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For cancers with mutations like BRAF or MET, where both immunotherapy and targeted therapy are viable options, smoking history can guide treatment sequencing. A heavy smoking history suggests immunotherapy may be more effective upfront, whereas targeted therapy might be preferred first for non-smokers due to differences in tumor immunogenicity.
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For never-smokers with HER2 mutations, immunotherapy is largely ineffective and risks severe immune-related adverse events when the patient is later switched to the correct TKI. This paradigm mirrors the approach for EGFR and ALK mutations, where targeted therapy is the standard upfront, even with high PD-L1 expression.
Comprehensive molecular testing (PD-L1, EGFR, ALK) is no longer reserved for advanced disease. It is now critical for all patients with stage 1B or higher resectable NSCLC *before* starting any treatment to guide neoadjuvant and adjuvant therapy decisions.
As multiple new drugs like antibody-drug conjugates (ADCs) become available for SCLC, the critical research question will shift from *if* they work to *when* they should be used. Future biomarker strategies must focus on optimizing treatment sequences, considering factors like the drug's target and payload.
When a lung cancer patient is too symptomatic to wait for genomic testing results, the expert consensus is to initiate treatment with chemotherapy alone. Adding immunotherapy upfront is ill-advised, as its use in EGFR-mutated patients (a common finding) can be detrimental.
Contrary to the standard 'TKI-first' approach for driver mutations, a study in MET exon 14 skipping NSCLC suggests a different strategy. Patients with high PD-L1 expression appeared to have better outcomes with first-line chemoimmunotherapy, reserving the targeted therapy for later. This challenges the conventional wisdom of prioritizing the driver mutation over immunotherapy biomarkers in this specific subgroup.
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.
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.
For de novo metastatic, PD-L1 positive TNBC patients with a BRCA mutation, experts prefer an ADC with immunotherapy over a PARP inhibitor. This choice is driven by the potential for longer-lasting responses with the ADC/IO combination, even though PARP inhibitors directly target the underlying genetic mutation.
Frontline treatment selection hinges on histology. Non-epithelioid mesothelioma responds poorly to chemotherapy, making dual immunotherapy (Nivo/Ipi) the clear choice. For epithelioid cases, chemo-immunotherapy is a strong option, especially for symptomatic patients, due to its higher and faster response rate.
For patients with actionable mutations like EGFR or ALK, targeted therapy is the priority, regardless of PD-L1 score. Starting immunotherapy first in these patients can significantly increase the risk of developing severe pneumonitis (ILD) when they later switch to targeted therapy like osimertinib.