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Contains fulltext : 215810.pdf (Publisher’s version ) (Closed access) BACKGROUND: Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction. PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation. RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2). CONCLUSIONS: : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

Purpose:Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically.Experimental Design:A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping (n = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS).Results:Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion (F11R–NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (P < 0.0001).Conclusions:This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.

Introduction: Multiple primary tumors (MPTs) are defined as two or more separate synchronous or metachronous neoplasms occurring in different sites in the same individual. These tumors differ in histology, as well as primary sites from which they arise. Risk factors associated with the occurrence of MPTs include germline alterations, exposure to prior cancer therapies, occupational hazards, and lifestyle and behavioral influences. Case report: We present a case of a patient who was diagnosed with four metachronous primary tumors. In 2013, she was diagnosed with serous proliferations associated with psammomatous bodies of primary peritoneal origin (pT3NxM0). This was followed by invasive ductal carcinoma of the breast (stage pT2N0Mx, histological grade III/III) in 2014, melanoma (stage pT2bNxMx) in 2016 that further advanced to the lung and brain in 2017, and a low-grade lung carcinoid in 2017. To better understand the biology of this patient's MPTs, we performed next-generation sequencing (NGS) to assess for both somatic and germline alterations. The treatment course for this patient aims to target the tumor with the strongest prognostic value, namely her malignant melanoma, and has contributed favorably to the overall survival of this patient. Conclusion: We report the clinical and genomic landscape of a patient with MPTs who had no identifiable unique somatic or germline mutations to explain her predilection to cancer. The treatment course and overall prognosis for this patient is important for understanding future cases with unrelated, metachronous MPTs, the occurrence of which cannot always be explained by underlying genetic mechanisms. Keywords: Multiple primary tumors, Next-generation sequencing, Tumor mutational burden, Immunotherapy

RET rearrangements are identified in 1% to 2% of non-small-cell lung cancers (NSCLCs).1,2 In patients with advanced, RET-rearranged lung cancers, systemic therapy can be highly active. We demonstrated previously that pemetrexed-based chemotherapy can achieve an objective response rate of 45% and a median progression-free survival (PFS) of 19 months.3 Furthermore, the activity of targeted therapy has improved dramatically with the introduction of selective RET inhibitors to the clinic. In early-phase testing, objective response rates with LOXO-2924 and BLU-6675 are 68% (26 of 38) and 50% (seven of 14), respectively. These outcomes exceed the modest activity observed previously with multikinase inhibitors such as cabozantinib6 and vandetanib.7 In contrast, the activity of immunotherapy in RET-rearranged lung cancers has not been well characterized. This represents a clear unmet need, given that all prior regulatory approvals of immune checkpoint inhibitors, either alone or in combination with chemotherapy, and in stage III or IV disease, have technically included patients with RET-rearranged lung cancers.8,9 Furthermore, although increasing levels of programmed death-ligand 1 (PD-L1) expression and high tumor mutational burden (TMB) have been associated with benefit from immune checkpoint blockade,10 the immunophenotype of RET-rearranged lung cancers and the role of PD-L1 and TMB status in relation to benefit with immunotherapy remain poorly described. We set out to characterize these factors.

Purpose Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. Methods We identified patients who were PD-(L)1–naïve with advanced non–small-cell lung cancer from two institutions—Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center—who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti–PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression. Results Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P < .001). Conclusion Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non–small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended.