HER2 exon 20 x EGFR

Not intended for UK Media BAY 2927088 is an oral, small molecule tyrosine kinase inhibitor under development as a potential new targeted therapy for patients with NSCLC harboring HER2 activating mutations Breakthrough Therapy designation is a process designed to expedite the development and review of investigational drugs that have potential to provide substantial improvement over available therapy in areas of high unmet medical need BERLIN--(BUSINESS WIRE)-- Bayer announced today that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for BAY 2927088 for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, and who have received a prior systemic therapy. BAY 2927088 is an oral, reversible tyrosine kinase inhibitor (TKI) that potently inhibits mutant human epidermal growth factor receptors 2 (HER2), including HER2 exon 20 insertions and HER2 point mutations, as well as epidermal growth factor receptors (EGFR), with high selectivity for mutant vs wild-type EGFR.1,2 Lung cancer is the leading cause of cancer-related deaths worldwide.3 NSCLC is the most common type of lung cancer, accounting for more than 85% of cases.4 Activating HER2 mutations are found in 2% to 4% of advanced NSCLC.5 Currently there are no available therapies that have received full approval in the U.S. for patients with NSCLC in the metastatic or advanced setting harboring HER2 activating mutations. The Breakthrough Therapy designation is supported by preliminary clinical evidence from the Phase I, open-label, multicenter first-in-human study (NCT05099172) evaluating the safety, pharmacokinetics and preliminary efficacy of BAY 2927088 in adult patients with advanced NSCLC harboring HER2 or EGFR. “Early clinical evidence suggests that BAY 2927088, our investigational novel oral tyrosine kinase inhibitor, has the potential to benefit patients with NSCLC harboring a HER2 mutation that have progressed on a prior systemic therapy and currently have no other approved treatment available,” said Dominik Ruettinger, M.D., Ph.D., Head of Research and Early Development for Oncology at Bayer’s Pharmaceuticals Division. “This Breakthrough Therapy designation is a significant milestone in our relentless efforts to develop innovative therapies for the treatment of lung cancer characterized by specific genomic markers. We will continue working closely with the FDA to advance BAY 2927088 through the clinic and look forward to providing these patients with lung cancer and their physicians with a targeted, effective treatment option.” The FDA's Breakthrough Therapy designation is intended to expedite the development and review of drug candidates that treat serious or life-threatening diseases or conditions, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on one or more clinically significant endpoints over available therapies.6 BAY 2927088 was derived from Bayer’s long-standing strategic research alliance with the Broad Institute of MIT and Harvard in Cambridge, MA, USA. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. Its products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2022, the Group employed around 101,000 people and had sales of 50.7 billion euros. R&D expenses before special items amounted to 6.2 billion euros. For more information, go to . Find more information at Follow us on Facebook: jds (2024-0039) Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at . The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. 1 Siegel F, Karsli-Uzunbas G, Kotynkova K, et al, Preclinical activity of BAY 2927088 in HER2 mutant non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4035. 2 Siegel F, Siegel S, Graham K, et al. BAY 2927088: The first non-covalent, potent, and selective tyrosine kinase inhibitor targeting EGFR exon 20 insertions and C797S resistance mutations in NSCLC. European Journal of Cancer. 2022;174:S9-S10. 3 Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021). 4 Leiter, A., Veluswamy, R.R. & Wisnivesky, J.P. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol 20, 624–639 (2023). 5 Stephens P, Hunter C, Bignell G, et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 2004;431:525-526. 6 View source version on businesswire.com: Contacts Bayer Media Contact: Julia Schulze, phone +49 175 5866 432 Email: julia.schulze@bayer.com Bayer U.S. Media Contact: Carolyn Nagle, phone +1 (201) 419-0337 Email: carolyn.nagle@bayer.com Source: Bayer View this news release online at:

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 Officerdominic.piscitelli@oricpharma.com info@oricpharma.com

In light of the withdrawal, Takeda says it will assess and likely update its revenue forecast for fiscal year 2023, which ends on March 31, 2024. After a confirmatory trial flop this past summer, Takeda is calling it quits on its targeted non-small cell lung cancer (NSCLC) drug Exkivity. Takeda on Tuesday said it will work with the FDA to chart a voluntary withdrawal of Exkivity in the U.S., where the drug is approved for certain adult NSCLC patients whose disease has progressed on or after platinum-based chemotherapy. Takeda is plotting voluntary withdrawals of Exkivity around the world, too, and says it’s working with regulators in other countries on next steps. Back in 2021, Exkivity snagged an accelerated nod as a second-line NSCLC treatment. As a condition of Exkivity’s accelerated approval, the FDA required progression-free survival data from a randomized trial to verify the drug’s clinical benefit. In late July, however, Exkivity missed the mark in the phase 3 trial Exclaim-2, which Takeda stopped early. The study tested Exkivity versus platinum-based chemotherapy for NSCLC patients with EFGR exon20 insertion mutations. Takeda says it will present full data from the trial at an upcoming medical meeting or in a peer-reviewed journal. Even as Takeda plans to withdraw its med, the company says it’s committed to ensuring patients receiving the drug can maintain access “as appropriate and in consultation” with their doctors. In light of the withdrawal, Takeda says it will assess and likely update its revenue forecast for fiscal year 2023, which ends on March 31, 2024. Exkivity’s recent confirmatory trial flop came just a few days after Johnson & Johnson’s rival drug Rybrevant succeeded at delaying cancer progression in first-line NSCLC patients. Both drugs used tumor shrinkage data from single-arm trials to win accelerated nods from the FDA in 2021. The FDA’s oncology department has lately taken a hard line on accelerated approval regulations. In the past, the regulator has kept certain accelerated approvals intact despite confirmatory trial flops because of unmet needs. But given J&J’s phase 3 win and Rybrevant’s availability in the same disease area, that argument is largely moot in this case. Exkivity was one of two growth drivers and launch products in Takeda’s oncology portfolio, alongside ALK lung cancer med Alunbrig. The company had projected $300 million to $600 million in peak sales for Exkivity. In the 12 months ended in March, the EGFR inhibitor pulled in 3.7 billion Japanese yen ($26 million) in sales.