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Use eyedropper tool to select colors from the expanded color palette: Nuvalent Overview October 30, 2025
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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; the period over which Nuvalent estimates its cash, cash equivalents and marketable securities will be sufficient to fund its future operating expenses and capital expenditure requirements; the expected timing of data announcements, clinical trial initiations, FDA submissions, and potential FDA product approvals, including the projections in our OnTarget 2026 operating plan; the clinical development programs for zidesamtinib, neladalkib (NVL-655) and NVL-330; the potential clinical effects of zidesamtinib, neladalkib and NVL-330; the design, timing and enrollment of the ARROS-1, ALKOVE-1, ALKAZAR and HEROEX-1 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; the implications of data readouts and presentations; timing and content of potential discussions with regulators and investigators; 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 Quarterly Report on Form 10-Q for the quarterly period ended September 30, 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 in global clinical development with potential for first FDA approval 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 2028
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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 Matthew Shair, PhD Harvard Professor of Chemistry & Chemical Biology 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 Matthew Shair, PhD Head Scientific Advisor Harvard Professor of Chemistry & Chemical Biology 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 Additional Discovery Research Programs Ongoing Zidesamtinib (NVL-520) for ROS1+ NSCLC Neladalkib (NVL-655) for ALK+ NSCLC NVL-330 for HER2-altered NSCLC Ongoing registration-directed Phase 2 for TKI-naïve and TKI pre-treated patients Ongoing registration-directed Phase 2 for TKI pre-treated patients Ongoing registration-directed Phase 3 for TKI-naïve patients Ongoing Phase 1a/1b
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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 Report pivotal data for TKI pre-treated ROS1+ NSCLC from ARROS-1 trial in 1H Complete rolling NDA submission for TKI pre-treated ROS1+ NSCLC in Q3 Report pivotal data for TKI pre-treated ALK+ NSCLC from ALKOVE-1 trial by year-end Initiate ALKAZAR Phase 3 trial for TKI-naïve ALK+ NSCLC in early 2H Progress HEROEX-1 Phase 1a/1b trial for HER2-altered NSCLC Completed & Anticipated 2025 Milestones: 2024 EXECUTE ON GLOBAL REGISTRATIONAL STRATEGIES 2025 FIRST PIVOTAL DATA 2026 FIRST APPROVED PRODUCT GOAL: : Planned : Complete
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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 AE, adverse event; CNS, central nervous system; NSCLC, non-small cell lung cancer. Sources: [1] Kwak E. et al., NEJM 2010. [2] Gainor J et al. JCO Precis Oncol. 2017. [3] Dagogo-Jack I. et al., Clin Cancer Res 2019. [4] Gainor J. et al. Cancer Discov. 2016. [5] Shaw A. et al., Lancet Onc 2017. [6] Shiba-Ishii et al., Nature Cancer 2022. [7] LORBRENA FDA prescribing information, revised 4/2023. [8] Drilon A. et al., Nat Rev Clin Oncol. 2021. [9] Jordan E.J. et al., Cancer Discovery 2017. [10] Ou S.I. and Zhu V.W., Lung Cancer 2019. [11] Patil T. et al., J Thorac Oncol. 2018. [12] AUGTYRO FDA prescribing information, revised 06/2024. ~3 – 5% of NSCLC 1 ~30 – 40% CNS disease at diagnosis 2 ~50% single resistance mutations 3, 4 > 60% CNS disease at 1L progression 5 ~25 – 50% compound mutations 3,6 52% CNS AEs with the brain-penetrant dual TRK/ALK inhibitor, lorlatinib 7 Lorlatinib No standard of care No standard of care ~1 – 3% of NSCLC 8,9 ~20 – 40% CNS disease at diagnosis 10,11 ~40% ROS1 G2032R mutation 2 ~30 – 55% CNS disease at 1L progression 2 77% CNS AEs with the brain-penetrant dual TRK/ROS1 inhibitor, repotrectinib 12 Alectinib Crizotinib 2L 1L 3L+ Emerging resistance mutations, CNS involvement, and treatment-related adverse events limit the utility of approved therapies: 2L+ 1L Standard of care: Standard of care: Standard of care: ROS1+ NSCLCALK+ NSCLC Observed in clinical investigation. Limitation / Not observed in clinical investigation. K E Y :
