HER2 exon 20 x EGFR exon 20

CNS activity observed at multiple dose levels, including the first reported confirmed CNS complete response by an EGFR exon 20 inhibitor in a patient with documented untreated brain metastases Systemic responses observed at multiple dose levels in heavily pre-treated NSCLC patients, characterized by 81% having received prior EGFR exon 20 targeted agents and 86% having CNS metastases at baseline At potential RP2D of 75 mg QD, responses observed in 2 of 3 EGFR exon 20 patients previously treated with amivantamab (67% ORR), including a confirmed complete response Responses observed at multiple dose levels in HER2 exon 20 patients, including a partial response with 100% target lesion regression Favorable safety profile with mainly Grade 1 and 2 treatment related adverse events; MTD not reached and dose escalation remains ongoing Company to host conference call and webcast today at 9:00 am ET SOUTH SAN FRANCISCO, Calif. and SAN DIEGO, Oct. 21, 2023 (GLOBE NEWSWIRE) -- ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, today announced initial data from the ongoing ORIC-114 Phase 1 dose escalation trial for patients with EGFR or HER2 exon 20 mutated non-small cell lung cancer (NSCLC) at the European Society of Medical Oncology (ESMO) Congress 2023 (clinical poster here). “We are excited to present the first look at ORIC-114 clinical data, which we believe supports the potential to address the key attributes of a potential best-in-class program for EGFR/HER2 exon 20 mutated NSCLC: minimal EGFR toxicity, minimal off-target toxicity, CNS activity, and systemic activity including post-amivantamab,” said Jacob M. Chacko, MD, chief executive officer. “Given the high rate of brain metastases in these patients and the high percentage of patients whose disease progresses in the brain, we believe that a well-tolerated CNS active agent has the potential to be transformative.” “We are pleased with the emerging profile of ORIC-114 in these heavily pretreated patients, which includes clinical activity across multiple dose levels and the first reported intracranial complete response in a patient with EGFR exon 20 lung cancer and documented untreated brain metastases,” said Pratik Multani, MD, chief medical officer. “This is the first comprehensive data set for EGFR exon 20 patients with such an exceptionally high rate of CNS disease at baseline and prior exon 20 inhibitor therapy. Based on the encouraging clinical activity and favorable safety profile, we plan to advance this program into dose optimization to select RP2D and, ultimately, into one or more registrational cohorts for potential accelerated approval.” ORIC-114 Phase 1 Study Design ORIC-114 is being evaluated in a Phase 1 dose escalation clinical trial in patients with advanced solid tumors with EGFR and HER2 exon 20 alterations or HER2 amplifications. Patients previously treated with an exon 20 targeted agent are eligible, including patients with CNS metastases that are either treated or untreated but asymptomatic. Nearly all other clinical studies with EGFR exon 20 inhibitors severely restricted the eligible patient population and excluded patients with active or untreated brain metastases and patients previously treated with an EGFR exon 20 inhibitor, making this data set one of the first and most comprehensive in this population. The primary objectives are to determine the recommended Phase 2 dose (RP2D), and additional objectives include characterization of the safety, tolerability, pharmacokinetic, and preliminary antitumor activity. ORIC-114 Phase 1 Dose Escalation Data As of September 26, 2023, 50 patients (21 EGFR exon 20, 24 HER2 exon 20 and 5 HER2+ patients) received ORIC-114 and were heavily pre-treated, with exceptionally high rates of prior exon 20 targeted therapies and brain metastases at baseline. Of the 21 EGFR exon 20 insertion mutated NSCLC patients, in addition to chemotherapy 81% were treated with ≥1 prior EGFR exon 20 targeted agent, nearly all of whom received prior amivantamab;19% were treated with multiple prior EGFR exon 20 targeted agents; and86% presented with CNS metastases at baseline Of the 24 HER2 exon 20 insertion mutated NSCLC patients 30% were treated with a prior HER2 targeted agent; and38% presented with CNS metastases at baseline Preliminary Pharmacokinetic Analysis and Safety ORIC-114 demonstrated a favorable pharmacokinetic profile with dose proportional increase in exposure, low intra-cohort variability, and a half-life of ~10-15 hours, which supports QD dosing. ORIC-114 was well-tolerated with mostly Grade 1 and 2 treatment-related adverse events (TRAEs) and little evidence of off-target toxicities. Rash was limited to Grade 1 and 2 events, and there was no Grade 3 or greater treatment related rash. Diarrhea was primarily Grade 1 and 2, with only 6% of patients experiencing Grade 3 diarrhea. There were only 4% discontinuations for TRAEs. The maximum tolerated dose has not been reached. Preliminary Activity Analysis Systemic and intracranial activity of ORIC-114 was demonstrated in this heavily pre-treated patient population across multiple dose levels. Preliminary activity data for patients treated at clinically active doses (total daily dose (TDD) ≥45 mg) as of the cut-off date were available for 15 response evaluable NSCLC patients with EGFR exon 20 insertion mutations and 13 response evaluable NSCLC patients with HER2 exon 20 insertion mutations. EGFR exon 20 patients: Observed systemic and CNS activity at multiple dose levels, consisting of multiple partial responses and one ongoing confirmed complete response, including a confirmed complete response in the brain.Within the 45 mg dose level, a patient had an ongoing confirmed partial response and two of three brain lesions resolved on therapy.Within the 75 mg dose level, identified as a potential RP2D, of the three patients previously treated with amivantamab All three patients experienced tumor shrinkage, andThere was an unconfirmed ORR of 67% and a confirmed ORR of 33%, including an ongoing systemic confirmed complete response and the first confirmed CNS complete response reported by an EGFR exon 20 inhibitor in a patient with documented untreated brain metastases at baseline. HER2 exon 20 patients: Observed systemic and CNS activity at multiple dose levels, consisting of multiple partial responses, including an ongoing confirmed partial response with 100% regression of all target lesions, with only persistent non-target lesions preventing a complete response.Within the 30 mg BID dose level, a patient had an ongoing confirmed partial response and shrinkage of multiple brain lesions on therapy. Next Steps The Phase 1 trial of ORIC-114 is ongoing to determine the candidate recommended RP2Ds for dose optimization, and subsequently the selection of the final RP2D. Since the September 26, 2023 data cutoff, the 40 mg BID dose level has cleared the DLT evaluation period, and the study is now evaluating 50 mg BID and 120 mg QD dose levels. The Phase 1 trial will enroll patients with EGFR exon 20 insertion mutations that are EGFR exon 20 inhibitor-naïve, and additional patients who are post-amivantamab. Additionally, enrollment will be expanded to include patients with atypical EGFR mutations based on the promising preclinical activity presented at ESMO 2023 (preclinical poster here). Conference Call and Webcast Details To join the conference call via phone and participate in the live Q&A session, please pre-register online here to receive a telephone number and unique passcode required to enter the call. A live webcast and audio archive of the conference call will be available through the investor section of the company’s website at www.oricpharma.com. The webcast will be available for replay for 90 days following the presentation. About ORIC-114 ORIC-114 is a highly selective, brain penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations, making it a promising therapeutic candidate to address the unmet medical need of having both meaningful systemic as well as CNS antitumor activity. About ORIC Pharmaceuticals, Inc. ORIC Pharmaceuticals is a clinical stage biopharmaceutical company dedicated to improving patients’ lives by Overcoming Resistance In Cancer. ORIC’s clinical stage product candidates include (1) ORIC-114, a brain penetrant inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations, being developed across multiple genetically defined cancers, (2) ORIC-533, an orally bioavailable small molecule inhibitor of CD73, a key node in the adenosine pathway believed to play a central role in resistance to chemotherapy- and immunotherapy-based treatment regimens, being developed for multiple myeloma, and (3) ORIC-944, an allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the EED subunit, being developed for prostate cancer. Beyond these three product candidates, ORIC is also developing multiple precision medicines targeting other hallmark cancer resistance mechanisms. ORIC has offices in South San Francisco and San Diego, California. For more information, please go to www.oricpharma.com, and follow us on X or LinkedIn. Cautionary Note Regarding Forward-Looking StatementsThis press release contains forward-looking statements as that term is defined in Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Statements in this press release that are not purely historical are forward-looking statements. Such forward-looking statements include, among other things, statements regarding the continued clinical development of ORIC-114; ORIC-114 clinical outcomes, which may materially change as patient enrollment continues or more patient data become available; ORIC-114’s development