ NSCLC Treatment Paradigm 1G, 1st generation; 1L, 1st line; 2G, 2nd generation; 3G, 3rd generation; CNS, central nervous system; DOR, duration of response; m, median; ORR, objective response rate; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. Sources: [1] Gainor J.F. and Shaw A.T., Oncologist. 2013. [2] Chia P.L. et al., Clin Epidemiol. 2014. [3] Roche 2025 Year-end Earnings Report. [4] Pfizer 2025 Year-end Earnings Report. [5] Johnson T.W. et al., J. Med. Chem. 2014. [6] NCCN Guidelines for NSCLC (version 8.2025). [7] Dagogo-Jack I. et al., Clin Cancer Res 2019.* [8] Gainor J. et al. Cancer Discov. 2016.* [9] Gainor J et al. JCO Precis Oncol. 2017. [10] Solomon BJ et al., NEJM 2014. [11] Uprety D et al., Lung Cancer 2025. [12] Shiba-Ishii et al., Nature Cancer 2022. [13] Lorlatinib FDA USPI. [14] Cocco E et al., Nat Rev Clin Oncol. 2018. [15] Shaw A. et al., Lancet Onc 2017. [16] Ensartinib FDA USPI. [17] Alectinib FDA USPI. [18] Shaw et al., JCO 2019; [19] Felip et al., Ann of Oncol. 2021. [*] Most patients also received prior crizotinib. 2L 1L 3L+ POTENTIAL OPPORTUNITY for PATIENT IMPACT 29
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Realize the full potential of an ALK TKI 30 Sources: [1] ALECENSA FDA prescribing information, revised 04/2024. [2] Cortellis, product sales accessed 01/2026. [3] Solomon B.J. et al., J Clin Oncol. 2024. [4] LORBRENA FDA prescribing information, revised 02/2024. [5] Roche 2025 Year-end Earnings Report. [6] Pfizer 2025 Year-end Earnings Report. [7] Estimated from Takeda 2025 Year-end Earnings Reports for brigatinib; 2025 sales not reported for crizotinib, ceritinib, ensartinib. [8] Jimenez Munarriz B.E. et al., Cancer 2025. NUVALENT VISION Address the liabilities of lorlatinib Deliver transformative durability and tolerability, across lines of therapy, with an ALK-selective TKI Realize the full potential within ALK+ NSCLC Grow a prevalent population of patients living with ALK+ NSCLC as a “chronic”, long-term condition & NUVALENT VISION Market Opportunity BACKGROUND: Next generation ALK TKIs that address key drivers of disease progression, including brain penetrance and resistance mutations, are transforming expectations for durability BACKGROUND: Reported sales reflect the continued global market leadership of alectinib INSIGHT: While long-term benefit is possible with lorlatinib, improvements are needed: Of patients receiving lorlatinib for 1L ALK+ NSCLC, 38% are no longer on therapy by 24 months 3 INSIGHT: For this patient population that is often diagnosed at a younger age, new options are needed to avoid the risk of CNS adverse events observed with the dual TRK/ALK inhibitor lorlatinib, and offer both durability and tolerability 4,8 Patient Outcomes Alectinib for ALK+ NSCLC 1L mPFS = 25.7 months 1 2nd Generation TKI & Global Market Leader 2 Lorlatinib for ALK+ NSCLC 1L mPFS = Not reached at 60 months 3 3rd Generation TKI & 1L Alternative Alectinib WW sales (2025): $1.9B 5 Lorlatinib WW sales (2025): $1.0B 6 WW sales of other ALK+ TKIs (2025): est. < $300M 7
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Neladalkib A Rationally Designed ALK-selective, TRK-sparing Inhibitor Neladalkib is an investigational candidate and has not been approved by FDA or any other regulatory authority. 1L, 1st line; 2G, 2nd generation (alectinib, brigatinib, ceritinib); 3G, 3rd generation (lorlatinib); CNS, central nervous system; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor. Source: [1] Gainor J.F. and Shaw A.T., Oncologist. 2013. [2] Dagogo-Jack I. et al., Clin Cancer Res 2019.* [3] Gainor J. et al. Cancer Discov. 2016.* [4] Shiba-Ishii et al., Nature Cancer 2022. [5] Solomon BJ et al., NEJM 2014. [6] Shaw A. et al., Lancet Onc 2017. [7] Uprety D et al., Lung Cancer 2025. [8] Shaw A. et al., Lancet Onc 2017. [9] LORBRENA FDA prescribing information, revised 4/2023. [*] Most patients also received prior crizotinib. N VL-655 Potential Best-in-Class Target Product Profile designed in collaboration with physician-scientists to address the limitations of existing agents for ALK+ NSCLC ALK Activity • Primary oncogenic driver in ~3 – 5% of NSCLC 1 ALK Single Mutant Activity • ~50% single resistance mutations, such as G1202R, after treatment with a 2G ALK TKI, and ~75% after sequential 2G and 3G ALK TKIs 2, 3 CNS Activity • ~30 – 40% CNS disease at diagnosis 5, 6, 7 • ~50% develop CNS disease overall 7 Avoiding TRK • Treatment-limiting neurological adverse events observed with brain-penetrant, dual TRK/ALK inhibitors 8, 9 D ES I G N G OAL for N E L ADA L K I B ALK Compound Mutant Activity • ~25 – 50% compound mutations after sequential treatment with 2G and 3G ALK TKIs 2, 4 + + + + 31
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 32 Preclinical Characterization Demonstrates Desired Target Product Profile Inhibited Diverse ALK Fusions and Resistance Mutations Fo BID, twice daily; IC50, half-maximal inhibitory concentration; PO, orally; QD, once daily; v, EML4 breakpoint variant. Sources: Lin J.J. et al., AACR-NCI-EORTC 2023. 