Interleukin-6 receptor blockade with tocilizumab to reduce immune-related toxicity with ipilimumab and nivolumab in metastatic melanoma.
Jeffrey S. Weber, Amrutesh S. Puranik, Teruyuki Mitzutani, Tomoaki Muramatsu, Judith D. Goldberg, Janice M. Mehnert, Xiaochun Li, Benjamin Levinson, Omid Hamid, Inderjit Mehmi, Mark B. Faries, F. Stephen Hodi, Elizabeth I. Buchbinder, Patrick A. Ott, Sofia Bajwa, Perla Arriola, Naika Legros, Ryan J. Sullivan
Abstract
9538 Background: Interleukin-6(IL-6) blockade has reversed steroid-refractory immune-related toxicity in patients receiving immune checkpoint blockade (ICB). IL-6 and its downstream acute phase reactants are also associated with short survival and therapeutic resistance in patients receiving single agent or combination ICB. We undertook a phase II trial of IPI, NIVO and the IL-6 receptor blocking antibody tocilizumab (TOCI) in unresectable melanoma. Methods: In a phase II, Simon-design two-stage trial, 70 patients with untreated metastatic melanoma received IPI at 1 mg/kg and NIVO at 3 mg/kg for 4 induction doses to week 12, and TOCI at 4 mg/kg every 6 weeks up to week 24. Maintenance NIVO was administered at 240 mg intravenously (IV) from weeks 12 to 24, then at a dose of 480 mg IV every 4 weeks for up to 2 years of treatment. To proceed past the first stage of 18 patients, 12/18 RECIST responses or more and/or a grade 3-5 treatment related immune-related adverse event (irAE) rate of ≤5/18 were required. Those criteria were both fulfilled, and in the second stage 49 patients were treated, with 3 additional patients accrued. Serum and peripheral blood samples were collected for biomarker assays at baseline and week 7. Results: There were 40/70 RECIST responders with a 57% best overall response rate (BORR), (exact 95% confidence interval (CI) of 44-68%) of partial response (PR) or complete response (CR); 6 patients had stable disease (SD), 24 with progression, at a median of 2.4 years of follow-up. A total of 46 patients had clinical benefit (CR+PR+SD) = 65% (exact 95% CI 37-81%). Median progression-free survival was 13 months. The expected BORR was 47% in the randomized Checkmate-511 trial at the same doses of IPI/NIVO. There have been 16 cases of grades 3-4 irAE including 3 episodes of colitis for a total of 16/71 patients eligible for toxicity = 22% (exact 95% CI: 12-31%), all grade 3/4; the expected rate of grades 3-5 TRAEs was 34% per Checkmate-511. The rate of irAE leading to discontinuation was 14%; it was 25% for CheckMate 511. Twenty-one deaths (30%) occurred, all due to progression. All grade 3-4 irAES were reversible and no grade 5 toxicity was seen. Osteopontin + IL6 + CD45RA neg classical monocytes were associated with response, and higher levels of naive CD8 T cells were associated with progression. CD16 + CD56 + CD57 + mature natural killer cells were significantly lower in patients with grade 3-4 immune-related toxicity. Conclusions: Prophylactic TOCI resulted in a low rate of grade 3-4 irAEs by week 24 in patients with stage IV melanoma receiving induction IPI 1 mg/kg and NIVO 3 mg/kg while maintaining a favorable overall response rate and survival. Novel biomarkers of response and toxicity including NK cells and monocytes as well as naïve and effector memory CD8 T cells were defined by high-resolution flow cytometry. Additional correlative data will be presented. Clinical trial information: NCT03999749 .