We would like to thank Montfort and colleagues for their correspondence (Montfort, A. et al. Combining TNF blockade with immune checkpoint inhibitors in patients with cancer. Nat. Rev. Rheumatol. https://doi.org/10.1038/s41584-021-00653-8 (2021))1 on our Review (Chen, A. Y., Wolchok, J. D. & Bass, A. R. TNF in the era of immune checkpoint inhibitors: friend or foe? Nat. Rev. Rheumatol. 17, 213–223 (2021))2.
We appreciate their highlighting early results of TICIMEL, an open-label phase Ib two-arm study of 14 patients that combined one of two TNF inhibitors, certolizumab or infliximab, with two immune checkpoint inhibitors (ICIs), ipilimumab and nivolumab, for the treatment of melanoma3. This study was published after our manuscript was submitted to reviewers.
The finding in TICIMEL that all seven evaluable patients treated with certolizumab plus ICI therapy achieved an objective response3 is tantalizing, but the numbers are too small to compare to historical cohorts of patients not treated with a TNF inhibitor. In addition, given that certolizumab and infliximab are both biologic drugs that target TNF (the two drugs differ in that certolizimab is a PEGylated, Fc-free monovalent antibody), how to evaluate the two arms individually is challenging.
An unexpected finding was the high rate of grade 3 or 4 immune-related adverse events (irAEs) in patients in the TICIMEL trial, despite concomitant TNF inhibitor treatment (75% in the certolizumab arm and 50% in the infliximab arm)3. The rate of high-grade irAEs was similar to that in CheckMate 067, a large melanoma trial that also used combination ICI therapy in which 59% of patients experienced high grade irAEs4. This finding suggests that in TICIMEL, TNF inhibition might not have lessened the rate of adverse events. As with the efficacy analysis, however, the small number of enrolled patients in TICIMEL precludes firm conclusions about toxicity. We look forward to future results, after additional patients have been enrolled in TICIMEL, and congratulate the authors on performing this important study.
References
Montfort, A. et al. Combining TNF blockade with immune checkpoint inhibitors in patients with cancer. Nat. Rev. Rheumatol. https://doi.org/10.1038/s41584-021-00653-8 (2021).
Chen, A. Y., Wolchok, J. D. & Bass, A. R. TNF in the era of immune checkpoint inhibitors: friend or foe? Nat. Rev. Rheumatol. 17, 213–223 (2021).
Montfort, A. et al. Combining nivolumab and ipilimumab with infliximab or certolizumab in patients with advanced melanoma: first results of a phase Ib clinical trial. Clin. Cancer Res. 27, 1037–1047 (2021).
Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019).
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J.D.W. is a consultant for Adaptive Biotech, Amgen, Apricity, Arsenal, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F Star, Imvaq, Kyowa Hakko Kirin, Merck, Neon Therapeutics, Psioxus, Recepta, Sellas, Serametrix, Surface Oncology, Syndax and Syntalogic, Takara Bio, Trieza and Truvax; receives research support from AstraZeneca, Bristol Myers Squibb and Sephora; and has equity in Adaptive Biotechnologies, Apricity, Arsenal, BeiGene, Imvaq, Linnaeus, Tizona Pharmaceuticals. The other authors declare no competing interests.
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Chen, A.Y., Wolchok, J.D. & Bass, A.R. Reply to: Combining TNF blockade with immune checkpoint inhibitors in patients with cancer. Nat Rev Rheumatol 17, 577–578 (2021). https://doi.org/10.1038/s41584-021-00654-7
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DOI: https://doi.org/10.1038/s41584-021-00654-7
