Optimal use of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC) and actionable driver mutations is an important field of ongoing research.
An academic, international study shows that outcome in patients treated with immune checkpoint inhibitor monotherapy was consistent with immune checkpoint inhibitor registration trials in the KRAS subgroup but were inferior for patients with actionable driver mutations. Prof. Julien Mazières of the Thoracic Oncology Department, Hôpital LARREY, CHU Toulouse, Toulouse, France and colleagues, therefore concluded that immune checkpoint inhibitor should only be considered after exhaustion of targeted and standard therapies. The results from the IMMUNOTARGET registry were published on 24 May 2019 in the Annals of Oncology.
The authors wrote in the study background that activity of immune checkpoint inhibitors across NSCLC harbouring oncogenic alterations is poorly characterised. The aim of the study was to address the efficacy of immune checkpoint inhibitors in the context of oncogenic addiction.
The study team performed a retrospective study for patients who received immune checkpoint inhibitors monotherapy for advanced NSCLC with at least one oncogenic driver alteration. The authors used their established network to analyse a wide international cohort of patients with molecularly defined NSCLC.
They evaluated anonymized data for clinicopathologic characteristics and outcomes for therapy with immune checkpoint inhibitors in terms of best response according RECIST v1.1, progression-free survival (PFS) and overall survival (OS) from immune checkpoint inhibitors initiation. The primary endpoint was PFS under immune checkpoint inhibitors. Secondary endpoints werebest response (RECIST v1.1) and overall survival (OS) from immune checkpoint inhibitor initiation.
The authors studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS in 271 cases, EGFR in 125 cases, BRAF in 43 cases, MET in 36 cases, HER2 in 29 cases, ALK in 23 cases, RET in 16 cases, ROS1 in 7 cases and multiple drivers in 1 case.
In the Annals of Oncology, they published the results from the whole cohort, and for individual molecular subgroups.
Median age was 60 years, gender-ratio was 1:1, never/former/current smokers were 28%/51%/21%, respectively. The majority of tumours were adenocarcinoma.
The objective response rate by driver alteration was 26% in KRAS, 24% in BRAF, 17% in ROS1, 16% in MET, 12% in EGFR, 7% in HER2, 6% in RET, and 0% in ALK positive tumours.
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 was 2.1 month for EGFR, 3.2 month for KRAS, 2.5 month for ALK, 3.1 month for BRAF, 2.5 month for HER2, 2.1 month for RET, and 3.4 month for MET positive tumours. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).
The authors concluded that immune checkpoint inhibitor therapy induced regression in some tumours with actionable driver alterations, but clinical activity was lower compared to the KRAS group and the lack of response in the ALK group was notable. In general, outcomes for NSCLC patients with actionable driver mutations were inferior and immune checkpoint inhibitor should only be considered after exhaustion of targeted therapies and in some cases, potentially in all other therapies including standard and salvage chemotherapies.
The authors proposed that there are two ways to optimise the use of immunotherapy in the context of oncogenic addicted NSCLC. The first one is to combine immunotherapy with other drugs such as chemotherapy and anti-angiogenic agents. The second one is to identify new relevant biomarkers besides PD-L1 expression and tumour mutational burden considering the complex molecular biology of NSCLC.
This work was supported by public funding from Toulouse University Hospital, France and Lucerne Cantonal Hospital, Switzerland. The research was carried out with no industry support.
Reference
Mazières J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Annals of Oncology; Published online 24 May 2019.mdz167. https://doi.org/10.1093/annonc/mdz167