PURPOSE: The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non-small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease. EXPERIMENTAL DESIGN: To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with ligand programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (<10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB). RESULTS: In low TMB cases, STK11/KEAP1/EGFR alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one STK11/KEAP1/EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival. CONCLUSIONS: The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1, and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in context, the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.

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Genomic profiling is critical for the identification of treatment options for patients with metastatic cancer, but it remains unclear how frequently this procedure should be repeated during the course of the disease. To address this, we analyzed whole-genome sequencing (WGS) data of 250 biopsy pairs, longitudinally collected over the treatment course of 231 adult patients with a representative variety of metastatic solid malignancies. Within the biopsy interval (median, 6.4 months), patients received one or multiple lines of (mostly) standard-of-care (SOC) treatments, with all major treatment modalities being broadly represented. SOC biomarkers and biomarkers for clinical trial enrollment could be identified in 23% and 72% of biopsies, respectively. For SOC genomic biomarkers, we observed full concordance between the first and the second biopsy in 99% of pairs. Of the 219 biomarkers for clinical trial enrollment that were identified in the first biopsies, we recovered 94% in the follow-up biopsies. Furthermore, a second WGS analysis did not identify additional biomarkers for clinical trial enrollment in 91% of patients. More-frequent genomic evolution was observed when considering specific genes targeted by small-molecule inhibitors or hormonal therapies (21% and 22% of cases, respectively). Together, our data demonstrate that there is limited evolution of the actionable genome of treated metastases. A single WGS analysis of a metastatic biopsy is generally sufficient to identify SOC genomic biomarkers and to identify investigational treatment opportunities.

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Non-small cell lung cancer (NSCLC) survival is compared between patients treated in all academic (n = 1289) versus all non-academic (n = 12,698) Dutch hospitals, using Kaplan-Meier estimates and a Cox proportional hazards model. For 1009 patients, treatment patterns are described. Diagnosis in an academic hospital is associated with decreased mortality. Possibilities for improvement of NSCLC care are suggested. Background The aims of this study are to analyze differences in survival between academic and non-academic hospitals and to provide insight into treatment patterns for non-small cell lung cancer (NSCLC). Results show the state of NSCLC survival and care in the Netherlands. Methods The Netherlands Cancer Registry provided data on NSCLC survival for all Dutch hospitals. We used the Kaplan-Meier estimate to calculate median survival time by hospital type and a Cox proportional hazards model to estimate the relative risk of mortality (expressed as hazard ratios) for patients diagnosed in academic versus non-academic hospitals, with adjustment for age, gender, and tumor histology, and stratifying for disease stage. Data on treatment patterns in Dutch hospitals was obtained from 4 hospitals (2 academic, 2 non-academic). A random sample of patients diagnosed with NSCLC from January 2009 until January 2011 was identified through hospital databases. Data was obtained on patient characteristics, tumor characteristics, and treatments. Results The Cox proportional hazards model shows a significantly decreased hazard ratio of mortality for patients diagnosed in academic hospitals, as opposed to patients diagnosed in non-academic hospitals. This is specifically true for primary radiotherapy patients and patients who receive systemic treatment for non-metastasized NSCLC. Conclusion Patients diagnosed in academic hospitals have better median overall survival than patients diagnosed in non-academic hospitals, especially for patients treated with radiotherapy, systemic treatment, or combinations. This difference may be caused by residual confounding since the estimates were not adjusted for performance status. A wide variety of surgical, radiotherapeutic, and systemic treatments is prescribed.@en