Background

Interim overall survival (OS) analysis from the Phase 3 EMPOWER-Cervical 1 study showed that cemiplimab monotherapy significantly improved OS vs investigator’s choice (IC) single-agent chemotherapy (chemo) in patients (pts) with R/M cervical cancer after progression on first-line (1L) platinum-based chemo (median follow-up: 18.2 months). Cemiplimab had an acceptable safety profile, with Grade ≥3 adverse events occurring in 45.0% of cemiplimab-treated pts vs 53.4% of chemo-treated pts. We report the final survival analysis after a further 1-year of follow-up.

Methods

608 pts enrolled regardless of programmed cell death ligand 1 (PD-L1) status were randomised (1:1) to cemiplimab 350 mg IV Q3W or IC single-agent chemo for up to 96 weeks. Randomisation was stratified by histology (squamous cell carcinoma [SCC] or adenocarcinoma including adenosquamous carcinoma [AC]), ECOG performance status score, prior bevacizumab use, and geographic region. Primary endpoint was OS, analysed hierarchically in pts with SCC followed by overall population. Exploratory analyses of OS in pts with AC and OS by PD-L1 expression were performed. In this analysis, 371 (61.0%) pts had tumor samples evaluable for PD-L1 expression vs 254 (41.8%) pts in the prior analysis. We report OS for both PD-L1 populations. Data cutoff is Jan 4, 2022.

Results

Median (range) duration of follow-up was 30.2 (18.0–50.2) months. Cemiplimab significantly improved OS vs chemo, lowering risk of death by 31% and 34% in SCC and overall populations, respectively (Table). In the AC population, cemiplimab increased OS vs chemo with 45% lower risk of death. In the n=254 and n=371 PD-L1 populations, those with PD-L1 ≥1% and PD-L1 <1% had longer OS vs chemo. Table: 519MO

Conclusions

With long-term follow-up, cemiplimab continues to show, in the overall population, a statistically significant and clinically meaningful improvement in OS vs chemo in pts with R/M cervical cancer after 1L platinum-based chemo.

Clinical trial identification

NIH: NCT03257267 EudraCT: 2017-000350-19.

Editorial acknowledgement

Medical writing support was provided by Atif Riaz, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc. and Sanofi.

Legal entity responsible for the study

Regeneron Pharmaceuticals Inc. and Sanofi.

Funding

Regeneron Pharmaceuticals Inc. and Sanofi.

Disclosure

A. Oaknin: Financial Interests, Personal, Advisory Board: Roche, PharmaMar, Clovis Oncology, Tesaro Inc., ImmunoGen, Genmab, Mersana Therapeutics, GlaxoSmithKline, Deciphera Pharmaceuticals, AstraZeneca; Financial Interests, Personal, Other, Support for travel or accommodation: Roche, AstraZeneca, PharmaMar. B.J. Monk: Financial Interests, Personal, Other, Consulting honoraria: Aravive, Inc., Asymmetric Therapeutics, Boston Biomedical, Inc., ChemoCare, ChemoID, Circulogene, Conjupro Biotherapeutics, Inc., Eisai, Geistlich, Genmab/Seattle Genetics, Gynecologic Oncology Group Foundation, ImmunoGen, Immunomedics, Incyte, Laekna Health Care, Mateon/Oxigene, Merck, Mersana Therapeutics, Myriad, NuCana, OncoMed Pharmaceuticals, Inc., OncoQuest Inc., OncoSec, Perthera, Pfizer, Precision Oncology, Puma Biotechnology, Regeneron Pharmaceuticals, Inc., Samumed, Takeda, VBL Therapeutics , Vigeo Therapeutics; Financial Interests, Personal, Speaker’s Bureau, Consulting/speaker honoraria: AstraZeneca, Clovis Oncology, Janssen/Johnson & Johnson, Roche/Genentech, Tesaro/GSK. A. Cristina de Melo: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme Corp., Bristol-Myers Squibb, Libbs Farmaceutica; Financial Interests, Institutional, Research Grant: Clovis Oncology, Bristol-Myers Squibb, Roche, Novartis, Amgen, Merck Sharp & Dohme Corp. , Lilly, Pierre Fabre, Sanofi, Pfizer; Financial Interests, Personal, Other, Support for travel or accommodation: AstraZeneca, Merck Sharp & Dohme Corp. , Bristol-Myers Squibb, Roche. Y.M. Kim: Financial Interests, Personal, Other, Consulting honoraria: Merck Sharp & Dohme Corp; Financial Interests, Institutional, Research Grant: Regeneron Pharmaceuticals, Inc. , Roche; Financial Interests, Personal, Stocks/Shares: Johnson & Johnson, Genolution. V. Samouëlian: Financial Interests, Personal, Advisory Board: Merck, GlaxoSmithKline; Financial Interests, Personal, Other, Consultancy role: Merck, GlaxoSmithKline. D. Lorusso: Financial Interests, Personal, Other, Consultancy fees: Amgen, PharmaMar; Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis Oncology, GlaxoSmithKline, Merck, Sharp & Dohme; Financial Interests, Institutional, Research Grant: Clovis Oncology, Genmab, GlaxoSmithKline, Merck, Sharp & Dohme; Non-Financial Interests, Personal, Other, Member of the Board of Directors: Gynecologic Cancer InterGroup. S. Takahashi: Financial Interests, Personal, Other, Consulting honoraria: Daiichi Sankyo, Eisai, Bayer, Taiho Pharmaceutical, Merck Sharp & Dohme, Novartis, Chugai Pharma, AstraZeneca, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Nihonkayaku , Pfizer , Eli Lilly Japan; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Sanofi, Eisai, Bayer, Taiho Pharmaceutical, Merck Sharp & Dohme, Novartis, Chugai Pharma, AstraZeneca, Bristol-Myers Squibb, Eli Lilly Japan, Ono Pharmaceutical, PharmaMar, Pfizer/EMD Serono; Financial Interests, Personal, Other, Support for travel and accommodation: Daiichi Sankyo, Novartis. B. Maćkowiak-Matejczyk: Financial Interests, Personal, Other, Honoraria: Roche, GlaxoSmithKline, AstraZeneca; Financial Interests, Personal, Advisory Board: Seagen Inc., GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Seagen Inc., Mersana Therapeutics, Merck Sharp & Dohme Polska Sp.zo.o., AstraZeneca AB, AstraZeneca Pharma Poland Sp. z o.o., Parexel International Limited , Tesaro Bio Netherlands BV, Tesaro, Inc., Clovis Oncology, Seagen Inc., Quiniles Eastern Holdings, Regeneron Pharmaceuticals, Inc. J. Li: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. S. Jamil: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.D. Mathias: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.G. Fury: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. K.S. Tewari: Financial Interests, Personal, Other, Honoraria: Tesaro Inc., Clovis Oncology; Financial Interests, Personal, Other, Consulting fees: Genentech, Tesaro Inc., Clovis Oncology, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Genentech, AstraZeneca, Merck, Tesaro Inc., Clovis Oncology; Financial Interests, Institutional, Research Grant: AbbVie, Genentech, Morphotek, Merck, Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Other, Support for travel and accommodation: Genentech. All other authors have declared no conflicts of interest.

