Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor–Based Therapy in Patients With Advanced Non–Small-Cell Lung Cancer | Cancer Biomarkers | JAMA Oncology | JAMA Network
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Figure.  Overall Survival in Programmed Cell Death Ligand 1–High Non–Small-Cell Lung Cancer by KRAS Status and First-line Treatment Regimen
Overall Survival in Programmed Cell Death Ligand 1–High Non–Small-Cell Lung Cancer by KRAS Status and First-line Treatment Regimen

ICI indicates immune checkpoint inhibition.

Table.  Hazard Ratios for Death in PD-L1–High NSCLC by KRAS Status and Treatment Regimen
Hazard Ratios for Death in PD-L1–High NSCLC by KRAS Status and Treatment Regimen
1.
Herbst  RS.  LBA4 Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in Keynote-042.   Annals of Oncology. 2019;30:xi63-xi64. doi:10.1093/annonc/mdz453.001Google ScholarCrossref
2.
Liu  C, Zheng  S, Jin  R,  et al.  The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity.   Cancer Lett. 2020;470:95-105. doi:10.1016/j.canlet.2019.10.027PubMedGoogle ScholarCrossref
3.
Coelho  MA, de Carné Trécesson  S, Rana  S,  et al.  Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA.   Immunity. 2017;47(6):1083-1099.e6. doi:10.1016/j.immuni.2017.11.016PubMedGoogle ScholarCrossref
4.
Mok  TSK, Wu  YL, Kudaba  I,  et al; KEYNOTE-042 Investigators.  Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.   Lancet. 2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7PubMedGoogle ScholarCrossref
5.
Ma  X.,,  et al,  Comparison of population characteristics in real-world clinical oncology databases in the US: Flatiron Health, SEER, and NPCR.   medRxiv, 2020: p. 2020.03.16.20037143. doi:10.1101/2020.03.16.20037143Google Scholar
6.
Kartolo  A, Feilotter  H, Hopman  W, Fung  AS, Robinson  A.  A single institution study evaluating outcomes of PD-L1 high KRAS-mutant advanced non-small cell lung cancer (NSCLC) patients treated with first line immune checkpoint inhibitors.   Cancer Treat Res Commun. 2021;27:100330. doi:10.1016/j.ctarc.2021.100330PubMedGoogle Scholar
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    Can KRAS variants Status be used for directing ICI monotherapy or chemo-ICI treatment in advanced NSCLC with PD-L1≥50%?
    Yanbin Kuang, phD | Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
    Lova Sun, et al. 1 analyzed advanced non-squamous NSCLC patients with PD-L1≥50%, no alteration in EGFR/ALK/ROS1, and treated with first-line ICI mono-therapy or chemo-immunotherapy(Chemo-ICI). Results suggest that KRASwt(wild type) is associated with poor OS compared with KRASv(variants) patients treated with ICI monotherapy, whereas there are no difference between these two arms treated with chemoimmunotherapy. Interesting questions are emerging:
    1. Is there association between KRASv Status and immunotherapy outcome?
    Besides this study, an exploratory analysis of KEYONTE-042 suggested that KRASv is associated with longer OS in patients with ICI monotherapy. 2 The significant difference seems to be due to the shorter OS
    in KRASwt patients with ICI monotherapy. An integrated analysis reported KRASv is correlated with an inflammatory tumor microenvironment and tumor immunogenicity, resulting in superior patient response to PD-1/PD-L1 inhibitors. 3
    2. Can KRASv Status be used for directing ICI monotherapy or chemo-ICI treatment in advanced NSCLC with PD-L1≥50%?
    Pembrolizumab monotherapy is a standard first-line treatment for advanced NSCLC with PD-L1≥50% and no driver mutations. Chemo-ICI treatment improved OS of advanced NSCLC regardless of PD-L1 expression. Then, which one is better for NSCLC patients with PD-L1≥50%?
    S. Peters, et al. 4 found no difference of OS between ICI monotherapy and chemo-ICI in NSCLC with PD-L1≥50%. In contrast, Baohui Han, et al. 5 found pembrolizumab+chemotherapy significant improved OS, PFS and ORR compared with pembrolizumab alone in in Chinese patients. As we known, chemo-ICI has much higher incidence of TRAEs, which should be considered as well.
    Both Lova Sun, et al. 1 and S. Peters, et al. 4 used the Flatiron Health database in US. Among 1127 patients involved, 573(50.8%) had KRASv status 1. However, the prevalence of KRASv is much lower in Chinese population3. The different of KRASv status might be the key-point which makes the distinct conclusions between two retrospective studies4-5, since KRASwt might be associated with poor OS in patients with ICI monotherapy. In addition, Chemo-ICI fail to promote anti-tumor response compared with ICI monotherapy in KRAS-mutant mouse model 3.
    Altogether, KRASv status is potential for directing first-line ICI monotherapy or chemo-ICI treatment in advanced NSCLC with PD-L1≥50%. However, we need more prospective randomized controlled clinical trials to verify, and more mechanism studies to explain this hypothesis. Biomarkers exploration for immunotherapy is of great clinical value, KRASv might be a promising start point of further research.

