- Email: [email protected]
Efficacy of Immune Checkpoint Inhibitors in KRAS-Mutant Non-Small Cell Lung Cancer (NSCLC)
BRIEF REPORT
Efficacy of Immune Checkpoint Inhibitors in KRASMutant Non-Small Cell Lung Cancer (NSCLC) Arnaud Jeanson, MD,a,b Pascale Tomasini, MD,a,b Maxime Souquet-Bressand, MD,a Nicolas Brandone, PhD,c Mohamed Boucekine, PhD,d Mathieu Grangeon, MD,a Solène Chaleat, MD,a Natalyia Khobta, MD,a,e Julie Milia, MD,f Laurent Mhanna, MD,f Laurent Greillier, MD, PhD,a,b Julie Biemar, PhD,a Isabelle Nanni, MD,g L’houcine Ouafik, MD, PhD,g,h Stéphane Garcia, MD, PhD,c Julien Mazières, MD, PhD,f Fabrice Barlesi, MD, PhD,a,b,* Céline Mascaux, MD, PhDa,b a
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, France b Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Marseille, France c Department of Pathology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Aix-Marseille Université, Marseille, France d EA 3279 - Public Health, Chronic Diseases and Quality of Life–Research Unit, Aix-Marseille University, Marseille, France e Centre Hospitalier Departemental de Castellucio, Oncology Department, Ajaccio, France f Department of Pulmonology, Hôpital Larrey, Centre Hospitalier Universitaire, Paul Sabatier University, Toulouse, France g Aix-Marseille University, APHM, CHU Nord, Service de Transfert d’Oncologie Biologique, Marseille, France h Aix-Marseille University, CNRS, INP, Neurophysiopathology Institute, Marseille, France Received 6 July 2018; revised 30 December 2018; accepted 6 January 2019 Available online - 6 February 2019
ABSTRACT Introduction: 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 progressionfree 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
*Corresponding author. 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. 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. E-mail: fabrice. [email protected] ª 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 https://doi.org/10.1016/j.jtho.2019.01.011
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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. 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. Keywords: NSCLC; Immunotherapy; KRAS mutation; PD-L1 expression
Introduction KRAS mutations are found in approximately 30% of NSCLC1 and confer a poor prognosis.2 Nevertheless, all of the studies testing targeted therapies against KRAS and its downstream pathways have failed to show any clinical benefit.3 Current international guidelines recommend a first-line platinum-based treatment for most NSCLC cases, including those harboring a KRAS mutation.4 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 NSCLC5–7 and first-line therapy for patients with high expression of PD-L1,8 and they will likely become a standard first-line treatment when associated with chemotherapy for all comers with NSCLC.9 In clinical trials comparing ICIs with chemotherapy in second-line treatment, a benefit was suggested in patients with KRAS-mutant NSCLC5 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.10 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
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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, phosphatidylinositol4,5-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 dideoxySanger 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.11
PD-L1 Expression Analyses 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.8
Statistical Analyses The evaluation of tumor response was performed every 2 months by using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.12 Median overall survival (OS) and median progression-free survival (PFS) were estimated by using the KaplanMeier 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
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Table 1. Characteristics of the Baseline Population and ICI Received Variable Age at diagnosis, y Median Range Sex, n (%) Male Female Smoking status, n (%) Current smoker Former smoker Never smoked Unknown Histological type Adenocarcinoma Squamous Large cell carcinoma Other Unknown PS before ICI therapy, n (%) 0 1 2 3 4 Unknown Molecular abnormalities, n (%) KRAS EGFR ALK BRAF HER2 NRAS PIK3CA STK11 METamp ROS1 FGFR TP53 Wild type Type of KRAS mutation, n (%) G12A G12C G12D G12R G12S G12V G13C G13D G13R G13V Unknown
Value 59.8 32.84 168 (59.5) 114 (40.5) 102 143 25 1
(36.2) (50.7) (8.9) (4.2)
263 6 9 3 1
(93.3) (2.1) (3.2) (1.1) (0.4)
70 111 41 9 3 50
(24.8) (39.4) (14.5) (3.2) (0.3) (17.7) (.04)
162 8 2 6 2 1 1 1 3 1 1 1 93
(57.4) (2.8) (0.7) (2.1) (0.7) (0.35) (0.35) (0.35) (1.1) (0.35) (0.35) (0.35) (33)
15 69 25 3 4 24 11 3 1 1 6
(9.3) (42.6) (15.4) (1.8) (2.5) (14.8) (6.8) (1.8) (0.6) (0.6) (3.7) (continued)
comparing two quantitative variables, and a MannWhitney test was used for comparing means. To compare different groups, odds ratios were calculated with a statistical regression method with a CI of 95%.