1Lee, J. et al. AACR 2023; 2Fujino, T. et al. EORTC-NCI-AACR 2022; 3Mizuta, H. et al. WCLC-IASLC 2022; 4Tangpeerachaikul, A. et al. AACR 2022; 5Tangpeerachaikul, A. et al. AACR-NCI-EORTC 2021; 6Pelish, H. et al. AACR 2021. Data also reflect additional repeat testing and models. N E L A D A L K I B ( N V L - 655) In Vitro Activity Potent activity (IC50 = 0.1 – 30 nM) against ALK-driven cell lines, including ALK single and compound mutants 1-6 In Vivo Activity Tumor regression at well-tolerated doses in ALK models, including ALK single and compound mutants 1-6 D1203N | Ba/F3 (v1) 10 -1 10 0 10 1 10 2 10 3 10 4 IC50 (nM) F1174L | Ba/F3 (v3) G1202R | YU-1077 (v3) T1151M | Ba/F3 (v3) V1180L | Ba/F3 (v1) L1198F | Ba/F3 (v1) L1196M | MGH045-1 (v1) G1202R/T1151M | MR448re (v3) G1202R/F1174L | Ba/F3 (v3) G1202R/L1196M | MGH953-7 (v3) G1202R/L1198F | Ba/F3 (v1) I1171N | Ba/F3 (v1) Alectinib Brigatinib Lorlatinib NVL-655CeritinibCrizotinib Cell lines harboring EML4-ALK fusion 3-day cell viability assay No resistance mutations | MGH048-1 (v1) I1171N/L1198F | Ba/F3 (v1) Compound mutant Single mutant 35 nM G1202R/G1269A | Ba/F3 (v1) Xenograft models harboring ALK fusion -100 -50 0 50 500 1000 Change in tumor size (%) G1202R | MR619 (STRN-ALK) G1202R/L1196M | MGH953-7 (EML4-ALK v3) G1202R/T1151M | MR448re (EML4-ALK v3) G1202R/G1269A | Ba/F3 (EML4-ALK v1) NVL-655 I1171N | Ba/F3 (EML4-ALK v1) Vehicle No resistance mutations | Lu-01-0015 (HIP1-ALK) Single mutant Compound mutant Lorlatinib NVL-655: 0.5 - 7.5 mg/kg, PO, BID; Lorlatinib: 5 mg/kg, PO, BID or 10 mg/kg, PO, QD In some cases, dosing was not performed on weekends
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 33 Preclinical Characterization Demonstrates Desired Target Product Profile Brain-Penetrant with the Potential to Avoid TRK-Related CNS Adverse Events Head-to-head clinical studies comparing neladalkib (NVL-655) with currently approved or investigational therapies have not been conducted. Above data from preclinical studies and no clinical conclusions can be drawn. CNS, central nervous system; IC50, half-maximal inhibitory concentration; PO, orally; pTRKB, BDNF-stimulated TRKB phosphorylation. Source: Lin J.J. et al., AACR-NCI-EORTC 2023. Mizuta, H. et al. WCLC-IASLC 2022; Tangpeerachaikul, A. et al. AACR-NCI-EORTC 2021; Pelish, H. et al. AACR 2021. Data presented here reflect updated values following additional repeat testing. N E L A D A L K I B ( N V L - 655) Brain Penetrance Pharmacokinetic data similar to preclinical observations for lorlatinib Avoiding TRK Inhibition Selective inhibition of ALK and ALK mutants over TRK Wistar Han rats 10 mg/kg, single dose PO 1 hour timepoint More active for TRKB More active for ALK Selectivity index 0.1 1 10 100 1000 Lorlatinib NVL-655 No resistance mutations T1151M I1171N F1174L V1180L L1196M L1198F G1202R D1203N G1202R/T1151M G1202R/F1174L G1202R/L1196M G1202R/L1198F G1202R/G1269A I1171N/L1198F Single mutant Compound mutant IC50 (pTRKB) IC50 (Ba/F3 EML4-ALK) Selectivity index = 20x Selectivity for ALK over TRKB Lorlatinib NVL-655 0.0 0.1 0.2 0.3 0.4 0.5 Unbound brain:plasma ratio NVL-655
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes ALK+ NSCLC | Global Development Strategy Parallel development paths ongoing to establish neladalkib as a best-in-class drug for all patients with ALK+ NSCLC Randomized, controlled study designed to assess superiority to current 1L standard of care: • No prior ALK TKI (N ~450), with 1:1 randomization of neladalkib (NVL-655) vs. alectinib • Plan for ~160 sites across North America, Europe, Asia, and Latin America Designed for line-agnostic label expansion Topline data supports opportunity for broad TKI pre-treated label: • TKI pre-treated ALK+ NSCLC receiving neladalkib at RP2D (N = 235) Phase 2: TKI Pre-treated Cohorts Global enrollment complete* Randomized Phase 3: TKI-naïve Global enrollment ongoing 2 L + 1L Enrollment ongoing for adult and pediatric patients with other ALK+ solid tumors * Continued enrollment available for adolescent patients with ALK+ NSCLC. 34 NDA submission for TKI pre-treated ALK+ NSCLC planned for 1H’26
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes CBR, clinical benefit rate; DOR, duration of response; ORR, objective response rate; OS, overall survival; PFS, progression free survival; PK, pharmacokinetics; PRO, patient reported outcomes; QD, once daily; RP2D, recommended phase 2 dose; TKI, tyrosine kinase inhibitor; TTR, time to response. a Excludes patients who received lorlatinib as the 1st prior ALK TKI. P H A SE 2 I N I T I ATE D F E B RUARY 2024 (R P 2D : 150 m g Q D ) Global open-label, multi-cohort design with registrational intent for TKI pre-treated ALK+ NSCLC, and exploratory cohort for TKI-naïve ALK+ NSCLC A Global First-in-Human Phase 1/2 Clinical Trial of Neladalkib in Advanced ALK-Positive NSCLC and Other Solid Tumors (NCT05384626) P H A SE 1 I N I T I ATE D J UN E 2022 First-in-human dose-escalation in heavily pre-treated ALK+ NSCLC & other solid tumors Preliminary data demonstrated clinical proof-of- concept for neladalkib’s target product profile: OCTOBER 2024 Updated Phase 1 Data: Durable responses in heavily pre-treated population Drilon et al., ESMO 2024 OCTOBER 2023 Preliminary Phase 1 Data: Clinical proof-of concept in heavily pre-treated population Lin et al., AACR-NCI-EORTC 2023 ALKOVE-1 PHASE 2 PRIOR ALK TKI PRIOR CHEMO/I-O ALKOVE-1 PHASE 2 OBJECTIVES ALK+ NSCLC 2-3 prior, any generation (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib a) 0-2 lines • Primary: ORR by blinded, independent central review (BICR) • Secondary: Additional efficacy measures (DOR, TTR, CBR, PFS, OS), intracranial activity, overall safety and tolerability, confirmation of PK profile 1 prior 2G (ceritinib, alectinib, or brigatinib) 0-2 lines 1 prior 3G (lorlatinib) ≤ 1 None (TKI-naïve) ≤ 1 Any (not eligible for other cohorts) Any Other ALK+ Solid Tumors ≥ 1 prior ALK TKI or systemic therapy (or for whom no satisfactory standard therapy exists) Any 35
