[Translation] A randomized, controlled, open-label, global, multicenter phase III trial to evaluate the efficacy and safety of zipalertinib combined with chemotherapy compared with chemotherapy alone in patients with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations

主要目的：比较治疗组之间的无进展生存期（PFS）次要目的：进一步比较治疗组之间的有效性。评价zipalertinib与化疗联用相比单纯化疗的安全性和耐受性。对于接受zipalertinib治疗的患者，评价zipalertinib联合培美曲塞和铂类药物的PK特征。比较治疗组间的患者报告结局（PRO）。探索性目的：探索zipalertinib与培美曲塞和铂类药物联用的有效性和安全性的暴露量-效应关系。评价EGFR突变状态和zipalertinib的生物标志物。

[Translation]

Primary objective: To compare progression-free survival (PFS) between treatment groups Secondary objectives: To further compare the efficacy between treatment groups. To evaluate the safety and tolerability of zipalertinib combined with chemotherapy compared with chemotherapy alone. For patients receiving zipalertinib, to evaluate the PK characteristics of zipalertinib combined with pemetrexed and platinum drugs. To compare patient-reported outcomes (PROs) between treatment groups. Exploratory objectives: To explore the exposure-effect relationship of the efficacy and safety of zipalertinib combined with pemetrexed and platinum drugs. To evaluate the EGFR mutation status and biomarkers of zipalertinib.

Start Date01 Apr 2024

Sponsor / Collaborator

Zai Lab (Shanghai) Co., Ltd.

[+2]

CTIS2023-503865-48-00 / Recruiting

An Open-Label, Phase 2b, Global Multicenter Cohort Trial to Assess the Safety and Efficacy of Zipalertinib in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer with Exon 20 Insertion and Uncommon/Single or Compound Epidermal Growth Factor Receptor Mutations - TAS6417-201

Start Date21 Feb 2024

Sponsor / Collaborator

Taiho Oncology, Inc.

NCT05967689 / Active, not recruitingPhase 2

An Open-Label, Phase 2b, Global Multicenter Cohort Trial to Assess the Safety and Efficacy of Zipalertinib in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer With Exon 20 Insertion and Uncommon/Single or Compound Epidermal Growth Factor Receptor Mutations.

The purpose of this study is to evaluate the safety and efficacy of zipalertinib in patients with locally advanced or metastatic NSCLC harboring EGFR ex20ins mutations and other mutations.

Start Date27 Jul 2023

Sponsor / Collaborator

Taiho Oncology, Inc.

100 Clinical Results associated with Zipalertinib

100 Translational Medicine associated with Zipalertinib

100 Patents (Medical) associated with Zipalertinib

Literatures (Medical) associated with Zipalertinib

05 Nov 2024·PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Biochemical analysis of EGFR exon20 insertion variants insASV and insSVD and their inhibitor sensitivity

Article

Author: Eck, Michael J. ; Beyett, Tyler S. ; Rana, Jaimin K. ; Schaeffner, Ilse K. ; Zhao, Hanchen ; Jiang, Jie ; Santana, Jhasmer ; Jänne, Pasi A.

Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non–small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely respond to EGFR tyrosine kinase inhibitors (TKIs). Therefore, there is a significant need to develop inhibitors that are active against this class of activating mutations. Here, we conducted biochemical analysis of the two most frequent exon 20 insertion variants, V769_D770insASV (insASV) and D770_N771insSVD (insSVD) to better understand their drug sensitivity and resistance. From kinetic studies, we found that EGFR insASV and insSVD are similarly active, but have lower K m, ATP values compared to the L858R variant, which contributes to their lack of sensitivity to 1st-3rd generation EGFR TKIs. Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants.

01 Nov 2024·LUNG CANCER

The prediction of treatment outcome in NSCLC patients harboring an EGFR exon 20 mutation using molecular modeling

Article

Author: Groen, H J M ; van der Wekken, A J ; van Veggel, B.A.M.H. ; Zwierenga, F. ; van der Wekken, A.J. ; Zwierenga, F ; Zhang, L. ; Groves, M R ; Melcr, J ; Groen, H.J.M. ; de Langen, A J ; Schuuring, E. ; van Veggel, B A M H ; Groves, M.R. ; Melcr, J. ; Schuuring, E ; Zhang, L ; de Langen, A.J.

INTRODUCTION:

The structural effect of uncommon heterogenous in-frame deletion and/or insertion mutations within exon 20 (EGFRex20+) in relation to therapy response is poorly understood. This study aims to elucidate the structural alterations caused by EGFRex20+ mutations and correlate these changes with patient responses.