plans and timelines; the potential advantages of ORIC-114; plans underlying ORIC’s clinical trials and development; and statements by the company’s chief executive officer and chief medical officer. Words such as “believes,” “anticipates,” “plans,” “expects,” “intends,” “will,” “goal,” “potential” and similar expressions are intended to identify forward-looking statements. The forward-looking statements contained herein are based upon ORIC’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those projected in any forward-looking statements due to numerous risks and uncertainties, including but not limited to: risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics and operating as an early clinical stage company; ORIC’s ability to develop, initiate or complete preclinical studies and clinical trials for, obtain approvals for and commercialize any of its product candidates; changes in ORIC’s plans to develop and commercialize its product candidates; the potential for clinical trials of ORIC-114 to differ from preclinical, initial, interim, preliminary or expected results; negative impacts of health emergencies, economic instability or international conflicts on ORIC’s operations, including clinical trials; the risk of the occurrence of any event, change or other circumstance that could give rise to the termination of ORIC’s license and collaboration agreements; the potential market for our product candidates, and the progress and success of competing therapeutics currently available or in development; ORIC’s ability to raise any additional funding it will need to continue to pursue its business and product development plans; regulatory developments in the United States and foreign countries; ORIC’s reliance on third parties, including contract manufacturers and contract research organizations; ORIC’s ability to obtain and maintain intellectual property protection for its product candidates; the loss of key scientific or management personnel; competition in the industry in which ORIC operates; general economic and market conditions; and other risks. Information regarding the foregoing and additional risks may be found in the section entitled “Risk Factors” in ORIC’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (the “SEC”) on August 10, 2023, and ORIC’s future reports to be filed with the SEC. These forward-looking statements are made as of the date of this press release, and ORIC assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Contact:Dominic Piscitelli, Chief Financial [email protected] [email protected]

Application is supported by data from PAPILLON, the first randomized Phase 3 study to show clinically meaningful results in patients with NSCLC with EGFR exon 20 insertion mutations RARITAN, NJ, USA I August 25, 2023 I The Janssen Pharmaceutical Companies of Johnson & Johnson announced today the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) seeking the expanded approval of RYBREVANT (amivantamab-vmjw) in combination with chemotherapy (carboplatin-pemetrexed) for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. The sBLA is being reviewed by the FDA through the Real-Time Oncology Review (RTOR) program.* "PAPILLON is the first randomized Phase 3 study in patients with NSCLC with EGFR exon 20 insertion mutations to show clinically meaningful results. This creates an opportunity to make a significant improvement to the standard of care for this patient population with high unmet medical need," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Janssen Research & Development, LLC. "We look forward to working with the FDA through the RTOR pathway in pursuit of an approval for RYBREVANT plus chemotherapy as we simultaneously progress the development of this novel bispecific antibody in additional patient populations." Following Breakthrough Therapy Designation from the U.S. FDA in 2020, RYBREVANT received accelerated approval in 2021 as the first fully-human, bispecific antibody for the treatment of patients with NSCLC with EGFR exon 20 insertion mutations. The sBLA submission for RYBREVANT is also intended to satisfy the regulatory requirements of the accelerated approval confirming the clinical benefit observed in the Phase 1 CHRYSALIS study. The sBLA is supported by data from the Phase 3 PAPILLON ( NCT04538664 ) clinical trial, a randomized, open-label study evaluating the efficacy and safety of RYBREVANT in combination with chemotherapy as first-line treatment in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. In July, Janssen announced the PAPILLON study met its primary endpoint with a statistically significant and clinically meaningful improvement in PFS (as measured by BICR) in patients receiving RYBREVANT plus chemotherapy versus chemotherapy alone. The combination of RYBREVANT and chemotherapy demonstrated a safety profile consistent