Contrary to its role in lung cancer, PD-L1 expression does not predict benefit from immunotherapy in mesothelioma. Data from major trials shows similar outcomes regardless of PD-L1 status, leading clinicians to omit this test entirely and streamline treatment decisions.

Early Phase 3 trials like JAVELIN adding immunotherapy to chemoradiation failed to improve outcomes. However, subgroup analyses consistently showed a potential benefit in PD-L1 high-expressing patients, a crucial lesson that informed the design of subsequent, more successful studies.

Despite both being keratinocyte-derived skin cancers, basal cell carcinoma (BCC) responds much less robustly to immunotherapy than cutaneous squamous cell carcinoma (CSCC). The pathologic complete response rate to perioperative PD-1 inhibition in BCC is only 23%, less than half the 51% seen in CSCC, highlighting their distinct immunobiology.

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.

Despite major advances in immunotherapy, patient selection remains crude compared to targeted therapies. PD-L1 is still the primary, yet imperfect, biomarker used. Dr. Carbone highlights an urgent need to develop better predictive biomarkers to customize immunotherapy regimens, as is standard for targeted agents.

Nonmelanoma skin cancers' sensitivity to checkpoint inhibitors is due to high tumor mutational burden (TMB) caused by chronic UV light damage. This high TMB creates numerous neoantigens, which the immune system can effectively target once immunotherapy reverses immune suppression.

Despite stratifying patients by PD-L1 status, the AGO-OV-229 trial found it was not a predictive marker. Hazard ratios for survival were similar for both PD-L1 positive and negative tumors, challenging its utility for patient selection.

The high efficacy of checkpoint inhibitors in cutaneous squamous cell carcinoma is enabling a "de-escalation" strategy. Upfront systemic therapy can be so effective that it eliminates the need for subsequent morbid local treatments like extensive surgery or radiation, a major benefit for elderly patients.

An emerging area of research is intralesional immunotherapy, where anti-PD-1 drugs are injected directly into early-stage cutaneous squamous cell carcinomas. This approach may provide effective local control for tumors in anatomically challenging locations while minimizing systemic toxicity.