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October 23, 2025 Natera, Inc. Post-ESMO Investor Call
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This presentation contains forward-looking statements under the meaning of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts contained in this presentation, including statements regarding our market opportunity, our anticipated products and launch schedules, our reimbursement coverage and our product costs, our commercial and strategic partnerships and potential acquisitions, our user experience, our clinical trials and studies, our strategies, our goals and general business and market conditions, are forward-looking statements. These forward-looking statements are subject to known and unknown risks and uncertainties that may cause actual results to differ materially, including: we face numerous uncertainties and challenges in achieving our financial projections and goals; we may be unable to further increase the use and adoption of our products through our direct sales efforts or through our laboratory partners; we have incurred net losses since our inception and we anticipate that we will continue to incur net losses for the foreseeable future; our quarterly results may fluctuate from period to period; our estimates of market opportunity and forecasts of market growth may prove to be inaccurate; we may be unable to compete successfully with existing or future products or services offered by our competitors; we may engage in acquisitions, dispositions or other strategic transactions that may not achieve our anticipated benefits and could otherwise disrupt our business, cause dilution to our stockholders or reduce our financial resources; our products may not perform as expected; the results of our clinical studies may not support the use and reimbursement of our tests, particularly for microdeletions screening, and may not be able to be replicated in later studies required for regulatory approvals or clearances; if either of our primary CLIA-certified laboratories becomes inoperable, we will be unable to perform our tests and our business will be harmed; we rely on a limited number of suppliers or, in some cases, single suppliers, for some of our laboratory instruments and materials and may not be able to find replacements or immediately transition to alternative suppliers; if we are unable to successfully scale our operations, our business could suffer; the marketing, sale, and use of Panorama and our other products could result in substantial damages arising from product liability or professional liability claims that exceed our resources; we may be unable to expand, obtain or maintain third-party payer coverage and reimbursement for our tests, and we may be required to refund reimbursements already received; third-party payers may withdraw coverage or provide lower levels of reimbursement due to changing policies, billing complexities or other factors; we could incur substantial costs and delays complying with governmental regulations, including recently enacted FDA regulations regarding LDTs; litigation and other regulatory or governmental proceedings, related to our intellectual property or the commercialization of our tests, are costly, time- consuming, could result in our obligation to pay material judgments or incur material settlement costs, and could limit our ability to commercialize our tests; and any inability to effectively protect our proprietary technology could harm our competitive position or our brand. We discuss these and other risks and uncertainties in greater detail in the sections entitled “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in our periodic reports on Forms 10-K and 10- Q and in other filings we make with the SEC from time to time. Moreover, we operate in a very competitive and rapidly changing environment. New risks emerge from time to time. It is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statement. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this presentation may not occur and our actual results could differ materially and adversely from those anticipated or implied. As a result, you should not place undue reliance on our forward-looking statements. Except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations. We file reports, proxy statements, and other information with the SEC. Such reports, proxy statements, and other information concerning us is available at http://www.sec.gov. Requests for copies of such documents should be directed to our Investor Relations department at Natera , Inc., 13011 McCallen Pass, Building A Suite 100, Austin, TX 78753. Our telephone number is (650) 980-9190. Safe harbor statement Not for reproduction or further distribution. 2