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Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines. Use eyedropper tool to select colors from the expanded color palette: Please try to avoid covering the logo Please do not move the page number or footer boxes 0 100 200 300 400 500 600 700 800 900 1000 Jan-22 Jan-23 Jan-24 Jan-25 Jan-26 Phase 1 Initiation JUNE 2022 Phase 1 AUGUST 2023 93 Transition to Phase 2 FEBRUARY 2024 133 AUGUST 29, 2025 781 133 Phase 1 + 648 Phase 2 Phase 1 + 2 SEPTEMBER 2024 362 PHASE 1 + PHASE 2 PATIENT ENROLLMENT Strong enrollment momentum demonstrates enthusiasm for neladalkib & clear medical need for TKI pre-treated patients Phase 1 + 2 DECEMBER 31, 2024 596 Phase 1 + 2 MARCH 2025 762 * * Transition to Expanded Access Protocol for adult patients with advanced ALK+ TKI pre-treated NSCLC. Enrollment continues for adult and adolescent patients with ALK+ solid tumors other than NSCLC, and adolescent patients with ALK+ NSCLC. 36
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Use eyedropper tool to select colors from the expanded color palette: Keep content within provided margin guidelines: 12” width – It is ok to adjust width of title vs content boxes as needed. Keep content within provided margin guidelines. It is ok to adjust height of title vs. content boxes as needed. Please try to avoid covering the logoPlease do not move the page number or footer boxes Pivotal Data Populations BICR, blinded independent central review; DOR, duration of response; NSCLC, non-small cell lung cancer; RP2D, recommended phase 2 dose (150 mg QD); TKI, tyrosine kinase inhibitor. a Includes 25 patients with other oncogenic driver(s) in addition to ALK: MET amplification (n = 9), KRAS G12C (n = 4*), MET mutation (n = 4), BRAF mutation (n = 4*), RET fusion (n = 2), ERBB2 mutation (n = 1), NTRK fusion (n = 1), FGFR3 fusion (n = 1). [*One patient had both KRAS G12C and BRAF mutations.] b No patients with other oncogenic driver(s) in addition to ALK. ALK+ NSCLC Pivotal Safety Population 656 Treated at RP2D as of August 29, 2025 Total Enrolled as of August 29, 2025: Phase 1 + Phase 2 781 Any ALK+ solid tumor, any dose TKI Pre-treated ALK+ NSCLC a Pivotal Primary Analysis Population 253 Treated at RP2D by September 30, 2024 to allow for at least 6 months DOR follow up for nearly all responders by August 29, 2025 TKI-Naïve ALK+ NSCLC b Preliminary Data 44 ALK+ NSCLC treated at RP2D with measurable disease by BICR • Pivotal ALK+ NSCLC safety population (n = 656) and TKI pre-treated efficacy population (n = 253) • Preliminary data available from exploratory cohort of 44 TKI-naïve patients with ALK+ NSCLC in ALKOVE-1 ❖ Enrollment of TKI-naïve patients is ongoing in the ALKAZAR Phase 3 randomized controlled trial E X P L O R A T O R Y C O H O R T 37
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Pre-treated ALK+ NSCLC Population at RP2D 2G, 2nd generation (i.e., alectinib, brigatinib, ceritinib, ensartinib); BICR, blinded independent central review; CNS, central nervous system; NSCLC, non-small cell lung cancer; RP2D, recommended phase 2 dose (150 mg QD); TKI, tyrosine kinase inhibitor. a ALK mutations as per local or central testing of blood (ctDNA) or tissue. b Patients may have had other mutations in addition to ALK G1202R. c 36% (91/253) of patients overall had any ALK mutation, including 22 lorlatinib-naïve patients. 17% (43/253) of patients overall had compound resistance mutations, including 3 lorlatinib-naïve patient(cis-allelic configuration not confirmed in all cases). TKI Pre-treated Pivotal Data N E L A D A L K I B ( N V L - 655) Distinct overall TKI pre-treated population (n = 253): 3 median lines of prior anticancer treatment (Range: 1 – 11) 51% received prior chemotherapy 78% received ≥ 2 prior ALK TKIs, of whom 91% received prior lorlatinib 19% with secondary ALK G1202R mutation a,b,c 40% with active CNS disease (BICR) Lorlatinib-naïve subpopulation (n = 63): 25% of overall TKI pre-treated population 25% received prior chemotherapy 100% received ≥ 1 prior 2G ALK TKI, of whom 70% received prior alectinib only d 19% with secondary ALK G1202R mutation a,c 35% with active CNS disease (BICR) d 73% (46/63) had 1 prior ALK TKI only (alectinib, n = 44; brigatinib, n = 2). No patients received crizotinib as their only prior ALK TKI. 14% (9/63) received crizotinib in addition to ≥ 1 prior 2G ALK TKI. 13% (8/63) received ≥ 2 prior 2G ALK TKIs only. Patients may have also received prior chemotherapy. 38
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 0 3 6 9 12 15 18 21 24 0 50 100 Event-Free Probability Months ALK ACTIVITY ALK MT ACTIVITY CNS ACTIVITY AVOIDING TRK + + + Topline Efficacy Results: TKI Pre-treated ALK+ NSCLC TKI Pre-treated Pivotal Data N E L A D A L K I B ( N V L - 655) Data pooled for patients treated by September 30, 2024 at RP2D in the Phase 1 or Phase 2 portion of ALKOVE-1 with a data cut-off of August 29, 2025 allowing for 6 months of follow-up for nearly all responders. Responses were confirmed per RECIST 1.1 as assessed by blinded independent central review (BICR). CI, confidence interval; DOR, duration of response; ORR, objective response rate; PR, partial response; RP2D, recommended phase 2 dose (150 mg QD); TKI, tyrosine kinase inhibitor; u, unconfirmed. a Median duration of follow-up of 11.3 months; b Patients may have had other mutations in addition to ALK G1202R; c Includes 2 uPRs; d Responses also observed in patients with ALK mutations other than G1202R, including C1156Y, I1171N, I1171T, F1174C, F1174L, V1180L, L1196M, L1198F, D1203N, E1210K, and G1269A; e Includes 1 uPR; f Analyses of DOR based on Kaplan-Meier estimates; g Includes 2 uPRs; h Includes 1 uPR; i mDOR not evaluable. Kaplan-Meier Plot of DOR All TKI