701P - NCI10221: Phase II multicenter biomarker driven combination trial of copanlisib and nivolumab in patients with molecularly-selected advanced solid tumors (BaCoN)

Background

Preclinical data showed antitumor efficacy with PI3K and PD-1 combined blockade. We hypothesized that efficacy will be enriched in tumors with PIK3CA hotspot and PTEN mutations vs those without. This provided rationale for this 3-arm trial of copanlisib (pan-PI3K inhibitor) and nivolumab (PD-1 inhibitor) in patients (pts) with: (1) activating PIK3CA hotspot mutations, (2) inactivating PTEN mutations or (3) wildtype (WT) for PIK3CA/PTEN mutations (NCT04317105).

Methods

Copanlisib was started as monotherapy in cycle 1 at 60 mg IV D1, 8, 15, before nivolumab was added from cycle 2 at 480 mg IV every 28 days. Fresh tumor biopsies and ctDNA were mandated in all pts at baseline, copanlisib monotherapy, on combo and at progression. Prior PD-1/L1 or PI3K inhibitors (PD-1/L1i or PI3Ki) were allowed. Objectives were safety, antitumor activity and analyses of sequential tumors (WES; RNA-Seq; RPPA) and ctDNA.

Results

50 pts (M:F 17:33; ECOG PS 0:1 18:32; mean age 58 years (27-79) with ovarian (n=12), breast (n=10), HNSCC (n=4), bile duct (n=3), NSCLC (n=3), prostate (n=3), colon (n=3), gallbladder (n=2), leiomyosarcoma (n=2), salivary gland (2), bladder, cervical, endometrial, liposarcoma, sarcoma, skin (n=1) cancers enrolled. Pts with PIK3CA hotspot (n=16), PTEN (n=18), and WT (n=16) tumors enrolled. 31/50 pts had ≥3 lines of prior therapy; 23 (46%)/50 pts had prior PD-1/L1i and 3 (6%)/50 prior mTOR inhibitors. Common toxicities: G1/2 nausea (35%), rash (24%), diarrhea (24%), mucositis (20%), anemia (20%), fatigue (18%), hyperglycemia (18%); ≥ G3 transient hypertension (24%). RECISTv1.1 CR/PR in PIK3CA and PTEN cohorts were achieved in 4 (27%)/15 (1 cPR; 3 uCR/PR) pts and 3 (20%)/15 (3 cPR) pts, vs 0/15 (0%) pts in WT cohort. Responses were deep (up to -100%) and durable (up to 15+ months). Clinical benefit rate (SD>4 months/CR/PR) was 29% across cohorts; 40% in PIK3CA hotspot cohort, 33% in PTEN cohort and 13% in WT cohort.

Conclusions

The combination of copanlisib and nivolumab is well tolerated with antitumor activity in pts with PIK3CA hotspot and PTEN mutations including PD-1/L1i-exposed pts. Translational analyses are ongoing.

Clinical trial identification

NCT04317105.

Editorial acknowledgement

Legal entity responsible for the study

National Cancer Institute (NCI).

Funding

National Cancer Institute (NCI).

Disclosure

T.A. Yap: Financial Interests, Personal, Other, Consultant: Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Clovis, Cybrexa, EMD Serono, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Varian, Zai Labs, AbbVie, Acrivon, Adagene, Amphista, Artios, Athena, Avoro, Baptist Health Systems, BeiGene, Boxer, C4 Therapeutics, Calithera, Cancer Research UK, Diffusion, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Idience, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Kyn, MEI Pharma, Mereo, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Piper-Sandler, Prolynx, resTORbio, Theragnostics, Versant, Vibliome, Xinthera, ZielBio, Radiopharm Theranostics, Sanofi, CUHK Committee, Ellipses.Life, LRG1, Panangium, Pliant Therapeutics, Seagen, Synthis, Tessellate Bio, TD2 Theragonostics, Tome Biosciences, Zentalis; Financial Interests, Personal, Other, University of Texas MD Anderson Cancer Center, where I am Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios): MD Anderson Cancer Center, Institute for Applied Cancer Sciences; Financial Interests, Personal, Stocks/Shares: Seagan; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GSK, Karyopharm, Pfizer, Repare, Sanofi, Artios, AstraZeneca, BeiGene, BioNTech, Blueprint, BMS, Clovis, Constellation, Eli Lilly, Forbius, ImmuneSensor, F-Star; Financial Interests, Institutional, : Genentech. E.E. Dumbrava: Financial Interests, Institutional, Other, Research/grant funding: Bayer HealthCare Pharmaceuticals, Immunocore Ltd., Amgen, Aileron Therapeutics, Compugen Ltd., Gilead, BOLT Therapeutics, Aprea Therapeutics, Bellicum, PMV Pharma, Triumvira, Seagen Inc, Mereo BioPharma 5 Inc, Sanofi, Rain Oncology, Astex Therapeutics, SOTIO, Mersana Therapeutics, Poseida, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: PMV Pharma; Financial Interests, Personal, Advisory Board: BOLT Therapeutics, Mersana Therapeutics, Orum Therapeutics, Summit Therapeutics. 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. J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, IONCTURA SA; Financial Interests, Personal, Other, Consultancy: Aadi Bioscience, Clarion Healthcare, Debiopharm, Monte Rosa Therapeutics, Cullgen, Pfizer, Merus N.V., Macrogenics, Oncology One, Envision Pharma, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC, Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GSK; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer; Other, Other: VHIO/Ministero De Empleo Y Seguridad Social; Other, Travel: European Society for Medical Oncology. 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. All other authors have declared no conflicts of interest.