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- Lillian L. Siu (Toronto, Canada)
- Elena Garralda (Barcelona, Spain)
652O - Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC)
- Kathryn C. Arbour (New York, United States of America)
Abstract
Background
RMC-6236 is a novel, oral RASMULTI(ON) inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms. Preclinical studies have demonstrated deep and sustained regressions across multiple RASMUT tumor types, particularly PDAC and NSCLC harboring KRAS glycine-12 substitutions (KRASG12X).
Methods
Patients with previously treated, advanced KRASG12X mutant solid tumors were enrolled at escalating doses (10mg to 160mg once daily (QD)) of single agent RMC-6236. Additional patients with PDAC or NSCLC were enrolled at dose levels that cleared dose-limiting toxicity evaluation.
Results
As of April 24, 2023, 22 patients with KRASG12X PDAC (13 G12D, 7 G12V, 2 G12R) and 11 with KRASG12X NSCLC (5 G12D, 4 G12V, 2 G12A) were enrolled, and 14 patients with PDAC and 9 patients with NSCLC continue treatment with RMC-6236. Median prior therapies was 3 (range, 1-7). Treatment-related adverse events (TRAEs) occurring in ≥10% of patients were rash (52%), diarrhea (21%), nausea (21%), and vomiting (15%). The only Grade ≥3 TRAE was in a patient with PDAC who had a Grade 4 large intestine perforation at the site of an invasive tumor that reduced in size on treatment. Preclinical modeling predicts tumor regressions at 80mg QD or higher in humans. Preliminary clinical activity in PDAC and NSCLC was assessed at 80mg and 120mg QD. Among 14 patients (10 PDAC, 4 NSCLC) dosed at least 8 weeks prior to the data cut-off date, the objective response rate was 36% (2 confirmed and 3 unconfirmed; 2/10 PDAC and 3/4 NSCLC). Median time to onset of initial response was 6 weeks (range, 5-11). Disease control rate was 86% (12/14; 8/10 PDAC and 4/4 NSCLC). Tumor reduction was observed in 4 patients with stable disease (range, -2% to -21% by RECIST v1.1). Of the 12 patients with partial response or stable disease, 11 continue on treatment.
Conclusions
RMC-6236 exhibits promising anti-tumor activity in patients with KRASG12X PDAC and NSCLC at doses that are well tolerated. Dose escalation is ongoing and data from additional patients will be available at the time of the meeting.
Clinical trial identification
NCT05379985.
Legal entity responsible for the study
Revolution Medicines, Inc.
Funding
Revolution Medicines, Inc.
Disclosure
K.C. Arbour: Financial Interests, Personal, Advisory Board: G1 Therapeutics, Novartis, Sanofi-Genzyme; Financial Interests, Institutional, Local PI: Revolution Medicines, Mirati, Genentech. S. Punekar: Financial Interests, Institutional, Local PI, Clinical Trial PI: Revolution Medicine, Simcere Pharmaceuticals, Astellas Pharmaceuticals, Constellation, A2Bio, Vitrac; Non-Financial Interests, Principal Investigator, Clinical Trial PI: Revolution Medicine, A2Bio, Simcere, Constellation, Vitrac, Astellas Pharmaceuticals. I. Garrido-Laguna: Financial Interests, Personal, Other, Consulting: Kanaph, OncoXerna; Financial Interests, Personal, Other, DSMC: SOTIO; Financial Interests, Personal, Advisory Board: Jazz Pharmaceuticals; Financial Interests, Institutional, Local PI: Revolution Medicine, Yingli, BridgeBio Pharma, Repare Therapeutics, Sumitomo, Pfizer, Genentech, Amgen. D.S. Hong: Financial Interests, Personal, Other, Travel, accommodations, expenses: AACR, ASCO, Bayer, Genmab, Gilead, SITC, Telperian; Financial Interests, Personal, Other, Consulting, Speaker, or Advisory Role: AbbVie, Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, COR2ed, COG, Cowen, Ecor1, Gennao Bio, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, MedaCorp, Medscape, Numab, Oncologia