MATERIAL AND METHOD:

We selected EGFRex20+ mutations from advanced NSCLC patients in the Position20 and AFACET studies for computational analysis. Homology models representing both inactive and active conformations of these mutations were generated using the Swiss-Model server. Molecular docking studies with EGFR-TKIs was conducted using smina, followed by Molecular Dynamic (MD) simulations performed with GROMACS. These computational findings were compared with clinical outcomes to evaluate their potential in predicting patient response.

RESULTS:

Our docking studies of 29 EGFRex20+ mutations revealed that the binding energies of afatinib, osimertinib, zipalertinib, and sunvozertinib, compared to the wild type, do not significantly impact either TKI's efficacy. MD simulations for eight EGFRex20+ mutations (A763_Y764insFQEA, A767_V769dup, S768_D770dup, D770_N771insG, D770_P772dup, N771_H773dup, H773_V774insY and H773_V774delinsLM) revealed varying degrees of instability. For six variants, predicted activation based on the αC-helix stability and orientation, as well as TKI sensitivity, aligned well with clinical observations from the Position20 and AFACET studies. Two mutations (D770_N771insG and N771_H773dup) predicted as poor to moderate responders, showed minimal activation of the αC-helix region, warranting further investigation.

CONCLUSION:

In conclusion, MD simulations can effectively predict patient outcomes by connecting computational results with clinical data and advancing our understanding of EGFR mutations and their therapeutic responses.

13 Jun 2024·JOURNAL OF MEDICINAL CHEMISTRY

Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations

Article

Author: Dong, Zhiqiang ; McWilliams, Lisa ; Braybrooke, Erin ; Hargreaves, David ; Ye, Yang ; McCoull, William ; Thomson, Clare ; Li, Songlei ; Barton, Peter ; Ward, Richard A. ; Evans, Laura ; Packer, Martin J. ; Guérot, Carine ; Floc’h, Nicolas ; Lister, Andrew ; Colclough, Nicola ; Winlow, Poppy ; Orme, Jonathan P. ; Khurana, Puneet ; Li, Xiuwei ; Swaih, Aisha M.

Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.

News (Medical) associated with Zipalertinib

07 Nov 2024

·www.globenewswire.com

Cullinan Therapeutics Provides Corporate Update and Reports Third Quarter 2024 Financial Results

