Activating Lung Cancer Mutations Do Not Predict ICI Efficacy

Activating oncogene mutations do not represent predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy among patients with non–small-cell lung cancer (NSCLC), according to results of the retrospective ImmunoTarget study (abstract 9010) presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.

Patients treated with ICI monotherapy had outcomes consistent with those from clinical trials-but inferior to outcomes with targeted therapies, said lead study author Julien Mazieres, MD, PhD, of Hôpital Larrey, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

“Selection of patients can be guided in some cases by smoking or PD-L1 [programmed death ligand] expression, but biomarkers are needed in this setting,” Mazieres said.

Up to half of NSCLC cases are driven by activated oncogenes and few treatment options are available after tyrosine kinase inhibitors stop working, Mazieres said.

Noting sparse data on ICI activity among patients with these cancers, the researchers analyzed data for 551 patients with rare oncogenic drivers (HER2, BRAF, MET, RET, ROS1) who were administered ICIs. They also analyzed PD-L1 expression data obtained using immunohistochemistry.

Nearly half (49%) of the cohort had KRAS mutation–harboring NSCLC, and 23% had EGFR mutations. BRAF, MET, HER2, ALK, RET, and ROS1 mutations were found in 8%, 7%, 5%, 4%, 3% and 1% of the cohort, respectively.

At a median follow-up of 16.1 months, progression-free survival (PFS, the primary study endpoint) was significantly poorer for patients whose NSCLC had EGFR or ALK/ROS1/RET driver mutations (median PFS: 2.1 months and 2.2 months, respectively) than those with KRAS or BRAF/HER2/MET mutations (median PFS: 3.2 months and 2.9 months, respectively; P < .001), Mazieres reported.

PFS was also modulated by smoking status (with smokers experiencing better PFS than never smokers or former smokers; P < .001) and PD-L1 positivity (P = .02).

Among patients with driver mutations, however, overall survival outcomes were “quite comparable,” and subgroup analyses found no modulating effect for tobacco smoking status, he acknowledged.

Among patients whose lung cancers had KRAS mutations, PFS overall was not related to KRAS mutation subtype or the number of previous lines of treatment before immunotherapy was initiated. However, PFS was longer among patients with PD-L1–positive disease (P = .01).

PFS in patients with BRAF-mutant NSCLC was associated with smoking status, with smokers having better PFS than never-smokers (P = .03). In contrast, among patients with ALK/ROS1/RET-group tumor mutations, never-smokers had longer PFS than current or former smokers (P = .03).

ICI could be considered after conventional treatments for patients whose NSCLC harbors HER2 and MET mutations, and might be considered in smokers with BRAF-mutant lung cancers, Mazieres said.

“Combinations of chemotherapy and immunotherapy with or without antiangiogenic agents should be more efficient than single-agent checkpoint blockade, and should be further investigated in aimed trials,” Mazieres said.

The study is ongoing and continues to enroll patients. It was funded without industry support by Toulouse University Hospital and Lucerne Cantonal Hospital, Mazieres said.