Brazil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, RAIN, Seagen, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point Therapeutics, WebMD, YingLing Pharma, Ziopharm; Financial Interests, Personal, Advisory Board: 28Bio, Affini-T, Astellas, Fate Therapeutics, CARSgen, InduPro, Projects in Knowledge, Quanta, Ridgeline, Stanford; Financial Interests, Personal, Ownership Interest, Advisor: Molecular Match; Financial Interests, Personal, Ownership Interest, Founder, Advisor: OncoResponse, Telperian; Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Adlai-Nortye, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Endeavor, Erasca, F. Hoffmann-LaRoche, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa Kirin, Loxo, Merck, Medimmune, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, Seagen, Takeda, TCR2, Teckro, Turning Point Therapeutics, VM Oncology, Biomea, ImmunoGenesis, Revolution Medicine, STCube. B. Wolpin: Financial Interests, Institutional, Other, Consultant (under institutional contract): Celgene, Inc; Financial Interests, Institutional, Other, Consultant: Grail; Financial Interests, Institutional, Other, Consultant (PI): Mirati Therapeutics, Inc.; Financial Interests, Institutional, Other, Research funding: Celgene, Inc; Financial Interests, Institutional, Other, Research funding (under institutional contract): Eli Lilly and Company, Novartis, Revolution Medicines. M.S. Pelster: Financial Interests, Institutional, Other, Consulting: AstraZeneca, Bayer, CytomX, Daiichi Sankyo, Ipsen, Novartis, Pfizer, Seagen; Financial Interests, Institutional, Local PI: Agenus, Arcus Biosciences, Astellas, BeiGene, BioNTech, Bristol Myers Squibb, Codiak Biosciences, Eisai, Gilead, Gritstone Oncology, HiberCell, Immune-Onc Therapeutics, Leap Therapeutics, Novartis, OncXerna Therapeutics, Panbela Therapeutics, Revolution Medicines, Surface Oncology, SQZ Biotechnologies, Translational Genomics, TransThera Sciences, ZielBio, 1200 Pharma. M. Barve: Financial Interests, Personal, Full or part-time Employment, Private practice: Texas Oncology/ US Oncology; Financial Interests, Personal, Stocks/Shares, Physician shareholder: Texas Oncology; Financial Interests, Institutional, Local PI, Research funding to the institution: 1200 Pharma, Agenus, Amgen, Inc, Artios Pharma Limited, Astellas Pharma Global Development, Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals, Inc., BeiGene USA, Inc., Bicycle Therapeutics, Bio-Path Holdings, Black Diamond Therapeutics, Boehringer Ingelheim, BriaCell Therapeutics, Bristol Myers Squibb, Compass Therapeutics Inc., Coordination Pharma, Corvus Pharmaceuticals, CStone Pharmaceuticals, Dialectic Therapeutics, Inc., Elevation Oncology, Eli Lilly and Company, EMD Serono, EpicentRx Inc, Erasca, Eutilex, Exelixis Inc., F. Hoffmann-La Roche Ltd. (Genentech), Gan & Lee Pharmaceuticals, Genprex Inc., Gilead Sciences, GSK, Gradalis, Harpoon Therapeutics, Inc., IGM Biosciences, Inc., ImmuneOnco Biopharmaceutics (Shanghai), Immvira Pharma Co. Ltd., Incyte Corporation, Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Jiangsu HengRui Medicine, Klus Pharma, Inc., Kronos Bio, LaNova Medicines Ltd., Loxo Oncology, MedImmune, Merck Sharp & Dohme Corp., Mersana Therapeutics, Inc., Mirati Therapeutics, Inc., Molecular Templates Inc, Monte Rosa Therapeutics, Nektar Therapeutics, NeoImmuneTech, Inc., Nitto BioPharma, Inc., Novartis Pharmaceuticals, Pfizer, Pionyr Immunotherapeutics, Protagonist Therapeutics, Inc., Qilu Puget Sound Biotherapeutics Corporation, Qurient Co., Ltd., RAPT Therapeutics, Inc., Revolution Medicines, Sanofi, Scholar Rock, Sermonix Pharmaceuticals, Servier Pharmaceuticals, Stemline Therapeutics, Inc., Sumitomo Dainippon Pharma Oncology (SDPO), Suzhou