3
Table 1. Continued Variable Line of ICI, n (%) Maintenance First line Second line Third line Fourth line Fifth line Sixth line Seventh line Lines of ICI, n (%) 1 2 Type of ICI, n (%) Anti–PD-1 Anti–PD-L1 Anti–CTLA4 Anti–PD-1 + anti–CTLA4 Anti–PD-L1 + anti–CTLA4 Other association Name of ICI, n (%) Nivolumab Pembrolizumab Atezolizumab Avelumab Durvalumab Ipilimumab Tremelimumab Durvalumab + tremelimumab Nivolumab + ipilimumab Nivolumab + urelumab
Value 5 24 149 68 24 8 2 2
(1.8) (8.5) (52.8) (24.1) (8.5) (2.8) (0.7) (0.7)
264 (93.6) 18 (6.4) 252 19 4 2 4 1
(89.4) (6.7) (1.4) (0.7) (1.4) (0.35)
249 3 8 4 7 1 3 4 2 1
(88.3) (1.1) (2.8) (1.4) (2.5) (0.4) (1.1) (1.4) (0.7) (0.4)
PS, performance status; ICI, immune checkpoint inhibitor; ALK, ALK receptor tyrosine kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3kinase catalytic subunit alpha gene; HER2, erb-b2 receptor tyrosine kinase 2 gene; STK11, serine/threonine kinase 11 gene; METamp, MNNG HOS Transforming gene amplification; FGFR, fibroblast growth factor receptor gene; TP53, tumor protein p53 gene; anti–PD-1, anti–programmed death 1 antibody; anti–PD-L1, anti–programmed death ligand 1 antibody; antiCTLA4, anti-cytotoxic T-lymphocyte associated protein 4 antibody.
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. The ORR was numerically higher for KRAS-mutant NSCLC (18.7%) than for KRAS wild-type NSCLC
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(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 ¼ 15) versus with G12C (n ¼ 69) versus with G12D (n ¼ 25) versus with G12V (n ¼ 24) versus with G13C (n ¼ 11) mutations were compared (Table 3).
OR ¼ 1.25 (0.7–22.1) 0.451 OR ¼ 1.17 (0.52–2.62) 0.704 OR, odds ratio; HR, hazard ratio; CI, confidence interval; ORR, overall response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival.
0.649 25.8% 0.722 10.8% OR ¼ 1.24 (0.49–3.12) OR ¼ 0.81 (0.25–2.58) OR ¼ 1.25 (0.73–2.11) 0.417 25.9% OR ¼ 1.07 (0.52–2.21) 0.863 14.8% 30.2% 12.3%
25.8% 11.7%
HR ¼ 0.93 (0.68–1.29) 0.682 13.04 (7.71–18.37) HR ¼ 1.14 (0.64–2)
0.660 10.97 (4.74–17.21) HR ¼ 0.89 (0.62–1.24) 0.465
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14.29 (9.64–18.95) 11.14 (7.4–14.9)
OR ¼ 1.18 (0.6–2.34) 0.633 OR ¼ 0.98 (0.58–1.64) 0.936 HR ¼ 0.91 (0.69–1.21) 0.519 OR ¼ 2.76 (0.62–12.35) 0.184 16.3% OR ¼ 0.94 (0.41–2.15) 0.879 48.9% HR ¼ (0.62–1.6) 1.000 2.66 (1.71–3.62) OR ¼ 1.37 (0.71–2.63) 0.348 7.7% OR ¼ 0.97 (0.6–1.57) 0.900 50% HR ¼ 0.93 (0.71–1.21) 0.584 2.66 (1.39–3.93) 14.4% 49.2% 2.66 (1.98–3.34) 18.7% 48.4% 3.09 (2.36–3.82)
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ORR DCR Mean PFS, mo (range) Mean OS, mo (range) PFS >6 mo PFS >12 mo
p NSCLC with Value Other Mutation Non–KRASOR or HR Mutated NSCLC (95% CI) KRAS-Mutated NSCLC Indicator
Table 2. Comparison of ICI Efficacy in KRAS-Mutant NSCLC and Other Types of NSCLC
OR or HR (95% CI)
p Wild-Type Value NSCLC
OR or HR (95% CI)
p Value
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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. 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 KRASmutant 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. 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).
