An exploratory study of nivolumab (nivo) with or without ipilimumab (ipi) according to the percentage of tumoral CD8 cells in advanced metastatic cancer.
Authors: Tsimberidou Apostolia Maria , Drakaki Alexandra , Khalil Danny , Kummar Shivaani , Hodi F. Stephen , Oh David Yoonsuk , Cabanski Christopher R. , Tezlaff Michael , LaVallee Theresa , Spasic Marko , Nissola Leo , Kitch Lacey J. , Bayless Nicholas L. , Selinsky Cheryl , Ayran Jennifer C , O'Donnell-Tormey Jill , Hubbard-Lucey Vanessa M. , Dugan Ute , Allison James Patrick , Sharma Padmanee 
Published: June 2021

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Background: Immune checkpoint inhibitors (ICIs) have demonstrated durable clinical responses and improved survival in patients (pts) across numerous indications. Despite this progress, the benefit of ICIs is limited to a minority of overall metastatic cancer patients. There is a critical need for biomarkers agnostic of tumor type to inform which pts will benefit from nivo alone versus ipi/nivo combination treatment. Both pre-treatment tumoral CD8 + cells and recruitment of CD8+ T cells in response to ICIs are associated with improved clinical outcomes in patients treated with anti-PD-1 therapy. 1,2,3,4 Here we report the final results of a prospective clinical study in which pts with varying advanced solid tumors were assigned to nivo, with or without ipi, based on the percentage of tumoral CD8 cells at the time of treatment. Methods: We performed a prospective, non-randomized, open-label, multicenter study in which pts with tumoral CD8+ cells ≥ 15% (CD8+ high) received nivo 360mg IV Q3W, followed by nivo maintenance 480mg Q4W. Pts with tumoral CD8+ cells < 15% (CD8+ low) received nivo 360 mg IV Q3W, and ipi at 1 mg/kg IV Q3W for 2 doses and then Q6W for 2 doses, followed by nivo maintenance 480 mg IV Q4W until PD or intolerable toxicity. Primary endpoints were Disease Control Rate (DCR: CR, PR, or SD ≥ 6 months) and CD8 low to high conversion (< 15% to ≥ 15%). Baseline and on-treatment tumor, blood and stool samples were collected for multiomic biomarker analyses. This study was not powered for formal statistical analysis. Up to 200 pts could be enrolled to allow for adaptive exploration of response and CD8 changes. Results: N = 79 pts were enrolled:7 in CD8+ high arm (nivo) and 72 in CD8+ low arm (ipi/nivo). The study enrolled a wide variety of primary solid tumors; the most common were gynecological (n = 15), prostate (12), and head and neck (7). DCR was 14% (1/7; 95% CI 1 - 44) and 24% (17/72; 95% CI 15 - 34) in the CD8 high and CD8 low arms, respectively. Of 39 pts in CD8 low arm with an on-treatment biopsy, 14 (36%; 95% CI 22 - 51) had CD8 conversion; 7/14 pts (50%) who converted had DCR. Immune-related AEs (irAEs) were consistent with known safety profile of both drugs. Conclusions: Ipi/nivo demonstrated clinical responses and increased CD8% in a range of “cold” tumors with low tumoral CD8 cells. There may be an association between increasing CD8% and response. Baseline high CD8% alone does not appear to be sufficient as a pan-cancer predictive biomarker of response to nivo monotherapy. CD8 conversion, response, and irAEs associated with circulating and stool-based biomarkers are under evaluation as composite biomarkers may improve their predictive value. Clinical trial information: 03651271.