Patients with KRAS-Mutated NSCLC Benefit from First-line Combination Therapy

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Lung cancer has 2 main categories: small-cell lung cancer and non–small-cell lung cancer (NSCLC), with NSCLC compromising 85% of all cases.1 Adenocarcinoma makes up 60% of NSCLC histologic types.1 Immune checkpoint inhibitors (ICIs) have improved the prognosis for metastatic NSCLC and have 3 main targets: programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4).1 The Kirsten rat sarcoma (KRAS) mutation is the most commonly found mutation and is mainly found in adenocarcinoma NSCLC.1 KRAS mutation conveys a poor response to chemotherapy and a poor prognosis for advanced NSCLC.1

Retrospective analysis has shown that ICI as first-line treatment in patients with NSCLC with KRAS mutation is beneficial. To evaluate this, a study was performed on pooled data from 12 registrational clinical trials that investigated first-line ICI therapy with or without chemotherapy in 1430 patients with NSCLC harboring a KRAS mutation (39%) or KRAS wildtype (61%). Among patients with KRAS mutation, 11% had KRAS G12C. Demographics of the study group were as follows: 89% of patients were white, 67% were former or current smokers, 60% were men, and 60% were PD-L1 positive.

The objective response rate (ORR) and overall survival (OS) rate of patients receiving ICI alone, chemotherapy alone, or ICI in combination with chemotherapy were determined from the pooled data and evaluated by KRAS status, which included G12C, wildtype, or mutated. Subgroup analysis was also performed on KRAS and PD-L1 statuses. PD-L1 status was stratified by positive (combined positive score ≥1), negative (combined positive score <1), high (combined positive score ≥50), or low (combined positive score <50).

In patients with mutated KRAS, the median OS for first-line ICI alone was 16.2 months, for chemotherapy alone it was 17.1 months, and for ICI plus chemotherapy it was 22.4 months. The ORR for these patients was 37% for ICI alone, 35% for chemotherapy alone, and 46% for chemotherapy plus ICI. For patients with KRAS G12C mutation, the median OS for first-line ICI alone was 11.8 months, for chemotherapy alone it was 17.5 months, and for combination therapy it was 20.8 months. The ORR was 33% for ICI alone, 44% for chemotherapy alone, and 47% for chemotherapy plus ICI. Patients with wildtype KRAS had a median OS of 16.4 months for first-line ICI alone, 14.9 months for chemotherapy alone, and 18.7 months for combination therapy. The ORR for this patient group was 33% for ICI alone, 32% for chemotherapy alone, and 51% for chemotherapy plus ICI.


  1. Torralvo J, Friedlaender A, Achard V, Addeo A. The activity of immune checkpoint inhibition in KRAS mutated non-small cell lung cancer: a single centre experience. Cancer Genomics Proteomics. 2019;16(6):577-582.

Source: Nakajima E, Ren Y, Vallejo JJ, et al. Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis. J Clin Oncol. 2022;40(16):suppl,9001-9001.

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