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Table 3. Comparison of ICI Efficacy with Respect to Different KRAS Mutation Subtypes Type of KRAS Mutation Indicator
G12A (n ¼ 15)
G12C (n ¼ 69)
G12D (n ¼ 25)
G12V (n ¼ 24)
G13C (n ¼ 11)
p Value
ORR DCR PFS, mo OS, mo PFS >6 PFS >12
13.30% 46.70% 2.66 Not reached 20% 6.70%
18.50% 46.20% 3.09 11.34% 33.30% 10.10%
20% 52% 3.91 9.76 32% 20%
18.20% 40.90% 2.69 8.9 25% 16.70%
18.20% 54.50% 4.6 18.99 36.40% 18.20%
0.99 0.93 0.96 0.59 0.83 0.58
ORR, overall response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival.
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,5 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 PDL1 expression. PD-L1 has predicted response to checkpoint inhibitors in most of the clinical trials investigating its role in NSCLC.7,9 However, the results are discordant
in some trials, showing benefits for ICI therapy whatever the PD-L1 status.13 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 PDL1–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.10 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 tumorassociated 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.14,15 This resistance of KRAS-mutant lung
Table 4. Analysis of PD-L1 Expression in the Different Groups Indicator
All Patients
KRAS Mutation
Other Mutations
Wild Type
p Value
Patients analyzed/all patients, n (%) Mean PD-L1 tumor expression (95% CI) PD-L1 expression >1%, n (%) PD-L1 expression >50%, n (%)
128/282 (45.4) 19.95 (14.13–25.77) 58 (45.3) 25 (19.5)
85/162 (52.5) 22.13 (14.66–29.6) 42 (49.5) 18 (21.2)
7/27 (26) 17.83 (–5.37 to 28.23) 2 (28.6) 1 (14.3)
36/93 (38.7) 15.65 (6.11–26.83) 14 (38.9) 6 (16.7)
0.420 0.59
PD-L1, programmed death ligand 1; CI, confidence interval.
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Table 5. Analysis of PD-L1 Expression for the Different KRAS Mutation Groups Indicator
G12A
G12C
G12D
G12V
G13C
p Value
Patients analyzed/ all patients, n (%) Mean PD-L1 tumor expression (95% CI) PD-L1 expression >1%, n (%) PD-L1 expression >50%, n (%)
7/15 (46.6)
41/60 (59.4)
12/25 (48)
12/24 (50)
5/11 (45.5)
23.43% (–6.91 to 36.91) 3 (42.9)
22.98% (3.97–20.76) 14 (34.1)
22.7% (5.18–76.49) 7 (58.3)
23.66% (9.34–54.33) 10 (83.3)
21.18% (–6. 54 to 70.94) 3 (60)
0.033
1 (14.3)
4 (9.8)
5 (41.7)
4 (33.3)
2 (40)
0.039
PD-L1, programmed death ligand 1; CI, confidence interval.
adenocarcinomas that have lost serine/threonine kinase 11 (liver kinase B1) activity in response to an ICI has recently been clinically confirmed in patients.16 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
A
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.
Supplementary Data Note: To access the supplementary material accompanying this article, visit the online version of the Journal of Thoracic Oncology at www.jto.org and at https://doi. org/10.1016/j.jtho.2019.01.011.
ORR (%)
40
PFS (months) 8
KRASm NSCLC
35 30
5 4
35,3
15 19
19,2
18,8
5
4,86
2
14,3
3,94
3,22
2,69
1
0
3,94
0 PD-L1 < 1%
1% ≤ PD-L1 < 50%
B
PD-L1 ≥ 50%
PD-L1 < 1%
ORR (%)
120
G12A G12V G12C
10
G12D
G13C
6
100 66,7
50 0
23,1
7,7
0
PD-L1 < 1%
20
28,6
20
1% ≤ PD-L1 < 50%
PD-L1 ≥ 50%
G12C
2
33,3 0
G13C
12,72 10,3810,38
4
66,7
20
G12V
8
60 40
PD-L1 ≥ 50%
G12D
12
80
1% ≤ PD-L1 < 50%
PFS (months)
G12A 14
100
0
7,09
3
25,6
10
non KRASm NSCLC
6
non KRASm NSCLC
25 20
KRASm NSCLC
7
0
0
0
1,74
0
2,732,96
5,32
3,91 1,64
0,46
PD-L1 < 1%
1% ≤ PD-L1 < 50%
7,1 4,6 4,6 1,18
PD-L1 ≥ 50%
Figure 1. Association between PD-L1 expression and ICI efficacy: A. Between KRASm NSCLC and non-KRASm NSCLC. B. Between the different subtypes of KRAS mutation. ORR ¼ Overall Response Rate; PFS ¼ Progression-Free Survival; KRAS ¼ Kirsten Rat Sarcoma Virus; PD-L1 ¼ Programmed death ligand 1; OS ¼ Overall Survival.
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10. Skoulidis F, Byers LA, Diao L, et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 2015;5(8):860–877. 11. International Association for the Study of Lung Cancer. IASLC atlas of ALK testing in lung cancer. https://www. iaslc.org/publications/iaslc-atlas-alk-testing-lung-cancer. Accessed May 31, 2018. 12. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247. 13. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:25–65. 14. Koyama S, Akbay EA, Li YY, et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 2016;76:999– 1008. 15. Nagaraj AS, Lahtela J, Hemmes A, et al. Cell of origin links histotype spectrum to immune microenvironment diversity in non-small-cell lung cancer driven by mutant Kras and loss of Lkb1. Cell Rep. 2017;18:673–684. 16. Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/ LKB1 mutations and PD-1 inhibitor resistance in KRASmutant lung adenocarcinoma. Cancer Discov. 2018;8:822–835.
Efficacy of Immune Checkpoint Inhibitors in KRASMutant Non-Small Cell Lung Cancer (NSCLC) Arnaud Jeanson, MD,a,b Pascale Tomasini, MD,a,b Maxime Souquet-Bressand, MD,a Nicolas Brandone, PhD,c Mohamed Boucekine, PhD,d Mathieu Grangeon, MD,a Solène Chaleat, MD,a Natalyia Khobta, MD,a,e Julie Milia, MD,f Laurent Mhanna, MD,f Laurent Greillier, MD, PhD,a,b Julie Biemar, PhD,a Isabelle Nanni, MD,g L’houcine Ouafik, MD, PhD,g,h Stéphane Garcia, MD, PhD,c Julien Mazières, MD, PhD,f Fabrice Barlesi, MD, PhD,a,b,* Céline Mascaux, MD, PhDa,b a
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, France b Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Marseille, France c Department of Pathology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Aix-Marseille Université, Marseille, France d EA 3279 - Public Health, Chronic Diseases and Quality of Life–Research Unit, Aix-Marseille University, Marseille, France e Centre Hospitalier Departemental de Castellucio, Oncology Department, Ajaccio, France f Department of Pulmonology, Hôpital Larrey, Centre Hospitalier Universitaire, Paul Sabatier University, Toulouse, France g Aix-Marseille University, APHM, CHU Nord, Service de Transfert d’Oncologie Biologique, Marseille, France h Aix-Marseille University, CNRS, INP, Neurophysiopathology Institute, Marseille, France Received 6 July 2018; revised 30 December 2018; accepted 6 January 2019 Available online - 6 February 2019
ABSTRACT Introduction: 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 progressionfree 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
*Corresponding author. 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. 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. E-mail: fabrice. [email protected] ª 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 https://doi.org/10.1016/j.jtho.2019.01.011
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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. 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. Keywords: NSCLC; Immunotherapy; KRAS mutation; PD-L1 expression