    Reference
    1. Lova Sun, et al. Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor–Based Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. JAMA Oncol. Published online April 15, 2021. doi:10.1001/jamaoncol.2021.0546
    2. Mok TSK, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830.
    3. Liu C, et al. The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity. Cancer Lett. 2020;470:95-105. doi:10.1016/j.canlet.2019.10.027
    4. S. Peters, et al. VP2-2021: Effectiveness of PD-(L)1 inhibitors alone or in combination with platinum-doublet chemotherapy in first-line (1L) non-squamous
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    April 15, 2021

    Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor–Based Therapy in Patients With Advanced Non–Small-Cell Lung Cancer

    Author Affiliations
    • 1Abramson Cancer Center, Division of Hematology/Oncology, University of Pennsylvania, Philadelphia
    JAMA Oncol. 2021;7(6):937-939. doi:10.1001/jamaoncol.2021.0546

    For patients with advanced non–small-cell lung cancer (NSCLC) without a driver alteration and programmed cell death ligand 1 (PD-L1) expression of 50% or greater, immune checkpoint inhibition (ICI) monotherapy or in combination with chemotherapy is standard first-line therapy. When deciding between these options, clinicians consider disease burden and comorbidities; however, to our knowledge, no biomarkers have been shown to predict differential benefit or harm.

    KRAS variants in NSCLC are associated with smoking history, higher PD-L1 expression, and responsiveness to ICI monotherapy.1-3 The KEYNOTE-042 study demonstrated an overall survival (OS) benefit for first-line pembrolizumab over chemotherapy in patients with PD-L1 expression of 1% or greater.4 In an exploratory analysis, this benefit was seen regardless of KRAS status, but was more pronounced in patients with KRAS variants (median OS [mOS], 28 vs 11 months; hazard ratio [HR], 0.42;, 95% CI, 0.22-0.81) than those without KRAS variants (mOS, 15 vs 12 months; HR, 0.86; 95% CI, 0.63-1.18).1 However, to our knowledge, no prior studies have evaluated the association of KRAS status with outcomes following ICI monotherapy vs chemoimmunotherapy in patients with PD-L1 of 50% or greater.

    Methods

    Using the Flatiron Health database, comprising 280 cancer clinics across the US,5 we analyzed patients with advanced nonsquamous NSCLC with PD-L1 expression of 50% or greater, known KRASv status, and no alteration in EGFR, ALK, or ROS1 who were treated with first-line ICI monotherapy or chemoimmunotherapy between January 2016 and May 2020. Institutional review board exemption was granted by the University of Pennsylvania after determination that the proposal met eligibility criteria for institutional review board review exemption. Kaplan-Meier methods compared OS (from first-line systemic therapy initiation to death from any cause) between groups stratified by treatment type and KRAS status (variant [v] or wild type [wt]). Cox proportional hazards models estimated adjusted HRs and 95% CIs for death associated with KRAS status and treatment regimen. Analyses were performed using Stata, version 15 (StataCorp). Statistical significance was set at 2-sided P < .05 for all tests.

    Results

    Among 1127 patients with advanced nonsquamous NSCLC with PD-L1 expression of 50% or greater, 573 (50.8%) had KRASv status and 554 (49.2%) had KRASwt status. Patients with KRASv status were more likely to be female (58.7% vs 47.1%; P = .002) and have smoking history (96.4% vs 87.7%; P < .001). Other characteristics, including age, race/ethnicity, performance status, and stage at diagnosis, were well balanced among the groups.

    Among patients treated with ICI monotherapy, KRASv was associated with superior survival compared with KRASwt (mOS, 21.1 vs 13.6 months; P = .03); this association remained significant on an adjusted Cox model (HR, 0.77; 95% CI, 0.61-0.98; Table). However, among patients treated with chemoimmunotherapy, there was no significant survival difference between patients with KRASv and KRASwt status (mOS, 20.0 vs 19.3 months; P = .93; adjusted HR, 0.99; 95% CI, 0.70-1.40; Table).

