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Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, FranceCentre de Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Marseille, France
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, FranceCentre de Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Marseille, France
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, France
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, France
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, France
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, FranceCentre Hospitalier Departemental de Castellucio, Oncology Department, Ajaccio, France
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, FranceCentre de Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Marseille, France
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, France
Aix-Marseille University, APHM, CHU Nord, Service de Transfert d’Oncologie Biologique, Marseille, FranceAix-Marseille University, CNRS, INP, Neurophysiopathology Institute, Marseille, France
Corresponding author. Address for correspondence: Fabrice Barlesi, MD, PhD, Service d’Oncologie Multidisciplinaire et d’Innovations thérapeutiques, Hôpital Nord–Assistance Publique des Hôpitaux de Marseille (AP-HM), Chemin des Bourrely, 13195 Marseille, Cedex 20, France.
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, FranceCentre de Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Marseille, France
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, FranceCentre de Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Marseille, France
KRAS mutation is the most frequent molecular alteration found in advanced NSCLC; it is associated with a poor prognosis without available targeted therapy. Treatment options for NSCLC have been recently enriched by the development of immune checkpoint inhibitors (ICIs), and data about its efficacy in patients with KRAS-mutant NSCLC are discordant. This study assessed the routine efficacy of ICIs in advanced KRAS-mutant NSCLC.
Methods
In this retrospective study, clinical data were extracted from the medical records of patients with advanced NSCLC treated with ICIs and with available molecular analysis between April 2013 and June 2017. Analysis of programmed death ligand 1 (PD-L1) expression was performed if exploitable tumor material was available.
Results
A total of 282 patients with ICI-treated (in the first line or more) advanced NSCLC (all histological subgroups) who were treated with ICIs (anti–programmed death 1, anti–PD-L1, or anti–cytotoxic T-lymphocyte associated protein 4 antibodies), including 162 (57.4%) with KRAS mutation, 27 (9.6%) with other mutations, and 93 (33%) with a wild-type phenotype, were identified. PD-L1 analysis was available for 128 patients (45.4%), of whom 45.3% and 19.5% had PD-L1 expression of 1% or more and 50%, respectively (49.5% and 21.2%, respectively, in the case of the 85 patients with KRAS-mutant NSCLC). No significant difference was seen in terms of objective response rates, progression-free survival, or overall survival between KRAS-mutant NSCLC and other NSCLC. No significant differences in overall survival or progression-free survival were observed between the major KRAS mutation subtypes (G12A, G12C, G12D, G12V, and G13C). In KRAS-mutant NSCLC, unlike in non–KRAS-mutant NSCLC, the efficacy of ICIs is consistently higher, even though not statistically significant, for patients with PD-L1 expression in 1% or more of tumor cells than for those with PD-L1 expression in less than 1% of tumor cells, and this finding is especially true when PD-L1 expression is high (PD-L1 expression ≥50%).
Conclusion
For patients with KRAS-mutant NSCLC (all mutational subtypes), the efficacy of ICI is similar to that for patients with other types of NSCLC. PD-L1 expression seems to be more relevant for predicting the efficacy of ICIs in KRAS-mutant NSCLC than it is in other types of NSCLC.
Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
Immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors recently became the standard of care in second-line treatment for NSCLC
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
on the basis of an unplanned subgroup analysis. More recent data indicate that KRAS-mutant NSCLCs display heterogeneous immune profiles and, consequently, various levels of sensitivity to immunotherapy.
Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
Herein, we have compared the efficacy of ICIs in patients with KRAS-mutant NSCLC and other types of NSCLC in a large retrospective cohort of patients routinely treated for NSCLC.
Methods
Population
All patients with metastatic NSCLC who received treatment with an ICI between April 2013 and June 2017 at the Assistance Publique-Hôpitaux de Marseille (France) and whose tumor was molecularly characterized were selected. Patients who were treated with an ICI for KRAS-mutant NSCLC at the University Hospital of Toulouse (France) were also included in this study. Demographic, biological, radiological, therapeutic, and survival data were retrospectively collected from the patients’ medical records. This study was approved by the national ethics committee Institutional Review Board of the French Learned Society for Respiratory Medicine–Société de Pneumologie de Langue Française (Comité d’Evaluation Des Protocoles De Recherche Observationnelle) (approval No. 2016-024, 2017-020 and 2017-043).
Molecular Analyses
Mutations in EGFR, KRAS, BRAF, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), and ERBB2 erb-b2 receptor tyrosine kinase 2 gene (HER2) in all samples were investigated by determining the high-resolution melting point subsequent to polymerase chain reaction profile followed by dideoxy-Sanger sequencing to determine the mutation of interest or by using the MiSeq panel (Illumina, San Diego, CA). ALK receptor tyrosine kinase gene (ALK) and ROS1 rearrangement were detected by using an immunohistochemical procedure, and positive cases were controlled for by fluorescent in situ hybridization.