Kintor Pharmaceuticals, Suzhou Transcenta Therapeutics Co., Ltd., SynerGene Therapeutics, Synthorx, Tesaro, Inc., Theratechnologies Inc, Verastem, Inc., Xbiotech. A. Starodub: Financial Interests, Local PI: Adenate, Ascendis, BioAtla, Cellectar, Exelixis, Gritstone, Jubilant, Kymera, LaNova, Merck, Miracogen, Revolution Medicine, Zailab, ZhuHai. D. Sommerhalder: Financial Interests, Personal, Other, Ad-hoc advisory role: Syneos SAG; Financial Interests, Personal, Other, Medical consulting: Guidepoint; Financial Interests, Institutional, Full or part-time Employment, Employed as a physician by Texas Oncology, a for-profit entity: Texas Oncology/US Oncology; Financial Interests, Institutional, Local PI: Astellas, Biomea Fusion, Boehringer Ingelheim, BJ Biosciences, BioNTech, Fate Therapeutics, Gilead Sciences, Immuneering, Kura Oncology, Monopteros Therapeutics, Navire, Nimbus Saturn, NGM Biopharmaceuticals, Parthenon, Pfizer, Revolution Medicines, Mirati Therapeutics, Symphogen, Teon Therapeutics, MediLink Therapeutics, ZielBio. S. Chang, Y. Zhang, Z. Salman: Financial Interests, Personal, Full or part-time Employment: Revolution Medicines; Financial Interests, Personal, Stocks/Shares: Revolution Medicines. X. Wang: Financial Interests, Personal, Officer, EVP Clinical Development; Officer of Revolution Medicines: Revolution Medicines; Financial Interests, Personal, Stocks/Shares, have stock options and own shares of RVMD stocks: Revolution Medicines. C. Gustafson: Financial Interests, Personal, Full or part-time Employment: Revolution Medicines; Financial Interests, Personal, Stocks/Shares: Revolution Medicines. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med.
653O - Glecirasib (KRAS G12C inhibitor) in combination with JAB-3312 (SHP2 inhibitor) in patients with KRAS p.G12C mutated solid tumors
- Jie Wang (Beijing, China)
Abstract
Background
Glecirasib is a direct oral KRAS G12C inhibitor (KRAS G12Ci) with favorable tolerability and promising efficacy. JAB-3312 is a potent oral SHP2 inhibitor that may overcome KRAS G12Ci resistance. Together these compounds were shown to exert synergistic anti-tumor effect when combined with glecirasib in multiple animal models. Here we present the preliminary clinical data from the dose escalation phase.
Methods
The phase 1/2a study [NCT05288205] evaluated glecirasib plus JAB-3312 in patients (pts) with
Results
As of April 7th, 2023, 60 pts (50 non-small cell lung cancer [NSCLC], 9 colorectal cancer, and 1 pancreatic cancer) were enrolled in six dose levels. About 40% had ≥ 2 prior lines of therapy, and 26.7% had received prior KRAS G12Ci treatment. Dose escalation concluded with one dose-limiting toxicity (grade 3 pneumonitis) at a higher dose level. The most common (>20%) treatment-related adverse events (TRAE) included anemia, ALT/AST increased, hypertriglyceridemia, bilirubin increased, neutropenia/leukopenia, creatine kinase increased, and edema. TRAE ≥ grade 3 occurred in 36.7% of pts. No TRAE led to discontinuation of both glecirasib and JAB-3312. PK of JAB-3312 of the combination was generally comparable with historical monotherapy, suggesting low risk of drug-drug interaction. Amongst the 50 pts with NSCLC, 35 were efficacy evaluable, 14 have not reached the first scan and one withdrew due to COVID-19. Out of 28 evaluable pts with KRAS G12Ci naïve NSCLC, ORR was 50% (14/28) and DCR was 100%. In pts with KRAS G12Ci treated NSCLC, ORR was 14.3% (1/7), and DCR was 57.1%. Additional safety, efficacy and PK data will be presented at this meeting.
Conclusions
Glecirasib plus JAB-3312 was well tolerated with promising efficacy in
Clinical trial identification
NCT05288205.
Legal entity responsible for the study
Jacobio Pharmaceuticals Group Co., Ltd.