    Among patients with KRASv status, OS did not differ between those treated with ICI monotherapy and chemoimmunotherapy (mOS, 21.1 vs 20.0 months; P = .78; Figure; adjusted HR, 1.03; 95% CI, 0.75-1.40; Table). Among patients with KRASwt status, those treated with ICI monotherapy had numerically worse survival than those treated with chemoimmunotherapy, although this difference was not statistically significant (mOS, 13.6 vs 19.3 months; P = .06; Figure; adjusted HR, 1.19; 95% CI, 0.89-1.58; Table).

    Discussion

    Our findings suggest that among patients with PD-L1 expression of 50% or greater NSCLC treated with ICI monotherapy, KRASwt is associated with worse survival compared with KRASv. In contrast, survival did not differ appreciably between patients with KRASv and KRASwt status who were treated with chemoimmunotherapy. Whereas patients with PD-L1–high NSCLC with KRASv had favorable survival (mOS ≥20 months) with either ICI monotherapy or chemoimmunotherapy, patients with KRASwt who were treated with ICI monotherapy had numerically inferior survival compared with those treated with chemoimmunotherapy, although this difference was not statistically significant. These data suggest that chemoimmunotherapy might be favored over ICI monotherapy for patients with KRASwt with high PD-L1 expression. While the specific prevalence of KRASv in the PD-L1–high subset is not definitively known, the 50% prevalence observed in our cohort is similar to that reported by others.6 The limitations of this analysis include unknown KRASv subtype and covariant status, including TP53 and STK11, as well as residual confounding despite adjustment for multiple covariates. Further investigation is needed to optimize selection between multiple available treatment strategies for patients with PD-L1–high NSCLC.

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    Article Information

    Accepted for Publication: February 22, 2021.

    Published Online: April 15, 2021. doi:10.1001/jamaoncol.2021.0546

    Corresponding Author: Charu Aggarwal, MD, MPH, Division of Hematology/Oncology, University of Pennsylvania, 3400 Civic Center Blvd, South Pavilion, 10-137, Philadelphia, PA 19104 (charu.aggarwal@pennmedicine.upenn.edu).

    Correction: This article was corrected on May 27, 2021, to fix the surname of Dr Hsu.

    Author Contributions: Drs Mamtani and Aggarwal were co–senior authors. Dr Sun had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Sun, Langer, Mamtani, Aggarwal.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Sun, Hsu, Aggarwal.

    Critical revision of the manuscript for important intellectual content: Sun, Cohen, Langer, Mamtani, Aggarwal.

    Statistical analysis: Sun, Aggarwal.

    Administrative, technical, or material support: Hsu, Aggarwal.

    Supervision: Langer, Mamtani, Aggarwal.

    Other - patient resources: Langer.

    Conflict of Interest Disclosures: Dr Cohen reported grants from Merck outside the submitted work. Dr Langer reported personal fees from Merck, Genentech, Roche, Lilly, Takeda, Gilead, and AstraZeneca and grants from Trizell, Merck, AstraZeneca, and Amgen outside the submitted work. Dr Mamtani reported personal fees from Astellas and Seagen, grants from Merck, and travel fees from Flatiron Health outside the submitted work. Dr Aggarwal reported personal fees from AstraZeneca, Bristol Myers Squibb, Celgene, Merck, and Roche outside the submitted work. No other disclosures were reported.

    References
    1.
    Herbst  RS.  LBA4 Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in Keynote-042.   Annals of Oncology. 2019;30:xi63-xi64. doi:10.1093/annonc/mdz453.001Google ScholarCrossref
    2.
    Liu  C, Zheng  S, Jin  R,  et al.  The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity.   Cancer Lett. 2020;470:95-105. doi:10.1016/j.canlet.2019.10.027PubMedGoogle ScholarCrossref
    3.
    Coelho  MA, de Carné Trécesson  S, Rana  S,  et al.  Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA.   Immunity. 2017;47(6):1083-1099.e6. doi:10.1016/j.immuni.2017.11.016PubMedGoogle ScholarCrossref
    4.
    Mok  TSK, Wu  YL, Kudaba  I,  et al; KEYNOTE-042 Investigators.  Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.   Lancet. 2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7PubMedGoogle ScholarCrossref
    5.
    Ma  X.,,  et al,  Comparison of population characteristics in real-world clinical oncology databases in the US: Flatiron Health, SEER, and NPCR.   medRxiv, 2020: p. 2020.03.16.20037143. doi:10.1101/2020.03.16.20037143Google Scholar
    6.
    Kartolo  A, Feilotter  H, Hopman  W, Fung  AS, Robinson  A.  A single institution study evaluating outcomes of PD-L1 high KRAS-mutant advanced non-small cell lung cancer (NSCLC) patients treated with first line immune checkpoint inhibitors.   Cancer Treat Res Commun. 2021;27:100330. doi:10.1016/j.ctarc.2021.100330PubMedGoogle Scholar
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