with the safety profiles of the individual components. About PAPILLON PAPILLON ( NCT04538664 ) is a randomized, open-label Phase 3 study evaluating the efficacy and safety of RYBREVANT in combination with chemotherapy, compared with chemotherapy alone, in newly diagnosed patients with advanced or metastatic NSCLC characterized by EGFR exon 20 insertion mutations. The primary endpoint of the study is PFS (using RECIST v1.1 guidelines**) as assessed by blinded independent central review (BICR). Secondary endpoints include overall response rate (ORR), PFS after first subsequent therapy, time to symptomatic progression and overall survival (OS). Patients who received chemotherapy alone were allowed to receive RYBREVANT monotherapy in the second-line setting after confirmation of disease progression. About RYBREVANT RYBREVANT (amivantamab-vmjw) received accelerated approval by the U.S. Food and Drug Administration (FDA) in May 2021 for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. This indication is approved under accelerated approval based on ORR and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. RYBREVANT has also received approval from health authorities in Europe , as well as other markets around the world. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Non-Small Cell Lung Cancer prefer NGS-based strategies over PCR-based approaches for the detection of EGFR exon 20 insertion variants and include amivantamab-vmjw (RYBREVANT ) as a subsequent therapy option with a Category 2A recommendation for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC. In addition to the Phase 3 PAPILLON study, RYBREVANT is being studied in multiple clinical trials in NSCLC, including: For more information, visit: https://www.RYBREVANT.com About Non-Small Cell Lung Cancer Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases. 20,21 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division. EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients. 22-28 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations. The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent. 30,31 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation. Patients with EGFR exon 20 insertion mutations have a real-world five-year OS of 8 percent in the frontline setting, which is worse than patients with EGFR ex19del or L858R mutations, who have a real-world five-year OS of 19 percent. Please read the full Prescribing Information for RYBREVANT About the Janssen Pharmaceutical Companies of Johnson & Johnson At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension. Learn more at www.janssen.com . Follow us at @JanssenGlobal @JanssenUS . Janssen Biotech, Inc. and Janssen Research & Development, LLC are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. *The Real-Time Oncology Review (RTOR) program aims to provide a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible, while improving review quality and engaging in early iterative communication with the applicant. **RECIST (version 1.1) refers to Response Evaluation Criteria in Solid Tumors, which is a standard way to measure how well solid tumors respond to treatment and is based on whether tumors shrink, stay the same or get bigger. The NCCN Content does not constitute medical advice and should not be used in place of seeking professional medical advice, diagnosis or treatment by licensed practitioners. NCCN makes no representations or warranties and explicitly disclaims the appropriateness or applicability of the NCCN Content to any specific patient's care or treatment. See the NCCN Guidelines for detailed recommendations, including other treatment options. The NCCN Guidelines for NSCLC provide recommendations for certain individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories. ClinicalTrials.gov. A Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Characterized by Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions (PAPILLON). Available at: https://clinicaltrials.gov/ct2/show/NCT04538664 . Accessed July 2023. RYBREVANT Prescribing Information. Horsham, PA: Janssen Biotech, Inc. Arcila, M. et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Molecular Cancer Therapeutics. 2013; Feb; 12(2):220-9. Vyse, S., Huang, P.H. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Sig Transduct Target Ther 4, 5 (2019). Oxnard, JR et. al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions . J Thorac Oncol . 2013 Feb;8(2):179-84. doi: 10.1097/JTO.0b013e3182779d18. Remon, J et al. EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins. Cancer Treatment Reviews . 90 (2020). Baraibar I et al. Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC. Critical Reviews in Oncology . 2020. O'Leary C, Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC). Pharmaceuticals . 2020, 13, 273; doi:10.3390/ph13100273/. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Non-Small Cell Lung Cancer V.3.2022. National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 22, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. ClinicalTrials.gov. A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA). Available at: https://clinicaltrials.gov/ct2/show/NCT04487080 . Accessed July 2023. ClinicalTrials.gov. A Study of Amivantamab and Lazertinib in Combination With Platinum-Based Chemotherapy Compared With Platinum-Based Chemotherapy in Patients With Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non- Small Cell Lung Cancer After Osimertinib Failure (MARIPOSA-2). Available at: https://clinicaltrials.gov/ct2/show/NCT04988295 . Accessed July 2023. ClinicalTrials.gov. A Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS). Available at: https://clinicaltrials.gov/ct2/show/NCT02609776 . Accessed July 2023. ClinicalTrials.gov. A Study of Lazertinib as Monotherapy or in Combination With Amivantamab in Participants With Advanced Non-small Cell Lung Cancer (CHRYSALIS-2). Available at: https://clinicaltrials.gov/ct2/show/NCT04077463 . Accessed July 2023. ClinicalTrials.gov. A Study of Amivantamab Subcutaneous (SC) Administration for the Treatment of Advanced Solid Malignancies (PALOMA). Available at: https://clinicaltrials.gov/ct2/show/NCT04606381 . Accessed May 2023. ClinicalTrials.gov. A Study of Amivantamab in Participants With Advanced or Metastatic Solid Tumors Including Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small Cell Lung Cancer (PALOMA-2). Available at: https://clinicaltrials.gov/ct2/show/NCT05498428 . Accessed July 2023. ClinicalTrials.gov. A Study of Lazertinib With Subcutaneous Amivantamab Compared With Intravenous Amivantamab in Participants With Epidermal Growth Factor Receptor (EGFR)-Mutated Advanced or Metastatic Non-small Cell Lung Cancer (PALOMA-3). Available at: https://clinicaltrials.gov/ct2/show/NCT05388669 . Accessed July 2023. ClinicalTrials.gov. A Study of Amivantamab and Capmatinib Combination Therapy in Unresectable Metastatic Non-small Cell Lung Cancer (METalmark). Available at: https://clinicaltrials.gov/ct2/show/NCT05488314 . Accessed July 2023. ClinicalTrials.gov. A Study of Combination Therapy With Amivantamab and Cetrelimab in Participants With Metastatic Non-small Cell Lung Cancer (PolyDamas). Available at: https://www.clinicaltrials.gov/study/NCT05908734?term=polydamas&rank=1 . Accessed July 2023. ClinicalTrials.gov. Premedication to Reduce Amivantamab Associated Infusion Related Reactions (SKIPPirr). Available at: https://classic.clinicaltrials.gov/ct2/show/NCT05663866 . Accessed July 2023. The World Health Organization. Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer . Accessed July 2023. American Cancer Society. What is Lung Cancer? https://www.cancer.org/content/cancer/en/cancer/lung-cancer/about/what-is.html . Accessed July 2023. Oxnard JR, et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol . 2013 Feb;8(2):179-84. doi: 10.1097/JTO.0b013e3182779d18. Bauml JM, et al. Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real World Datasets. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. Riess JW, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J Thorac Oncol . 2018;13(10):1560-1568. doi:10.1016/j.jtho.2018.06.019. Pennell NA, et al. A phase II trial pf adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small cell lung cancer. J Clin Oncol . 37:97-104. Burnett H, et al. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. Zhang YL, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-78993. Midha A, et al. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity. Am J Cancer Res . 2015;5(9):2892-2911. American Lung Association. EGFR and Lung Cancer. https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing/egfr . Accessed July 2023. Howlader N, et al. SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2016/ , based on November 2018 SEER data submission, posted to the SEER web site. Lin JJ, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol . 2016 Apr;11(4):556-65. Arcila, M. et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Molecular Cancer Therapeutics. 2013; Feb; 12(2):220-9. Girard N, et al. Comparative clinical outcomes for patients with NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. FDA.gov. Real-Time Oncology Review. Available at: https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review . Accessed August 2023. SOURCE: Janssen

