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


Patients' Characteristics

During an enrollment phase of almost 1 year, the registry included 551 patients from 24 centers in 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43, V600En = 17, other n = 18), MET (n = 36, MET amplification n = 13, exon 14 skipping mutation n = 23), HER2 (n = 29), ALK (n = 23), RET (n = 16), and ROS1(n = 7). A total of 34 patients with more than 1 driver were allocated to the dominant oncogenic driver. Details are provided in the supplementary Figure S1 and S2, available at Annals of Oncology online. Median age was 60 years (range 29–83). Gender ratio was 1 : 1. Smoking status was 28% never smokers, 51% former smokers, and 21% current smokers. The majority (96%) of tumors were adenocarcinoma. At the time of immunotherapy initiation, most patients had ECOG performance status (PS) of 1 (64%), while fewer patients were PS0 (21%), PS2 (11%), and PS3/4 (4%). All patients presented an advanced tumor stage at the beginning of immunotherapy. The clinical characteristics of each subgroup are reported in Table 1.

Treatment Characteristics and Safety

Most (94%) patients received anti-PD1-antibodies (nivolumab n = 466, pembrolizumab n = 48, other n = 6), fewer patients (6%) had anti-PD-L1-antibodies (atezolizumab n = 19, durvalumab n = 11, other n = 1). ICIs were given in the first (5%), second (41%), third (26%), fourth line (13%) or in later lines (14%) of treatment (Supplementary Table S3, available at Annals of Oncology online). The recording of significant (grades 3 and 4) irAE was optional. From 462 patients with available data, 50 (10.8%) had grade 3–5 irAEs, including 36 (7.8%) of grade 3, 13 (2.8%) of grade 4, and 1 of grade 5 (0.2%, endocrine disorder). The pneumonitis rate was in the expected range (13 cases, 2.8% including 8 grade 3 and 5 grade 4). No unexpected irAEs were recorded.

PD-L1 Expression

PD-L1 status was available for 214 patients. The median number of positive cells was 10%. Using a 1% cut-off, one-third was negative (33.2%) and two-third was positive (66.8%). Using a 10% cut-off, half of the tumors was negative (49.7%) and half positive (50.3%). Using a 50% cut-off, one-third of the tumors was positive (33.9%). Looking into each subgroup, we found that median percentage of cells expressing PD-L1 was 0 in HER2 (n = 13), 3.5 in EGFR (n = 38), 7.5 in ALK (n = 10), 12.5 in KRAS (n = 80), 26 in RET (n = 6), 30 in MET (n = 15), 50 in BRAF (n = 9), and 90 in ROS1 (n = 5) subgroups (Supplementary Table S4 and Supplementary Figure S5, available at Annals of Oncology online).

Clinical Outcomes

Response rate. The rate of any partial or complete response was 19% [95% CI 16% to 23%], ranging from 0% in ALK patients to 26% in KRAS-mutated patients. If we consider the KRAS patients as a control group and exclude them from the analysis, the best response rate for patients harboring all other molecular alterations was 12.7%. We then classified the subgroups according to the rate of progressive disease (PD). PD was observed in 46% for BRAF, 50% for MET, 51% for KRAS, 67% for HER2, 67% for EGFR, 68% for ALK, 75% for RET, and 83% for ROS1. (Figure 1; Supplementary Table S6, available at Annals of Oncology online). Details according to the mutation subtype are in Supplementary Table S7, available at Annals of Oncology online.

Figure 1.

Best response to ICI according to RECIST criteria (PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response).

Overall survival. In the entire cohort, median follow-up was 16.1 months, and median OS from start of ICI therapy was 13.3 months [10.0–14.9] (Figure 2). Median OS (in months) for individual molecular subgroups was 10.0 [6.7; 14.2] for EGFR mutated patients, 13.5 [9.4; 15.6] for KRAS, 17.0 [3.6; NR] for ALK, 13.6 [7.4; 22.5] for BRAF, 20.3 [7.8; NR] for HER2, 21.3 [3.8; 28.0] for RET, and 18.4 [7.0; NR] for MET (Supplementary Data S7, available at Annals of Oncology online). In the univariate analysis, OS did not correlate with gender, age, smoking, number of prior therapies, or PD-L1 expression (Supplementary Table S8, available at Annals of Oncology online).

Figure 2.