Funding
Jacobio Pharmaceuticals Group Co., Ltd.
Disclosure
A. Wang-Gillam, Y. Ding, Z. Rao, C. Bi: Financial Interests, Personal, Full or part-time Employment: Jacobio Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.
LBA33 - A first-in-human phase I study of a novel KRAS G12D inhibitor HRS-4642 in patients with advanced solid tumors harboring KRAS G12D mutation
- Caicun Zhou (Shanghai, China)
Abstract
Background
Methods
Pts with histologically confirmed advanced solid tumors harboring
Results
At data cutoff on Aug 4, 2023, 18 pts were enrolled (lung adenocarcinoma n=10, colorectal adenocarcinoma n=5, appendiceal mucinous adenocarcinoma, ovarian cancer, and pancreatic cancer n=1 each). Pts had received a median of 3 lines of prior treatment (range 2-7). No DLTs were observed and the MTD was not reached yet. Grade ≥3 adverse events (AEs) were observed in 9 pts (50.0%). 6 pts (33.3%) had grade ≥3 treatment-related AEs (TRAEs), being hypercholesterolemia (16.7%), increased lipase (11.1%), and anemia (11.1%). No dose dependent trend was observed in the incidence of AEs. Serious TRAEs were observed in one patient (grade 2 increased ALT and grade 1 increased AST). No pts discontinued treatment or died due to TRAEs. 13 pts with baseline target lesions had at least one post-baseline assessment, and one NSCLC patient at 200 mg had partial response. 11 pts (61.1%) had stable disease and 6 (33.3%) experienced target lesion shrinkage, including lung and colorectal cancers. HRS-4642 exposure was approximately proportional to dose with a half-life of around 40 hours.
Conclusions
HRS-4642 showed a tolerable safety profile and preliminary anti-tumor activity in advanced solid tumors harboring
Clinical trial identification
NCT05533463.
Editorial acknowledgement
Yanwen Wang (Jiangsu Hengrui Pharmaceuticals) provided editorial assistance in the writing of the abstract.
Legal entity responsible for the study
Jiangsu Hengrui Pharmaceuticals.
Funding
Jiangsu Hengrui Pharmaceuticals.
Disclosure
C. Zhou: Financial Interests, Personal, Speaker’s Bureau: Amoy Diagnostics, Boehringer Ingelheim, C-Stone, Hengrui, Innovent Biologics, Lilly China, LUYE Pharma, Merck Sharp & Dohme, Qilu, Roche, Sanofi, TopAlliance Biosciences Inc.; Financial Interests, Personal, Advisory Board: Hengrui, Innovent Biologics, Qilu, TopAlliance Biosciences Inc.. R. Mao: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals. C. Huang: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals. X. Li: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals. J. Wang: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals. All other authors have declared no conflicts of interest.
Invited Discussant 652O, 653O and LBA33
- Elena Garralda (Barcelona, Spain)
Q&A
- All Speakers (Lugano, Switzerland)
654O - Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with solid tumors harboring specific HER2-activating mutations (HER2m): Primary results from the international phase II DESTINY-PanTumor01 (DPT-01) study
- Bob T. Li (New York, United States of America)
Abstract
Background
T-DXd is an antibody–drug conjugate targeting HER2 approved in HER2-expressing breast cancer (BC), HER2-positive gastric cancer (GC), and
Methods
In an open-label, multicenter, phase 2 study (NCT04639219) in pts with advanced solid tumors harboring prespecified
Results
102 pts were assigned to T-DXd (data cutoff Jan 25 2023; median follow-up, 8.61 [range 1.5–22.1] months [mo]) with median 3 [range 1–13] prior lines of systemic therapy. The ORR was 29.4% (95% CI 20.8, 39.3); median DoR was not reached (54.2% of responders remained in response by ICR at 18 mo); median PFS was 5.4 mo (95% CI 2.7, 7.1). Responses were observed across HER2 expression levels, including HER2 IHC 0 tumors. The table shows ORR by tumor type and AC, adenocarcinoma aBy local testing;bL755S, D769H, Y772_A775dup/A775_G776insYVMA, V777L, G778_P780dup/P780_Y781insGSP, V842I, T862A; cS310F, S310Y; dR678Q
N ORR by ICR n % 102 30 29.4 Breast 20 10 50.0 Colorectal 20 4 20.0 Biliary tract 19 2 10.5 Esophageal/esophagogastric 11 1 9.1 Urothelial 7 2 28.6 Salivary gland/head and neck AC 6 4 66.7 Small intestinal AC 5 0 - Cervical 3 2 66.7 Endometrial 2 2 100 Other neuroendocrine 2 1 50.0 Pancreatic 2 0 - AC of unknown primary 1 1 100 Extramammary Paget's disease 1 1 100 Melanoma 1 0 0 Ovarian 1 0 0 Urachal 1 0 0 Tyrosine kinaseb 52 19 36.5 Extracellularc 34 10 29.4 Transmembrane/juxtamembraned 17 1 5.9
Conclusions
DPT-01 is the first tumor-agnostic global study of T-DXd in a range of solid tumors with prespecified
Clinical trial identification
NCT04639219.
