Phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: adrenocortical carcinoma cohort.

Multiple common cancers benefit from immunotherapy; however, less is known about efficacy in rare tumors. We report the results of the adrenocortical carcinoma cohort of NCI/SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors. A prospective, phase 2 clinical trial of ipilimumab plus nivolumab was conducted by the SWOG Early Therapeutics and Rare Cancers Committee for multiple rare tumor cohorts across >1,000 National Clinical Trial Network sites. 21 eligible patients were registered. Median age was 53 years (range 26-69); 16 (76%) were women. Ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks was administered until disease progression, symptomatic deterioration, treatment delay for any reason >56 days, unacceptable or immune-related toxicity with inability to decrease prednisone to <10 mg daily, or per patient request. The primary endpoint was the overall response rate (ORR) (RECIST V.1.1). Secondary endpoints include clinical benefit rate (CBR) (includes stable disease (SD)>6 months), progression-free survival (PFS), overall survival (OS), and toxicity. Immune-related outcomes included immune ORR (iORR), immune CBR (iCBR), and immune PFS (iPFS). A two-stage design was used assuming: null=5% alternative=30%, n=6 in the first stage, 16 max, one-sided alpha=13%. The median number of prior therapy lines was 2 (range: 1-9). 3 of 21 patients attained confirmed partial response (PR) (ORR=14%). In addition, one patient had an unconfirmed PR; one, stable disease (SD)>6 months; one, immune-related RECIST (iRECIST) PR (iPR); and one patient attained iSD>6 months: clinical benefit rate (response or SD>6 months)=5/21 (24%), iORR=4/21 (19%), iCBR=7/21 (33%). The 6-month PFS was 24%; 6-month iPFS, 33%. The PFS for patients (N=7) with iRECIST clinical benefit were 57, 52, 18, 15, 13, 7, and 7 months. The 6-month OS was 76%; the median OS, was 15.8 months. The most common toxicities were fatigue (62%) and rash (38%), and the most common grade 3/4 immune-related adverse events were hepatic dysfunction (9.5%) and adrenal insufficiency (9.5%). Treatment-related adverse events leading to discontinuation of therapy in four patients (21%). There were no grade 5 adverse events. Ipilimumab plus nivolumab is active in refractory metastatic adrenocortical cancer meeting the primary endpoint of the study, with a 19% iORR and 33% iCBR (includes SD/iSD>6 months) and with the longest PFS/iPFS of 52 and 57 months. NCT02834013 (registered 15 July, 2016; https://clinicaltrials.gov/ct2/show/NCT02834013).

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Competing interests: RK has had received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance and from the NCI; as well as consultant and/or speaker fees and/or advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi, EISAI, EOM Pharmaceuticals, Iylon, LabCorp, Merck, NeoGenomics, Neomed, Pfizer, Precirix, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch Inc. and IDbyDNA; serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. SP reports grants from Bristol-Myers Squibb, personal fees from Bristol-Myers Squibb, during the conduct of the study; grants from Eli Lilly, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery. Fate Therapeutics, Genocea, Iovance, personal fees from AstraZeneca, Illumina, Tempus, Novartis, outside the submitted work. YKC reports research grants from AbbVie, BMS, Biodesix, Lexent Bio, Freenome; Honoraria/Advisory Boards from Roche/Genentech, AstraZeneca, Foundation Medicine, Counsyl, Guardant Health, Boehringher Ingelheim, Biodesix, Immuneoncia, Lilly Oncology, Merck, and Takeda. ES previously was a full-time employee of the National Cancer Institute (NCI), an arm of the United States government. The NCI negotiated a collaborative research and development agreement (CRADA) with Bristol-Myers Squibb to provide nivolumab and ipilimumab for this clinical trial. MO: Consulting: Merck, Biosight; Data safety monitoring board: Glycomimetics, Grifols, BMS (Celgene). CB, HXC, HS, CM, and GL have no COI disclosures to report. TH: did not respond; assume none to report. BT: research grants from the following: AbbVie, Adaptimmune, Agios, AstraZeneca, Bristol Myers, Exelexis, Eisai, Merck Serono, Roche/Genentech, Tvradi. TK: Data monitoring committees-Merck/Bristol Meyers Squibb/SeaGen/Fidid/Engene; Ad Brds-Cardinal Health, Tempus; Royalties-UpToDate; Clinical Trial Grants-Ultimovacs, SeaGen, Bristol Myers Sqjibb, Eisai. CWR: Expert witness for GSK, Pfizer, Boehringer Ingelheim; Research Funding to Institution: Ayala, xynomic, bayer, osi, PF Argentum IP Holidngs llc, rain therapeutics, shasqi, PTC therapeutics, Nikang, merck, nektar, pfizer, karyopharm, Bristol-Meyer Squibb, Daiichi-Sankyo, Deciphera, Exelixis, Genentech, Novartis, MerckNektar, Pfizer, Xynomic, Bayer.