LBPO.CL04 · 临床研究 · Late-Breaking

RELATIVITY-020 A-C部分中nivolumab加relatlimab（NIVO+RELA）在实体瘤中的剂量递增和扩增

Dose escalation and expansion of nivolumab plus relatlimab (NIVO + RELA) in solid tumors in RELATIVITY 020 Parts A-C

编号 LB419 展板 9 时间 4/22 09:00–12:00 区域 Section 51 主讲 Takekazu Aoyama, MD;PhD

分会场 Late-Breaking Research: Clinical Research 4

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作者与单位 Authors & Affiliations

Paolo A. Ascierto¹, Carlo Gomez-Roca², Ignacio Melero³, Katriina Jalkanen⁴, Rachel E. Sanborn⁵, Juan Martin-Liberal⁶, James Larkin⁷, Rastilav Bahleda⁸, F. Stephen Hodi⁹, Margaret Callahan¹⁰, Marta Nykas¹¹, Giuseppe Curigliano¹², Sebastian Bauer¹³, Solange Peters¹⁴, Takekazu Aoyama¹⁵, Mark Semaan¹⁵, Sourav Mukherjee¹⁵, Sonia Dolfi¹⁵, Satyendra Suryawanshi¹⁵, Evan Lipson¹⁶

¹Università degli Studi di Napoli “Federico II“; Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale", Napoli, Italy,²Institut Claudius Requad, Toulouse, France,³Clinica Universidad de Navarra, Madrid, Spain,⁴Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland,⁵Providence Cancer Institute, Earle A. Chiles Research Institute, Portland, OR,⁶Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain,⁷The Royal Marsden Hospital, London, United Kingdom,⁸Institut Gustave Roussy, Villejuif Cedex, France,⁹Dana-Farber Cancer Institute, Boston, MA,¹⁰Memorial Sloan Kettering Cancer Center, New York, NY,¹¹The Norwegian Radium Hospital, Oslo, Norway,¹²Istituto Europeo Di Oncologia, IRCCS; University of Milano, Milan, Italy,¹³Westdeutsches Tumorzentrum, Essen, Germany,¹⁴University Hospital of Lausanne, Lausanne, Switzerland,¹⁵Bristol Myers Squibb, Princeton, NJ,¹⁶The Sidney Kimmel Comprehensive Cancer Center, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, New York, NY

摘要 Abstract

中文摘要

背景：基于RELATIVITY-047的结果，NIVO+RELA已获批用于不可切除或转移性黑色素瘤，剂量为480 mg NIVO+160 mg RELA，每4周一次（Q4W）。RELATIVITY-020（NCT01968109）是一项1/2a期、剂量递增和队列扩增的开放标签研究，考察RELA±NIVO在晚期实体瘤中的应用。A-C部分考察了剂量递增和向实体瘤类型的扩增。方法：肿瘤类型和缩写见表。A部分是在免疫肿瘤学（IO）治疗初治实体瘤患者（pts）中以RELA单药20-800 mg进行的剂量递增分析，并在IO难治（RF）NSCLC和RCC中进行剂量扩增研究（A1）。B部分是NIVO+RELA跨肿瘤类型加宫颈癌、卵巢癌和结直肠癌的剂量递增，从Q2W 80+20至240+240 mg或Q4W 480+160至480+1440 mg。A和B部分的主要终点为安全性。C部分为NIVO+RELA 240+80 Q2W的扩增（膀胱癌为480+160 Q4W）。终点为安全性以及BICR评估的ORR、疾病控制率和缓解持续时间。结果：基线LAG-3表达≥1%在各队列中相当（24-41%）。最短随访（月）为：87-110（A部分）、44（B）和61-84（C）。NIVO+RELA剂量递增显示出可接受的安全性特征，未确定最大耐受剂量（MTD）。3-4级治疗相关不良事件在所有部分中约16%的患者中发生，导致4-11%的患者停药。在C部分测试的所有肿瘤类型中均观察到疗效（见表）。RELA暴露量随剂量成比例增加，无论作为联合还是单药。未发现NIVO与RELA之间的药代动力学相互作用，且RELA和NIVO的抗药抗体和中和抗体发生率均较低。结论：NIVO+RELA在多种不同肿瘤类型中显示出初步疗效。在IO初治和IO RF患者中均观察到临床活性，毒性可耐受。尽管未达到MTD，但PK数据支持NIVO 480+RELA 160 mg剂量。表 MEL初治 n=66 NSCLC初治 n=24 RCC初治 n=26 头颈部初治 n=65 HCC初治 n=63 胃癌初治 n=93 膀胱癌初治 n=36 MEL RF n=150 NSCLC RF n=57 BICR ORR，%（95% CI）47（35-60）29（13-51）15（4-35）15（8-26）16（8-27）9（4-16）31（16-48）11（6-17）5（1-15） mPFS，月（95% CI）11.6（3.7-16.6）7.3（1.8-11.0）3.4（1.6-5.6）3.6（1.9-4.1）3.5（1.9-3.8）1.8（1.7-1.9）3.1（1.8-8.9）2.0（1.9-3.5）3.2（1.8-3.7） 12个月PFS率（95% CI）48（35-60）28（11-47）NA 17（8-27）24（14-36）9（4-16）25（12-41）13（8-20）11（4-21） mOS，月（95% CI）34.6（18.9-NA）16.3（8.6-42.2）17.2（9.0-43.8）12.0（7.2-17.5）10.3（8.3-15.3）6.1（4.9-9.0）12.1（5.8-26.0）14.4（10.5-17.8）11.9（8.6-15.0） 12个月OS率（95% CI）76（63-84）52（31-70）61（39-77）49（36-60）46（33-58）29（20-39）53（35-67）55（47-63）47（34-60） BICR，盲法独立中心评审；CI，置信区间；HCC，肝细胞癌；MEL，黑色素瘤；mo，月；mOS，中位总生存；mPFS，中位无进展生存；NA，不可用；NSCLC，非小细胞肺癌；ORR，客观缓解率；RCC，肾细胞癌；RF，难治。