When tumor material of an appropriate quality and quantity was available, PD-L1 protein expression (expression in tumor cells) was assessed by using immunohistochemistry with a ready-to-use PD-L1 commercial kit (HalioSeek, Halkio Dx, National Harbor, Maryland) or with QR1 antibody (Quartet, Quartett Immunodiagnosika & Biotechnologie GmBH, Berlin, Germany) on a Dako Link platform (Dako, Glostrop, Denmark), at the pathology platforms of Marseille and Toulouse, respectively.
The percentage of tumor cells positive for PD-L1 protein expression was reported. Furthermore, the positivity of the tumors for PD-L1 expression was considered for two thresholds currently used in clinical practice: 1% or more and ≥ 50% or more positive tumor cells.
Median overall survival (OS) and median progression-free survival (PFS) were estimated by using the Kaplan-Meier method with a confidence interval (CI) of 95%. A Cox model allowed the calculation of hazard ratios for comparison between different groups with a CI of 95%. A chi-square test or Fisher test was used for comparing two quantitative variables, and a Mann-Whitney test was used for comparing means. To compare different groups, odds ratios were calculated with a statistical regression method with a CI of 95%. Statistical analysis was performed with IBM SPSS software (version 20.0 for Windows, (IBM Inc., Armonk, NY). Statistical significance was declared at the threshold p value of 0.05.
Results
Comparison of KRAS-Mutant NSCLC with Other Types of NSCLC
A total of 282 patients were analyzed, of whom 162 had KRAS-mutant advanced NSCLC (Supplementary Fig. 1). The main characteristics of the population are reported in Table 1. In total, 273 patients were able to be evaluated for objective response rate (ORR) and disease control rate, and 282 were able to be evaluated for PFS and OS.
Table 1Characteristics of the Baseline Population and ICI Received
The ORR was numerically higher for KRAS-mutant NSCLC (18.7%) than for KRAS wild-type NSCLC (14.4%), but this difference was not statistically significant. There was no significant difference in terms of PFS or OS (Table 2). We also compared the efficacy and toxicity of ICIs with respect to KRAS mutation subtypes, and no significant difference was observed when patients with G12A (n = 15) versus with G12C (n = 69) versus with G12D (n = 25) versus with G12V (n = 24) versus with G13C (n = 11) mutations were compared (Table 3).
Table 2Comparison of ICI Efficacy in KRAS-Mutant NSCLC and Other Types of NSCLC
Tumor PD-L1 protein expression in 128 patients (45.4%) was analyzed. The mean expression of PD-L1 in different groups was not significantly different even though KRAS-mutant NSCLC had a numerically higher expression of PD-L1 than did the other types (Tables 4 and 5). With the cutoff value set at 1%, 49.5% of the tumors of patients with KRAS-mutant NSCLC were positive for PD-L1 (PD-L1 ≥1%) expression versus 28.6% of the tumors of patients with NSCLC with other mutations and 38.9% of the tumors of patients with wild-type NSCLC. No significant difference was observed between KRAS-mutant NSCLC tumors and the other groups of NSCLCs.
Table 4Analysis of PD-L1 Expression in the Different Groups
Indicator
All Patients
KRAS Mutation
Other Mutations
Wild Type
p Value
Patients analyzed/all patients, n (%)
128/282 (45.4)
85/162 (52.5)
7/27 (26)
36/93 (38.7)
Mean PD-L1 tumor expression (95% CI)
19.95 (14.13–25.77)
22.13 (14.66–29.6)
17.83 (–5.37 to 28.23)
15.65 (6.11–26.83)
PD-L1 expression >1%, n (%)
58 (45.3)
42 (49.5)
2 (28.6)
14 (38.9)
0.420
PD-L1 expression >50%, n (%)
25 (19.5)
18 (21.2)
1 (14.3)
6 (16.7)
0.59
PD-L1, programmed death ligand 1; CI, confidence interval.
However, we noted a statistically significant difference in PD-L1 expression between the different subtypes of KRAS mutation, with a higher proportion of PD-L1–positive tumors in patients with KRAS G12D, G12V, or G13C mutations and a higher proportion of PD-L1–negative tumors in those with G12A and G12C mutations.
Efficacy of ICIs with Respect to PD-L1 Expression
ORR, PFS, and OS were not significantly different between the different NSCLC groups (with or without KRAS mutation) with respect to PD-L1 expression (Supplementary Table 1). However, a trend toward a better ORR and a longer PFS was observed for KRAS-mutant NSCLC with PD-L1–positive versus PD-L1–negative tumors, with increased benefit for a higher rate of PD-L1–positive tumor cells (≥ 50%) (Fig. 1A). This association between PD-L1 expression and outcome with ICIs was not observed in NSCLC without KRAS mutations.
Figure 1Association between PD-L1 expression and ICI efficacy: A. Between KRASm NSCLC and non-KRASm NSCLC. B. Between the different subtypes of KRAS mutation. ORR = Overall Response Rate; PFS = Progression-Free Survival; KRAS = Kirsten Rat Sarcoma Virus; PD-L1 = Programmed death ligand 1; OS = Overall Survival.
