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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.

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    1 Comment for this article
    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.

    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