查看英文原文 English abstract

Background: NIVO + RELA is approved for unresectable or metastatic melanoma at 480 mg NIVO + 160 mg RELA Q4W based on results from RELATIVITY-047. RELATIVITY-020 (NCT01968109) was a phase 1/2a, dose escalation and cohort expansion open-label study investigating RELA +/− NIVO in advanced solid tumors. Parts A-C investigated dose escalation and expansion into solid tumor types. Methods: See Table for tumor types and abbreviations. Part A was a dose escalation analysis in patients (pts) with immuno-oncology (IO) treatment-naive solid tumors with RELA monotherapy at 20-800 mg with dose expansion studies in IO RF NSCLC and RCC (A1). Part B was NIVO + RELA dose‑escalation across tumor types plus cervical, ovarian, and colorectal cancer from Q2W 80 + 20 to 240 + 240 mg or Q4W 480 + 160 to 480 + 1440 mg. Primary endpoint in Parts A and B was safety. Part C was expansion at NIVO + RELA 240 + 80 Q2W (with bladder at 480 + 160 Q4W). Endpoints were safety and BICR‑assessed ORR, disease control rate, and duration of response. Results: Baseline LAG‑3 expression ≥ 1% was comparable across cohorts (24-41%). Minimum follow-up in mo was: 87-110 (Part A), 44 (B), and 61-84 (C). NIVO + RELA dose escalation demonstrated an acceptable safety profile, with no maximum tolerated dose (MTD) identified. Grade 3-4 treatment-related adverse events occurred in approximately 16% of pts across all Parts, leading to discontinuation in 4-11% of pts. Efficacy was noted across all tumor types tested in Part C (Table). RELA exposure increased dose‑proportionally as combination or monotherapy. No pharmacokinetic interaction between NIVO and RELA was identified and there was a low incidence of antidrug and neutralizing antibodies for both RELA and NIVO. Conclusions: NIVO + RELA demonstrated preliminary efficacy across several different tumor types. Clinical activity was observed in both IO naive and IO RF pts, with tolerable toxicity observed. Although no MTD was reached, PK data supported the NIVO 480 + RELA 160 mg dose. Table MEL naive n = 66 NSCLC naive n = 24 RCC naive n = 26 Head/neck naive n = 65 HCC naive n = 63 Gastric naive n = 93 Bladder naive n = 36 MEL RF n = 150 NSCLC RF n = 57 BICR ORR, % (95% CI) 47 (35-60) 29 (13-51) 15 (4-35) 15 (8-26) 16 (8-27) 9 (4-16) 31 (16-48) 11 (6-17) 5 (1-15) mPFS, mo (95% CI) 11.6 (3.7-16.6) 7.3 (1.8-11.0) 3.4 (1.6-5.6) 3.6 (1.9-4.1) 3.5 (1.9-3.8) 1.8 (1.7-1.9) 3.1 (1.8-8.9) 2.0 (1.9-3.5) 3.2 (1.8-3.7) 12-mo PFS rates(95% CI) 48 (35-60) 28 (11-47) NA 17 (8-27) 24 (14-36) 9 (4-16) 25 (12-41) 13 (8-20) 11 (4-21) mOS, mo (95% CI) 34.6 (18.9-NA) 16.3 (8.6-42.2) 17.2 (9.0-43.8) 12.0 (7.2-17.5) 10.3 (8.3-15.3) 6.1 (4.9-9.0) 12.1 (5.8-26.0) 14.4 (10.5-17.8) 11.9 (8.6-15.0) 12-mo OS rates (95% CI) 76 (63-84) 52 (31-70) 61 (39-77) 49 (36-60) 46 (33-58) 29 (20-39) 53 (35-67) 55 (47-63) 47 (34-60) BICR, blinded independent central review; CI, confidence interval; HCC, hepatocellular carcinoma; MEL, melanoma; mo, months; mOS, median overall survival; mPFS, median progression-free survival, NA, not available; NSCLC, non-small cell lung cancer, ORR, objective response rate; RCC, renal cell carcinoma; RF, refractory.

