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.

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.

In the SPOTLIGHT trial, adding zolbituximab to FOLFOX for Claudin-18.2 positive patients improved progression-free and overall survival. However, it did not significantly increase the objective response rate, demonstrating that survival benefit can be decoupled from tumor shrinkage metrics.

While neoadjuvant-only immunotherapy has a strong rationale, a patient-level cross-trial comparison of CheckMate 816 (neoadjuvant) and 770T (perioperative) suggests the addition of adjuvant therapy improves event-free survival, favoring a full perioperative approach.

Data from the ADRIATIC trial surprisingly suggests the survival benefit of consolidation Durvalumab was more pronounced in patients receiving carboplatin versus cisplatin. This finding reassures clinicians about using the better-tolerated carboplatin in combination with chemoradiation for limited-stage small cell lung cancer, challenging the traditional preference for cisplatin.

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.

Despite being the backbone for new combination therapies in trials like Matterhorn, the FLOT chemotherapy regimen has significant toxicity. Approximately 30% of patients discontinue treatment due to adverse events, and only half manage to complete the post-surgery adjuvant portion, posing a major clinical challenge in real-world settings.

Comparing control arms from the TOGA (11 months OS), KEYNOTE-811 (16 months), and HORIZON (19 months) trials reveals a steady improvement in patient outcomes. This trend, likely due to better second-line therapies and supportive care, makes it harder for new agents to show a relative benefit.

In the increasingly common scenario of a patient with multiple positive biomarkers, a clear hierarchy exists for treatment decisions. Based on the robustness and maturity of clinical trial data, HER2-directed therapy is the top priority, followed by PD-L1 immunotherapy, with Claudin-18.2 targeting considered third.