Overall survival (on the left) and progression-free survival (on the right) in the whole cohort (upper figures) and in each subgroup (lower figures).

Progression-free survival. In the entire cohort, median PFS was 2.8 months [95% CI 2.5–3.1]. Median PFS (in months) for individual molecular subgroups was 2.1 [1.8; 2.7] for EGFR, 3.2 [2.7; 4.5] for KRAS, 2.5 [1.5; 3.7] for ALK, 3.1 [1.8; 4.6] for BRAF, 2.5 [1.8; 3.5] for HER2, 2.1 [1.3; 4.7] for RET, and 3.4 [1.7; 6.2] for MET (Figure 2). Long-term responders were more frequent in KRAS (12 months PFS: 25.6%), MET (23.4%), and BRAF (18.0%) subgroups, than in EGFR (6.4%), ALK (5.9%), HER2 (13.6%), and RET (7.0%) subgroups (Table 2). If we exclude KRAS patients from the analysis (n = 279 patients with all other alterations), median PFS was 2.4 months.

In the univariate analysis, PFS significantly correlated with smoking (median PFS: 2.5, 2.8, and 3.5 months for never smokers, former smokers, and current smokers, respectively, P < 0.0001), and with PD-L1 expression (3.0 versus 4.2 months for negative and positive expression of PD-L1, P = 0.02). However, PFS did not correlate with gender (P = 0.5), age (P = 0.3), or number of previous lines of treatment (P = 0.08) (Supplementary Table S9 and Supplementary Table S10, available at Annals of Oncology online). Interestingly, a higher rate of rapid progression (within 2 months) was observed for EGFR (44.8%), ALK (45.5%), ROS1 (42.9%), and RET (43.8%) patients than for KRAS (36%) (Supplementary Table S11, available at Annals of Oncology online), respectively.

Molecular Subgroup Analyses

KRAS mutations were identified in 271 patients. PFS was not significantly different regarding KRAS mutation subtype if we compare G12C (n = 100) to other mutations (n = 143, P = 0.47) or G12D (n = 39) versus other KRAS mutations (n = 204, P = 0.40). PFS did also not correlate with smoking (P = 0.98), or with the number of previous lines of treatment. In patients with available PD-L1 expression data (n = 95), PD-L1 positive expression was significantly (P = 0.01) correlated with a longer PFS (median PFS: 7.2 versus 3.9 months) (Figure 3). We also separate patients harboring KRAStransition (G12D, G13D, G12S) from KRAS transversion (G12C, G12A, G12V, G13C). PFS was not impacted by the nature of KRAS alteration (2.9 months for transition, 4.0 for transversion, P = 0.27; Supplementary Table S12, available at Annals of Oncology online).


Overall survival and Progression free survival according to KRas type of mutation: Transition vs Transversion

Figure 3.

PFS according to oncogenic drivers' variants and PDL1 expression.

PFS was significantly different across EGFR molecular subgroups ranging from 1.4 month in T790M and complex mutations subgroup to 1.8 for exon 19, 2.5 for exon 21, and 2.8 for other mutations (P < 0.001). PFS correlated neither with smoking (P = 0.06), nor with the number of previous lines of treatment. PD-L1 positivity was significantly correlated with a longer PFS (2.8 months versus 1.7, P = 0.01) (Figure 3).

For BRAF patients, PFS was significantly higher in smokers versus never smokers (4.1 versus 1.9 months, P = 0.03). Median PFS was numerically shorter in the V600E subgroup (1.8 months) compared with other BRAF mutations (4.1 months, P = 0.20).

MET molecular alterations were found in 36 patients. Median PFS correlated neither with alteration subtype (exon 14 skipping mutation versus other MET alterations, P = 0.09), nor with smoking.

HER2 mutations were identified in 29 patients. PFS correlated with smoking (3.4 months for smokers versus 2.0 months for never smokers, P = 0.04).

Due to a low number of patients, ALK, ROS1, and RET were analyzed together in a subgroup termed 'rearrangements'. Median PFS was only slightly higher in never smokers (2.6 months) than in smokers (1.8 months, P = 0.03). PD-L1 was not available in enough patients but no tumor response was reported in patients from this group in the context of PD-L1 positivity (Supplementary Table S13 and Supplementary Figure S5, available at Annals of Oncology online). Main results for all cohorts are presented in supplementary Figure S14, available at Annals of Oncology online.