Introduction KRAS mutations are found in approximately 30% of NSCLC1 and confer a poor prognosis.2 Nevertheless, all of the studies testing targeted therapies against KRAS and its downstream pathways have failed to show any clinical benefit.3 Current international guidelines recommend a first-line platinum-based treatment for most NSCLC cases, including those harboring a KRAS mutation.4 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 NSCLC5–7 and first-line therapy for patients with high expression of PD-L1,8 and they will likely become a standard first-line treatment when associated with chemotherapy for all comers with NSCLC.9 In clinical trials comparing ICIs with chemotherapy in second-line treatment, a benefit was suggested in patients with KRAS-mutant NSCLC5 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.10 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
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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, phosphatidylinositol4,5-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 dideoxySanger 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.11
PD-L1 Expression Analyses 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.8
Statistical Analyses The evaluation of tumor response was performed every 2 months by using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.12 Median overall survival (OS) and median progression-free survival (PFS) were estimated by using the KaplanMeier 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
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Table 1. Characteristics of the Baseline Population and ICI Received Variable Age at diagnosis, y Median Range Sex, n (%) Male Female Smoking status, n (%) Current smoker Former smoker Never smoked Unknown Histological type Adenocarcinoma Squamous Large cell carcinoma Other Unknown PS before ICI therapy, n (%) 0 1 2 3 4 Unknown Molecular abnormalities, n (%) KRAS EGFR ALK BRAF HER2 NRAS PIK3CA STK11 METamp ROS1 FGFR TP53 Wild type Type of KRAS mutation, n (%) G12A G12C G12D G12R G12S G12V G13C G13D G13R G13V Unknown
Value 59.8 32.84 168 (59.5) 114 (40.5) 102 143 25 1
(36.2) (50.7) (8.9) (4.2)
263 6 9 3 1
(93.3) (2.1) (3.2) (1.1) (0.4)
70 111 41 9 3 50
(24.8) (39.4) (14.5) (3.2) (0.3) (17.7) (.04)
162 8 2 6 2 1 1 1 3 1 1 1 93
(57.4) (2.8) (0.7) (2.1) (0.7) (0.35) (0.35) (0.35) (1.1) (0.35) (0.35) (0.35) (33)
15 69 25 3 4 24 11 3 1 1 6
(9.3) (42.6) (15.4) (1.8) (2.5) (14.8) (6.8) (1.8) (0.6) (0.6) (3.7) (continued)
comparing two quantitative variables, and a MannWhitney test was used for comparing means. To compare different groups, odds ratios were calculated with a statistical regression method with a CI of 95%.
3
Table 1. Continued Variable Line of ICI, n (%) Maintenance First line Second line Third line Fourth line Fifth line Sixth line Seventh line Lines of ICI, n (%) 1 2 Type of ICI, n (%) Anti–PD-1 Anti–PD-L1 Anti–CTLA4 Anti–PD-1 + anti–CTLA4 Anti–PD-L1 + anti–CTLA4 Other association Name of ICI, n (%) Nivolumab Pembrolizumab Atezolizumab Avelumab Durvalumab Ipilimumab Tremelimumab Durvalumab + tremelimumab Nivolumab + ipilimumab Nivolumab + urelumab
Value 5 24 149 68 24 8 2 2
(1.8) (8.5) (52.8) (24.1) (8.5) (2.8) (0.7) (0.7)
264 (93.6) 18 (6.4) 252 19 4 2 4 1
(89.4) (6.7) (1.4) (0.7) (1.4) (0.35)
249 3 8 4 7 1 3 4 2 1
(88.3) (1.1) (2.8) (1.4) (2.5) (0.4) (1.1) (1.4) (0.7) (0.4)
PS, performance status; ICI, immune checkpoint inhibitor; ALK, ALK receptor tyrosine kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3kinase catalytic subunit alpha gene; HER2, erb-b2 receptor tyrosine kinase 2 gene; STK11, serine/threonine kinase 11 gene; METamp, MNNG HOS Transforming gene amplification; FGFR, fibroblast growth factor receptor gene; TP53, tumor protein p53 gene; anti–PD-1, anti–programmed death 1 antibody; anti–PD-L1, anti–programmed death ligand 1 antibody; antiCTLA4, anti-cytotoxic T-lymphocyte associated protein 4 antibody.
