Interleukin-6 receptor blockade with tocilizumab to reduce immune-related toxicity with ipilimumab and nivolumab in metastatic melanoma.
Authors: Weber Jeffrey S. , Puranik Amrutesh , Mitzutani Teruyuki , Muramatsu Tomoaki , Goldberg Judith D. , Mehnert Janice M. , Li Xiaochun , Levinson Benjamin A. , Hamid Omid , Mehmi Inderjit , Faries Mark B , Hodi F. Stephen , Buchbinder Elizabeth Iannotti , Ott Patrick Alexander , Bajwa Sofia , Arriola Perla , Legros Naika , Sullivan Ryan J. 
Published: July 2024

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+CD45RAnegclassical 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 .