利益披露 Disclosure

P. A. Ascierto, Bristol Myers Squibb Other, consultant/advisory role. Roche-Genentech Other, consultant/advisory role. Merck Sharp & Dohme Other, consultant/advisory role. Novartis Other, consultant/advisory role. Pierre-Fabre Other, consultant/advisory role. Sun Pharma Other, consultant/advisory role. Immunocore Other, consultant/advisory role. Italfarmaco Other, consultant/advisory role. Boehringer Ingelheim Other, consultant/advisory role. Regeneron Other, consultant/advisory role. Pfizer Other, consultant/advisory role. Nouscom Other, consultant/advisory role. Medicenna Other, consultant/advisory role. Bio-Al Health Other, consultant/advisory role. ValoTX Other, consultant/advisory role. Replimmune Other, consultant/advisory role. Erasca Other, consultant/advisory role. Philogen Other, consultant/advisory role. Biontech Other, consultant/advisory role. Anaveon Other, consultant/advisory role. C. Gomez-Roca, Pharma Mar ). Naconics ). Ellipses Pharma ). PSAD ). Roche ). UIR Biotechnology ). IDEAYA ). Amgen ). I. Melero, Bristol Myers Squibb Travel, Other, Grant. Genmab Other, Consulting. Pioneers Other, Consulting. Catalym Other, Consulting. Roche ), Other, Grant. AstraZeneca ), Other, Grant. Mestag Other, Consulting. Bright Peaks Other, Consulting. K. Jalkanen, Orion Pharmaceuticals Other, Advisory fee. MSD Other, Advisory fee. Ipsen Other, Advisory fee. Novartis Other, Advisory fee. Bayer Other, Advisory fee. Incyte Other, Advisory fee. Faron Pharmaceuticals Stock. Curify Labs Stock. R. E. Sanborn, Janssen Oncology/Johnson & Johnson Other, Advisory board. Daiichi Sanko Other, Advisory board. AstraZeneca Other, Advisory board. Nuvation Bio Other, Advisory board. Nuvation Bio Other, Advisory board. GlaxoSmithKline Other, Advisory board. Gilead Other, Advisory board. Summit Therapeutics Other, Advisory board. Curio Science Other, Advisory board. IDEOlogy Health Other, Advisory board. Abbvie Other, Advisory board. OncLive Other, Advisory board. BeiGene/BeiOne Other, Advisory board. Inhibrx Other, Advisory board. Boehringer Ingelheim Other, Advisory board. Targeted Oncology Other, Advisory board. Rigel Therapeutics Other, Advisory board. Pfizer Other, Advisory board. Natera Other, Advisory board. Binaytara Foundation Other, CME presentations. J. Martin-Liberal, Astellas Independent Contractor. Bristol Myers Squibb Independent Contractor. MSD Independent Contractor, Travel. Novartis Independent Contractor. Pierre Fabre Independent Contractor, Travel. Pfizer Independent Contractor. Regeneron Independent Contractor. Roche Independent Contractor. Ipsen Independent Contractor. Sanofi Independent Contractor. Trialing Health Independent Contractor. PharmaMar Independent Contractor. J. Larkin, Eisai Independent Contractor. Novartis Independent Contractor, ). Incyte Independent Contractor. Merck Independent Contractor. Pfizer Independent Contractor, ). Roche Independent Contractor. BMS Independent Contractor, ). Ipsen Independent Contractor. MSD Independent Contractor, ). Achilles Therapeutics ). Nektar Therapeutics ). Immunocore Independent Contractor, ). Aveo ). iOnctura Independent Contractor. GSK Independent Contractor. Pharmacyclics Independent Contractor. AstraZeneca Independent Contractor. eCancer Independent Contractor. Seagen Independent Contractor. Ervaxx Independent Contractor. R. Bahleda, None. F. Hodi, Bristol Myers Squibb Independent Contractor, ). Merck Independent Contractor. Bioentre Independent Contractor. Gossamer Independent Contractor. Iovance Independent Contractor. Catalym Independent Contractor. Immunocore Independent Contractor. Kairos Independent Contractor. Rheos Independent Contractor. Zumutor Independent Contractor. Puretech Independent Contractor. Curis Independent Contractor. Pliant Independent Contractor. Bicara Stock, Stock Option. Apricity Stock. Checkpoint Therapeutics Stock. Corner Therapeutics Stock. Solu Therapeutics Stock. Abalytics Stock Option. Novartis Independent Contractor. M. Callahan, Epitopea Other, SAB member. Bristol Myers Squibb ). AZ-Medimmune Other, DSMB. M. Nykas, BMS Other, Honorarium for lecture. Johnson & Johnson Other, Honorarium for lecture. G. Curigliano, Roche