In Reply We appreciate the interest in our article1 by Skelin and Lucijanić. We completely agree that immortal time bias is present in any analysis that studies the association between response and toxic effects because patients who remain on therapy for a longer duration are both more likely to receive benefits from therapy (hence the rationale to continue) and are at greater risk of developing later onset toxic effects (owing to longer duration of therapy exposure). For this reason, to at least partially mitigate this concern, we separated patients who developed early vs late cutaneous toxic effects (≤3 months vs >3 months). We chose this cutoff for 2 reasons: (1) early progression is common at the 3-month time point (with approximately 40% of patients progressing in clinical trials by this point)2 and (2) the median onset of cutaneous toxic effects in clinical trials is well before 3 months (5 weeks in 1 analysis).3 Thus, even most early progressors would have had time to develop early toxic effects. We noted that early toxic effects remained associated with superior outcomes, although the effect was modest. On the other hand, late toxic effects were strongly associated with improved outcomes, thus completely agreeing with the authors’ supposition, as well as our brief discussion in the research letter.
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Johnson DB, Ye F, Dewan AK. Longer Survival With Anti–Programmed Cell Death 1 and Development of Cutaneous Toxic Effects, an Expected Association—In Reply. JAMA Oncol. 2019;5(11):1642–1643. doi:10.1001/jamaoncol.2019.3817
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