Abstract 489: Association between immune-mediated adverse events and survival in patients with metastatic non-small cell lung cancer treated with durvalumab and tremelimumab
Authors: Dey Agnish , Austin Matthew , Kluger Harriet , Trunova Nataliya , Mann Helen , Shire Norah , Zhou Diansong , Mugundu Ganesh 
Published: July 2021

Background: The association between immune-mediated adverse events (imAEs) occurring after treatment with immunotherapy and patient outcomes is an important clinical question with prognostic relevance. When toxicity arises from anti-PD1/PD-L1, either alone or in combination with anti-CTLA-4 therapy, the immune system activation and auto-reactivity may also be reflective of an anti-tumor response. In this analysis, data from the MYSTIC clinical trial (NCT02453282) are used to evaluate whether there is an association between imAEs and efficacy in patients receiving anti-PD-L1 therapy alone or in combination with anti-CTLA-4.

Methods: MYSTIC is a phase 3, randomized, open-label, multicenter, global study of first-line durvalumab as monotherapy or in combination with tremelimumab versus chemotherapy in patients with metastatic NSCLC. Individual patient-level data from 902 patients who participated in the trial were used in the analysis (307 in the monotherapy arm, 310 in the combination arm and 285 in the chemotherapy arm). imAE development was observed in 221 patients (84 in the monotherapy arm, 131 in the combination arm and 6 in the chemotherapy arm). Since imAEs were observed in only 6 out of 285 patients in the chemotherapy arm, the chemotherapy arm was not used in our analysis. Survival analysis (univariate and multivariate) was performed to assess the relationship between imAE development and patient outcomes.

Results: Significant improvement in overall survival (OS) was observed in patients with any-grade imAEs compared to patients without imAEs, irrespective of their PD-L1 levels: HR 0.44 (95% CI 0.31-0.61) in the durvalumab monotherapy arm and HR 0.52 (95% CI 0.40-0.68) in the durvalumab + tremelimumab combination arm. After adjusting for confounders in multivariate analysis, significant OS benefit was seen in patients with imAEs in both IO arms: HR 0.49 (95% CI 0.35-0.69) in the monotherapy arm and HR 0.49 (95% CI 0.38-0.64) in the combination therapy arm. For patients with an early onset of imAE (within the first 3 months of treatment), significantly longer OS was observed in those who were able to continue with IO treatment after imAE occurrence compared to those who had to drop out: HR 0.36 (95% CI 0.09-0.39) in the monotherapy arm and HR 0.34 (95% CI 0.21-0.55) in the combination therapy arm. Similar trends were also observed for progression-free survival. High-grade (grade ≥3) imAEs were observed in very few patients in both IO arms, and no significant difference in patient outcome was observed when survival analysis was conducted taking severity of imAEs into account. Higher odds of imAE development was seen (odds ratio 3.02 [95% CI 1.56-5.83]) in RECIST responders compared to non-responders.

Conclusion: In this retrospective analysis, a strong association was identified between imAE development and favorable efficacy outcome.

Citation Format: Agnish Dey, Matthew Austin, Harriet Kluger, Nataliya Trunova, Helen Mann, Norah Shire, Diansong Zhou, Ganesh Mugundu. Association between immune-mediated adverse events and survival in patients with metastatic non-small cell lung cancer treated with durvalumab and tremelimumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 489.