Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry

Abstract

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 th...

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study

“…Importantly, our DCR of ICIs is superior to that presented before (60% vs. 25%), while PD-L1 expression is similar [17,42]. Although patients with selected druggable tumor alterations were considered as poor candidates for ICIs (for example, EGFR-mutant and ALKrearranged lung cancers), and diverse efficacy of ICIs in RET-positive patients was reported in previous studies [16], a subgroup of patients exists who can benefit from ICIs as shown in our study.…”

“…The median progression-free survival (PFS) of the pemetrexed/platinum regimen was 19 months, 7.5 months, and 6.4 months in a single center [15], a Chinese cohort [5], and an international cohort [10], respectively. Although ICIs have been widely accepted, the outcomes of these treatment strategies in RET-altered patients have not currently been well compared, and the immuno-characteristics in those patients have also not been well characterized in previous studies [16,17].…”

Response to Checkpoint Inhibition in Non-Small Cell Lung Cancer with Molecular Driver Alterations

“…There were also some responses in patients with MET exon 14 skipping mutation. To our knowledge, there are only few other studies investigating real-world response rates in patients with a range of clinically relevant molecular alterations [6-8]. The current cohort includes several relevant molecular drivers not reported in these studies, including PIK3Ca, TP53, KIT, MYC, and FGFR mutations.…”

“…However, information on the response to checkpoint inhibitors is lacking for most molecular driver alteration subgroups. While a recent large multicenter cohort study [6] described the response of patients with KRAS, EGFR, BRAF, MET, HER2, ALK, RET, and ROS1 alterations, only 1 patient in this cohort had multiple alterations, and no data were available for alterations in PIK3Ca, MYC, TP53, FGFR, KIT, NOTCH, and further not-yet-targetable alterations. For this reason, we performed a retrospective analysis of patients from 2 large German academic centers and analyzed response to checkpoint inhibition in patients with advanced NSCLC found to have single or multiple treatable or nontreatable molecular driver alterations.…”

What the Oncologist Needs From the Pathologist for Immune Therapies

“…Some oncogene-addicted tumors have high PD-L1 levels, but the impulse to start these patients on immunotherapy must be cooled until the mutational testing results come back; driver-mutated lung cancer has very poor responses to immunotherapy regardless of PD-L1 expression. 7,8 In addition, there are emerging data indicating that exposing driver-mutated lung cancer patients to immunotherapy early in their treatment course and following that with a tyrosine kinase inhibitor exposes them to a very high risk of pneumonitis. 9 Thus, it is more imperative than ever to get both the PD-L1 expression levels and the mutational profile before launching into therapy.…”