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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 2L+ patients with T790M *: Osimertinib for EGFR+ NSCLC 5 0 5 10 15 20 Erlotinib or Gefitinib Osimertinib HR = 0.46 1L mPFS: 18.9 months Months ORR: 65% mDOR: 11 months 1L intracranial ORR: C A S E S T U D Y Activity against resistance mutations + Improved CNS activity Significant 1L mPFS improvement & Movement up the treatment paradigm 10 CNS, central nervous system; CR, complete response; DOR, duration of response; NSCLC, non-small cell lung cancer; ORR, objective response rate; PFS, progression-free survival, TKI, tyrosine kinase inhibitor. Sources: [1] Dagogo-Jack I. et al., Clin Cancer Res 2019; [2] Gainor J. et al. Cancer Discov. 2016; [4] Gainor J.F. et al., JCO Precision Oncol. 2017; [4] Ohashi K. et al., JCO 2013; [5] Osimertinib FDA package insert. Osimertinib: 77% with 18% CR Erlotinib or Gefitinib: 63% with 0% CR * Comparable resistance mutation rates after 1L TKI: ~50% ALK single mutation 1,2 & ~40% ROS1 G2032R 3 vs. ~50% EGFR T790M 4
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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 ALK+ & ROS1+ NSCLC: Proven Targets with Established & Meaningful Commercial Markets 11 ~$3.1B Combined WW Sales in 2024 1L, 1st line; 2L, 2nd line; 3L, 3rd line; B, billion; F, forecasted; M, million; NSCLC, non-small cell lung cancer; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. * Crizotinib sales as of 2023; 2024 sales are not reported. Crizotinib is FDA approved for ROS1+ NSCLC, ALK+ NSCLC, ALK+ ALCL and ALK+ IMT. Sales are not reported by indication. ** Lorlatinib is also included in NCCN Guidelines for ROS1+ NSCLC patients progressed on entrectinib, crizotinib, or repotrectinib. Sources: 2024 Year-End Earnings Reports: Roche, Chugai, Pfizer, Takeda, and BMS; FDA Package Inserts; NCCN Guidelines for NSCLC (version 2.2025). 0 200 400 600 800 1,000 1,200 1,400 1,600 1,800 2,000 Alectinib (1L Standard of Care, ALK+ NSCLC) Crizotinib* (1L Standard of Care, ROS1+ NSCLC) Other ROS1 and ALK TKIs (Generally used 2L+) mPFS: 10.9 months mPFS: 25.7 months 2024 GLOBAL SALES FOR ALK & ROS1 TKIs ($M) ~$1.8B $374M ~$1.2B Lorlatinib (ALK)** Brigatinib (ALK) Entrectinib (ROS1) Repotrectinib (ROS1) (2023)
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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 12 Potential best-in-class profiles designed with the goal to supplant the current 1L standard of care Disrupt Treatment Paradigms Zidesamtinib for ROS1+ NSCLC Investigational Design Goal THE NUVALENT VISION Opportunity to Build a Sustainable Business Potential near-term registrational opportunity for TKI-pretreated patients Clinical proof-of-concept demonstrated in heavily pre-treated patient populations drives strong enrollment momentum Potential to grow the market through potentially deeper, more durable responses for TKI-naïve and TKI-pretreated patients Parallel development paths for TKI-naïve patients ongoing to address the 1L market Clinical trials designed to support line-agnostic label expansion ++ + + ++ + ROS1 Activity ROS1 Mutant Activity CNS Activity Avoiding TRK ALK Activity ALK Mutant Activity CNS Activity Avoiding TRKSingle Compound Neladalkib for ALK+ NSCLC Investigational Design Goal
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Use eyedropper tool to select colors from the expanded color palette: Zidesamtinib (NVL-520) for ROS1+ NSCLC A brain-penetrant, selective inhibitor of ROS1 and ROS1 resistance mutations with the potential to minimize TRK-related CNS adverse events while providing CNS antitumor activity 13 Mechanism of Action: ROS1-selective tyrosine kinase inhibitor Initial Development Indication: ROS1-positive NSCLC Stage of Development: ❖ NDA submitted for TKI pre-treated population ❖ Ongoing Ph 2 supports potential line-agnostic expansion FDA Designations: ❖ Breakthrough Therapy Designation ❖ Orphan Drug Designation