Global Phase 1 study of CLN-978 in systemic lupus erythematosus (SLE) cleared to initiate in U.S. and Australia; initial clinical data expected in Q4 2025 CLN-619 on-track for initial expansion cohort data in endometrial and cervical cancers in Q2 2025 Zipalertinib pivotal Phase 2b study enrollment completed ahead of schedule; results expected mid-year 2025 CAMBRIDGE, Mass., Nov. 07, 2024 (GLOBE NEWSWIRE) -- Cullinan Therapeutics, Inc. (Nasdaq: CGEM; “Cullinan”), a biopharmaceutical company focused on developing modality-agnostic targeted therapies, today reported recent and anticipated business highlights and announced its financial results for the third quarter ended September 30, 2024. “We are making meaningful progress in executing our strategic plans for CLN-978 in autoimmune diseases while simultaneously advancing our oncology pipeline,” said Nadim Ahmed, Chief Executive Officer of Cullinan Therapeutics. “We have secured clearance from the U.S. Food and Drug Administration (FDA) for our IND application and Human Research Ethics Committee (HREC) approval in Australia to initiate our global Phase 1 study for CLN-978 in moderate to severe SLE. These important regulatory clearances position us to share initial clinical data for CLN-978 in the fourth quarter of 2025. We also continue to make significant progress in advancing our oncology portfolio, with data from two of our key programs expected in 2025. For CLN-619, we remain on track to share initial expansion data for endometrial and cervical cancers in the second quarter of 2025. We also completed enrollment of the pivotal Phase 2b study of zipalertinib ahead of schedule, and we plan to provide the results at mid-year 2025.” Portfolio Highlights Immunology CLN-978 (CD19xCD3 T cell engager): Systemic lupus erythematosus and rheumatoid arthritis The company obtained health authority approvals to initiate its global Phase 1 study in moderate to severe SLE, securing U.S. FDA clearance of its IND application and HREC approval in Australia. Cullinan plans to share initial clinical data for SLE in the fourth quarter of 2025. The company also continues to engage with other global health authorities to expand the planned country and site footprint.The company plans to initiate a sponsored clinical trial in rheumatoid arthritis (RA) in the second quarter of 2025. The trial will be designed and executed in collaboration with FAU Erlangen-Nuremberg in Germany and Università Cattolica del Sacro Cuore, Rome in Italy.Cullinan is presenting preclinical data at the upcoming American College of Rheumatology (ACR) Convergence 2024, taking place in Washington, D.C. from November 14-19, 2024. Oncology CLN-619 (Anti-MICA/MICB monoclonal antibody): Solid tumors and hematological malignancies In September, Cullinan dosed the first patient in a Phase 1 study of CLN-619 in patients with relapsed/refractory multiple myeloma.New biomarker and translational data from the monotherapy dose escalation portion of the Phase 1 study in solid tumors will be presented at the Society for Immunotherapy of Cancer (SITC) in November.The company continues enrollment of disease-specific expansion cohorts of its Phase 1 study in solid tumors, enrolling cervical, endometrial and non-small cell lung cancer (NSCLC) patients. Cullinan remains on track to report initial data in endometrial and cervical cancers in the second quarter of 2025.Notably, the company was issued a key composition of matter patent by the United States Patent and Trademark Office, which is expected to extend protection until at least 2041, excluding possible patent term extension. Zipalertinib (EGFR ex20ins inhibitor), collaboration with Taiho Oncology: EGFR ex20ins NSCLC At the European Society for Medical Oncology (ESMO) Congress in September, Cullinan presented positive REZILIENT1 results in patients with EGFR ex20ins NSCLC who have progressed on or after prior amivantamab treatment. Zipalertinib demonstrated a consistent objective response rate of approximately 40% and a manageable safety profile.In September, Cullinan successfully completed enrollment of the pivotal Phase 2b study ahead of schedule, which was originally planned for the end of this year. Cullinan plans to share the results of the pivotal Phase 2b study at mid-year 2025. Taiho continues enrollment of the pivotal study REZILIENT3 in 1L EGFR ex20ins NSCLC. CLN-049 (FLT3xCD3 T cell-engaging bispecific antibody): AML and MDS Following the clinical update in Q2 2024 and discontinuation of subcutaneous administration, enrollment continues with IV administration in the ongoing Phase 1 study in patients with relapsed/refractory AML and MDS. CLN-617 (IL-2 and IL-12 cytokine fusion protein): Solid tumors Enrollment continues in the ongoing Phase 1 study in patients with advanced solid tumors. Corporate Updates In the third quarter, the company added two rheumatology and immunology experts to its Scientific Advisory Board (SAB): Dr. Ricardo Grieshaber-Bouyer and Dr. Chaim Putterman. Dr. Grieshaber-Bouyer and Dr. Putterman’s expertise will further strengthen the company’s Scientific Advisory Board. Dr. Grieshaber-Bouyer is head of the clinical trial unit at FAU Erlangen-Nurnberg Rheumatology and Immunology Department and cares for patients with rheumatic and immune-mediated diseases, in particular in the context of emerging therapies such as T cell redirecting therapies.Dr. Putterman is Professor Emeritus of the Division of Rheumatology at Albert Einstein College of Medicine and Montefiore Medical Center, where his research focuses on mechanisms of autoimmunity, pathogenesis of kidney and neuropsychiatric disease in SLE, novel therapies for lupus, and SLE biomarkers. Third Quarter 2024 Financial Results Cash Position: Cash, cash equivalents, short- and long-term investments, and interest receivable were $639.0 million as of September 30, 2024. Cullinan continues to expect its cash resources to provide runway into 2028 based on its current operating plan.R&D Expenses: Research and development expenses were $35.5 million for the third quarter of 2024, compared to $33.8 million for the same period in 2023.G&A Expenses: General and administrative expenses were $13.3 million for the third quarter of 2024, compared to $11.0 million for the same period in 2023.Net loss: Net loss was $40.6 million ($0.69 per common share) for the third quarter of 2024, compared to $39.2 million ($0.91 per common share) for the same period in 2023. About Cullinan Therapeutics Cullinan Therapeutics, Inc. (Nasdaq: CGEM) is a biopharmaceutical company dedicated to creating new standards of care for patients. Cullinan has strategically built a diversified portfolio of clinical-stage assets that inhibit key drivers of disease or harness the immune system to eliminate diseased cells in both autoimmune diseases and cancer. Cullinan’s portfolio encompasses a wide range of modalities, each with the potential to be best and/or first in class. Anchored in a deep understanding of oncology, immunology, and translational medicine, we create differentiated ideas, identify the most appropriate targets, and select the optimal modality to develop transformative therapeutics across a wide variety of autoimmune and cancer indications. We push conventional boundaries from candidate selection to differentiated therapeutic, applying rigorous go/no go criteria at each stage of development to fast-track only the most promising molecules to the clinic and, ultimately, commercialization. With deep scientific expertise, our teams exercise creativity and urgency to deliver on our promise to bring new therapeutic solutions to patients. Learn more about Cullinan at https://cullinantherapeutics.com/, and follow us on LinkedIn and X. Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding the company’s beliefs and expectations regarding: our preclinical and clinical developments plans and timelines for our product candidates, the clinical and therapeutic potential of our product candidates, the strategy of our product candidates, our research and development activities, our plans regarding future data presentations, our cash runway, and other statements that are not historical facts. The words “believe,” “continue,” “could,” “estimate,” “expect,” “intends,” “may,” “plan,” “potential,” “project,” “pursue,” “will,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs of future events and are subject to known and unknown risks and uncertainties that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. These risks include, but are not limited to, the following: uncertainty regarding the timing and results of regulatory submissions; the risk that any INDs or other global regulatory submissions we may file with the United States Food and Drug Administration or other global regulatory agencies are not cleared on our expected timelines, or at all; the success of our clinical trials and preclinical studies; the risks related to our ability to protect and maintain our intellectual property position; the risks related to manufacturing, supply, and distribution of our product candidates; the risk that any one or more of our product candidates, including those that are co-developed, will not be successfully developed and commercialized; the risk that the results of preclinical studies or clinical studies will not be predictive of future results in connection with future studies; and the success of any collaboration, partnership, license or similar agreements. These and other important risks and uncertainties discussed in our filings with the Securities and Exchange Commission, including under the caption “Risk Factors” in our most recent Annual Report on Form 10-K and subsequent filings with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change, except to the extent required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. Moreover, except as required by law, neither the company nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. Cullinan Therapeutics, Inc.Selected Condensed Consolidated Balance Sheet Data(unaudited)(in thousands) September 30, 2024 December 31, 2023 Cash, cash equivalents, investments, and interest receivable $638,996 $468,264 Total assets $653,254 $484,182 Total current liabilities $24,204 $28,137 Total liabilities $25,392 $30,287 Total stockholders’ equity $627,862 $453,895 ` Cullinan Therapeutics, Inc.Consolidated Statements of Operations(unaudited)(in thousands, except per share amounts) Three Months Ended Nine Months Ended September 30, 2024 September 30, 2023 September 30, 2024 September 30, 2023Operating expenses: Research and development $35,506 $33,821 $102,411 $113,308 General and administrative 13,349 10,982 39,460 31,856 Total operating expenses 48,855 44,803 141,871 145,164 Impairment of long-lived assets — (440) — (440)Loss from operations (48,855) (45,243) (141,871) (145,604)Other income (expense): Interest income 8,384 5,880 22,148 15,710 Other income (expense), net (89) 180 (205) 356 Net loss (40,560) (39,183) (119,928) (129,538)Net loss attributable to noncontrolling interests — — (192) (179)Net loss attributable to common stockholders of Cullinan $(40,560) $(39,183) $(119,736) $(129,359) Net loss per share attributable to common stockholders of Cullinan: Basic and diluted $(0.69) $(0.91) $(2.30) $(3.15) Weighted-average shares used in computing net loss per share attributable to common stockholders of Cullinan: Basic and diluted 58,337 42,734 52,157 41,130 Contacts: InvestorsNick Smith+1 401.241.3516nsmith@cullinantx.com Media  Rose Weldon +1 215.801.7644 rweldon@cullinantx.com