Editorial acknowledgement
Under the guidance of authors, medical writing and editorial support was provided by Jennifer L Mitchell, PhD, of Helios Medical Communications, and was funded by AstraZeneca.
Legal entity responsible for the study
Daiichi Sankyo and AstraZeneca.
Funding
Daiichi Sankyo and AstraZeneca.
Disclosure
B.T. Li: Financial Interests, Personal, Royalties, Intellectual property rights as a book author: Karger Publishers, Shanghai Jiao Tong University Press; Financial Interests, Institutional, Other, Inventor on institutional patents at MSK (US62/685,057, US62/514,661): Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Coordinating PI, Institutional clinical trials funding to Memorial Sloan Kettering Cancer Center: Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui, Lilly; Non-Financial Interests, Advisory Role, Uncompensated advisor and consultant: Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Lilly; Non-Financial Interests, Other, Academic travel support, but without compensation: MORE Health, Jiangsu Hengrui Pharmaceuticals; Non-Financial Interests, Member: American Society of Clinical Oncology, International Association for the Study of Lung Cancer. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, F. Hoffmann-La Roche Ltd., Zymeworks, OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Advisory Board: Zentalis, Karyopharm, Biovica, Eisai, Protai, TheraTechnologies; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics, Lengo Therapeutics, Loxo Oncology, Black Diamond, Infinity Pharmaceuticals, AbbVie, GT Aperion, Ecor1; Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Travel Support: Cholangiocarcinoma Foundation. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Sanofi, Eisai, Lilly, Mersana, AstraZeneca/ Daiichi Sankyo, Menarini, Gilead; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Coordinating PI: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly.; Non-Financial Interests, Principal Investigator: Gilead, Mersana, AstraZeneca/ Daiichi Sankyo, Novartis, Pfizer, Genentech, Lilly, Merck, Sanofi. Y. Naito: Financial Interests, Personal, Invited Speaker, Speakers Bureau: Chugai, Pfizer, Eli Lilly, Eisai, AstraZeneca, PDR pharma, Novartis, Gardant, Ono, Takeda, Taiho, Bayer, Nihon Kayaku, Daiichi Sankyo, Bristol, MSD; Financial Interests, Personal, Funding: Roche; Financial Interests, Personal, Local PI: AbbVie, Boehringer Ingelheim, Ono, Chugai, Taiho, Pfizer, AstraZeneca, Gilead, Takeda; Financial Interests, Personal, Steering Committee Member: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, JCOG: Natera. S. Siena: Financial Interests, Personal, Advisory Board, Advisory Board Member: Agenus, AstraZeneca, BMS, Checkmab, Daiichi Sankyo, GSK, Novartis, Seagen, T-One-Therapeutics. P.G. Aftimos: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, Menarini, Gilead, Novartis, Eisai, Lilly; Financial Interests, Personal, Invited Speaker: Synthon, Amgen; Financial Interests, Institutional, Research Grant: Roche. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Coordinating PI, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Member of Board of Directors, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO. M.J. De Miguel Luken: Financial Interests, Institutional, Invited Speaker: Janssen, MSD; Non-Financial Interests, Principal Investigator: Janssen, MSD, Roche, PharmaMar, Replimune, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, BioNTech, Catalym, Dizal, Genentech, Loxo, Numab, Seagen. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. J.O. Park: Financial Interests, Personal, Advisory Board: MedPacto, BMS (Celgene), Servier, MediRama, Adicet Bio, AstraZeneca, Merck Sereno; Financial Interests, Personal, Other, Travel support for a poster presentation at ASCO GI 2023 : Minneamrita Therapeutics LLC; Financial Interests, Personal, Research Grant, Clinical research grant: MedPacto, Servier, BMS (Celgene); Financial Interests, Personal, Research Grant: Eutilex, ABL Bio. S. Postel-Vinay: Financial Interests, Institutional, Advisory Board, Steering Committee: Daiichi Sankyo; Financial Interests, Institutional, Local PI, As part of the Drug Development Department (DITEP) SPV is Principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd., Forma Tharapeutics, Gamamabs, Genentech, GSK, H3 Biomedicine, F. Hoffmann-La Roche AG, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus: Various drug companies; Financial Interests, Institutional, Research Grant, Translational research funding: IMCore F. Hoffmann-LaRoche; Financial Interests, Institutional, Research Grant, preclinical research funding: AstraZeneca; Non-Financial Interests, Principal Investigator, Principal investigator of phase I/II clinical trials: AstraZeneca, GSK, PEP therapy, BMS, Novartis; Amgen, Oxford Biotherapeutics, Clovis, Roche. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Daiichi Sankyo; Financial Interests, Personal, Steering Committee Member: Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, Durg supply for clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, Drug supply for clinical trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: zy,meworks; Financial Interests, Institutional, Local PI, drug supply for clincial trial: BeiGene; Financial Interests, Coordinating PI, Drug supply for clinical trial: Incyte. T. Satoh: Financial Interests, Personal, Invited Speaker, invited speaker and advisory: Ono Pharmaceutical, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Invited speaker and adovisory: Bristol-Myers; Financial Interests, Personal, Invited Speaker, Invited speaker and advisory: Elli-Lilly, Yakult-HOnsha; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Merck-Biopharm, Takeda, Taiho; Financial Interests, Personal, Advisory Board: Takara-Bio; Financial Interests, Institutional, Local PI: Merck-Biopharm; Financial Interests, Institutional, Local PI, Research Grant and Endosed Department: Ono Pharmaceutical, Chugai Pharmaceutical, Yakult Honsha; Financial Interests, Institutional, Local PI, Research Grant: Bristol-Myers, Elli-Lilly, Daiichi Sankyo, Parexell, Giliad, Taiho, Hutch-Med. I. Spanggaard: Financial Interests, Institutional, Local PI: Roche, Puma Biotechnology, MSD, Genentech, Incyte, AstraZeneca, Orion, Pfizer; Non-Financial Interests, Principal Investigator: Roche, Puma Biotechnology, MSD, Genentech, Incyte, AstraZeneca, Orion, Pfizer. F. Michelini, A. Smith, K. Kalil Machado: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. C. Saura Manich: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd., Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, Seagen, Zymeworks, Genentech, Innoup, Millenium, Pharmalex Spain SLU; Financial Interests, Personal, Other, SC: Byondis B.V., GSK, Macrogenics, Menarini, Merus, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, GSK, Immunomedics, Innoup Farma, Macrogenics, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, Sanofi-Aventis, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), Geicam (Spanish Breast Cancer Research Group), European Society for Medical Oncology (ESMO), Sinology Society of the Official College of Physicians of Barcelona (COMB); Non-Financial Interests, Member, Junta Directiva y Comité Científico: SOLTI group (Academic research group in breast cancer). All other authors have declared no conflicts of interest.
655O - Phase Ib study of cofetuzumab pelidotin, an anti-PTK7 antibody-drug conjugate, in patients with PTK7-expressing recurrent non-small cell lung cancer (rNSCLC)
- Melissa L. Johnson (Nashville, United States of America)
Abstract
Background
Cofetuzumab pelidotin (Cofe-P), a protein tyrosine kinase 7 (PTK7)–targeting antibody-drug conjugate, was tolerable and had preliminary antitumor activity in patients (pts) with advanced solid tumors (Phase 1; NCT02222922). Results are presented from an ongoing Phase 1b, open-label, single-arm, multicenter study (NCT04189614) of Cofe-P in pts with PTK7-expressing rNSCLC.