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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 14 Head-to-head clinical studies comparing the currently approved or investigational therapies have not been conducted and no comparative clinical conclusions can be drawn. AE, adverse event; 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] Ou S.I. and Zhu V.W., Lung Cancer 2019. [4] Patil T. et al., J Thorac Oncol. 2018. [5] Gainor J et al. JCO Precis Oncol. 2017. [6] AUGTYRO FDA prescribing information, revised 06/2024. [7] FDA Prescribing Information for XALKORI (crizotinib), ROZLYTREK (entrectinib), AUGTYRO (repotrectinib), and IBTROZI (taletrectinib), and Shaw et al., Lancet Oncol. 2019. for lorlatinib. No standard of care ~1 – 3% of NSCLC 1,2 ~20 – 40% CNS disease at diagnosis 3,4 ~40% ROS1 G2032R mutation 5 ~30 – 55% CNS disease at 1L progression 5 77% CNS AEs with the brain-penetrant dual TRK/ROS1 inhibitor, repotrectinib 6 Crizotinib ROS1+ NSCLC LANDSCAPE Emerging resistance mutations, CNS involvement, and treatment-related adverse events are associated with available ROS1 TKIs 2L+ 1L Standard of care: ROS1+ NSCLC ROS1 Activity ROS1 Mutant Activity CNS Activity Avoiding TRK Crizotinib FDA Approved Entrectinib FDA Approved Lorlatinib NCCN Guidelines Repotrectinib FDA Approved Taletrectinib FDA Approved Observed in clinical investigation. 7 LIMITATION: Not observed in clinical investigation. 7 K E Y: TKIs for 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 Zidesamtinib A Rationally Designed ROS1-selective, TRK-sparing Inhibitor 15 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. Source: [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 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
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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 16 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 Brain Penetrance Pharmacokinetic data similar to preclinical observations for lorlatinib Avoiding TRK Inhibition Selectivity for ROS1 and ROS1 G2032R over TRK Wistar Han rats 10 mg/kg, single dose PO 1 hour timepoint NVL-520 Lorlatinib 0.0 0.1 0.2 0.3 0.4 0.5 Unbound brain:plasma ratio Zidesamtinib 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 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 17 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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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) • 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 Pivotal data demonstrated potential for zidesamtinib to address medical needs for patients with TKI pre-treated ROS1-positive NSCLC: Preliminary TKI-naïve data support potential to improve outcomes in earlier lines of therapy Pivotal Data for TKI Pre-treated ROS1-positive NSCLC 25 BICR, blinded independent central review; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor; TRK, proteins encoded for by the neurotrophic tyrosine receptor kinase (NTRK) family of genes. Meaningful clinical responses by BICR in TKI pre-treated ROS1-positive NSCLC population Clinical activity in patients with key drivers of disease progression Generally well-tolerated safety profile consistent with ROS1-selective, TRK-sparing design
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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 26 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 Zidesamtinib | Global Development Strategy 27 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 Designed for line-agnostic label expansion 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 Rolling NDA submission completed under FDA’s RTOR program 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
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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 28 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: Neladalkib (NVL-655) for ALK+ NSCLC A brain-penetrant, selective inhibitor of ALK and ALK resistance mutations with the potential to minimize TRK-related CNS adverse events while providing CNS antitumor activity 29 Mechanism of Action: ALK-selective tyrosine kinase inhibitor Stage of Development: ❖ Global Phase 2 with registrational intent for TKI pre-treated patients ❖ Global Phase 3 with registrational intent for TKI-naïve patients Initial Development Indication: ALK-positive NSCLC FDA Designations: ❖ Breakthrough Therapy Designation ❖ Orphan Drug Designation