Phase 2Phase 1Clinical ResultImmunotherapyIND

23 Oct 2024

·www.globenewswire.com

ORIC® Pharmaceuticals Presents Data Further Supporting Potential Best-In-Class Profile of ORIC-114 to Treat EGFR Exon 20 Insertions and Other Atypical Mutations at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

SOUTH SAN FRANCISCO, Calif. and SAN DIEGO, Oct. 23, 2024 (GLOBE NEWSWIRE) -- ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, today announced the company presented a poster highlighting certain best-in-class properties of ORIC-114, a brain penetrant, orally bioavailable, irreversible EGFR/HER2 inhibitor, to treat EGFR exon 20 insertions and other atypical mutations at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. “Preclinical data presented today underscore ORIC-114’s superior potency and selectively across EGFR mutational classes compared to other EGFR inhibitors,” said Lori Friedman, PhD, chief scientific officer. “These results build on clinical findings that highlight ORIC-114’s potential best-in-class profile, showing notable systemic and CNS responses, along with a favorable safety profile, even in heavily pre-treated NSCLC patients. We are continuing to evaluate ORIC-114 in multiple Phase 1b expansion cohorts for NSCLC patients with EGFR exon 20, HER2 exon 20, and atypical EGFR mutations, with updated data expected in the first half of 2025.” Poster presentation details: ORIC-114, a highly selective, brain penetrant EGFR and HER2 inhibitor, demonstrates best-in-class properties against exon 20 insertions and other atypical EGFR mutations ORIC-114 previously demonstrated systemic and intracranial clinical responses in heavily pre-treated patients with EGFR and HER2 exon 20 insertion mutations. Key findings of this poster presentation: Demonstrates regressions in all EGFR mutant in vivo models tested, including cell-derived xenografts, patient-derived xenografts and intracranial models that encompass exon 20 insertion and atypical mutant models. An in vivo model with complex atypical mutant EGFR dosed with ORIC-114 notably shows 100% tumor regressions and all tumors experienced a complete response.In an expanded preclinical comparative analysis of exon 20 insertion, atypical PACC and other mutations, overall ORIC-114 is the most potent across EGFR mutational classes whilst displaying comparative wild-type selectivity in cell-based assays, relative to firmonertinib, zipalertinib, lazertinib and BDTX-1535.In head-to-head comparisons with firmonertinib, zipalertinib, lazertinib and BDTX-1535, ORIC-114 has superior kinome selectivity with no off-target kinase liabilities identified.Shows complete molecular responses in ctDNA from patients with EGFR exon 20 insertion and PACC mutations from Phase 1 dose escalation study. Evidence of molecular responses observed across dose escalation cohorts supports broad therapeutic window for ORIC-114.ORIC-114 is a promising therapeutic candidate with best-in-class potential for patients with non-small cell lung cancer harboring exon 20 insertions and atypical mutations in EGFR, including those presenting with active CNS metastases, and is being evaluated in a global clinical trial (NCT05315700). About ORIC-114ORIC-114 is a highly selective, brain penetrant, orally bioavailable, irreversible inhibitor that selectively targets EGFR exon 20, HER2 exon 20 and EGFR atypical 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 that selectively targets EGFR exon 20, HER2 exon 20 and EGFR atypical mutations, being developed across multiple genetically defined cancers, (2) ORIC-944, an allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the EED subunit, being developed for prostate cancer, and (3) 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. 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 best-in-class properties of ORIC-114; the continued clinical development of ORIC-114; the potential advantages of ORIC-114 and ORIC’s other product candidates and programs; timing of updated data from the clinical trial of ORIC-114; development plans for ORIC’s product candidates and programs; and statements by the company’s chief scientific 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’s product candidates 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 or its clinical trial collaboration and supply agreements; the potential market for ORIC’s 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 titled “Risk Factors” in ORIC’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (the “SEC”) on August 12, 2024, 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.cominfo@oricpharma.com

Phase 1Clinical ResultAACR

09 Oct 2024

·www.biospace.com

ORIC® Pharmaceuticals Announces Presentation at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

