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.

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.

The failure of the concurrent chemo-immuno-radiation approach has not stalled progress. Instead, new clinical trials are actively exploring novel strategies like SBRT boosts, dual checkpoint inhibitors, radiosensitizing nanoparticles, and induction immunotherapy to improve upon the current standard of care.

Unlike rare biomarkers that necessitate a 'test-and-wait' approach, IB6 is expressed in over 80-90% of NSCLC tumors. This ubiquity could make pre-screening unnecessary for drugs like Sigvotatug Vedotin, allowing clinicians to initiate targeted therapy much faster and for a broader patient population.

Dr. Carbone argues that traditional metrics like median survival or response rate are less relevant for immunotherapies. The true measure of success is the percentage of patients alive at five or six years—the "tail of the curve"—as this indicates a durable, potentially curative, response.

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.

Despite billions invested over 20 years in targeted and genome-based therapies, the real-world benefit to cancer patients has been minimal, helping only a small fraction of the population. This highlights a profound gap and the urgent need for new paradigms like functional precision oncology.

The success of perioperative osimertinib means oncologists cannot choose the optimal strategy (targeted therapy vs. chemoimmunotherapy) for resectable lung cancer without first knowing the patient's EGFR, ALK, and PD-L1 status. This elevates biomarker profiling from a metastatic-setting tool to a critical first step in early-stage disease.

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.