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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 30 Head-to-head clinical studies comparing the currently approved or investigational therapies have not been conducted and no comparative clinical conclusions can be drawn. AE, adverse event; 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] Kwak E. et al., NEJM 2010. [2] Gainor J et al. JCO Precis Oncol. 2017. [3] Dagogo-Jack I. et al., Clin Cancer Res 2019. [4] Gainor J. et al. Cancer Discov. 2016. [5] Shaw A. et al., Lancet Onc 2017. [6] Shiba-Ishii et al., Nature Cancer 2022. [7] LORBRENA FDA prescribing information, revised 4/2023. [8] FDA Prescribing Information for XALKORI (crizotinib), ZYKADIA (ceritinib), ALECENSA (alectinib), ALUNBRIG (brigatinib), and LORBRENA (lorlatinib). ALK+ NSCLC LANDSCAPE Emerging resistance mutations, CNS involvement, and treatment-related adverse events are associated with available ALK TKIs Observed in clinical investigation. 8 LIMITATION: Not observed in clinical investigation. 8 K E Y: TKIs for ALK+ NSCLC~3 – 5% of NSCLC 1 ~30 – 40% CNS disease at diagnosis 2 ~50% single resistance mutations 3, 4 > 60% CNS disease at 1L progression 5 ~25 – 50% compound mutations 3,6 52% CNS AEs with the brain-penetrant dual TRK/ALK inhibitor, lorlatinib 7 Lorlatinib No standard of care Alectinib 2L 1L 3L+ Standard of care: Standard of care: ALK+ NSCLC Crizotinib 1st Generation Ceritinib 2nd Generation Alectinib 2nd Generation Brigatinib 2nd Generation Lorlatinib 3rd Generation ALK Activity ALK Mutant Activity CNS Activity Avoiding TRKSingle Compound
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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 31 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] Kwak E. et al., NEJM 2010. [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] Gainor J et al. JCO Precis Oncol. 2017. [6] Shaw A. et al., Lancet Onc 2017. [7] LORBRENA FDA prescribing information, revised 4/2023. 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 2, 3 CNS Activity • ~30 – 40% CNS disease at diagnosis 5 • > 60% CNS disease at 1L progression 6 Avoiding TRK • Treatment-limiting neurological adverse events observed with brain-penetrant, dual TRK/ALK inhibitors 7 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 + + + +
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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 34 A Global First-in-Human Phase 1/2 Clinical Trial of Neladalkib (NVL-655) in Advanced ALK-Positive NSCLC and Other Solid Tumors (NCT05384626) Durable activity in heavily TKI pre-treated ALK-positive NSCLC population Demonstrated ability to address key drivers of treatment progression Favorable ALK-selective safety profile supports tolerability of long-term treatment Potential to improve outcomes in earlier lines of therapy with best-in-class profile Updated Ph 1 data presented at ESMO 2024 • 133 patients enrolled ➢ Differentiated, heavily pre-treated patient population • 150 mg QD selected as RP2D • Preliminary clinical proof-of-concept: NSCLC, non-small cell lung cancer; QD, once daily; RP2D, recommended phase 2 dose; TKI, tyrosine kinase inhibitor.
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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 Differentiated, Heavily Pre-treated ALK+ Solid Tumor Population a 35 CNS, central nervous system; NSCLC, non-small cell lung cancer; ORR, objective response rate; TKI, tyrosine kinase inhibitor. a 98% NSCLC at all doses. Other solid tumor types: pancreatic adenocarcinoma (n=1); atypical carcinoid, lung (n=1). b Categories are not mutually exclusive. c ALK mutations as per local or central testing of blood (ctDNA) or tissue. d Cis-allelic configuration not confirmed in all cases. e Includes patients with untreated CNS lesions and patients with prior disease progression on the brain-penetrant TKI lorlatinib. Source: Adapted from data presentation by Drilon A. et al., ESMO 2024 (Data cut-off: 15 June 2024). Preliminary Phase 1 Insights N E L A D A L K I B ( N V L - 655) 51% with any secondary ALK mutation c 26% with compound ALK mutation c, d 56% with history of CNS metastasis e Ability to evaluate activity against key drivers of disease progression b Ability to evaluate benefit for patients who have exhausted available treatment options b 3 median lines of prior anticancer treatment (Range: 1 – 9) 56% received prior chemotherapy 84% received prior lorlatinib 46% received ≥3 prior ALK TKIs 44% received ≥3 prior ALK TKIs, including a 2G TKI and lorlatinib (3G)