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. The ORR was numerically higher for KRAS-mutant NSCLC (18.7%) than for KRAS wild-type NSCLC
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(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 ¼ 15) versus with G12C (n ¼ 69) versus with G12D (n ¼ 25) versus with G12V (n ¼ 24) versus with G13C (n ¼ 11) mutations were compared (Table 3).
OR ¼ 1.25 (0.7–22.1) 0.451 OR ¼ 1.17 (0.52–2.62) 0.704 OR, odds ratio; HR, hazard ratio; CI, confidence interval; ORR, overall response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival.
0.649 25.8% 0.722 10.8% OR ¼ 1.24 (0.49–3.12) OR ¼ 0.81 (0.25–2.58) OR ¼ 1.25 (0.73–2.11) 0.417 25.9% OR ¼ 1.07 (0.52–2.21) 0.863 14.8% 30.2% 12.3%
25.8% 11.7%
HR ¼ 0.93 (0.68–1.29) 0.682 13.04 (7.71–18.37) HR ¼ 1.14 (0.64–2)
0.660 10.97 (4.74–17.21) HR ¼ 0.89 (0.62–1.24) 0.465
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14.29 (9.64–18.95) 11.14 (7.4–14.9)
OR ¼ 1.18 (0.6–2.34) 0.633 OR ¼ 0.98 (0.58–1.64) 0.936 HR ¼ 0.91 (0.69–1.21) 0.519 OR ¼ 2.76 (0.62–12.35) 0.184 16.3% OR ¼ 0.94 (0.41–2.15) 0.879 48.9% HR ¼ (0.62–1.6) 1.000 2.66 (1.71–3.62) OR ¼ 1.37 (0.71–2.63) 0.348 7.7% OR ¼ 0.97 (0.6–1.57) 0.900 50% HR ¼ 0.93 (0.71–1.21) 0.584 2.66 (1.39–3.93) 14.4% 49.2% 2.66 (1.98–3.34) 18.7% 48.4% 3.09 (2.36–3.82)
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ORR DCR Mean PFS, mo (range) Mean OS, mo (range) PFS >6 mo PFS >12 mo
p NSCLC with Value Other Mutation Non–KRASOR or HR Mutated NSCLC (95% CI) KRAS-Mutated NSCLC Indicator
Table 2. Comparison of ICI Efficacy in KRAS-Mutant NSCLC and Other Types of NSCLC
OR or HR (95% CI)
p Wild-Type Value NSCLC
OR or HR (95% CI)
p Value
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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. 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 KRASmutant 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. 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).
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Table 3. Comparison of ICI Efficacy with Respect to Different KRAS Mutation Subtypes Type of KRAS Mutation Indicator
G12A (n ¼ 15)
G12C (n ¼ 69)
G12D (n ¼ 25)
G12V (n ¼ 24)
G13C (n ¼ 11)
p Value
ORR DCR PFS, mo OS, mo PFS >6 PFS >12
13.30% 46.70% 2.66 Not reached 20% 6.70%
18.50% 46.20% 3.09 11.34% 33.30% 10.10%
20% 52% 3.91 9.76 32% 20%
18.20% 40.90% 2.69 8.9 25% 16.70%
18.20% 54.50% 4.6 18.99 36.40% 18.20%
0.99 0.93 0.96 0.59 0.83 0.58
ORR, overall response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival.
