Immune Checkpoint Inhibitors for Patients With Advanced Lung Cancer and Oncogenic Driver Alterations

Results From the IMMUNOTARGET Registry

J. Mazieres; A. Drilon; A. Lusque; L. Mhanna; A. B. Cortot; L. Mezquita; A. A. Thai; C. Mascaux; S. Couraud; R. Veillon; M. Van den Heuvel; J. Neal; N. Peled; M. Früh; T. L. Ng; V. Gounant; S. Popat; J. Diebold; J. Sabari; V. W. Zhu; S. I. Rothschild; P. Bironzo; A. Martinez-Marti; A. Curioni-Fontecedro; R. Rosell; M. Lattuca-Truc; M. Wiesweg; B. Besse; B. Solomon; F. Barlesi; R. D. Schouten; H. Wakelee; D. R. Camidge; G. Zalcman; S. Novello; S. I. Ou; J. Milia; O. Gautschi


Ann Oncol. 2019;30(8):1321-1328. 

In This Article

Abstract and Introduction


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.


The management of patients with stage 4 non-small-cell lung cancer (NSCLC) is currently undergoing significant transformation. Molecular testing, targeted therapies, and immunotherapy are now part of routine clinical care.[1] Targeted therapies are efficient in the context of oncogenic driver mutations.[2] These treatments are associated not only with high response rate, but also with unavoidable development of resistance and tumor recurrence.[3] Therapeutic options are restrained in patients after exhaustion of targeted therapies and chemotherapy. Immune checkpoint inhibitors (ICI) that block the programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) axis is a new standard of care.[4–6] ICI response rates in general are ~20% in unselected NSCLC, but overall survival (OS) benefit was well documented in registration trials.[7–10]

Whether ICIs alone or even in combination with TKIs would offer comparable benefit in oncogene addicted subtypes of NSCLC as much as in the general unselected NSCLC population has been raised as a relevant question.[11] We may expect that immunotherapy may transform the important tumor responses achieved with targeted inhibitors in prolonged remissions. Nevertheless, data obtained from subgroups in clinical trials[9,10,12] and from investigators observations have shown rather weak activity of ICI in NSCLC patients harboring actionable driver mutations.[13] Therefore, the optimal use of ICI therapy in patients with actionable driver mutations remains an important field of ongoing research.

The purpose of this study was to analyze the clinical activity of ICI therapy in the context of oncogenic driver alterations. We previously conducted registry studies on targeted therapies for NSCLC with ROS1, HER2, BRAF, and RET alterations.[14–18] We used our established network to perform a wide international cohort of patients with molecularly defined NSCLC. Hereinafter, we present the results for the whole cohort, and for individual molecular subgroups.