Pre-treated # At Risk Any prior TKI: 77 74 48 31 20 11 8 5 2 With G1202R 31 31 23 18 13 9 7 5 2 With ALK G1202R mutation Any prior ALK TKI ± chemo RECIST 1.1, BICR Any prior ALK TKI ± chemotherapy a (n = 253) With G1202R Mutation b (n = 47) ORR, % (n/N) (95% CI) 31% (79/253) c, d (26, 37) 68% (32/47) e (53, 81) % DOR ≥ 6 months f (95% CI) 76% (64, 84) 84% (65, 93) % DOR ≥ 12 months f (95% CI) 64% (51, 75) 80% (61, 91) % DOR ≥ 18 months f (95% CI) 53% (34, 68) 70% (42, 86) Responses were also observed in: • Lorlatinib-experienced patients, where no approved therapies have demonstrated activity: ORR = 26% (50/190) g, mDOR = 17.6 months (95% CI: 6.9, NE) • Patients with compound ALK mutations after ≥ 2 prior ALK TKIs: ORR = 58% (25/43) h, DOR ≥ 12 months = 69% (95% CI: 45, 84) i Neladalkib demonstrated durable activity against ALK and ALK G1202R in a uniquely heavily pre-treated patient population: 84% 64% 76% 53% 80% 70% mDOR not evaluable 39
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 0 3 6 9 12 15 18 21 24 0 50 100 Event-Free Probability Months ALK ACTIVITY ALK MT ACTIVITY CNS ACTIVITY AVOIDING TRK + + + Topline Efficacy Results: TKI Pre-treated, Lorlatinib-naïve TKI Pre-treated Pivotal Data N E L A D A L K I B ( N V L - 655) RECIST 1.1, BICR TKI pre-treated, Lorlatinib-naïve (n = 63) With G1202R Mutation (n = 12) ORR, % (n/N) (95% CI) 46% (29/63) (33, 59) 83% (10/12) (52, 98) % DOR ≥ 6 months a (95% CI) 89% (69, 96) 90% (47, 99) % DOR ≥ 12 months a (95% CI) 80% (58, 91) 77% (34, 94) % DOR ≥ 18 months a (95% CI) 60% (19, 85) 77% (34, 94) • No patients received crizotinib as their only ALK TKI • Similar activity was observed in patients receiving 1 prior 2nd generation ALK TKI (alectinib [n = 44] or brigatinib [n = 2]) ± chemo: ORR = 48% (22/46), DOR ≥ 12 and 18 months = 74% (95% CI: 48, 88) b Neladalkib demonstrated potential for differentiated durability in TKI pre-treated patients who are lorlatinib-naïve: Data pooled for patients treated by September 30, 2024 at RP2D in the Phase 1 or Phase 2 portion of ALKOVE-1 with a data cut-off of August 29, 2025 allowing for 6 months of follow-up for nearly all responders. Responses were confirmed per RECIST 1.1 as assessed by blinded independent central review (BICR). CI, confidence interval; DOR, duration of response; MT, mutation; ORR, objective response rate; PR, partial response; RP2D, recommended phase 2 dose (150 mg QD); TKI, tyrosine kinase inhibitor; u, unconfirmed. a Analyses of DOR based on Kaplan-Meier estimates; b mDOR not evaluable. # At Risk Lorlatinib-naïve 29 27 21 15 7 3 2 1 1 With G1202R 10 10 7 6 4 2 2 1 1 Kaplan-Meier Plot of DOR TKI Pre-treated, Lorlatinib-naïve With ALK G1202R mutation TKI pre- treated, lorlatinib -naive 90% 89% 60% 77% 77% 80% mDOR not evaluable 40
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 0 3 6 9 12 15 18 21 24 0 50 100 Event-Free Probability Months ALK ACTIVITY ALK MT ACTIVITY CNS ACTIVITY AVOIDING TRK + + + Intracranial Activity TKI Pre-treated Pivotal Data N E L A D A L K I B ( N V L - 655) Measurable CNS lesions RECIST 1.1, BICR Any prior ALK TKI ± chemotherapy (n = 92) TKI pre-treated, Lorlatinib-naïve (n = 24) IC-ORR, % (n/N) (95% CI) 32% (29/92) a (22, 42) 63% (15/24) a (41, 81) IC-CR, % (n/N) 13% (12/92) b 21% (5/24) b % IC-DOR ≥ 6 months c (95% CI) 81% (59, 91) 92% (57, 99) % IC-DOR ≥ 12 months c (95% CI) 71% (48, 85) 92% (57, 99) % IC-DOR ≥ 18 months c (95% CI) 71% (48, 85) 92% (57, 99) • Intracranial responses were also observed in lorlatinib-experienced patients with measurable CNS lesions: IC-ORR = 21% (14/68), IC-DOR ≥ 6 months = 71% (95% CI: 41, 88), IC-DOR ≥ 12 and 18 months = 55% (95% CI: 26, 77) d Durable intracranial responses observed in patients with measurable CNS lesions: Data pooled for patients treated by September 30, 2024 at RP2D in the Phase 1 or Phase 2 portion of ALKOVE-1 with a data cut-off of August 29, 2025 allowing for 6 months of follow-up for nearly all responders. Responses were confirmed per RECIST 1.1 as assessed by blinded independent central review (BICR). CI, confidence interval; CR, complete response; DOR, duration of response; IC, intracranial; ORR, objective response rate; PR, partial response; RP2D, recommended phase 2 dose (150 mg QD); TKI, tyrosine kinase inhibitor; u, unconfirmed. a Includes 2 IC-uPRs; b Includes 1 IC-uCR with prior confirmed IC-PR; c Analyses of DOR based on Kaplan-Meier estimates; d Median IC-DOR not evaluable. # At Risk Any prior TKI 27 26 19 16 10 4 4 4 2 Lorlatinib-naïve 13 12 9 8 4 2 2 2 1 TKI pre- treated, lorlatinib- naïve ǂ Any prior ALK TKI ± chemo ǂ ǂ Emerging mDOR of 21.6 months continues to mature 92% 71% 81% 92% 92% 71% Kaplan-Meier Plot of IC-DOR Intracranial Responders 41
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes ALK ACTIVITY ALK MT ACTIVITY CNS ACTIVITY AVOIDING TRK + + + Topline Safety Profile TKI Pre-treated Pivotal Data N E L A D A L K I B ( N V L - 655) • Dose reduction due to TEAE: 17% o Events in ≥1% of patients: ALT increased (10%), AST increased (8%) a • Discontinuation due to TEAE: 5% o Events in ≥1% of patients: ALT increased (1.8%), AST increased (1.2%) • Most common TEAE were transaminase elevations o Most were asymptomatic lab abnormalities, and observed to be low-grade, transient, and reversible with dose interruptions or reductions o Preliminary data suggest increased incidence in less heavily pre-treated patients o Enhanced monitoring and prompt dose interventions implemented in the protocol for the Phase 3 ALKAZAR trial • Overall safety profile consistent with avoiding TRK-related neurotoxicities Safety