Background

GX-188E (tirvalimogene teraplasmid) is a therapeutic DNA vaccine that encodes HPV-16 and HPV-18 E6 and E7 and induces HPV-specific T-cell responses. Pembrolizumab was approved for the treatment of advanced cervical cancer, based on an objective response rate (ORR) of 14.3% in patients with PD-L1 positive (CPS≥1). However, patients who were PD-L1 negative (CPS<1) showed no response to treatment with pembrolizumab. We aimed to investigate whether a combination of GX-188E plus pembrolizumab showed antitumor activity against advanced cervical cancer regardless of PD-L1 expression.

Methods

In this open-label, single-arm, phase 2 trial, patients with HPV-16 or HPV-18 positive advanced cervical cancer, and who had progressed after standard-of-care therapy were recruited in South Korea. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, 19 and optional dose at week 46, and intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years or until disease progression. The primary endpoint was ORR assessed by the blinded independent central reviewers (BICR) using RECIST v1.1.

Results

A total of 65 patients have been enrolled and 60 patients were analyzed as efficacy population based on having at least one post-baseline tumor assessment. Among 60 patients, 36 patients had PD-L1 positive tumors and 24 patients were PD-L1 negative. According to BICR evaluation, 19 of 60 patients (31.7%) achieved best overall response; 6 patients had a complete response and 13 patients had a partial response. Especially, in PD-L1 negative population with 24 patients, this combination treatment showed significant efficacy (25.0% ORR). Median DOR was 12.3 months and median OS was 17.2 months. 22 of 65 patients (33.8%) had treatment-related adverse events (TRAEs) of any grade with three patients (4.6%) presenting with grade 3 or 4 TRAEs.

Conclusions

GX-188E vaccine combined with pembrolizumab in advanced cervical cancer was safe and tolerable, and showed significant efficacy compared with pembrolizumab alone particularly in patients with PD-L1 negative. This combination therapy could represent a new potential treatment for this patient population.

Clinical trial identification

NCT03444376.

Legal entity responsible for the study

Genexine, Inc.