We analyzed the association between PD-L1 expression and efficacy of ICIs for the different KRAS mutation subtypes. No statistically significant association was found (Supplementary Table 2), but a trend for a positive association between PD-L1 expression and both ORR and PFS with ICI therapy was seen in the groups of patients with KRAS G12A or G12V mutations (Fig. 1B).
Discussion
This retrospective study of 282 patients with NSCLC treated with an ICI showed that the efficacy, in terms of objective response and survival, of treatment with an ICI was similar for patients with NSCLC with or without KRAS mutation. In the CheckMate 057 study,
which showed a potential advantage for immunotherapy in KRAS-mutant NSCLC, the mutation status was unknown for 21% of the patients, and only 62 patients (11%) had a known KRAS mutation. These data were thus based on a small number of patients and on unplanned subgroup analyses with a potential bias. In our larger cohort, which included 162 patients with KRAS-mutant NSCLC, we did not find any increased benefit for KRAS-mutant NSCLC. The proportion of patients with KRAS-mutant NSCLC was high in our study (57.4%). The proportion of adenocarcinomas was very high in the current cohort, in which only 2.1% of the patients exhibited the squamous histologic type, which rarely harbors KRAS mutations. In addition, activating mutations other than KRAS mutation were less frequent. This is explained by the fact that targeted therapies, when available, are the standard of care with a lower use of ICIs.
In patients with KRAS-mutant NSCLC, but not in patients with other NSCLCs, a trend toward an association between PD-L1 expression in tumor cells and the ORR and PFS was observed, and the benefit increased with the higher threshold for positivity of the tumors for PD-L1 expression. PD-L1 has predicted response to checkpoint inhibitors in most of the clinical trials investigating its role in NSCLC.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
In addition, its specific role in KRAS-mutant patients has not been investigated so far. Our data showing the predictivity of PD-L1 expression for ICI efficacy in KRAS-mutant NSCLC has to be validated in other cohorts. The expression of PD-L1 was found to be significantly different between different subtypes of KRAS mutation: a higher proportion of PD-L1–positive tumors was observed in groups with KRAS G12D, G12V or G13C mutations, and a higher proportion of PD-L1–negative tumors was observed in those with G12A and G12C mutations. However, because of the small number of patients in each subgroup, these data require validation.
In addition to the different mutation subtypes of KRAS and beyond PD-L1 expression, recent data have confirmed that KRAS-mutant NSCLCs are not all equal in terms of the immunogenic profile and response to immunotherapy.
Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
A group of KRAS-mutant lung adenocarcinomas with high rates of kelch like ECH associated protein 1 gene (KEAP1) mutational inactivation (the KL group) demonstrated lower rates of expression of immune markers, including PD-L1. In this subgroup, the inactivation of serine/threonine kinase 11 (also known as liver kinase B1) resulted in an accumulation of tumor-associated neutrophils with suppressive effects on T cells and a reduced number of tumor-infiltrating lymphocytes; the KL group is consequently refractory to anti–PD-1 antibody therapy, and other therapeutic strategies that target neutrophils have been proposed.
STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment.
This resistance of KRAS-mutant lung adenocarcinomas that have lost serine/threonine kinase 11 (liver kinase B1) activity in response to an ICI has recently been clinically confirmed in patients.
In conclusion, the clinical benefit of ICIs is similar in NSCLC with and without KRAS mutation. An association between PD-L1 expression and ICI efficacy was found in KRAS-mutant NSCLC. The efficacy of ICIs against all mutation types did not seem to be equal, but further validation on larger series of samples is needed. The immunological features of KRAS-mutant NSCLC and their effect on susceptibility to immunotherapy are thus heterogeneous and are largely underexplored, except in recent studies exploring the KL group. In addition, combining several immunotherapies or combining immunotherapy with specific targeted therapies or with chemotherapy will thus likely be useful to overcome the resistance of tumors to the PD-L1/PD-1 inhibitors used in monotherapy.
Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment.
Disclosure: Dr. Tomasini reports personal fees for congress accommodations from Roche, AstraZeneca, MSD, BMS, and Takeda. Dr. Mazières reports serving on advisory boards of Roche, BMS, AstraZeneca, Novartis, and Pfizer. Dr. Barlesi reports personal fees and grants from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda. Dr. Mascaux reports personal fees and nonfinancial support from Roche, BMS, and AstraZeneca; personal fees from Boehringer Ingelheim and Kephren, and nonfinancial support from MSD outside the submitted work. The remaining authors declare no conflict of interest.
KRAS mutation is the most common oncogenic aberration found in NSCLC, with an incidence of 25% to 30% in patients with adenocarcinoma in Western countries1,2 and about 10% to 15% in patients with lung adenocarcinoma in Asia.3 Worldwide, NSCLC harboring a KRAS mutation is the most frequent potentially targetable molecular subtype.4 The vast majority (95%) of the KRAS mutations in lung adenocarcinoma occur in codons 12 (>80%) and 13.5 The G12C point mutation accounts for more than one-third of all cases, with G12V and G12D being other frequently found variants.
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