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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 25 50 75 100 Duration of Response (Months) Patients in Response (%) Durable Activity in Heavily TKI Pre-treated ALK+ NSCLC Population 36 Response-evaluable patients with ALK+ NSCLC. DOR, duration of response; NSCLC, non-small cell lung cancer; ORR, objective response rate; RP2D, recommended phase 2 dose; TKI, tyrosine kinase inhibitor. Source: Adapted from data presentation by Drilon A. et al., ESMO 2024 (Data cut-off: 15 June 2024). • All NSCLC response evaluable, across all doses: ─ ORR: 38% (39/103) ─ mDOR: 14.4 months; 78% DOR > 6 months • All NSCLC response evaluable, at RP2D: ─ ORR: 38% (15/39) ─ mDOR: Not reached; 100% DOR > 6 months Neladalkib demonstrated activity for patients with ALK+ NSCLC, even where other therapies have failed (1 – 5 prior ALK TKIs ± chemotherapy) Preliminary Phase 1 Insights N E L A D A L K I B ( N V L - 655) Any Prior ALK TKI(s) ± chemotherapy RP2D 15 15 9 3 2 0 All Doses 39 39 21 11 6 0 # At Risk
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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 25 50 75 100 Duration of Response (Months) Patients in Response (%) 0 3 6 9 12 15 0 25 50 75 100 Duration of Response (Months) Patients in Response (%) ~3 – 5% of NSCLC ~30 – 40% CNS disease at diagnosis ~50% single resistance mutations > 60% CNS disease at 1L progression ~25 – 50% compound mutations 52% CNS AEs with brain-penetrant dual TRK/ALK inhibitors Lorlatinib No standard of care Alectinib Standard of care: Standard of care: ALK+ NSCLC Preliminary Phase 1 Insights Demonstrated Ability To Address Key Drivers of Treatment Progression 37 Response-evaluable patients with ALK+ NSCLC. CNS, central nervous system; DOR, duration of response; NSCLC, non-small cell lung cancer; ORR, objective response rate; RP2D, recommended phase 2 dose; TKI, tyrosine kinase inhibitor. a Includes all patients with ≥1 identified ALK resistance mutation as per local or central testing of blood (ctDNA) or tissue. Responses observed in patient with ALK I1171N/S, V1180L, L1196Q, G1202R, D1203N, or E1210K, including where multiple mutations co-occur. b Analyses of DOR based on Kaplan-Meier estimates; c ≥2 mutations (cis-allelic configuration not confirmed for all patients). Source: Adapted from data presentation by Drilon A. et al., ESMO 2024 (Data cut-off: 15 June 2024). Neladalkib demonstrated activity in the presence of ALK single and compound resistance mutations, including after prior lorlatinib N E L A D A L K I B ( N V L - 655) 2L 1L 3L+ RP2D 7 7 6 2 1 0 All Doses 15 15 11 6 4 0 RP2D 12 12 9 3 2 0 All Doses 30 30 20 10 6 0 # At Risk Any ALK Resistance Mutation Any Prior ALK TKIs ± Chemotherapy Compound ALK Resistance Mutation Prior Lorlatinib (≥2 Prior ALK TKIs ± Chemotherapy) • ORR at RP2D: 55% (12/22) a • mDOR at RP2D: Not Reached; 100% DOR > 6 months b • ORR at RP2D: 64% (7/11) c • mDOR at RP2D: Not reached; 100% DOR > 6 months b # At Risk
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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 Phase 1 Insights Demonstrated Ability To Address Key Drivers of Treatment Progression 38 CNS, central nervous system; IC-ORR, intracranial ORR for patients with measurable CNS lesions; ORR, objective response rate; uPR, unconfirmed partial response. Source: Adapted from data presentation by Drilon A. et al., ESMO 2024 (Data cut-off: 15 June 2024). Neladalkib demonstrated durable CNS activity, including in patients who previously received the brain-penetrant TKI lorlatinib N E L A D A L K I B ( N V L - 655) • No CNS progression among confirmed CNS responders (n = 9, with measurable or unmeasurable CNS lesions) ─ Treatment duration: 6.7 – 14.4+ months • IC-ORR (patients with measurable CNS lesions): ─ Lorlatinib-naïve: 50% (1/2) ─ Prior lorlatinib: 15% (2/13) o 31% (4/13) including 2 CNS uPRs not confirmed due to discontinuation of treatment in absence of CNS progression ~3 – 5% of NSCLC ~30 – 40% CNS disease at diagnosis ~50% single resistance mutations > 60% CNS disease at 1L progression ~25 – 50% compound mutations 52% CNS AEs with brain-penetrant dual TRK/ALK inhibitors Lorlatinib No standard of care Alectinib Standard of care: Standard of care: ALK+ NSCLC 2L 1L 3L+
