Lessons Learned from Anti-CTLA-4 and Anti-PD-1 Combination
Mario Sznol, MD Yale Comprehensive Cancer Center, New Haven, CT
Clinical development of anti-CTLA-4 and anti-PD-1 combinations began in December, 2009, with an initial phase 1 trial in metastatic melanoma. Observed toxicity of the combination was greater than expected for either agent alone and was more than additive. Determination of dose-limiting toxicity and maximum tolerated dose was complicated by the nature of immune-related adverse events, which are reversible with steroids or secondary immune suppressive agents. Determination of an optimal dose and schedule to maximize anti-tumor effects and minimize toxicity was also confounded by inadequate understanding of proximal and distal immunologic effects which correlate best with patient benefit. Nevertheless, the combination produces immunologic changes distinct from either single agent. Although activity as measured by response rate and progression-free survival was greater than either single agent in a phase 3 metastatic melanoma trial, in exploratory analyses, statistically significant survival differences between the combination and anti-PD-1 alone were not observed with follow-up of at least 3 years in all study entrants. Biomarkers to select patients most likely to benefit from adding anti-CTLA-4 to anti-PD-1 remain sub-optimal, and preliminary data suggest differences between diseases; for example, in melanoma, PD-L1 negative patients appear to benefit most the combination, whereas PD-L1+ patients appear to derive greatest benefit in non-small cell lung cancer (possibly limited to high tumor mutation burden in NSCLC) and metastatic renal cancer. The efficacy of concurrent versus sequential administration remains unanswered. In vivo baseline features of the tumor microenvironment and host-tumor interactions, and adaptive changes post-treatment, mediating resistance remain undefined. Mechanisms of toxicity also remain unknown, although recent data implicate a role for B-cell subsets in mediating toxicity.
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