Application is supported by data from PAPILLON, the first randomized Phase 3 study to show clinically meaningful results in patients with NSCLC with EGFR exon 20 insertion mutations RARITAN, N.J., Aug. 25, 2023 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson announced today the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) seeking the expanded approval of RYBREVANT® (amivantamab-vmjw) in combination with chemotherapy (carboplatin-pemetrexed) for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. The sBLA is being reviewed by the FDA through the Real-Time Oncology Review (RTOR) program.* "PAPILLON is the first randomized Phase 3 study in patients with NSCLC with EGFR exon 20 insertion mutations to show clinically meaningful results. This creates an opportunity to make a significant improvement to the standard of care for this patient population with high unmet medical need," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Janssen Research & Development, LLC. "We look forward to working with the FDA through the RTOR pathway in pursuit of an approval for RYBREVANT plus chemotherapy as we simultaneously progress the development of this novel bispecific antibody in additional patient populations." Following Breakthrough Therapy Designation from the U.S. FDA in 2020, RYBREVANT® received accelerated approval in 2021 as the first fully-human, bispecific antibody for the treatment of patients with NSCLC with EGFR exon 20 insertion mutations.2 The sBLA submission for RYBREVANT® is also intended to satisfy the regulatory requirements of the accelerated approval confirming the clinical benefit observed in the Phase 1 CHRYSALIS study. The sBLA is supported by data from the Phase 3 PAPILLON (NCT04538664) clinical trial, a randomized, open-label study evaluating the efficacy and safety of RYBREVANT® in combination with chemotherapy as first-line treatment in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.1,2 In July, Janssen announced the PAPILLON study met its primary endpoint with a statistically significant and clinically meaningful improvement in PFS (as measured by BICR) in patients receiving RYBREVANT® plus chemotherapy versus chemotherapy alone.1 The combination of RYBREVANT® and chemotherapy demonstrated a safety profile consistent with the safety profiles of the individual components.1 About PAPILLON PAPILLON (NCT04538664) is a randomized, open-label Phase 3 study evaluating the efficacy and safety of RYBREVANT® in combination with chemotherapy, compared with chemotherapy alone, in newly diagnosed patients with advanced or metastatic NSCLC characterized by EGFR exon 20 insertion mutations.1 The primary endpoint of the study is PFS (using RECIST v1.1 guidelines**) as assessed by blinded independent central review (BICR). Secondary endpoints include overall response rate (ORR), PFS after first subsequent therapy, time to symptomatic progression and overall survival (OS).1 Patients who received chemotherapy alone were allowed to receive RYBREVANT® monotherapy in the second-line setting after confirmation of disease progression.1 About RYBREVANT® RYBREVANT® (amivantamab-vmjw) received accelerated approval by the U.S. Food and Drug Administration (FDA) in May 2021 for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.2 This indication is approved under accelerated approval based on ORR and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. RYBREVANT® has also received approval from health authorities in Europe, as well as other markets around the world. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer◊ prefer NGS-based strategies over PCR-based approaches for the detection of EGFR exon 20 insertion variants and include amivantamab-vmjw (RYBREVANT®) as a subsequent therapy option with a Category 2A recommendation for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.9†^ In addition to the Phase 3 PAPILLON study, RYBREVANT® is being studied in multiple clinical trials in NSCLC, including: The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT® in combination with lazertinib, a novel third generation EGFR TKI, versus osimertinib and versus lazertinib alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions (ex19del) or L858R substitution mutations.10 The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT® (with or without lazertinib) and carboplatin-pemetrexed versus carboplatin-pemetrexed in patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC after disease progression on or after osimertinib.11 The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT® in participants with advanced NSCLC.12 The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT® in combination with lazertinib and lazertinib as a monotherapy in patients with advanced NSCLC with EGFR mutations.13 The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous (SC) administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab SC delivery.14 The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in participants with advanced or metastatic solid tumors including EGFR-mutated NSCLC.15 The Phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous amivantamab compared to intravenous amivantamab in participants with EGFR-mutated advanced or