Data from the Podium 303 crossover arm shows that giving retafanilumab monotherapy after progression on chemotherapy yields a dismal 5.8% response rate. This confirms that the synergistic effect of combining chemo and immunotherapy upfront is critical and cannot be replicated by sequential treatment.

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.

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.

Genomic profiling reveals PIK3CA is the most frequent mutation in anal cancer, occurring in about one-third of cases. However, unlike in other cancers, there are no effective targeted therapies for this mutation in anal cancer, creating a therapeutic dead-end and a major opportunity for drug development.

For patients with localized (non-metastatic) squamous cell carcinoma of the anal canal, adding systemic chemotherapy before standard chemoradiation does not improve outcomes. Randomized trial data has shown no positive impact from this neoadjuvant approach, reinforcing that concurrent chemoradiation remains the standard of care for curative intent in this setting.

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 HER2-positive colorectal cancer, the choice of targeted therapy depends on RAS mutation status. The tucatinib/trastuzumab combination is effective only in RAS wild-type patients. In contrast, the antibody-drug conjugate trastuzumab deruxtecan (TDXD) shows efficacy regardless of whether a RAS mutation is present.

Unlike immunotherapy, neoadjuvant osimertinib yields poor pathologic complete response (pCR) rates. However, it significantly improves major pathologic response (MPR) and survival, suggesting pCR may be the wrong efficacy endpoint for cytostatic EGFR TKIs, which have a different mechanism of action than immunotherapy.

HER2 amplification is a primary resistance mechanism to anti-EGFR therapies in colorectal cancer. Therefore, oncologists should avoid using drugs like panitumumab or cetuximab in HER2-positive patients, even if they are RAS wild-type, as these patients experience rapid progression on such regimens.