SOUTH SAN FRANCISCO, Calif. and SAN DIEGO, Oct. 09, 2024 (GLOBE NEWSWIRE) -- ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, today announced that the company will present a poster at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics to be held October 23-25, 2024, in Barcelona, Spain. Poster presentation details: Title: ORIC-114, a highly selective, brain penetrant EGFR and HER2 inhibitor, demonstrates best-in-class properties against exon 20 insertions and other atypical EGFR mutations Poster #: PB050 Poster Session: Molecular Targeted Agents Date & Time: Wednesday, October 23, 2024, 9:00 – 11:00 a.m. CEST Location: Exhibition Hall Abstract highlights: ORIC-114 is a highly selective, brain penetrant, orally bioavailable, irreversible inhibitor that selectively targets EGFR and HER2 with high potency against exon 20 insertion mutations and other atypical EGFR mutations. It has previously demonstrated systemic and intracranial clinical responses in patients with EGFR and HER2 exon 20 insertion mutations. In an expanded preclinical comparative analysis, ORIC-114 demonstrated best-in-class properties including brain penetrance, superior kinome selectivity, potent activity across EGFR PACC mutations and exon 20 insertion mutations, relative to firmonertinib, zipalertinib, and BDTX-1535. Additionally, evidence of molecular response in ctDNA from patients whose tumors harbored PACC mutations and exon 20 insertion mutations was observed with ORIC-114 treatment. ORIC-114 is a promising potential therapy for patients with non-small cell lung cancer harboring atypical mutations in EGFR, including those presenting with active CNS metastases, and is being evaluated in a global clinical trial ( NCT05315700 ). Full abstracts are available for viewing on the symposium website here . 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 that selectively targets EGFR exon 20, HER2 exon 20 and EGFR atypical mutations, being developed across multiple genetically defined cancers, (2) ORIC-944, an allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the EED subunit, being developed for prostate cancer, and (3) 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. 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 , and follow us on X or LinkedIn . Cautionary Note Regarding Forward-Looking Statements This 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 best-in-class properties of ORIC-114; the continued clinical development of ORIC-114; the potential advantages of ORIC-114 and ORIC’s other product candidates and programs; and development plans for ORIC’s product candidates and programs. 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’s product candidates 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 or its clinical trial collaboration and supply agreements; the potential market for ORIC’s 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 titled “Risk Factors” in ORIC’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (the “SEC”) on August 12, 2024, 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 Officer dominic.piscitelli@oricpharma.com info@oricpharma.com

AACRClinical Result

100 Deals associated with Zipalertinib

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
EGFR-mutated non-small Cell Lung Cancer	Phase 3	US	Taiho Oncology, Inc.	30 Jun 2023
EGFR-mutated non-small Cell Lung Cancer	Phase 3	JP	Taiho Oncology, Inc.	30 Jun 2023
EGFR-mutated non-small Cell Lung Cancer	Phase 3	BE	Taiho Oncology, Inc.	30 Jun 2023
EGFR-mutated non-small Cell Lung Cancer	Phase 3	CA	Taiho Oncology, Inc.	30 Jun 2023
EGFR-mutated non-small Cell Lung Cancer	Phase 3	FR	Taiho Oncology, Inc.	30 Jun 2023
EGFR-mutated non-small Cell Lung Cancer	Phase 3	DE	Taiho Oncology, Inc.	30 Jun 2023
EGFR-mutated non-small Cell Lung Cancer	Phase 3	GR	Taiho Oncology, Inc.	30 Jun 2023
EGFR-mutated non-small Cell Lung Cancer	Phase 3	IL	Taiho Oncology, Inc.	30 Jun 2023
EGFR-mutated non-small Cell Lung Cancer	Phase 3	IT	Taiho Oncology, Inc.	30 Jun 2023
EGFR-mutated non-small Cell Lung Cancer	Phase 3	NL	Taiho Oncology, Inc.	30 Jun 2023

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04036682 (REZILIENT1, ESMO2024) Manual	Phase 2	EGFR ex20ins mutation in non-small cell lung cancer Second line EGFR Exon 20 Insertion	45	Zipalertinib 100 mg oral twice daily	wdcwitnrev(ifmiiwnejq) = pznprvwybi wbrjuwdsht (nyohfmewkb ) View more	Positive	14 Sep 2024
Pubmed	Phase 1/2	EGFR-mutated non-small Cell Lung Cancer	73	Zipalertinib	ljvpzeuaqo(dgfbqlffqe) = tdvqapjrff phxqamvwsy (xlueusqyil ) View more	-	29 Jun 2023
NCT04036682 (Ins20, ASCO2022) Manual	Phase 1/2	Non-Small Cell Lung Cancer EGFR Exon 20 Insertion	73	CLN-081	jvrlxwtocc(gusnedgquk) = aghrwlyhrj udkdmucmfx (rcibdwtood ) View more	Positive	02 Jun 2022
NCT04036682 (Ins20, ASCO2021) Manual	Phase 1/2	Non-Small Cell Lung Cancer EGFR Mutation	37	CLN-081	jkxocegwoo(mzyffffdya) = pwjazwoyio haazgdpxho (imxhkitkhf ) View more	Positive	20 May 2021
NCT04036682 (ESMO2020)	Phase 1/2	Non-Small Cell Lung Cancer	9	CLN-081	lkfyxtrhfp(hoxcpasltz) = 8% hckulqxpbm (dztvfasnrx ) View more	Positive	17 Sep 2020

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