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Today’s speakers Professor Thomas Powles, Lead Principal Investigator of IMvigor011 Professor of Genitourinary Oncology Chair of Barts Cancer Centre at St. Bartholomew’s Hospital Steve Chapman, Chief Executive Officer, Natera Mike Brophy, Chief Financial Officer, Natera Solomon Moshkevich, President of Clinical Diagnostics, Natera Alexey Aleshin, M.D., General Manager of Oncology & Chief Medical Officer, Natera Not for reproduction or further distribution. 3
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4 (N=250) (N=761) 4
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Published in The New England Journal of Medicine Not for reproduction or further distribution. 7
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Adjuvant nivolumab vs placebo for high-risk muscle-invasive urothelial carcinoma: 5-year efficacy and ctDNA results from CheckMate 274 Matthew D. Galsky,1 Jürgen E. Gschwend,2 Matthew I. Milowsky,3 Michael Schenker,4 Begoña P . Valderrama,5 Yoshihiko Tomita,6 Aristotelis Bamias,7 Thierry Lebret,8 Shahrokh F . Shariat,9 Se Hoon Park,10 Mads Agerbaek,11 Gautam Jha, 12 Frank Stenner,13 Dingwei Ye,14 Fabio Giudici, 15 Jessica Connors, 16 Saurabh Gupta, 16 Joshua Zhang,16 Dean F . Bajorin,17 Johannes Alfred Witjes18 1Icahn School of Medicine at Mount Sinai, New York, NY , USA; 2Technical University Munich, Munich, Germany; 3University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; 4Sf. Nectarie Oncology Center, Craiova, Romania; 5Hospital Universitario Virgen del Rocío, Sevilla, Spain; 6Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 7National and Kapodistrian University of Athens, Athens, Greece; 8Hôpital Foch, Paris-Saclay University UVSQ, Versailles, France; 9Medical University of Vienna, Vienna General Hospital, Vienna, Austria; 10Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 11Aarhus University Hospital, Aarhus, Denmark; 12M Health Fairview Clinics and Surgery Center, Minneapolis, MN, USA; 13University Hospital Basel, Basel, Switzerland; 14Fudan University Shanghai Cancer Center, Shanghai, China; 15Bristol Myers Squibb, Boudry, Switzerland; 16Bristol Myers Squibb, Princeton, NJ, USA; 17Memorial Sloan Kettering Cancer Center, New York, NY , USA; 18Radboud University, Nijmegen, the Netherlands Presentation number 3068O Single timepoint ctDNA analysis, no serial testing 8
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CheckMate 274 • Within the ctDNA-detectable subgroup, NIVO improved median DFS and median OS by > 2-fold and > 1.5-fold vs PBO, respectively • Despite a small number of samples analyzed, the trend of improvement for DFS and OS is evident in patients with detectable ctDNA ctDNA detectable NIVO (n = 27) PBO (n = 27) Median OS (95% CI), months 36.2 (23.0-NE) 19.3 (8.1-28.2) OS HR (95% CI) 0.41 (0.20-0.83) ctDNA undetectable NIVO (n = 50) PBO (n = 29) Median OS (95% CI), months NR (62.0-NE) NR (40.7-NE) OS HR (95% CI) 0.87 (0.41-1.84) ctDNA detectable NIVO (n = 27) PBO (n = 27) Median DFS (95% CI), months 7.4 (2.8-19.2) 2.8 (2.4-5.0) DFS HR (95% CI) 0.35 (0.18-0.66) ctDNA undetectable NIVO (n = 50) PBO (n = 29) Median DFS (95% CI), months 91.9 (19.2-NE) 52.2 (16.9-NE) DFS HR (95% CI) 0.99 (0.51-1.93) Minimum follow-up, 61.3 months; median follow-up, 41.8 months in ctDNA-evaluable patients. Post hoc exploratory analyses. Baseline ctDNA was measured using the SignateraTM assay. ctDNA detectable status relationship with DFS and OS in each treatment arm 100 Disease-free survival probability (%) Months 75 50 25 0 0 6 12 18 No. at risk NIVO: detectable 27 14 11 8 6 5 5 5 5 5 1 1 1 1 1 1 0 27 7 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0PBO: detectable NIVO: undetectable 50 42 35 31 24 24 23 21 20 20 2 2 1 1 1 1 0 29 25 21 19 16 16 14 13 12 10 2 0 0 0 0 0 0PBO: undetectable 24 30 36 42 48 54 60 66 72 78 84 90 96 100 Overall survival probability (%) Months 75 50 25 0 0 6 12 18 No. at risk NIVO: detectable 27 25 22 21 18 17 13 11 11 11 11 11 6 6 4 4 1 0 27 19 15 14 8 6 5 4 4 4 4 4 1 0 0 0 0 0PBO: detectable NIVO: undetectable 50 50 50 43 39 38 36 35 34 32 30 24 20 17 13 9 2 2 29 29 29 27 24 21 20 16 16 14 14 13 12 12 10 5 2 0PBO: undetectable 24 30 36 42 48 54 60 66 72 78 84 90 96 102 NIVO: detectable PBO: detectable DFS OS NIVO: undetectable PBO: undetectable NIVO: detectable PBO: detectable NIVO: undetectable PBO: undetectable 9
