The NCI 9673 trial demonstrated that adding the CTLA-4 inhibitor ipilimumab to the PD-1 inhibitor nivolumab did not improve response rate, PFS, or overall survival in patients with previously treated anal cancer. This finding discourages this combination approach, avoiding unnecessary toxicity.

In the EV+pembrolizumab combination, if a patient achieves an excellent response but develops prohibitive EV-related toxicities like neuropathy, a viable strategy is to discontinue EV and maintain the patient on pembrolizumab monotherapy. This can sustain the response while improving quality of life.

The CheckMate 9LA regimen provides exceptional benefit to PD-L1 negative and squamous histology NSCLC patients. This is significant because these subgroups often respond poorly to other immunotherapy combinations, with Dr. Carbone noting some trials where the control arm outperformed pembrolizumab in these patients.

ITP caused by immune checkpoint inhibitors (ICIs) is rare (0.25% incidence) but generally has a good prognosis. Most patients respond to standard first-line ITP therapies, and approximately 70% of those re-challenged with the ICI can continue treatment without a recurrence of ITP.

Data from the Checkmate 743 trial shows that patients who stopped dual immunotherapy (Nivo/Ipi) due to toxicity can still achieve long-term benefits. A third of these patients had an ongoing response at three years, despite stopping treatment after only four months on average, providing confidence in the regimen.

The study utilized "interruption-free survival" as a primary endpoint, a pragmatic measure derived from real-world data. This serves as a valuable surrogate for treatment toxicity, as clinicians typically pause treatment in response to adverse events, providing a quantifiable measure of a drug's real-world tolerability.

While the feared side effect of severe lung inflammation (pneumonitis) did not increase, other immune-mediated adverse events did. This led to higher rates of treatment discontinuation in the experimental arm, potentially negating any benefits of the concurrent approach and contributing to the trial's failure.

The next frontier in CSCC isn't just about new drugs, but about optimizing existing ones. A key research area is determining the minimum number of immunotherapy doses required for an optimal response—potentially just one or two—to limit toxicity, reduce treatment burden, and personalize care for high-risk patients.

In solid tumor immunotherapy, significant efficacy gains almost always correlate with increased toxicity. This study's claim of nearly doubled progression-free survival with identical toxicity rates is biologically implausible and was a primary reason for skepticism, even before analyzing the trial's methodology.