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.

Real-world data suggests that using one antibody-drug conjugate (ADC) immediately after another is often ineffective. A potential strategy to overcome this resistance is to administer a different class of chemotherapy before starting the second ADC.

Data from the Podium-303 trial's crossover arm suggests that waiting to use a PD-1 inhibitor after progression on chemotherapy is less effective than using it concurrently from the start. This supports the synergistic effect of chemo-immunotherapy and favors the concurrent approach as the standard of care.

The Podium 303 study's design allowed placebo patients to receive retafanilumab upon progression. This crossover contaminated the control arm, likely diluting the true overall survival benefit and making the first-line combination therapy appear less statistically significant than it actually is.

For endometrial or cervical cancer patients who progress after receiving a checkpoint inhibitor, re-challenging with a single-agent immunotherapy is a less desirable approach. Emerging data suggests that a combination therapy—such as an ICI paired with a TKI like lenvatinib or a bispecific antibody—offers a more promising chance of response.

A PD-L1 CPS score of zero should not automatically disqualify patients with metastatic anal cancer from receiving immunotherapy. The clinical distinction between a CPS of zero and one is marginal, and given the therapy's potential for benefit and low toxicity, clinicians should give patients the benefit of the doubt and offer the treatment.

In the Podium-303 trial, adding retifanlimab to chemotherapy improved the overall response rate by 11%. However, its most significant impact was doubling the median duration of response from 7.2 to 14 months, providing a much more durable benefit for patients after chemotherapy is stopped.

The Podium 303 regimen provides a clear 'maintenance' phase with retafanilumab. This solves the clinically and psychologically difficult conversation of stopping all treatment after six months of chemotherapy, which was the previous standard and often unsettling for American patients.

A common clinical pitfall is treating RAS/BRAF wild-type anal cancer with anti-EGFR antibodies, extrapolating from rectal adenocarcinoma protocols. Retrospective data shows this approach has only modest efficacy (4-5 month PFS) and is not a recommended strategy, highlighting a key difference between the two diseases.