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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 Phase 1 Insights Favorable Safety Profile Supports Tolerability of Long-term Treatment 39 Median follow-up for all treated population: 8.0 months (range 0.2, 22.5). ALT, alanine aminotransferase; AST, aspartate aminotransferase; QD, once daily; TRAE, treatment-related adverse event. a TRAEs resulting in treatment discontinuation were Grade 3-4 ALT/AST elevations (50 mg QD and 100 mg QD) and intolerable Grade 2 constipation (occurred at 100 mg QD following dose increase from 50 mg QD). b TRAEs resulting in dose-reduction in > 1 patient were ALT and/or AST increase (n = 7), dysgeusia (n = 2), peripheral sensory neuropathy (n = 2), and rash maculopapular (n = 2). Reductions by dose level were 200 mg QD (n = 7), 150 mg QD (n = 7), 100 mg QD (n = 4), and 50 mg QD (n = 2). Source: Adapted from data presentation by Drilon A. et al., ESMO 2024 (Data cut-off: 15 June 2024). • Discontinuation due to TRAE: 2% (3/133) a • Dose reduction due to TRAE: 15% (20/133) b Preliminary safety profile of neladalkib was consistent with its ALK-selective design and avoiding TRK-related neurotoxicities N E L A D A L K I B ( N V L - 655) Treatment-Related Adverse Events (TRAEs) in ≥ 10% of Patients All Treated (N = 133) Preferred Term Grade 1 n (%) Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) Any Grade n (%) ALT increased 21 (16%) 6 (5%) 17 (13%) 1 (1%) 45 (34%) AST increased 21 (16%) 7 (5%) 12 (9%) - 40 (30%) Constipation 15 (11%) 6 (5%) - - 21 (16%) Dysgeusia 15 (11%) 2 (2%) - - 17 (13%) Nausea 15 (11%) 1 (1%) - - 16 (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 0 3 6 9 12 15 0 25 50 75 100 Duration of Response (Months) Patients in Response (%) 0 3 6 9 12 15 0 25 50 75 100 Duration of Response (Months) Patients in Response (%) Preliminary Phase 1 Insights Potential to Improve Outcomes in Earlier Lines of Therapy with a Best-in-Class Profile 40 Response-evaluable patients with ALK+ NSCLC. 1G, 1st generation ALK TKI (i.e., crizotinib); 2G, 2nd generation ALK TKI (i.e., ceritinib, alectinib, or brigatinib); DOR, duration of response; NSCLC, non-small cell lung cancer; ORR, objective response rate; RP2D, recommended phase 2 dose; TKI, tyrosine kinase inhibitor. Source: Adapted from data presentation by Drilon A. et al., ESMO 2024 (Data cut-off: 15 June 2024). 2L+ NSCLC Response-Evaluable Lorlatinib-naïve, ≥1 2G ± 1G ALK TKI ± chemotherapy N E L A D A L K I B ( N V L - 655) ++ + + • ORR at RP2D: 57% (4/7) • mDOR at RP2D: Not Reached with all responses ongoing 2L+ NSCLC Response-Evaluable Lorlatinib-naïve, with ALK resistance mutation ≥1 2G ± 1G ALK TKI ± chemotherapy • ORR at RP2D: 80% (4/5) • mDOR at RP2D: Not Reached with all responses ongoing RP2D 4 4 3 1 1 0 All Doses 9 9 5 3 2 0 # At Risk # At Risk RP2D 4 4 3 1 1 0 All Doses 7 7 5 3 2 0
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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 41 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 L42 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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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 43 0 100 200 300 400 500 600 700 Jan-22 Jan-23 Jan-24 Dec-24 Phase 1 Initiation JUNE 2022 Phase 1 AUGUST 2023 93 Transition to Phase 2 FEBRUARY 2024 133 ALKOVE-1 DECEMBER 31, 2024 596 133 Phase 1 + 463 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