Methods
Eligible pts were ≥18 yrs with PTK7-expressing (central immunohistochemistry [IHC]) rNSCLC and prior platinum doublet and immune checkpoint inhibitor (tumors w/o actionable genetic alterations [AGA−]) or platinum doublet and targeted agent(s) (AGA+ tumors). Pts received 2.8 mg/kg Cofe-P IV Q3W until PD/unacceptable toxicity.
Results
As of August 9, 2022, 56 pts received Cofe-P (median age, 64 years; male, 63%; Asian, 50%, White, 46%); 27 pts (48%) were nonsquamous (NSQ) EGFR WT, 13 (23%) were NSQ EGFR mutant, and 16 (29%) were squamous (SQ). PTK7 IHC enrollment cutoff was refined during study; 42 pts (75%) had PTK7 expression above final ≥90%/≥2+ cutoff; of these, 21 (50%) were NSQ EGFR WT. Enrollment of SQ and NSQ EGFR mutant pts was halted to prioritize NSQ EGFR WT accrual due to response rates in each subgroup. Efficacy results are shown in the table. TEAEs were reported in all pts, most common (≥30%): alopecia (52%), neutropenia (45%), headache (36%), pruritis (36%), and decreased appetite (30%). Grade ≥3 TEAEs were reported in 68% of pts, most common (≥5%): neutropenia (39%), leukopenia (9%), pneumonia (7%), anemia (5%), fatigue (5%). Peripheral neuropathy was reported in 18% of pts; 2% had Grade 3. No deaths related to Cofe-P were reported. PK was similar to previous phase 1 study with Cofe-P conjugate elimination half-life ∼3 days. aResponse-evaluable pts (N=20) (≥1 postbaseline measurement). CI, confidence intervals; CBR, clinical benefit rate; CR, complete response; EGFR, epidermal growth factor; mDOR, median duration of response; mPFS, median progression free survival; NSQ, nonsquamous; ORR, objective response rate; PR, partial response; PTK7, protein tyrosine kinase 7; pts, patients; SD, stable disease; WT, wild type.
Parameter NSQ EGFR WT, PTK7 ≥90%/≥2+ N=21 Overall N=56 ORR, % (95% CI) 30.0 (11.9, 54.3)a 19.6 (10.2, 32.4) CBR (CR + PR + SD), % (95% CI) 90.0 (68.3, 98.8)a 78.6 (65.6, 88.4) mDOR, mo (95% CI) 5.8 (2.8, –) 7.2 (2.8, 9.7) mPFS, mo (95% CI) 5.5 (2.6, 8.5) 5.3 (3.6, 5.9)
Conclusions
Cofe-P was well-tolerated with encouraging antitumor activity observed in rNSCLC and 30% ORR in the subpopulation with NSQ EGFR WT NSCLC and PTK7 ≥90%/≥2+.
Clinical trial identification
NCT02222922.
Editorial acknowledgement
Medical writing support was provided by Caryne Craige, PhD, of Fishawack Facilitate Ltd., and funded by AbbVie.
Legal entity responsible for the study
AbbVie.