metastatic NSCLC.16 The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT® and capmatinib combination therapy in locally advanced or metastatic NSCLC.17 The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT® and cetrelimab combination therapy in locally advanced or metastatic NSCLC.18 The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion related reactions with RYBREVANT® in combination with lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.19 For more information, visit: . About Non-Small Cell Lung Cancer Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases.20,21 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.22 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.23 EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients.22-28 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.29 The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent.30,31 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.32 Patients with EGFR exon 20 insertion mutations have a real-world five-year OS of 8 percent in the frontline setting, which is worse than patients with EGFR ex19del or L858R mutations, who have a real-world five-year OS of 19 percent.33 RYBREVANT® IMPORTANT SAFETY INFORMATION2 WARNINGS AND PRECAUTIONS   Infusion Related Reactions RYBREVANT ® can cause infusion related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. Based on the safety population, IRR occurred in 66% of patients treated with RYBREVANT ®. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT ® due to IRR. Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT ® as recommended. Administer RYBREVANT ® via a peripheral line on Week 1 and Week 2. Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT ® infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT ® based on severity. Interstitial Lung Disease/Pneumonitis RYBREVANT ® can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT ®, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT ® due to ILD/pneumonitis. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT ® in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. Dermatologic Adverse Reactions RYBREVANT ® can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT ®, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT ® was permanently discontinued due to rash in 0.7% of patients. Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT ®. Advise patients to wear protective clothing and use broad spectrum UVA/UVB sunscreen. Alcohol free emollient cream is recommended for dry skin. If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce or permanently discontinue RYBREVANT ® based on severity. Ocular Toxicity RYBREVANT ® can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT ®. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT ® based on severity.  Embryo Fetal Toxicity Based on its mechanism of action and findings from animal models, RYBREVANT ® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT Adverse Reactions The most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%). Please read the full Prescribing Information for RYBREVANT®.   About the Janssen Pharmaceutical Companies of Johnson & Johnson At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension. Learn more at . Follow us at @JanssenGlobal and @JanssenUS. Janssen Biotech, Inc. and Janssen Research & Development, LLC are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of RYBREVANT® (amivantamab-vmjw). The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research and Development, LLC, Janssen Biotech, Inc., any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 1, 2023, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at , or on request from Johnson & Johnson. None of Janssen Research and Development, LLC, Janssen Biotech, Inc., the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. *The Real-Time Oncology Review (RTOR) program aims to provide a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible, while improving review quality and engaging in early iterative communication with the applicant.34 **RECIST (version 1.1) refers to Response Evaluation Criteria in Solid Tumors, which is a standard way to measure how well solid tumors respond to treatment and is based on whether tumors shrink, stay the same or get bigger. ◊The NCCN Content does not constitute medical advice and should not be used in place of seeking professional medical advice, diagnosis or treatment by licensed practitioners. NCCN makes no representations or warranties and explicitly disclaims the appropriateness or applicability of the NCCN Content to any specific patient's care or treatment. †See the NCCN Guidelines for detailed recommendations, including other treatment options. ^The NCCN Guidelines for NSCLC provide recommendations for certain individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories. 