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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 44 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 for potential line-agnostic label expansion: • 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 Pivotal data anticipated by year-end 2025 Multi-cohort design with opportunity to support broad TKI pre-treated label: • Prior 2G ALK TKI, ≤2 prior chemo/I-O (n ~92*) • Prior lorlatinib, ≤1 prior chemo/I-O (n ~20*) • 2-3 prior ALK TKI (any), ≤2 prior chemo/I-O (n ~137*) Phase 2: TKI Pre-treated Cohorts Global enrollment complete Randomized Phase 3: TKI-naïve Global enrollment ongoing 2L 3 L + 2L 1L * Estimated cohort enrollment target per protocol; does not reflect actual cohort enrollment. Enrollment ongoing for adult and pediatric patients with other ALK+ solid tumors
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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 45 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 46 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] Pillai et al., Cancer 2017. [2] Nagasaka et al., Clin Lung Cancer 2022. [3] Liu et al., Clin Cancer Res 2018. [4] Li et al., JTO 2016. [5] Offin et al., Cancer 2020. [6] KEYTRUDA (pembrolizumb) FDA package insert. [7] ENHERTU (T-DXd) FDA package insert. [8] (pyrotinib) Zhou C. et al., JCO 2020. [9] (tepotinib) Le X. et al., JCO 2022. [10] (sevabertinib) Girard N. et al., ELCC 2025. [11] 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 3,4 ~19% CNS disease at diagnosis 5 Opportunity for deeper, more durable responses: 48% ORR, 11.2 month mDOR, 8.8 month mPFS with chemo/I-O 6 ~50% CNS disease at 1L progression 5 Opportunity for more durable responses: 58% ORR, 8.7 month mDOR with T-DXd 7 T-DXd safety signals are indicative of chemotherapy: Serious Adverse Reactions occurred in 30% of patients 7 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) 8, 9, 10 Investigational TBD T-Dxd (Enhertu) 7 FDA Approved ADC (Accelerated Approval) May be suboptimal Zongertinib 11 Investigational TKI TBD Varies, TBD Investigational HER2 TKIs may also inhibit the related EGFR kinase, which is associated with skin rash and diarrhea 8,9,10
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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 NVL-330 A Rationally Designed HER2 and HER2ex20-selective, EGFR-sparing Inhibitor 47 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] NCCN Guidelines, NSCLC v5.2025. [2] Liu et al., Clin Cancer Res 2018. [3] Li et al., JTO 2016. [4] Pillai et al., Cancer 2017. [5] Nagasaka et al., Clin Lung Cancer 2022. [6] (pyrotinib) Zhou C. et al., JCO 2020. [7] (tepotinib) Le X. et al., JCO 2022. [8] (sevabertinib) Girard N. et al., ELCC 2025. [9] 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 • No TKIs are FDA approved for HER2-altered NSCLC 1 HER2 Activity • Oncogenic HER2 amplification is detected in ~1 – 5% of NSCLC 2,3 Avoiding EGFR • Treatment limiting adverse events, such as skin rash and diarrhea, are associated with dual EGFR/HER2 inhibitors 6,7,8 CNS Activity • ~19% CNS disease at diagnosis 9 • ~50% CNS disease at 1L progression 9 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 4,5 + + + +
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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 48 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 49 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) 50 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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51 MISSION: Bringing new, best-in-class medicines to patients with cancer 2024 EXECUTE ON GLOBAL REGISTRATIONAL STRATEGIES 2025 FIRST PIVOTAL DATA 2026 FIRST APPROVED PRODUCT GOAL: Program Status: • Zidesamtinib (ARROS-1 study for ROS1+ NSCLC) ─ Rolling NDA submission completed for TKI pre-treated ROS1+ NSCLC ─ Ongoing TKI-naïve cohort designed to support potential line-agnostic label expansion • Neladalkib (ALKOVE-1 & ALKAZAR studies for ALK+ NSCLC) ─ Topline pivotal data for TKI pre-treated ALK+ NSCLC from ALKOVE-1 anticipated by year-end 2025 ─ Trial initiated: ALKAZAR Phase 3 randomized controlled study for patients with TKI-naïve ALK+ NSCLC • NVL-330 (HEROEX-1 study for HER2-altered NSCLC): Phase 1a/1b ongoing • Additional Discovery Research Programs Ongoing
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