profile of neladalkib was generally well tolerated and consistent with its ALK-selective, TRK-sparing design Data pooled for patients in the Phase 1 or Phase 2 portion of ALKOVE-1 with a data cut-off of August 29, 2025. Patients received at least 1 dose of neladalkib at RP2D with median duration of exposure of 6.0 months (range: 0.1, 28.4); NSCLC, non-small cell lung cancer; RP2D, recommended phase 2 dose (150 mg QD); TEAE, treatment emergent adverse event; TRK, proteins encoded for by the neurotrophic receptor tyrosine kinase (NTRK) family of genes. a Not mutually exclusive: Dose reduction due to any transaminase elevation observed in 11% of patients. Treatment-Emergent Adverse Events (TEAEs) in ≥ 15% of TKI-naïve or TKI Pre-treated Patients with ALK-positive NSCLC Receiving Neladalkib at RP2D (N = 656) Preferred Term Any Grade Grade ≥3 ALT increased 47% 20% AST increased 44% 16% Constipation 28% 0.2% Dysgeusia 23% 0 Peripheral edema 18% 0.3% Cough 16% 0.5% Nausea 16% 0.8% 42
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Encouraging Preliminary Data for Exploratory TKI-naïve Population Data for patients treated in the TKI-naïve Phase 2 cohort of ALKOVE-1 with a data cut-off of August 29, 2025. Responses were confirmed per RECIST 1.1 as assessed by blinded independent central review (BICR). CI, confidence interval; CR, complete response; DOR, duration of response; IC, intracranial; NSCLC, non-small cell lung cancer; ORR, objective response rate; PR, partial response; TKI, tyrosine kinase inhibitor; u, unconfirmed. a Includes 2 uPRs and 1 uCR with prior confirmed PR; b Analyses of DOR based on Kaplan-Meier estimates; c Includes 1 IC-uCR with prior confirmed IC-PR. Preliminary TKI-naïve Insights N E L A D A L K I B ( N V L - 655) Global enrollment of TKI-naïve patients is ongoing in ALKAZAR, a Phase 3 randomized controlled trial of neladalkib versus alectinib TKI-naïve patients with ALK+ NSCLC enrolled in exploratory cohort of ALKOVE-1: Subset of patients with measurable intracranial lesions: • 2 progression events among responders • DOR range: 1.7+ to 14.8+ months • IC-DOR range: 3.1+ to 7.0+ months 86% (38/44, 4 CRs) a ORR 91% (95% CI: 70, 98) % DOR ≥ 6 and 12 months b 78% (7/9, 4 IC-CRs) c IC-ORR No CNS progression events observed among IC-responders 43
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes ALK Activity Intracranial Activity Sustain Target Efficacious Doses Overall Duration of Response (Kaplan-Meier Estimate) Emerging Median (Kaplan-Meier Estimate) 6 months 12 months 18 months TKI-naïve ± chemo (n = 44) ORR = 86% (ALKOVE-1) IC-ORR = 78% (44% IC-CR) Low discontinuation rate due to TEAE (5%) Low dose reduction rate due to TEAE (17%) Once daily oral pill (n = 656) TKI Pre-treated, Lorlatinib-naïve 1 – 3 TKIs ± chemo (n = 63) ORR = 46% ALK G1202R: ORR = 83% IC-ORR = 63% (21% IC-CR) mDOR: NE Any Prior TKI* 1 – 5 TKIs ± chemo (n = 253) ORR = 31% ALK G1202R: ORR = 68% IC-ORR = 32% (13% IC-CR) mDOR: NE Lorlatinib- experienced (n = 190) ORR = 26% mDOR: 17.6 months 89% 80% 60% 76% 64% 53% PRELIMINARY + + Neladalkib: Designed for all patients with ALK+ NSCLC • Follow-up ongoing for patients enrolled in exploratory cohort of ALKOVE-1 • Enrollment ongoing in ALKAZAR Phase 3 randomized, controlled trial versus alectinib TOPLINE 44 91% 91%
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes Realize the full potential of an ALK TKI 45 Illustrative projections are based on management assumptions as of January 2026 and are subject to change. m, median; NSCLC, non-small cell lung cancer; PFS, progression-free survival. [a] “Peak” for adv/met indication estimated in 2023 due to FDA approval for adjuvant ALK+ NSCLC indication in April 2024. [b] “Peak” for adv/met indication estimated in 2020 due to FDA approval for adjuvant EGFR+ NSCLC indication in December 2020. [c] 2023 - 2024 reference: alectinib US = 30 - 34% of global net revenue, lorlatinib US = 42% of global net revenue. Sources: [1] Year-end earnings reports for Roche (2023) and AstraZeneca (2020); [2] ALECENSA FDA prescribing information, revised 04/2024. [3] TAGRISSO FDA prescribing information, revised 09/2024. [4] Solomon B.J. et al., J Clin Oncol. 2024. [5] NAVLIN, accessed January 2026. The ALK+ NSCLC market has the potential to match or exceed today’s opportunity in advanced/metastatic EGFR+ NSCLC Illustrative ALK+ NSCLC “Peak” Sales Opportunity (US) US “Peak” Sales Benchmark for ALK+ NSCLC $519M (Alectinib, 2023) [a] x Potential Durability Increase (i.e., “Time on therapy”) ~2 - 3x mPFS Alectinib 1L mPFS: 25.7 months 2 Lorlatinib 1L mPFS: NR at 60 months 4 x Illustrative 2026 Price/Month ~1.3x ~$17,500 (Alectinib, 2023) 5 → ~$22,500 (Lorlatinib, 2026) 5 Illustrative Potential US “Peak” Sales Opportunity ~$1.35B - 2B Illustrative Potential WW “Peak” Sales Opportunity ~$3.4B - 5B Illustrative if US = 40% of global [c] $0 $500 $1,000 $1,500 $2,000 Alectinib ALK US "Peak" Sales Advanced NSCLC (2023 [a]) Illustrative ALK US Opportunity (2026 Pricing) Osimertinib EGFR US "Peak" Sales Advanced NSCLC (US, 2020 [b]) $519M 1 ~$2.0B $1.6B 1 ILLUSTRATIVE: 3x mPFS + 2026 pricing Millions, USD mPFS: 25.7 months 2 mPFS: 18.9 months 3