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,5 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 PDL1 expression. PD-L1 has predicted response to checkpoint inhibitors in most of the clinical trials investigating its role in NSCLC.7,9 However, the results are discordant
in some trials, showing benefits for ICI therapy whatever the PD-L1 status.13 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 PDL1–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.10 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 tumorassociated 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.14,15 This resistance of KRAS-mutant lung
Table 4. Analysis of PD-L1 Expression in the Different Groups Indicator
All Patients
KRAS Mutation
Other Mutations
Wild Type
p Value
Patients analyzed/all patients, n (%) Mean PD-L1 tumor expression (95% CI) PD-L1 expression >1%, n (%) PD-L1 expression >50%, n (%)
128/282 (45.4) 19.95 (14.13–25.77) 58 (45.3) 25 (19.5)
85/162 (52.5) 22.13 (14.66–29.6) 42 (49.5) 18 (21.2)
7/27 (26) 17.83 (–5.37 to 28.23) 2 (28.6) 1 (14.3)
36/93 (38.7) 15.65 (6.11–26.83) 14 (38.9) 6 (16.7)
0.420 0.59
PD-L1, programmed death ligand 1; CI, confidence interval.
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Table 5. Analysis of PD-L1 Expression for the Different KRAS Mutation Groups Indicator
G12A
G12C
G12D
G12V
G13C
p Value
Patients analyzed/ all patients, n (%) Mean PD-L1 tumor expression (95% CI) PD-L1 expression >1%, n (%) PD-L1 expression >50%, n (%)
7/15 (46.6)
41/60 (59.4)
12/25 (48)
12/24 (50)
5/11 (45.5)
23.43% (–6.91 to 36.91) 3 (42.9)
22.98% (3.97–20.76) 14 (34.1)
22.7% (5.18–76.49) 7 (58.3)
23.66% (9.34–54.33) 10 (83.3)
21.18% (–6. 54 to 70.94) 3 (60)
0.033
1 (14.3)
4 (9.8)
5 (41.7)
4 (33.3)
2 (40)
0.039
PD-L1, programmed death ligand 1; CI, confidence interval.
adenocarcinomas that have lost serine/threonine kinase 11 (liver kinase B1) activity in response to an ICI has recently been clinically confirmed in patients.16 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
A
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.
Supplementary Data Note: To access the supplementary material accompanying this article, visit the online version of the Journal of Thoracic Oncology at www.jto.org and at https://doi. org/10.1016/j.jtho.2019.01.011.
ORR (%)
40
PFS (months) 8
KRASm NSCLC
35 30
5 4
35,3
15 19
19,2
18,8
5
4,86
2
14,3
3,94
3,22
2,69
1
0
3,94
0 PD-L1 < 1%
1% ≤ PD-L1 < 50%
B
PD-L1 ≥ 50%
PD-L1 < 1%
ORR (%)
120
G12A G12V G12C
10
G12D
G13C
6
100 66,7
50 0
23,1
7,7
0
PD-L1 < 1%
20
28,6
20
1% ≤ PD-L1 < 50%
PD-L1 ≥ 50%
G12C
2
33,3 0
G13C
12,72 10,3810,38
4
66,7
20
G12V
8
60 40
PD-L1 ≥ 50%
G12D
12
80
1% ≤ PD-L1 < 50%
PFS (months)
G12A 14
100
0
7,09
3
25,6
10
non KRASm NSCLC
6
non KRASm NSCLC
25 20
KRASm NSCLC
7
0
0
0
1,74
0
2,732,96
5,32
3,91 1,64
0,46
PD-L1 < 1%
1% ≤ PD-L1 < 50%
7,1 4,6 4,6 1,18
PD-L1 ≥ 50%
Figure 1. Association between PD-L1 expression and ICI efficacy: A. Between KRASm NSCLC and non-KRASm NSCLC. B. Between the different subtypes of KRAS mutation. ORR ¼ Overall Response Rate; PFS ¼ Progression-Free Survival; KRAS ¼ Kirsten Rat Sarcoma Virus; PD-L1 ¼ Programmed death ligand 1; OS ¼ Overall Survival.
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