Funding
AbbVie and Pfizer provided financial support for the Ph 1b study and an AbbVie/Pfizer Joint Steering Committee oversaw design and conduct of Ph 1b study. AbbVie provided support for analysis, data collection, interpretation of data, and the review and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Disclosure
B.C. Cho: Financial Interests, Personal, Other, Consulting role: Abion, BeiGene, Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Janssen; Financial Interests, Personal, Advisory Board: KANAPH Therapeutic Inc., Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc.; Financial Interests, Personal, Other, Advisory role: Medpacto, Blueprint medicines, RandBio, Hanmi; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc., Gencurix Inc., Bridgebio therapeutics, KANAPH Therapeutic Inc., Cyrus therapeutics, Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Royalties: Champions Oncology, Crown Bioscience, Imagen; Financial Interests, Institutional, Research Grant: MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Onoclogy, CJ bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine., Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridgebio therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph therapeutics, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center; Other, Founder: DAAN Biotherapeutics. M.L. Johnson: Financial Interests, Institutional, Other, Consulting: AbbVie, Amgen, Arcus Biosciences, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Daiichi Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, Seagen, VBL Therapeutics, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, Black Diamond, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Jounce Therapeutics, Immunocore, Incyte, Janssen, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Rain Therapeutics, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Sanofi, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, Y-mAbs Therapeutics. J. Bar: Financial Interests, Personal, Advisory Board: AbbVie, AstraZeneca, Bayer, BMS, Causalis, Eisai, MSD, Novartis, Roche, Takeda; Financial Interests, Institutional, Research Funding: ImmuneAI, OncoHost, MSD, AstraZeneca. K. Yoh: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi sankyo, Lilly, Boehringer Ingelheim, Amgen, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, Lilly, Daiichi sankyo, AbbVie, Taiho, MSD, Takeda, Amgen, Boehringer Ingelheim, Chugai; Financial Interests, Personal, Steering Committee Member: AstraZeneca. A. Zer: Financial Interests, Personal, Invited Speaker: Roche, BMS, MSD, Takeda, Pfizer, Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca, Steba, Oncohost; Financial Interests, Personal, Stocks/Shares: Nixio; Financial Interests, Institutional, Research Grant: BMS. M.T. Moskovitz: Financial Interests, Institutional, Research Funding: AstraZeneca; Non-Financial Interests, Institutional, Other, Honorarium: BMS, MSD, Roche, AstraZeneca, Merck, AbbVie, Takeda, Novartis, Amgen; Financial Interests, Personal, Other, Consulting Fees: MSD, Takeda, Bayer, Amgen. S. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca/MedImmune, Roche, Merck, Pfizer, Lilly, BMS/Ono, Takeda, Janssen, IMBdx; Financial Interests, Personal, Invited Speaker: AstraZeneca/MedImmune, Roche, Merck, Lilly, Amgen; Financial Interests, Institutional, Research Grant: Merck, AstraZeneca, Lunit. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. M.J. De Miguel Luken: Financial Interests, Institutional, Invited Speaker: Janssen, MSD; Non-Financial Interests, Principal Investigator: Janssen, MSD, Roche, PharmaMar, Replimune, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, BioNTech, Catalym, Dizal, Genentech, Loxo, Numab, Seagen. Y. Okuma: Financial Interests, Personal, Invited Speaker: AstraZeneca, K. K., Nippon Boehringer Ingelheim, Chugai Pharmaceutical Co., Ltd., Eli Lilly K. K., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Japan Inc.; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Local PI: AbbVie, G.K., Chugai Co., Ltd.; Financial Interests, Personal, Steering Committee Member: AstraZeneca; Financial Interests, Institutional, Local PI: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: MSD. P.J. Ansell, C. Biesdorf de Almeida, R. Saab, K. Freise, D. Ramies, E. Jeng: Financial Interests, Personal, Full or part-time Employment: AbbVie; Financial Interests, Personal, Stocks/Shares: AbbVie. D.R. Camidge: Financial Interests, Institutional, Principal Investigator: AbbVie, AstraZeneca, Blueprint, Dizal, Inhibrx, Karyopharm, Nuvalent, Pfizer, Phosplatin, Psioxus, Rain, Roche/Genentech, Seattle Genetics, Takeda, Turning Point, Verastem; Financial Interests, Personal, Advisory Board: AbbVie, Anheart, Appolomics, AstraZeneca/ Daiichi Sankyo, BeiGene, EMD Serono, Elevation, Hummingbird, Janssen, Medtronic, Mersana, Mirati, Nalo Therapeutics, Onkure, Regeneron, Roche/Genentech, Sanofi, Takeda, Theseus, Xcovery, Amgen, AstraZeneca, Bio-Thera, Blueprint, Daiichi Sankyo, Hengrui, Eli Lilly, Dizal, Helsinn, Kestrel, Nuvalent, Puma, Ribon, Seattle Genetics, Turning Point. All other authors have declared no conflicts of interest.
Invited Discussant 654O and 655O
- Alex A. Adjei (Cleveland, United States of America)
Q&A
- All Speakers (Lugano, Switzerland)