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Lung cancer is a heterogeneous disease, and the availability of comprehensive genomic profiling has allowed for the characterization of its molecular subtypes. This has increased the ability to deliver “personalized medicines” by tailoring therapies to target driver mutations in a patient's cancer. The development of targeted therapies for non-small cell lung cancer (NSCLC) has helped define the era of precision medicine throughout oncology. This article aims to contextualize recent research and provide an updated summary of targeted therapies available for patients with NSCLC. With practitioners and clinical researchers in mind, we note standard of care therapies, important approvals, practice guidelines, and treatments in development. The first section discusses mutations in the epidermal growth factor receptor (EGFR) gene, and the second section examines rearrangements in the anaplastic lymphoma kinase (ALK) and ROS1 fusions. Finally, we explore the rarer molecular alterations in BRAF, RET, MET, HER2, and KRAS. Given the many available therapies, it is important to understand the molecular alterations in NSCLC, and how to target them.

BACKGROUND: Despite the significant antitumor activity of pembrolizumab in non-small cell lung cancer (NSCLC), clinical benefit has been less frequently observed in patients whose tumors harbor epidermal growth factor receptor (EGFR) mutations compared to EGFR wild-type patients. Our single center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with PD-L1 expression ≥50%. METHODS: We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation positive, advanced NSCLC and PD-L1 positive (≥1%, 22C3 antibody) tumors. Pembrolizumab was administered 200mg q3wks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab. RESULTS: Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. 82% of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD-L1 expression ≥50%. Only 1 patient had an objective response (ORR: 9%), but repeat analysis of this patient’s tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern. CONCLUSIONS: Pembrolizumab’s lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.

We retrospectively analyzed non–small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to Common Terminology Criteria for Adverse Events v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated. Ninety-seven NSCLC patients treated on KEYNOTE-001 at the University of California, Los Angeles were evaluated. Ten percent (85/826) of AEs were trAEs, occurring in 40% (39/97) of patients. The most frequent trAEs were rash (21% patients), fatigue (6% patients), and hypothyroidism (6% patients). The 39 patients that experienced a trAE had increased objective response rate (ORR, 38.5%), progression-free survival (PFS: median, 248 days), and overall survival (OS: median, 493 days), compared with the 58 patients that did not (ORR: 8.9%, PFS: median 60 days, OS: median 144.5 days). The observed association between trAEs and improved clinical outcome persisted when using Cox proportional hazards regression models to assess the confounding effect of covariates and mitigate guarantee-time bias. The association also remained when data were substratified by grade, degree of association, and treatment-related select AE designation. This single-center analysis revealed that trAEs predicted for improved clinical outcome with pembrolizumab, and when controlling for guarantee-time bias and plausible confounders, this association remained. This observed relationship adds to our understanding of anti–PD-1 therapy and could aid clinicians in identifying patients most likely to benefit from therapy. Cancer Immunol Res; 6(3); 288–94. ©2018 AACR.

e20662Background: The 6 FDA drug approvals for non-small cell lung cancer (NSCLC) in 2015 included 2 programmed cell death protein 1 (PD-1) inhibitors and a 3rd generation (gen) epidermal growth fa...

7517 Background: Trials for NSCLC have increasingly targeted specific molecular abnormalities. This approach has led to approval of multiple drugs based on results in specific BioM populations prio...