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


The standard of care for patients with actionable driver alterations is a targeted therapy. After exhaustion of targeted agents and chemotherapy, immunotherapy may be considered as a salvage treatment. Nevertheless, evidence to support the role of ICI in this setting is controversial, as EGFR and ALK alterations have been associated with low ICI efficacy in prior studies.[19] To address this issue, we conducted a global 'real world' study. Our study was retrospective and had other limitations, including reporting bias, lack of central molecular and radiologic assessment, and variable scanning intervals. Nevertheless, we obtained new findings of clinical relevance.

In the overall cohort, the best response with ICI therapy by RECIST was 19%, and median PFS was 2.8 months. This result was mainly driven by the large KRAS-subgroup, and it is in concordance with registration trials testing immunotherapy in pretreated patients, regardless EGFR or ALK status.[9,10] Regarding molecular subgroups, we confirmed that patients with KRAS-mutant NSCLC derived a greater benefit from ICI than EGFR-mutant NSCLC, as previously reported.[9] It has been reported that KRAS-mutant NSCLC are more likely to express PD-1 and PD-L1.[20] In our study, we have not been able to detect a significant correlation between KRASmutation subtypes and PFS, but we confirmed that PD-L1 expression is associated with a better outcome. The limited number of patients with available PDL1 status and the heterogeneity of the tests did not allow us to draw a definitive conclusion on its potential interest. Recently, STK11/LKB1 co-mutation in KRAS-mutant NSCLC was reported as a new predictive marker for tumor resistance to ICI therapy.[21] STK11was not part of routine testing and our study did not include tissue collection, therefore, future studies will have to validate this interesting finding in a larger cohort. ICI are thus an adequate treatment of KRAS-mutated patients.

Concerning patients with EGFR mutation, the role of ICI therapy is still controversial. Recent studies showed an inverse relationship between PD-L1 expression and EGFR mutations. Moreover, an uninflamed tumor microenvironment is often reported in the context of oncogenic addiction.[22,23] Gainor et al. also suggested that a dearth of tumor-infiltrating CD8+ lymphocytes, may explain the low response rate to PD-1 axis inhibitors observed amongst EGFR- and ALK-driven NSCLC.[24] A recent meta-analysis including three randomized trials of immunotherapy in TKI-pretreated patients reported that ICI do not improve OS compared with docetaxel in patients with EGFR-mutant NSCLC.[25] In addition, a recent phase II trial of pembrolizumab in TKI-naive patients with PD-L1 positive EGFR-mutant NSCLC showed no RECIST responses in the first 11 patients.[26] In the phase II trial ATLANTIC of durvalumab in EGFR/ALK mutant NSCLC, response rate was 3.6% for PD-L1 <25%, and 12.2% for PD-L1 >25%. Median PFS was 1.9 month.[19] Benefit has, however, been reported in patients with EGFR mutations with the combination of carboplatin, paclitaxel, bevacizumab, and atezolizumab in the IMpower150 trial.[5]

BRAF mutations were associated with slightly better outcomes compared with EGFRmutations (RR 24% and PFS 3.1 months). The potential efficacy of immunotherapy in BRAF-mutant melanoma has already been suggested.[27] Recently, Dudnik et al. reported frequent expression of PDL1 and comparable PFS (3.7 months) in BRAF V600E-mutated patients.[28] In our study, PFS in patients with BRAF-mutant NSCLC was positively associated with smoking status. It thus appears that immunotherapy may be considered in BRAF positive patients after targeted therapy and one line of chemotherapy.

ALK, ROS1, and RET translocation represent a small subgroup of NSCLC. In our study, PD-L1 expression was relatively high in those cases. However, most tumors were refractory to ICI therapy. These observations were consistent with other studies, namely with ATLANTIC for ALK, and with a cohort study from MSKCC for RET.[29] Although these data are preliminary, we do not recommend ICI as single agents in patients with ALK/ROS1/RET rearranged NSCLC.

In conclusion, patients' outcome treated with ICI monotherapy overall were consistent with ICI registration trials, based on the large KRAS-subgroup in our study. However, outcomes for patients with actionable driver mutations (EGFR, ALK, ROS1) were inferior and ICI should only be considered after exhaustion of targeted therapies and in some cases, potentially in all other therapies including standard and salvage chemotherapies. We think that there are two ways to optimize the use of immunotherapy in the context of oncogenic addiction. The first one is to combine immunotherapy with other drugs such as chemotherapy and antiangiogenic agents. The second one is to identify new relevant biomarkers besides PD-L1 expression and TMB considering the complex molecular biology of NSCLC.