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 46 Opportunity for an ALK-selective Inhibitor Beyond NSCLC a Incidence reported for ALK fusions. [1] Majewska et al., Virchows Archiv 2021. [2] Kwak E. et al., NEJM 2010. [3] TCGA PanCancer Atlas, internally accessed September 2025. [4] Antonescu et al., Am J Surg Pathol. 2015. [5] Davis et al., Mol Cancer Res. 2019. [6] Groisberg et al., Connective Tissue Oncology Society 2020. [7] Shreenivas et al., NPJ Precis. Oncol. 2023. [8] De Brouwer et al., Clin Cancer Res 2010. [9] Bresler et al. Cancer Cell 2014. [10] Bellini et al. JCO 2021. [11] O’Donohue et al., JCO Precis Oncol 2021. [12] Sukov et al., Modern Pathology 2012. [13] Hung et al., JAMA Oncology 2018. [14] Ying et al., PLOS One 2015. [15] Singhi et al., JNCCN 2017. N E L A D A L K I B ( N V L - 655) Breast: ~2 – 13% 7 Inflammatory myofibroblastic tumor (IMT): ~50% 4 Digestive tract cancers (including esophageal, gastric, and colorectal) <1 – ~5% 3,14 Sarcomas: ~1 – ~2.4% 5,6 Peritoneal mesothelioma: ~3 – 13% 13 Pancreatic: <1% 3,15 Salivary gland carcinoma: <1% 1 a Renal cell: <1 – ~2% 3,12 Neuroblastoma: ~6 – 16% 8-11 NSCLC: ~3 – 5% 2 • ALK alterations have been identified as oncogenic drivers in a wide range of solid tumors beyond NSCLC, and in hematologic malignancies such as ALCL ─ ALK alteration types may include overexpression, amplification, copy number variation, mutation, and fusion • Today, ALK TKIs are only approved for NSCLC, IMT, and ALCL • Patients with advanced or metastatic ALK+ solid tumors other than NSCLC were enrolled in the ALKOVE-1 study of neladalkib as part of the completed Phase 1 dose escalation and in one cohort within the ongoing Phase 2 study Reported incidence of ALK alterations across diverse solid tumors
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes C O N F I D E N T I A L47 Preliminary Activity in ALK+ Solid Tumors Beyond NSCLC Enrollment for ALK+ solid tumors beyond NSCLC continues in the Phase 2 portion of ALKOVE-1 clinical trial Data cut-off: August 7, 2025. Patients received RP2D of 150 mg QD unless otherwise noted. a Includes 1 ongoing single-timepoint PR pending confirmation. b One response-evaluable ALK TKI-naïve patient with cholangiocarcinoma is not shown due to no post-baseline tumor assessment in the setting of symptomatic deterioration. c *Enrolled by FISH or IHC; ALK fusion partner not determined. d Received Phase 1 starting dose of 25 mg QD. e Received Phase 1 starting dose of 100 mg QD. f Received prior entrectinib. Source: Solomon B. et al., ESMO 2025. N E L A D A L K I B ( N V L - 655) -100 -80 -60 -40 -20 0 20 40 60 80 100 Best % change in target lesions Adenocarcinoma of unknown origin Clear cell odontogenic carcinoma CRC IMT Salivary duct carcinoma Medullary glioma Pancreatic adenocarcinoma RCC Sarcoma Small bowel adenocarcinoma Neuroendocrine carcinoma of pancreas Neuroendocrine carcinoma of lung Compound ALK resistance mutation Single ALK resistance mutation Peritoneal mesothelioma Best overall response SD SD SD PR PR PR PR PR PR PR PR uPR PD PD d PD SD SD PD NE SD PD SD PD SD SD SD SD PR PR PR PR e PR PR Prior ALK TKIs - - - - - - - - - - - - 1 1 2 1 2 2 2 1 2 1 4 3 1 2 1 1 f 1 1 2 1 1 crizotinib ● ● ● ● ● ● alectinib ● ● ● ● ● ● ● ● ● ● ● ● ● ● brigatinib ● ● ceritinib ● ● lorlatinib ● ● ● ● ● ● ● ● Prior lines, chemo - 2 - 1 2 3 2 1 1 - 1 - - 2 - - 2 1 1 - 1 3 1 - - 2 - 2 - 1 2 - 1 Prior anticancer therapies - 2 - 1 2 4 2 1 1 1 1 - 1 3 2 1 6 4 3 1 3 4 8 4 1 3 1 3 1 2 5 1 2 * c MTA3* c EML4 EML4 SPTBN1 STRN SPTBN1* c STRN IGFBP5 TIMP3 * c KANK1 PLEKHH2 EML4 EML4 EML4* c * c EML4 EML4 DCTN1 CLTC* c STRN EML4 TPM3 EML4 EML4 EML4 RANBP2 STRN ALK TKI-naïve b ALK TKI Pre-treated G1202R, V1180L, F1174L, I1268L, S1206F V1180L I1171N L1196M D1203N G1202R I1171N L1196M V1180L Radiographic tumor responses in patients with ALK+ solid tumors other than NSCLC Encouraging activity seen in both ALK TKI-naïve and previously treated patients, including those refractory to prior therapies RECIST 1.1, investigator assessed: • Overall ORR: 44% (15/34) ─ ALK TKI-naïve: 9/13 ─ ALK TKI Pre-treated: 6/21 • Durable responses observed in patients with ALK+ solid tumors, including an intracranial complete response in a patient who previously received the brain- penetrant TKI, alectinib • 80% (12/15) of responders remained on treatment without disease progression as of the data cutoff date KEY: -100 -80 -60 -40 -20 0 20 40 60 80 100 Best % change in target lesions Adenocarcinoma of unknown origin Clear cell odontogenic carcinoma CRC IMT Salivary duct carcinomaMedullary glioma Pancreatic adenocarcinoma RCC Sarcoma Small bowel adenocarcinoma Neuroendocrine carcinoma of pancreas Neuroendocrine carcinoma of lung compd mut single mut Single ALK resistance mutation Compound (≥ 2) ALK resistance mutation ALK fusion partner listed above column; ALK resistance mutations listed below -100 -80 -60 -40 -20 0 20 40 60 80 100 Best % change in target lesions Adenocarcinoma of unknown origin Clear cell odontogenic carcinoma CRC IMT Salivary duct carcinomaMedullary glioma Pancreatic adenocarcinoma RCC Sarcoma Small bowel adenocarcinoma Neuroendocrine carcinoma of pancreas Neuroendocrine carcinoma of lung compd mut single mut Adenocarcinoma of unknown origin (n = 1) Clear cell odontogenic carcinoma (n = 1) Colorectal cancer (CRC, n = 4) Inflammatory myofibroblastic tumor (IMT, n = 10) Medullary glioma (n = 1) Neuroendocrine carcinoma of lung (n = 2) Neuroendocrine carcinoma of pancreas (n = 2) Pancreatic adenocarcinoma (n = 3) Peritoneal mesothelioma (n = 2) Renal cell cancer (RCC, n = 1) Salivary duct carcinoma (n = 2) Sarcoma (n = 3) Small bowel adenocarcinoma (n = 1) -100 -80 -60 -40 -20 0 20 40 60 80 100 Best % change in target lesions Adenocarcinoma of unknown origin Clear cell odontogenic carcinoma CRC IMT Salivary duct carcinoma Medullary glioma Pancreatic adenocarcinoma RCC Sarcoma Small bowel adenocarcinoma Neuroendocrine carcinoma of pancreas Neuroendocrine carcinoma of lung Compound ALK resistance mutation Single ALK resistance mutation Peritoneal mesothelioma -100 -80 -60 -40 -20 0 20 40 60 80 100 Best % change in target lesions Adenocarcinoma of unknown origin Clear cell odontogenic carcinoma CRC IMT Salivary duct carcinoma Medullary glioma Pancreatic adenocarcinoma RCC Sarcoma Small bowel adenocarcinoma Neuroendocrine carcinoma of pancreas Neuroendocrine carcinoma of lung Compound ALK resistance mutation Single ALK resistance mutation Peritoneal mesothelioma -100 -80 -60 -40 -20 0 20 40 60 80 100 Best % change in target lesions Adenocarcinoma of unknown origin Clear cell odontogenic carcinoma CRC IMT Salivary duct carcinoma Medullary glioma Pancreatic adenocarcinoma RCC Sarcoma Small bowel adenocarcinoma Neuroendocrine carcinoma of pancreas Neuroendocrine carcinoma of lung Compound ALK resistance mutation Single ALK resistance mutation Peritoneal mesothelioma -100 -80 -60 -40 -20 0 20 40 60 80 100 Best % change in target lesions Adenocarcinoma of unknown origin Clear cell odontogenic carcinoma CRC IMT Salivary duct carcinoma Medullary glioma Pancreatic adenocarcinoma RCC Sarcoma Small bowel adenocarcinoma Neuroendocrine carcinoma of pancreas Neuroendocrine carcinoma of lung Compound ALK resistance mutation Single ALK resistance mutation Peritoneal mesothelioma
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Use eyedropper tool to select colors from the expanded color palette: NVL-330 for HER2-altered NSCLC A brain-penetrant, HER2-selective inhibitor with activity against HER2 mutations and the potential to minimize EGFR-related adverse events 48 Mechanism of Action: HER2-selective tyrosine kinase inhibitor Stage of Development: Phase 1 Initial Development Indication: HER2-altered NSCLC
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxesPlease do not move the page number or footer boxes Head-to-head clinical studies comparing the currently approved or investigational therapies have not been conducted and no comparative clinical conclusions can be drawn. ADC, antibody-drug conjugate; CNS, central nervous system; HER2ex20, HER2 exon 20 insertion mutations; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor. Sources: [1] Liu et al., Clin Cancer Res 2018. [2] Li et al., JTO 2016. [3] Offin et al., Cancer 2020. [4] KEYTRUDA (pembrolizumb) FDA package insert. [5] ENHERTU (T-DXd) FDA package insert. [6] (pyrotinib) Zhou C. et al., JCO 2020. [7] (ORIC-114) Hong et al., ESMO 2023. [8] (sevabertinib) Le X. et al., NEJM 2025. [9] HERNEXEOS (zongertinib) FDA package insert. [10] Heymach J.V. et al., NEJM 2025. HER2 -ALTERED NSCLC LANDSCAPE CNS involvement and treatment-related adverse events are associated with available and investigational HER2 targeted therapies Observed in clinical investigation. LIMITATION: Not observed in clinical investigation. K E Y: Targeted therapies for HER2-altered NSCLCMutant: ~2 – 4% of NSCLC 1,2 | Amplified: ~1 – 5% of NSCLC 1,2 ~19% CNS disease at diagnosis 3 Opportunity for deeper, more durable responses: 48% ORR, 11.2 month mDOR, 8.8 month mPFS with chemo/I-O 4 ~50% CNS disease at 1L progression 3 Opportunity for more durable responses: 58% ORR, 8.7 month mDOR with T-DXd 5 T-DXd safety signals are indicative of chemotherapy: Serious Adverse Reactions occurred in 30% of patients 5 Trastuzumab deruxtecan (T-DXd) No standard of care Pemetrexed + Platinum + Pembrolizumab 2L 1L 3L+ Standard of care: Standard of care: HER2-altered NSCLC HER2 Activity HER2ex20 Activity CNS Activity Avoiding EGFR Oral Small Molecule HER2ex20 TKIs (Other) 6, 7, 8 Investigational TBD T-Dxd (Enhertu) 5 FDA Approved ADC (Accelerated Approval) May be suboptimal Zongertinib 9, 10 FDA Approved TKI (Accelerated Approval) Varies, TBD Investigational HER2 TKIs may also inhibit the related EGFR kinase, which is associated with skin rash and diarrhea 6,7,8 May be suboptimal 49
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes NVL-330 A Rationally Designed HER2 and HER2ex20-selective, EGFR-sparing Inhibitor NVL-330 is an investigational candidate and has not been approved by FDA or any other regulatory authority. CNS, central nervous system; HER2ex20, HER2 exon 20 insertion mutations; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor. Sources: [1] Liu et al., Clin Cancer Res 2018. [2] Li et al., JTO 2016. [3] Pillai et al., Cancer 2017. [4] Nagasaka et al., Clin Lung Cancer 2022. [5] (pyrotinib) Zhou C. et al., JCO 2020. [6] (ORIC-114) Hong et al., ESMO 2023. [7] (sevabertinib) Le X. et al., NEJM 2025. [8] Offin et al., Cancer 2020. Potential Best-in-Class Target Product Profile designed in collaboration with physician-scientists to address the limitations of existing agents for HER2-altered NSCLC Oral Small Molecule HER2 Activity • Oncogenic HER2 amplification is detected in ~1 – 5% of NSCLC 1,2 Avoiding EGFR • Treatment limiting adverse events, such as skin rash and diarrhea, are associated with dual EGFR/HER2 inhibitors 5,6,7 CNS Activity • ~19% CNS disease at diagnosis 8 • ~50% CNS disease at 1L progression 8 D ES I G N G OAL for N V L-330 HER2ex20 Activity • Oncogenic mutations in HER2, of which exon 20 insertions are most common, are detected in ~2 – 4% of NSCLC 1,2 + + + + 50