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Conclusions1,2 • Adjuvant immunotherapy improved DFS and OS by 1.5-2x in the SignateraTM ctDNA-positive groups o Similar treatment efficacy was observed in patients who tested positive in first test vs. subsequent tests, and those with and without neoadjuvant therapy • Signatera ctDNA-negative patients saw no clinical benefit from adjuvant immunotherapy, and those who remained serially negative for 1y had excellent outcomes and may be spared from unnecessary treatment • Similar approach should be considered in other histologies, expanding the adjuvant window and treating only after ctDNA positivity • ctDNA testing methodologies have significant differences, so test performance should not be generalized without sufficient clinical data Not for reproduction or further distribution. 1. Adjuvant nivolumab vs placebo for high-risk muscle-invasive urothelial carcinoma: 5-year efficacy and ctDNA results from CheckMate 274; Galsky M et al., Annals of Oncology, 2025. 2. IMvigor011: a Phase 3 trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer; Powles T et al., New England Journal of Medicine, 2025 10
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12 Niagara visual, 9 pie charts (blue/green) or outcomes clearance
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New standard of care emerging Not for reproduction or further distribution. 13 Neoadjuvant (pre-surgery) Options: - Chemotherapy - Chemo + IO - ADC + IO - None Serial ctDNA surveillance every 6 weeks (up to 7x in y1) Signatera-negative No additional treatment Continued surveillance at reduced intervals after y1, per standard practice Surgery (cystectomy) Diagnosis Signatera-positive Systemic treatment • Adjuvant treatment decision can benefit from ctDNA guidance, regardless of neoadjuvant regimen • The duration of ADC therapy could be tailored by ctDNA analysis in the perioperative setting • Frequent ctDNA assessment (q6w in y1) is needed to catch MRD before visible on CT scan
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14 MIBC indication overview • ~30k new MIBC patients per year in the U.S.1,2,3, ~150k worldwide4,5 • Envision 10-14 tests per MIBC patient over 5-year journey, <10% penetration • Majority of our MIBC patients have Medicare6, opportunity to expand coverage with commercial payers • In the US, bladder cancer physicians treat multiple other GU cancers, such as renal cell carcinoma, testicular, prostate, etc. Not for reproduction or further distribution. 1. https://seer.cancer.gov/statfacts/html/urinb.html 2. Patel VG, Oh WK, Galsky MD. Treatment of muscle-invasive and advanced bladder cancer in 2020. CA Cancer J Clin. 2020;70(5):404-423. doi:10:3322/caac.21631 3. Kantar Health (Cerner) Report. 4. Global Cancer Observatory. Cancer Today GLOBOCAN 2022 Factsheet – Bladder [Internet; cited 2025 October]. 5. Ghandour R, et al. Treatment Options and Outcomes in Nonmetastatic Muscle Invasive Bladder Cancer. Trends Cancer. 2019;5(7):426-39. 6. Natera Internal Data.
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15 Significant ongoing investments and clinical pipeline in MIBC Phase 2/3 MODERN trial (Alliance A032103) • Targeting enrollment of >3k patients from >300 clinical sites across North America • Randomized: escalation for Signatera-positives, observation for Signatera-negatives Phase 3 ARCHER trial (NRG-GU015) • Randomized trial >100 sites across North America, evaluating whether a shorter course of radiation can achieve outcomes comparable to current SOC • Signatera ctDNA incorporated prospectively as a secondary endpoint, and urine tumor DNA (utDNA) evaluated as exploratory endpoint >20 additional studies to evaluate bladder-sparing treatment approaches, and escalation / de-escalation in other stages of disease Not for reproduction or further distribution.
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MRD-enriched randomized trials Surrogate endpoints Integration with new regimens • Randomize Signatera-positive; observe Signatera-negative with prespecified TOMR / conversion triggers • Incorporate Signatera kinetics/clearance as an early indicator reasonably likely to predict clinical benefit (mounting multi-tumor evidence) • Build Signatera-guided perioperative designs alongside ADC+IO combinations and bladder-sparing approaches to refine escalation/de-escalation strategies Implications for future trial designs 16 Not for reproduction or further distribution.
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Summary IMvigor011 establishes new SOC for post-surgical Signatera-guided IO treatment Not all MRD assays are the same, need prospective validation Additional studies planned in MIBC with Signatera across entire care continuum TOMR concept derisked and likely applicable in other histologies Not for reproduction or further distribution.
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