Efficacy and Safety of Anti–PD-1 Immunotherapy in Patients With Advanced NSCLC With BRAF, HER2, or MET Mutations or RET Translocation: GFPC 01-2018

Abstract

Introduction: Immune-checkpoint inhibitor (ICI) efficacy in patients with NSCLC harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against BRAF-, HER2-, MET-, and RET-NSCLC in a real-world setting.Methods: In this retrospective, multicenter study in ICItreated BRAF-, HER2-, MET-or RET-NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS).Results: There were 107 patients with NSCLC (mean age, 65.5 y) included from 21 centers: 37% were neversmokers, 54% were men, and 93% had adenocarcinoma. Among them, 44 had BRAF mutation (V600: 26), 23 had HER2 mutation, 30 had MET mutation, and nine had RET translocation. Programmed cell death ligand 1 (PD-L1) status was known for 70 patients and was greater than or equal to 1% in 34 patients. Before ICI, patients had received a median of one treatment line. Median duration of response, PFS, and OS were 15.4 (95% confidence interval [CI]: 12.6-not reached [NR]) months, 4.7 (95% CI: 2.3-7.4) months, and 16.2 (95% CI: 12.0-24.0) months, respectively, for the entire cohort. The response rates for BRAF-V600, BRAF-non-V600, HER2, MET, and RET-altered NSCLC were 26%, 35%, 27%, 36%, and 38%, respectively. For patients who were PD-L1 negative and those who were PD-L1 positive, PFS was 3.0 (95% CI: 1.2-NR) and 4.3 (95% CI: 2.1-8.5) months, respectively, and OS was 11.7 (95% CI: 4.1-NR) and 35.8 (95% CI: 9.0-35.2) months, respectively. Toxicities were reported in 28 patients (26%), including 11 patients (10%) with a grade greater than or equal to three. Conclusions:In this real-world setting, ICI efficacy against patients with BRAF-, HER2-, MET-, or RET-NSCLC seemed close to that observed in unselected patients with NSCLC. Large prospective studies on these subsets of patients are needed.

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

“…In the IMMUNOTARGET study, 36 MET -positive NSCLC patients receiving immunotherapy experienced limited activity (ORR 16%) and survival outcomes (mPFS and mOS of 3.4 and 18.4 months, respectively), similar to other analyses [ 34 , 35 ]. However, durable responses were also observed by other studies in the same setting [ 36 , 37 ].…”

RET Rearrangement as a Predictor of Unresponsiveness to Immunotherapy in Non-Small Cell Lung Cancer: Report of Two Cases with Review of the Literature

“…However, it is still unclear whether RET-positive NSCLC is sensitive to ICI treatment. We performed a literature search on this subject and identified three published reports describing the response of RET-positive NSCLC to ICI treatment administered either as monotherapy or as dual combination therapy (Table 1) [9][10][11]. Two of these reports describe very disappointing results for ICI treatment, with responses in only a very few patients.…”

The clinical benefit of molecular re-assessments in management of progressive lung cancer

“…While molecular re-assessment guided selection of targeted second-line treatment has been established for more frequent molecular subtypes of NSCLC (24,25), BRAF-mutated patients progressing on BRAF/MEKinhibition are usually switched to immuno(chemo) therapy (20). This seems reasonable as response rates to immuno(chemo)therapy in BRAF-mutated patients are comparable to the non-mutated situation (26)(27)(28). However, an increase in the frequency of re-biopsies with renewed molecular diagnostic will be necessary to elucidate and potentially target resistance mechanism in this rare mutation subtype.…”