Funding

Sponsor: Genexine, Inc. Government funding: National Cancer Center Onco-Innovation Unit. Supply of pembrolizumab: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Disclosure

S. Lee: Financial Interests, Institutional, Other, Sub-investigator: Catholic University of Korea, Seoul St. Mary's Hospital. M. Lim: Financial Interests, Institutional, Principal Investigator: National Cancer Center. Y.M. Kim: Financial Interests, Institutional, Principal Investigator: Asan Medical Center. J.H. No: Financial Interests, Institutional, Principal Investigator: Seoul National University Bundang Hospital. B. Kim: Financial Interests, Institutional, Principal Investigator: Samsung Medical Center. C.H. Cho: Financial Interests, Institutional, Principal Investigator: Keimyung University Dongsan Medical Center. S.H. kim: Financial Interests, Institutional, Principal Investigator: Yonsei University College of Medicine. D.H. Jeong: Financial Interests, Institutional, Principal Investigator: Inje University Busan Paik Hospital. J. lee: Financial Interests, Institutional, Principal Investigator: Korea University Guro Hospital. J.S. Park: Non-Financial Interests, Institutional, Full or part-time Employment: Genexine, Inc.; Financial Interests, Institutional, Sponsor/Funding, Genexine, Inc.: Genexine, Inc.; Financial Interests, Institutional, Stocks/Shares: Genexine, Inc.. Y. Choi: Non-Financial Interests, Institutional, Full or part-time Employment: Genexine, Inc.; Financial Interests, Institutional, Project Lead: Genexine, Inc.; Financial Interests, Institutional, Sponsor/Funding: Genexine, Inc.. K.O. Jeon: Non-Financial Interests, Institutional, Full or part-time Employment: Genexine, Inc.; Financial Interests, Institutional, Sponsor/Funding: Genexine, Inc.. J.W. Woo: Non-Financial Interests, Institutional, Member of the Board of Directors: Genexine, Inc.; Financial Interests, Institutional, Stocks/Shares, Genexine, Inc.: Genexine, Inc.; Financial Interests, Institutional, Sponsor/Funding: Genexine, Inc.. Y.C. Sung: Non-Financial Interests, Institutional, Advisory Board: Genexine, Inc.; Financial Interests, Institutional, Stocks/Shares: Genexine, Inc.. S. Hur: Financial Interests, Institutional, Principal Investigator: Catholic University of Korea, Seoul St. Mary's Hospital.

Background

Anti–PD–1–based treatment (tx) is approved in 1st (1L)– and 2nd (2L)–line settings for programmed death ligand 1 (PD–L1)+ R/M Cx Ca; however, objective response rate (ORR) with single–agent tx is <15% (Chung et al SGO 2021 abstract). Here, we report safety and efficacy of NIVO ± IPI in pts with R/M Cx Ca in CheckMate 358 (NCT02488759), a phase 1/2 study of NIVO and NIVO–based combinations in virus–associated solid tumors.

Methods

Adults with R/M squamous Cx Ca and ≤2 prior systemic therapies received NIVO 240 mg Q2W, NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W (N3I1), or NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 cycles followed by NIVO 240 mg Q2W (N1I3), for ≤24 mo or until disease progression, unacceptable toxicity or consent withdrawal. N3I1 vs N1I3 was initially randomized (rand); promising signal led to an expansion cohort with N1I3 (exp). Investigator–assessed ORR was the primary endpoint; overall survival (OS), progression free survival (PFS) and duration of response (DOR) were secondary endpoints; safety and select tissue and blood biomarkers were exploratory endpoints. Cross–cohort comparison was not planned.

Results

Among 176 pts treated, (NIVO n = 19; N3I1 n = 45; pooled N1I3 n = 112 [rand n = 45; exp n = 67]), median follow–up was 30.4 mo. Responses (table) were observed regardless of tumor PD-L1 status. Median DOR (mo; 95% CI) was not reached [NR] (35.3–NR), 24.4 (8.7–NR) and 34.1 (11.5–NR), respectively. Median OS was 21.6 (8.3–46.9), 15.2 (9.0–36.2) and 20.9 (14.4–32.8); median PFS was 5.1 (1.9–9.1), 3.8 (2.1–10.3) and 5.8 (3.8–9.3). The incidence of individual grade 3/4 IMAEs was <6% (NIVO), <7% (N3I1), and <6% except for hepatitis (16%) (pooled N1I3) with no new safety signals. There was one tx–related death (colitis) in the exp N1I3 arm. Table: 520MO

Efficacy of NIVO±IPI in R/M Cx Ca

Conclusions

Chemotherapy-free dual immunotherapy NIVO + IPI regimens can provide durable tumor regression with significant but manageable toxicity in R/M Cx Ca regardless of PD–L1 status and warrant further investigation.

Clinical trial identification

NCT02488759.

Editorial acknowledgement

Writing and editorial assistance was provided by Thai Cao, MS, and Meenakshi Subramanian, PhD, of Evidence Scientific Solutions, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb, Princeton, NJ, USA.

Funding

Bristol Myers Squibb, Princeton, NJ, USA and Ono Pharmaceutical Company Ltd. (Osaka, Japan).

Disclosure

A. Oaknin: Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis Oncology, Deciphera Pharmaceuticals, Genmab, GSK, ImmunoGen, Mersana Therapeutics, PharmaMar, Roche, Tesaro, Merck Sharps & Dohme de España, SA, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, prIME Oncology, Sattucklabs, Itheos, Eisai, F. Hoffmann-La Roche,; Financial Interests, Personal, Other, Travel and accomodation: AstraZeneca, PharmaMar, Roche; Financial Interests, Institutional, Funding: Abbvie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Clovis Oncology Inc, EISAI limited LTD, F. Hoffmann –La Roche LTD, Regeneron Pharmaceuticals, Immunogen Inc, Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc, PharmaMar SA, Tesaro Inc., Bristol Myers Squibb; Non-Financial Interests, Leadership Role, Executive Board member as a Co-Chair: GEICO; Non-Financial Interests, Leadership Role, Phase II Committee and Cervix Cancer Committee Representative on behalf of GEICO: GCIG; Non-Financial Interests, Officer, Chair of Gynaecological Track ESMO 2019. Scientific Track Member Gynaecological Cancers ESMO 2018, ESMO 2020, ESMO 2022. Member of Gynaecological Cancers Faculty and Subject Editor Gyn ESMO Guidelines: ESMO; Non-Financial Interests, Member: ESMO, ASCO, GCIG, SEOM, GOG. K.N. Moore: Financial Interests, Personal, Advisory Board: AstraZeneca, Aravive, Alkemeres, Blueprint Pharma, Eisai, Emd Serono, Gsk/Tesaro, Genentech/Roche, Hengrui, Immunogen, Imab, Mereo, Myriad, Caris, Mersana, Novartis, Novocure, Oncxerna, OncoNova, tarveda, VBL Therapeutics; Financial Interests, Personal, Full or part-time Employment: GOG Partners Associate Director; Financial Interests, Institutional, Full or part-time Employment: NRG Ovarian Cancer Chair; Financial Interests, Personal, Royalties: UP to Date; Financial Interests, Institutional, Invited Speaker, international CO-PI, local site PI: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Immunogen, GSK/Tesaro, Lilly, PTC Therapeutics, Daiichi Sankyo, Regeneron, Artios, Bolt, Verastem; Non-Financial Interests, Invited Speaker: GOG. T. Meyer: Financial Interests, Personal, Advisory Board: Ipsen, AstraZeneca, Eisai, Bayer, Roche, Adaptimmune, Boston Scientific; Financial Interests, Institutional, Research Grant: Bayer, BTG. L. Devriese: Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board: Merck. A. Amin: Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb. C.D. Lao: Financial Interests, Institutional, Invited Speaker, Research funding: BMS, Novartis, Genentech, Oncosec. V. Boni: Financial Interests, Personal, Full or part-time Employment: NEXT Madrid, Universitary Hospital Quironsalud Madrid; Financial Interests, Personal, Advisory Role: Puma Biotechnology, Ideaya Biosciences, Loxo Therapeutics, CytomX Therapeutics, Guidepoint, Oncoart; Financial Interests, Personal, Invited Speaker: Eli Lilly, MSD; Financial Interests, Personal, Other, Travel/Accomodations: Bayer; Financial Interests, Institutional, Research Grant: Abbvie, ACEO, Adaptaimmune, Amcure, AMGEN, Amunix, AstraZeneca, Bristol Myers Squibb Cytomx, GSK, Genentech/Roche, H3, Incyte, Janssen, Kura, Lilly, Nektar, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, PUMA, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Innovio, MSD, PsiOxus, Seattle Genetics, Mersana, Daiichi, Nektar, Astellas, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Boehringer Ingelheim, Regeneron, Millennium, Synthon, Spectrum, Rigontec, Zenith. W.H. Sharfman: Financial Interests, Personal, Invited Speaker, non-branded speaker series consultant and speaker: BMS; Financial Interests, Personal, Other, Leads discussion groups on melanoma therapy: Merck; Financial Interests, Personal, Advisory Board: Regeneron, Pfizer, AmerisourceBergen; Financial Interests, Institutional, Invited Speaker: BMS, Merck, Genentech, AstraZeneca, Novartis. M. Tahara: Financial Interests, Personal, Advisory Board: Merck Biopharma, Ono pharma, Bristol- Myers Squibb, MSD, Pfizer, Bayer, Lilly, Rakuten Medical, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Institutional, Invited Speaker: MSD, AstraZeneca, Ono Pharma, Novartis, Pfizer, Bristol-Myers Squibb, Loxo, GlaxoSmithKline, Lilly, Rakuten Medical; Financial Interests, Institutional, Research Grant: Bayer. S.L. Topalian: Financial Interests, Personal, Advisory Role: AstraZeneca, Dragonfly Therapeutics, Five Prime Therapeutics, Immunocore; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Dragonfly Therapeutics, Five Prime Therapeutics. M.E. Magallanes Maciel: Financial Interests, Institutional, Leadership Role: Centro Oncologico Internacional. A. Molina Alavez: Financial Interests, Personal and Institutional, Advisory Board: Eli Lilly, AstraZeneca, Amgen; Financial Interests, Personal and Institutional, Principal Investigator: Bayer, Bristol Myers Squibb, Janssen, MSD, Eli Lilly, AstraZeneca, Amgen; Financial Interests, Personal, Speaker’s Bureau: Glaxo; Financial Interests, Institutional, Other: Roche. A. Khan: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Board: Bristol Myers Squibb. C. Copigneaux: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. M. Lee: Financial Interests, Personal, Other, Consultant: Bristol Myers Squibb. C. Garnett-Benson: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. X. Wang: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. R.W. Naumann: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Clovis, OncoMed, Eisai, Bristol Myers Squibb, Agenus, SutroBio, GOG Partners, GSK; Other, Institutional, Principal Investigator: OncXerna, SutroBio, Bristol Myers Squibb, Mersana; Financial Interests, Personal, Speaker’s Bureau: Seagen; Non-Financial Interests, Personal, Leadership Role: GOG Partners; Other, Institutional, Research Grant: GOG Partners; Non-Financial Interests, Personal, Other, Steering Committee: OncXerna; Financial Interests, Personal, Other, DSMB Member: Genelux. All other authors have declared no conflicts of interest.

Background

Advanced CCGC has poor prognosis with 2nd line objective response rates (ORR) to standard chemotherapy ranging from 0-8%. As PD-L1 expression, PD-1+ tumour infiltrating lymphocytes, pro-inflammatory cytokine signalling, high tumour mutational burden and preliminary clinical activity with PD-1 inhibitors are described in CCGC, we investigated PM for advanced CCGC.

Methods

PEACOCC is a Phase II, multicentre, single arm, academic, UK trial in patients (pts) with advanced CCGC who had ≥1 prior line of chemotherapy with progression (PD) at study entry. Pembrolizumab 200mg iv q21 days was given until PD (RECIST v1.1), unacceptable adverse event (AE), 2 years (y) PM reached, patient or clinician decision. The primary endpoint was progression-free survival (PFS) rate at 12 weeks (w) (H₀≤15%; H₁≥33%; 5% 1-sided a; 90% power). Secondary endpoints included ORR, duration of response (DOR), PFS, overall survival (OS) and safety.

Results

From 4/3/19–20/10/21 49pts were enrolled, 48 evaluable. Median age 58.5y (32–77y), ECOG 0/1 54.2%/45.8%, 85.4% ovarian CCGC. Median prior lines systemic therapy 2 (1–6); 19pts (39.6%) had received anti-angiogenic therapy. 42pts completed median 4 cycles PM (1–25), 6pts (12.5%) continue PM. 16.7% pts had Grade (G)3 treatment-related AE (TRAE) of hyperthyroidism (n=2), acute kidney injury (AKI), raised alanine aminotransferase, raised alkaline phosphatase, anaemia, encephalitis and diabetic ketoacidosis (DKA). There were no G4 or G5 TRAE. 3pts (6.3%) discontinued PM due to TRAEs. The PFS rate at 12w was 43.8% (90%CI:31.5-56.6) exceeding the pre-stated lower bound of 15%. Best ORR was 25.0% (90%CI:15.1-37.3) [1 complete, 11 partial], with 1y DOR rate 47.7% (95%CI:14.1-75.6). After a median follow-up of 2.1y, median PFS was 12.2w (95%CI:5.9-32.9) and median OS 71.0w (95%CI:29.1-137.6).

Conclusions

The PEACOCC trial indicates that PM is a highly effective therapy in heavily pre-treated pts with advanced CCGC: 43.8% pts were alive and progression-free at 12w. Furthermore, clinical outcomes were durable with limited toxicity. These promising results justify consideration of pembrolizumab monotherapy as a new standard-of-care for advanced CCGC.

Clinical trial identification

EudraCT 2017-004168-36.

Legal entity responsible for the study

University College London.

Funding

MSD.

Disclosure

R. Kristeleit: Financial Interests, Personal, Advisory Board: GSK, Eisai, Basilea Pharmaceutica, iTEOS, Clovis Oncology, Shattuck Labs, AstraZeneca, Regeneron; Financial Interests, Personal, Invited Speaker: GSK, Zydus Cadila, Clovis Oncology, AstraZeneca, GSK; Financial Interests, Personal, Expert Testimony: Amgen; Financial Interests, Personal, Other, Member of Oncology and Haematology Expert Advisory Group: Commission on Human Medicines; Financial Interests, Institutional, Invited Speaker: GSK, Clovis Oncology, Clovis Oncology, Eisai, InCyte, AstraZeneca, MSD, Roche, BerGenBio, Allarity, IoVance, Artios, Regeneron; Financial Interests, Institutional, Research Grant: MSD. C. Gourley: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board, Both personal and institutional: AstraZeneca, MSD, GlaxoSmithKline; Financial Interests, Personal, Invited Speaker, Both personal and institutional: AstraZeneca, MSD, GSK, Clovis, Chugai, Takeda; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Aprea, Nucana, Medannexin; Financial Interests, Institutional, Invited Speaker: GlaxoSmithKline, BerGenBio. M. Hall: Financial Interests, Personal, Advisory Board, Ad boards. speaker engagements: GSK; Financial Interests, Personal, Advisory Board, Ad boards: Amgen; Financial Interests, Personal, Advisory Board, Ad Boards: AZ; Financial Interests, Personal, Advisory Board, Ad Boards, speaker engagement: Clovis Oncology; Financial Interests, Institutional, Research Grant, Funding and drug for CeNtuRIOn clinical trial - Glasgow Clinical trials Unit: Clovis Oncology; Financial Interests, Institutional, Research Grant, Research funding and drugs for CeNtuRIOn clinical trial - Glasgow Clinical Trials Unit: BMS; Financial Interests, Institutional, Research Grant, Research Funding and drug for CoRinTh clinical trial - Cardiff clinical trials Unit: Merck. R. Miller: Financial Interests, Personal, Advisory Board: GSK, AZD, Merck; Financial Interests, Personal, Invited Speaker: GSK, AZD, Clovis Oncology; Financial Interests, Personal, Expert Testimony: Shionogi, Ellipses. All other authors have declared no conflicts of interest.

Background

Recurrent ovarian clear cell carcinoma (OCCC) has an abysmal prognosis with only 6∼8% ORR in chemotherapy. Antiangiogenic therapy and immunotherapy might have potential efficacy in OCCC due to the unique clinicopathological characteristics, gene expression profile, and immune microenvironment. Moreover, anti-PD-1 + Bev has shown certain efficacy in renal clear cell carcinoma, which exhibits similar gene expression profiles to OCCC. Herein, we aim to investigate the potential benefit of Sintilimab (PD-1 antibody) + Bev combination therapy for recurrent/persistent OCCC patients.

Methods

This INOVA study followed Simon's 2-stage design. A total of 38 recurrent/persistent OCCC patients with at least one-line pretreated platinum-containing chemotherapy were planned to be recruited. Patients receive Sin (200mg iv. q3w) and Bev (15mg/kg iv. q3w) until disease progression or intolerable toxicity, up to 2 year and 22 cycles, respectively. The primary endpoint was investigator evaluated objective response rate (ORR) per RECIST 1.1. If more than 1 of 17 patients achieved objective response in stage 1, the study will enter stage 2.

Results

Between April 8, 2021 and April 25, 2022 (data cutoff), 23 patients had been enrolled, with median age of 58 (range,28-67) and 73.9% were Bev naive. All patients received prior platinum-containing chemotherapy. The median lines of treatment were 3 (range, 2-8). 18 of 22 patients (81.8%) were platinum-resistant relapsed. 20 patients were evaluable with at least one radiological evaluation after base line. 8 patients achieved objective response which inferred an ORR of 40.0% (1 CR, 7 PR; 95% CI, 19.1%-63.9%) and a DCR of 75.0% (8 OR, 7 SD; 95% CI, 50.9%-91.3%). Frequently occurring adverse events were grade 1-2, including proteinuria (33.3%), hypothyroidism (27.8%) and ALT, AST elevation (16.7%). Only one (5.6%) patient had a grade 3 immune myocarditis.

Conclusions

Sintilimab and bevacizumab combination therapy as a chemo-free regimen exhibites promising efficacy and favorable safety for recurrent/persistent OCCC patients. The trial is still recruiting, more data would be further analyzed and reported.

Clinical trial identification

NCT04735861.

Legal entity responsible for the study

The authors.

Funding

Beijing CSCO Clinical Oncology Research Foundation.

Disclosure

All authors have declared no conflicts of interest.

Background

Ubamatamab is a mucin-16 x cluster of differentiation 3 (MUC16xCD3) bispecific antibody that promotes T cell–mediated cytotoxicity by binding MUC16-expressing OC cells and CD3+ T cells. We present safety, pharmacokinetics (PK) and efficacy from a first-in-human Phase 1 study of ubamatamab (NCT03564340).

Methods

Patients with advanced platinum-experienced OC and elevated serum cancer antigen 125 were administered ubamatamab monotherapy intravenously weekly at a dose range of 0.1–800 mg after initial step-up dosing. Dose escalation followed a modified 3+3 design. Primary endpoints were safety and PK. Secondary endpoints included preliminary estimate of objective response rate (ORR) per RECIST 1.1.

Results

78 patients received ubamatamab; median number of prior therapies was 4.5 (range 1–17). Median duration of exposure was 12 (range 0.4–117) weeks. The most common treatment-emergent adverse events (TEAE) were cytokine release syndrome (73.1%, all Grade 1/2) and pain (87.2%) that primarily occurred during Weeks 1–2 of initial step-up dosing. The most common Grade ≥3 TEAEs were anaemia (23.1%) and abdominal pain (19.2%). Objective responses were observed between 20–800 mg doses (n=50). ORR of those receiving ≥1 full dose (n=42) was 14.3% (95% CI 5.4–28.5) and disease control rate (DCR) was 57.1% (41.0–72.3). Median duration of response was 12.2 months. In a subset of these patients without baseline visceral metastases (n=29) ORR was 20.7% (8.0–39.7) and DCR was 72.4% (52.8–87.3). Exploratory analysis of patients with >75% of tumour cells with 2+ baseline MUC16 immunohistochemical staining and ≥1 dose of ≥20 mg (n=13) showed ORR of 30.8% (9.1–61.4), and DCR 61.5% (31.6–86.1). Serum ubamatamab concentrations increased dose-proportionally. No definitive dose-response relationship was observed in safety or efficacy between 20–800 mg.

Conclusions

Ubamatamab safety profile was acceptable with evidence of durable responses in this heavily pretreated population with OC across a wide dose range. Based on data from this study, a randomised Phase 2 expansion has been initiated.

Clinical trial identification

NCT03564340.

Editorial acknowledgement

Medical writing support was provided by Rachel McGrandle, BSc, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc.

Funding

Regeneron Pharmaceuticals, Inc.

Disclosure

D. O'Malley: Financial Interests, Personal, Advisory Role: AstraZeneca, Tesaro/GSK, Immunogen, Janssen/Johnson & Johnson, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, GOGFoundation, Iovance, Eisai, Agenus, SeaGen, Mersana, Clovis , SDP Oncology (BBI), Ambry, Myriad Genetics, Tarveda, Novartis, Rubis, Elevar, Takeda, Toray, InxMed, Arquer Diagnostics, Roche Diagnostics MSA, Sorrento, Corcept Therapeutics , Celsion Corp; Financial Interests, Personal, Research Grant: AstraZeneca, Tesaro/GSK, Immunogen, Janssen/Johnson & Johnson, AbbVie, Regeneron, Amgen, Novocure , Genentech/Roche, GOGFoundation, Iovance, Eisai, Agenus, SeaGen, Mersana, Clovis , SDP Oncology (BBI), VentiRx, Array Biopharma, EMD Serono, Ergomed, Ajinomoto Inc., Ludwig Cancer Research, Stemcentrx, Inc., Cerulean Pharma, Bristol-Myers Squibb Co., Serono Inc., TRACON Pharmaceuticals, New Mexico Cancer Care Alliance, INC Research, Inc., inVentiv Health Clinical PRA Intl, Merck , GenMab. R.E. O'Cearbhaill: Financial Interests, Personal, Advisory Role: Genmab Therapeutics , Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Research Grant: AbbVie, Atara Biotherapeutics, Celgene, Genentech, Genmab Therapeutics, GlaxoSmithKline, Juno, Kite Pharma, Ludwig Cancer Institute, Marker Therapeutics, Regeneron Pharmaceuticals, Inc., Sellas Therapeutics, Syndax Pharmaceuticals, TCR2 Therapeutics, Tesaro. K.N. Moore: Financial Interests, Personal, Advisory Role: AstraZeneca, Aravive, Alkemeres, Blueprint pharma, Caris, Elevar, Eisai, Genentech/Roche, GSK/Tesaro, Hengrui, Immunogen, Inxmed, IMab, Iovance, Lilly, Mereo, Myriad, Mersana, Novocure, Novartis, Tarveda, Verastem, VBL Therapeutic; Financial Interests, Institutional, Research Grant: AstraZeneca, Regeneron, Novocure, Genentech/Roche, AbbVie, GSK/Tesaro, Immunogen, PTC Therapeutics, Merck, Lilly, Mereo, Artios, Daichii. E.P. Hamilton: Financial Interests, Institutional, Research Grant: Regeneron, AbbVie, Acerta Pharma, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Arvinas, AstraZeneca, AtlasMedX, Black Diamond, Boehringer Ingelheim, Clovis, Compugen, Curis, CytomX, Dana Farber Cancer Inst, Daiichi Sankyo, Deciphera, eFFECTOR Therapeutics, Ellipses Pharma, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, InvestisBio, Jacobio, Karyopharm, Leap Therapeutics, Lilly, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millenium, Molecular Templates, Myriad Genetic Labs, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Radius Health, Repertoire Immune Medicine, Rgenix, Roche/Genentech, SeaGen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics , Zymeworks ; Financial Interests, Institutional, Other, Consulting: Arcus, Arvinas, AstraZeneca, Black Diamond, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Dantari, Deciphera Pharmaceuticals, Eisai, H3 Biomedicine, iTeos, Janssen, Lilly, Loxo, Merck, Mersana, Novartis, Pfizer, Puma Biotechnology, Relay Therapeutics, Roche/Genentech, SeaGen , Silverback Therapeutics . O. Yeku: Financial Interests, Personal, Advisory Role: Celldex, GIMV NV, TigaTx , hC Bioscience. S. Bouberhan: Financial Interests, Personal, Advisory Role, consulting fees: ImmunoGen. S. Yoo: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. J. Brouwer-Visser: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. H.K. Cheung: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M. Peterman: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. P. Goncalves: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. T. Schmidt: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M. Zhu: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. I. Lowy: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. T. Rowlands: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. T.S. Uldrick: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. E.A. Miller: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. J.F. Liu: Financial Interests, Personal, Advisory Role, personal consulting fees: AstraZeneca, Clovis Oncology, Eisai, EpsilaBio, Genentech/Roche, GlaxoSmithKline, Regeneron Pharmaceuticals, Inc.; Financial Interests, Institutional, Research Grant: 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, CytomX therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro, Vigeo Therapeutics, Zentalis. All other authors have declared no conflicts of interest.

Background

Cortisol activity at the glucocorticoid receptor (GR) contributes to chemotherapy resistance by suppressing apoptotic pathways that taxanes utilize, and high tumor GR expression is associated with poor chemotherapy response in ovarian cancer. A phase 2 ovarian cancer study (NCT03776812) demonstrated the clinical benefit of adding relacorilant (RELA), a selective GR modulator, to nab-paclitaxel (NP) compared to NP alone. We present biomarker analyses from this study.

Methods

A phase 2, open-label, randomized study of RELA in combination with NP compared with NP alone was conducted in patients with ovarian cancer. 127 formalin-fixed paraffin-embedded tumor samples collected as part of the study were analyzed using a CLIA-validated GR immunohistochemistry (IHC) assay. RNA expression was measured in whole blood using a custom NanoString^TM panel focused on GR target genes.

Results

Tumor GR expression (IHC H-score >0) was observed in 96% (122/127) of tumor samples. High tumor GR expression (H-score ≥100) was observed in 65% (82/127) of samples and associated with non-response to NP-only (stable or progressive disease). In contrast, high GR expression was associated with good response (partial or complete response) in patients receiving RELA + NP (χ² P= 0.037). Subjects with low baseline plasma TGF-β1 (<30,000 pg/mL) treated with RELA + NP had significantly longer overall survival (OS) compared to those with high TGF-β1 (P<0.0001). Of 239 genes previously shown to be GR target genes, 221 were suppressed after RELA + NP treatment. Significantly fewer GR target genes were suppressed by NP (P<0.00001). GR target genes that were suppressed by RELA + NP but not NP alone included SGK1 (P=0.013), PIK3CG (P=0.018), and GSK3B (P=0.05).

Conclusions

GR expression was abundant in the ovarian tumors assessed in this study. High GR expression was associated with poor outcomes in patients treated with NP alone. In contrast, high baseline tumor GR expression was associated with good response in patients treated with RELA + NP. Low plasma TGF-β1 predicted longer OS. Suppression of GR-target genes indicated systemic GR antagonism by RELA.

Clinical trial identification

NCT03776812.

Editorial acknowledgement

Writing and editorial support for this abstract was provided by Tina Schlafly, PhD, an employee of Corcept Therapeutics.

Legal entity responsible for the study

Corcept Therapeutics.

Funding

Corcept Therapeutics.

Disclosure

D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: PharmaMar, Amgen, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards: Merck Serono; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Seagen, Immunogen, Genmab, Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for funding academic trial: MSD, Clovis Oncology, PharmaMar; Financial Interests, Institutional, Funding, Grant for founding academic trial: GSK; Financial Interests, Institutional, Invited Speaker, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, ENGOT trial with insitutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clnical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab; Non-Financial Interests, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Principal Investigator, PI of clinical trial. No personal compensation received: immunogen, clovis, Incyte; Non-Financial Interests, Principal Investigator, PI of clinical trial. No personal compensation receive: roche; Non-Financial Interests, Member, Board of Directors: GCIG. A.E. Greenstein: Financial Interests, Personal, Project Lead, Employee: Corcept Therapeutics; Financial Interests, Personal, Stocks/Shares: Corcept Therapeutics. S.A. Wadekar: Financial Interests, Personal, Other, Employee: Corcept Therapeutics. I.C. Tudor: Financial Interests, Personal, Project Lead, Employee: Corcept Therapeutics. H.J. Hunt: Financial Interests, Personal, Officer: Corcept Therapeutics. B. Guyer: Financial Interests, Personal, Officer: Corcept Therapeutics.