Other, Advisory Board and Expert Talk. AstraZeneca Other, Advisory Board and Expert Talk. Daichii Sankyo Other, Advisory Board and Expert Talk. Pfizer Other, Advisory Board and Expert Talk. Lilly Other, Advisory Board and Expert Talk. Novartis Other, Advisory Board and Expert Talk. Bristol Myers Squibb Other, Advisory Board and Expert Talk. Merck Other, Advisory Board and Expert Talk. Gilead Other, Advisory Board and Expert Talk. Seagen Other, Advisory Board and Expert Talk. Menarini Other, Advisory Board and Expert Talk. S. Bauer, SpringWorks Other, Advisory role, honoraria (CME). Deciphera Other, Advisory role, honoraria (CME). Blueprint Medicine Other, Advisory role, honoraria (CME). IDRX Other, Advisory role, institutional funding for research. Merck Other, Advisory role. Von Pfeffel Pharmaceuticals Travel, Other, Advisory role, research funding (institutional). S. Peters, Amgen Other, Principal investigator in trials (institutional financial support for clinical trials) s. Arcus Other, Principal investigator in trials (institutional financial support for clinical trials). AstraZeneca Other, Principal investigator in trials (institutional financial support for clinical trials). Beigene Other, Principal investigator in trials (institutional financial support for clinical trials). Boehringer Ingelheim Other, Principal investigator in trials (institutional financial support for clinical trials). Bristol Myers Squibb Other, Principal investigator in trials (institutional financial support for clinical trials). Eli Lilly Other, Principal investigator in trials (institutional financial support for clinical trials). GSK Other, Principal investigator in trials (institutional financial support for clinical trials). iTeos Other, Principal investigator in trials (institutional financial support for clinical trials). Merck Sharp and Dohme Other, Principal investigator in trials (institutional financial support for clinical trials). Mirati Other, Principal investigator in trials (institutional financial support for clinical trials). Pharma Mar Other, Principal investigator in trials (institutional financial support for clinical trials). Pfizer Other, Principal investigator in trials (institutional financial support for clinical trials). Promontory Therapeutics Other, Principal investigator in trials (institutional financial support for clinical trials). Roche/Genentech Other, Principal investigator in trials (institutional financial support for clinical trials). Seattle Genetics Other, Principal investigator in trials (institutional financial support for clinical trials). AbbVie Other, Consulting fees. Amgen Other, Consulting fees. Arcus Other, Consulting fees. Bayer Other, Consulting fees. T. Aoyama, Bristol Myers Squibb Employment, Stock, Stock Option, Other, Other financial or non-financial interests. M. Semaan, Bristol Myers Squibb Employment. S. Mukherjee, Bristol Myers Squibb Employment. S. Dolfi, Bristol Myers Squibb Employment, Stock. S. Suryawanshi, Bristol Myers Squibb Employment, Stock. E. Lipson, Bristol Myers Squibb ), Other, Consulting. Haystack ). Merck ). Regeneron ), Other, Consulting. Sanofi, 1104Health ). HUYA Bioscience International Other, Consulting fees. Immunocore, IO Biotech, Sun Pharma, Replimune Other, Consulting. Novartis Other, Consulting fees. OncoSec Other, Consulting fees. Merck KGaA Other, Consulting fees. Bristol Myers Squibb Other, Payment or honoraria. CareDx Other, Participation on a Data Safety Monitoring Board or Advisory Board. Eisai, Genentech Other, Participation on a Data Safety Monitoring Board or Advisory Board. Iovance Stock. Instil Bio Other, Participation on a Data Safety Monitoring Board or Advisory Board. Merck Other, Participation on a Data Safety Monitoring Board or Advisory Board. Natera Other, Participation on a Data Safety Monitoring Board or Advisory Board. Nektar Other, Participation on a Data Safety Monitoring Board or Advisory Board. Pfizer Other, Participation on a Data Safety Monitoring Board or Advisory Board Consulting. Rain Therapeutics Other, Participation on a Data Safety Monitoring Board or Advisory Board.

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