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 51 Preclinical Characterization Demonstrates Desired Target Product Profile Head-to-head clinical studies comparing NVL-330 with currently approved or investigational therapies have not been conducted. Above data from preclinical studies and no clinical conclusions can be drawn. HER2ex20, HER2 exon 20 insertion; IC50, half-maximal inhibitory concentration; PO, orally. Source: Updated data on file.; Sun, Y. et al., AACR 2024. NVL - 330 In Vitro Activity, HER2 AND HER2ex20 Brain Penetrance Avoiding EGFR Inhibition Wistar Han rats 10 mg/kg, single dose PO 1 hour timepoint Lorlatinib Zongertinib NVL-330 0.0 0.1 0.2 0.3 0.4 0.5 Brain Exposure (rats) Kp,uu 1 10 100 1000 IC50 (nM) NCI-N87 HER2YVMA knock-inNCI-H2170 (HER2amp) BT-474 (HER2amp) NCI-N87 (HER2amp) NCI-H1781 (HER2VC) Ba/F3 HER2YVMA Ba/F3 HER2VC Ba/F3 HER2GSP Ba/F3 HER2 S310F Ba/F3 HER2 R678Q Ba/F3 HER2 L755S Ba/F3 HER2 V777L 5637 (HER2 S310F) J82 (HER2 R678Q) CW2 (HER2 L755S) LN-229 (HER2 G776V) OVCAR-8 (HER2 V777M) SNU-1040 (HER2 L755S) DV-90 (HER2 V842I) CTG NCI-H2170 (HER2amp) CTG BT-474 (HER2amp) CTG NCI-N87 (HER2amp) CTG Ba/F3 HER2YVMA CTG Ba/F3 HER2VC CTG Ba/F3 HER2GSP CTG NCI-H1781 (HER2VC) CTG Ba/F3 HER2 S310F CTG Ba/F3 HER2 R678Q CTG Ba/F3 HER2 L755S CTG Ba/F3 HER2 V777L A431 (EGFRWT) NVL-330 Zongertinib Poziotinib Phospho-HER2 Phospho-EGFR 1 10 100 1000 IC50 (nM) NCI-N87 HER2YVMA knock-inNCI-H2170 (HER2amp) BT-474 (HER2amp) NCI-N87 (HER2amp) NCI-H1781 (HER2VC) Ba/F3 HER2YVMA Ba/F3 HER2VC Ba/F3 HER2GSP Ba/F3 HER2 S310F Ba/F3 HER2 R678Q Ba/F3 HER2 L755S Ba/F3 HER2 V777L 5637 (HER2 S310F) J82 (HER2 R678Q) CW2 (HER2 L755S) LN-229 (HER2 G776V) OVCAR-8 (HER2 V777M) SNU-1040 (HER2 L755S) DV-90 (HER2 V842I) CTG NCI-H2170 (HER2amp) CTG BT-474 (HER2amp) CTG NCI-N87 (HER2amp) CTG Ba/F3 HER2YVMA CTG Ba/F3 HER2VC CTG Ba/F3 HER2GSP CTG NCI-H1781 (HER2VC) CTG Ba/F3 HER2 S310F CTG Ba/F3 HER2 R678Q CTG Ba/F3 HER2 L755S CTG Ba/F3 HER2 V777L A431 (EGFRWT) NVL-330 Zongertinib Poziotinib 1 10 100 1000 IC50 (nM) NCI-N87 HER2YVMA knock-inNCI-H2170 (HER2amp) BT-474 (HER2amp) NCI-N87 (HER2amp) NCI-H1781 (HER2VC) Ba/F3 HER2YVMA Ba/F3 HER2VC Ba/F3 HER2GSP Ba/F3 HER2 S310F Ba/F3 HER2 R678Q Ba/F3 HER2 L755S Ba/F3 HER2 V777L 5637 (HER2 S310F) J82 (HER2 R678Q) CW2 (HER2 L755S) LN-229 (HER2 G776V) OVCAR-8 (HER2 V777M) SNU-1040 (HER2 L755S) DV-90 (HER2 V842I) CTG NCI-H2170 (HER2amp) CTG BT-474 (HER2amp) CTG NCI-N87 (HER2amp) CTG Ba/F3 HER2YVMA CTG Ba/F3 HER2VC CTG Ba/F3 HER2GSP CTG NCI-H1781 (HER2VC) CTG Ba/F3 HER2 S310F CTG Ba/F3 HER2 R678Q CTG Ba/F3 HER2 L755S CTG Ba/F3 HER2 V777L A431 (EGFRWT) NVL-330 Zongertinib Poziotinib Phospho-HER2 Viability Selectivity index = IC50 (phospho-EGFRWT in A431) IC50(phospho-HER2 or viability) More active for wild-type EGFR More active for HER2 Selectivity index Broad activity on HER2 oncogenic alterations, including HER2 exon20ins, activating point mutations, and amplified wild-type HER2 Pharmacokinetic data similar to preclinical observations for lorlatinib Greater selectivity for HER2ex20 mutations over EGFR than pan-ERBB inhibitors (e.g. poziotinib) NVL-330 NVL-330 0.1 1 10 100 1000 Poziotinib Zongertinib NVL-330 NVL-330
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes 52 Potential for Differentiated Brain-penetrant Profile Head-to-head clinical studies comparing NVL-330 with currently approved or investigational therapies have not been conducted. Above data from preclinical studies and no clinical conclusions can be drawn. BID, twice daily; QD, once daily. Source: Sun Y. et al., AACR-NCI-EORTC 2025 NVL - 330 • In the intracranial NCI-N87 tumor model, NVL-330 (30 mg/kg BID) induced intracranial tumor regression in mice progressing in the CNS on zongertinib (30 mg/kg BID) • Zongertinib 30 mg/kg BID provided exposures estimated to be above its approved human doses of 120 and 180 mg QD, and did not induce regression in this model Day 1 Day 15 Day 29 Vehicle NVL-330 30 mg/kg BID Zongertinib 30 mg/kg BID Crossover: Zongertinib → NVL-330 2 6 2 6 0.00 0.05 0.10 0.15 0.20 Kp Hours after final dose Brain Partitioning CrossoverIntracranial Activity 0 7 14 21 28 1 10 100 1000 Days on treatment Brain bioluminesence ( 106 photons/s) ** +251% -73% 0 7 14 21 28 1 10 100 1000 Days on treatment Brain bioluminesence ( 106 photons/s) zongertinib NVL-330 +124% -84% 2 6 2 6 1 10 100 1000 10000 Hours after final dose Drug concentration (nM) Plasma Brain Plasma and Brain PK
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Use eyedropper tool to select colors from the expanded color palette: Please do not move or change the size of the Title box Keep content within provided margin guidelines: 12” width Keep content within provided margin guidelines: 5.5” height Please try to avoid covering the logoPlease do not move the page number or footer boxes A First-in-Human Phase 1a/1b Clinical Trial of NVL-330 in Advanced HER2-Altered NSCLC (NCT06521554) 53 Phase 1a BOIN Dose-Escalation HER2 mutation or HER2 amplification allowed Phase 1b Dose Expansion HER2 mutation only Dose Expansion at Candidate RP2Ds P U R P O S E : ✓ Safety / Tolerability ✓ Select Candidate RP2D(s) ✓ Safety / Tolerability ✓ Confirm RP2D DL 1 DL 2 DL 4 DL 3 DL 5 DL 6 DL 7 Enrollment ongoing (up to N ~120) P A T I E N T P O P U L A T I O N • ≥ 1 prior systemic therapy, including platinum-based chemotherapy +/- immunotherapy o Excluded: Prior selective HER2 TKI a o Prior HER2-directed antibodies and HER2-directed ADCs are allowed. • Excluded: concurrent oncogenic drivers (e.g., EGFR, BRAF, MET, ROS1, ALK, or RET) • Evaluable but non-measurable disease allowed in Phase 1a • Phase 1a: HER2 mutation or HER2 amplification allowed • Phase 1b: HER2 mutation only ADC, antibody-drug conjugate; BOIN, Bayesian optimal interval; NSCLC, non-small cell lung cancer; RP2D, recommended phase 2 dose; TKI, tyrosine kinase inhibitor. a For at least 6 patients in each Phase 1a dose level cohort expansion, and for all patients in Phase 1b.
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