1 ClinicalTrials.gov. A Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Characterized by Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions (PAPILLON). Available at: . Accessed July 2023. 2 RYBREVANT® Prescribing Information. Horsham, PA: Janssen Biotech, Inc. 3 Arcila, M. et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Molecular Cancer Therapeutics. 2013; Feb; 12(2):220-9. 4 Vyse, S., Huang, P.H. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Sig Transduct Target Ther 4, 5 (2019). 5 Oxnard, JR et. al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 2013 Feb;8(2):179-84. doi: 10.1097/JTO.0b013e3182779d18. 6 Remon, J et al. EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins. Cancer Treatment Reviews. 90 (2020). 7 Baraibar I et al. Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC. Critical Reviews in Oncology. 2020. 8 O'Leary C, Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC). Pharmaceuticals. 2020, 13, 273; doi:10.3390/ph13100273/. 9 Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2022.© National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 22, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. 10 ClinicalTrials.gov. A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (MARIPOSA). Available at: . Accessed July 2023. 11 ClinicalTrials.gov. A Study of Amivantamab and Lazertinib in Combination With Platinum-Based Chemotherapy Compared With Platinum-Based Chemotherapy in Patients With Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non- Small Cell Lung Cancer After Osimertinib Failure (MARIPOSA-2). Available at: . Accessed July 2023. 12 ClinicalTrials.gov. A Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS). Available at: . Accessed July 2023. 13 ClinicalTrials.gov. A Study of Lazertinib as Monotherapy or in Combination With Amivantamab in Participants With Advanced Non-small Cell Lung Cancer (CHRYSALIS-2). Available at: . Accessed July 2023. 14 ClinicalTrials.gov. A Study of Amivantamab Subcutaneous (SC) Administration for the Treatment of Advanced Solid Malignancies (PALOMA). Available at: . Accessed May 2023. 15 ClinicalTrials.gov. A Study of Amivantamab in Participants With Advanced or Metastatic Solid Tumors Including Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small Cell Lung Cancer (PALOMA-2). Available at: . Accessed July 2023. 16 ClinicalTrials.gov. A Study of Lazertinib With Subcutaneous Amivantamab Compared With Intravenous Amivantamab in Participants With Epidermal Growth Factor Receptor (EGFR)-Mutated Advanced or Metastatic Non-small Cell Lung Cancer (PALOMA-3). Available at: . Accessed July 2023. 17 ClinicalTrials.gov. A Study of Amivantamab and Capmatinib Combination Therapy in Unresectable Metastatic Non-small Cell Lung Cancer (METalmark). Available at: . Accessed July 2023. 18 ClinicalTrials.gov. A Study of Combination Therapy With Amivantamab and Cetrelimab in Participants With Metastatic Non-small Cell Lung Cancer (PolyDamas). Available at: . Accessed July 2023. 19 ClinicalTrials.gov. Premedication to Reduce Amivantamab Associated Infusion Related Reactions (SKIPPirr). Available at: . Accessed July 2023. 20 The World Health Organization. Cancer. . Accessed July 2023. 21 American Cancer Society. What is Lung Cancer? . Accessed July 2023. 22 Oxnard JR, et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 2013 Feb;8(2):179-84. doi: 10.1097/JTO.0b013e3182779d18. 23 Bauml JM, et al. Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real World Datasets. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. 24 Riess JW, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J Thorac Oncol. 2018;13(10):1560-1568. doi:10.1016/j.jtho.2018.06.019. 25 Pennell NA, et al. A phase II trial pf adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small cell lung cancer. J Clin Oncol. 37:97-104. 26 Burnett H, et al. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. 27 Zhang YL, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-78993. 28 Midha A, et al. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity. Am J Cancer Res. 2015;5(9):2892-2911. 29 American Lung Association. EGFR and Lung Cancer. . Accessed July 2023. 30 Howlader N, et al. SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. Bethesda, MD, , based on November 2018 SEER data submission, posted to the SEER web site. 31 Lin JJ, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol. 2016 Apr;11(4):556-65. 32 Arcila, M. et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Molecular Cancer Therapeutics. 2013; Feb; 12(2):220-9. 33 Girard N, et al. Comparative clinical outcomes for patients with NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. 34 FDA.gov. Real-Time Oncology Review. Available at: . Accessed August 2023. Media Contacts: Jackie Zima-Evans +1 215-534-2973 Suzanne Frost +1 416-317-0304 Investor Relations: