Chemotherapy in combination with KRAS inhibitors in KRAS-mutated non-small cell lung cancer

Kirsten rat sarcoma viral oncogene homolog (KRAS) is a common, targetable, treatable allele-specific KRAS G12C mutation that occurs in 10% of patients in Western countries and 3% in Asian countries or in patients with Asian ancestry (1) with a considerable variability across regions: prevalence ranges from 8.9% to 19.5% in the United States and 9.3% to 18.4% in Europe, compared with 6.9% to 9.0% in Latin America, and the lowest levels in Asia, from 1.4% to 4.3% (2,3).

Akamatsu and colleagues (4) have recently reported a phase 2 study of sotorasib plus carboplatin and pemetrexed in KRAS G12C-mutated non-small cell lung cancer (NSCLC) (WJOG1148211L, SCARLET trial). Thirty patients received as first-line therapy sotorasib 960 mg daily and four cycles of carboplatin (area under the curve =5) and pemetrexed 500 mg/m², followed by sotorasib plus pemetrexed until progression. The study included patients across different disease stages and metastatic patterns. At baseline, 30% of patients had stage IVA disease (n=9), 53.3% had stage IVB disease (n=16), and 16.7% had recurrent disease after prior curative treatment (n=5). In addition, 23.3% of patients (n=7) had brain metastases at enrollment. Objective response rate (ORR) was impressive 88.9%, with median progression-free survival (PFS) of 6.6 months and median overall survival of 20.6 months. Although efficacy outcomes were not formally stratified by stage or brain involvement, the predominance of metastatic disease, particularly stage IVB, and the inclusion of patients with baseline brain metastases likely reflect a population with substantial disease burden, with a very poor prognosis.

In the SCARLET trial, the combination of sotorasib plus carboplatin and pemetrexed showed a manageable safety profile, with toxicity largely driven by chemotherapy related hematologic adverse events. All patients experienced treatment related adverse events, and grade ≥3 events occurred in 89.7%, most commonly anemia (37.9%), thrombocytopenia (27.6%), and neutropenia (27.6%). Non-hematologic toxicities, including gastrointestinal symptoms and hepatotoxicity, were generally mild. Pneumonitis occurred in 14% of patients, and one treatment-related fatal pneumonia was reported. Overall, treatment discontinuation due to adverse events occurred in 37.9% of patients, consistent with expectations for platinum-based triplet regimens.

Notably, analysis of plasma samples showed that patients with longer PFS were those without detectable KRAS G12C at baseline, those without co-mutations, and those who cleared KRAS G12C mutations by 3 weeks (median PFS was 16.7 months, 13.9 months and 8.7 months, respectively). For patients with persistent presence of KRAS G12C mutations in the plasma (“shedders”), the PFS was 4.4 months. In the SCARLET trial (4) further breakdown analysis of PFS with regard to other coexisting alterations, when examined by next-generation sequencing (NGS), revealed that tumor protein p53 (TP53) co-mutation was observed in 18 patients (67%), and other co-mutations were detected in 6 patients (59%). Median PFS was 9.0 months for 5 patients without TP53 mutations and 6.0 months for 15 patients with TP53 co-mutations (P=0.69). According to subgrouping by other co-mutations or alterations, PFS was 13.9 months in patients without other alterations versus 5.4 months for those with high-risk co-mutations (P=0.02) (4).

What is the value of chemotherapy in KRAS G12C NSCLC? Is the benefit limited to a fraction of patients in whom KRAS G12C co-mutations are not identifiable? And the third question, which could be the best chemotherapy regimen? To answer the first question, we surmise that chemotherapy could add a tangible benefit in clinical outcomes based on the seminal report about AMG510 (sotorasib) showing that the combination treatment of AMG510 with carboplatin yielded a significant inhibition of the xenografted NCI-H358 (KRAS G12C, TP53 deletion) cell line tumor growth in mice (5). This is the first paradigm-shifting contribution showing that the combination of a mutant allele-specific KRAS inhibitor with chemotherapy could pave the way for implementation in clinical trials (5). However, this concept has been underappreciated, and trials have focused on testing the bona fide efficacy of KRAS allele-specific inhibitors versus docetaxel as second-line therapy in KRAS G12C-mutated NSCLC, as seen in the CodeBreaK 200 and KRYSTAL-12 phase 3 trials (6,7). In the CodeBreak 200 trial, 345 KRAS G12C-mutated NSCLC patients who progressed to previous treatment were randomly assigned to receive sotorasib (171 patients) (960 mg once daily) or docetaxel (174 patients) (intravenously 75 mg/m² every 3 weeks). Median PFS for sotorasib was 5.6 months versus 4.5 months for docetaxel (P=0.001) (6). The similar phase 3 KRYSTAL-12 trial allocated 301 patients to receive either adagrasib (600 mg twice a day orally) or docetaxel (75 mg/m² every 3 weeks intravenously). The median PFS was 5.5 months with adagrasib and 3.8 months with docetaxel (P<0.001) (7).

Importantly, nowadays, NGS accurately provides significant predictive information, as reported in the SCARLET trial (4). Regarding the second point—whether co-mutations can universally compromise not only the PFS of KRAS G12C inhibitors but also chemotherapy—some answers can be found in the recent molecular subgroup analyses of biomarker efficacy from the phase 2 CodeBreaK and phase 3 CodeBreaK 200 studies (8). Skoulidis and colleagues (8) subdivide KRAS G12C NSCLC patients according to principal co-clustering mutations. For patients with KRAS G12C and TP53 co-mutations (KP subgroup), the median PFS was nearly identical: 7.75 months for sotorasib and 7.18 months for docetaxel, revealing a notable therapeutic effect of docetaxel. However, in the presence of other co-mutations, such as serine/threonine kinase 11 (STK11) and kelch-like ECH-associated protein 1 (KEAP1), the median PFS was 5.85 months with sotorasib and decreased to 2.69 months for docetaxel (8). Perhaps the most surprising finding was that the presence of ataxia telangiectasia mutated kinase (ATM) co-mutations, observed in 16.35% of patients, was associated with a numerically greater benefit from docetaxel. In KRAS G12C-mutated NSCLC patients harboring ATM co-mutations, PFS was 8.25 months with docetaxel compared with 4.17 months for sotorasib in this subgroup (P=0.13). Notably, in a pooled analysis of 205 patients treated with sotorasib in the CodeBreaK 100 and CodeBreaK 200 studies, ATM co-mutations were associated with shorter PFS (P=0.03) (8).

Moving to the third question: chemotherapy could enhance efficacy, as measured by PFS, but which type of cytotoxic agents and chemotherapy regimen might be most beneficial to combine with KRAS selective allele-specific inhibitors? Schalafen-11 (SLFN11) expression independently predicted response in ovarian cancer patients treated with cisplatin-based regimens. SLFN11 also shows a strong correlation with response to topoisomerase inhibitors but has no significant effect on other anticancer agents, such as antimitotic agents like paclitaxel (9). Recently, a surprising mechanism of resistance in HER2-mutated NSCLC was discovered, associated with the loss of SLFN11, which confers resistance to the topoisomerase payload of the drug conjugate trastuzumab deruxtecan (10). Speculatively, the loss of SLFN11 could commonly be associated with the use of platinum (carboplatin) combinations.

Mechanistically, we can further reason that the combination of KRAS G12C inhibitors, such as sotorasib, with chemotherapy could be mutually necessary. Sotorasib can induce resistance through upregulation of the inositol-requiring enzyme 1 alpha (IRE1α) branch of the unfolded protein response, and suppressing IREα overcomes resistance to KRAS G12C inhibitors (11). Moreover, IRE1α inhibits stimulator of interferon genes (STING) in pancreatic ductal adenocarcinoma models whereas chemotherapy induces downregulation of IRE1α (12).

In the SCARLET study, Akamatsu and colleagues (4) further unveil the participation of programmed death-ligand 1 (PD-L1) expression levels. For patients with PD-L1 <1%, PFS was 9.7 months versus 6.2 months for 16 patients with PD-L1 >1% (P=0.89). Along the same lines, in the KROCUS study, fulzerasib (KRAS G12C allele-specific inhibitor) plus cetuximab (EGFR monoclonal antibody) as first-line therapy in KRAS G12C-mutated advanced NSCLC patients yielded a median PFS of 12.5 months in 14 patients with PD-L1 <1%, compared with 7.0 months in 8 patients with PD-L1 1–49% and 7.3 months in 12 patients with PD-L1 >50% (13). Importantly, the SCARLET study (4) serves as a reference that highlights the critical clinical value of comprehensive evaluation of KRAS G12C-mutated NSCLC patients using NGS and PD-L1 expression assessments. There are important facets that we believe are beyond the scope of this commentary, but no less crucial, such as safety and efficacy in brain metastases. Numerous novel KRAS G12C inhibitors target both the guanosine triphosphate (GTP)-bound “ON” and GDP-bound “OFF” states (14) and, ideally, could pave the way for advancing a triple-combination approach of KRAS G12C inhibitors with chemotherapy—primarily docetaxel—and immune checkpoint inhibitors [anti-programmed death-1 (PD-1)/PD-L1 antibodies]. Lastly, monotherapy with pembrolizumab, another immune checkpoint inhibitor, has demonstrated remarkable benefit in a subgroup of patients with KRAS G12C-mutated NSCLC harboring concurrent TP53 mutations and PD-L1 >50% (15,16). See Figure 1 for a comprehensive rationale for combining KRAS G12C inhibitors with different classes of chemotherapy and immune checkpoint inhibitors. Table 1 summarizes the SCARLET trial and other ongoing studies evaluating chemotherapy and immunotherapy in KRAS G12C-mutant NSCLC, as well as in other tumor types with different KRAS genotypes (4,17-22).

Figure 1 Schematic depicting key elements for combinatory therapy in KRAS G12C-mutated NSCLC. The components include the basis for combining KRAS G12C inhibitors with immune checkpoint inhibitors and chemotherapy. The pros and cons of differential chemotherapy effects are also included. The references that form the basis for the schematic representation of combinatorial treatment are cited in the text. KRAS, Kirsten rat sarcoma virus oncogene homologue; mo, month; NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand-1; PFS, progression-free survival.

Important questions remain unresolved, including how to reconcile common therapeutic management regardless of PD-L1 expression levels and how to sensitize STK11—and/or KEAP1—co-mutated KRAS G12C NSCLC tumors, which often present as “cold” tumors lacking cluster of differentiation 8 (CD8)⁺ T cell infiltration (8). Deciphering signaling pathways and conducting preclinical translational research are expected to provide timely solutions for optimizing and rationally combining KRAS G12C inhibitors with chemotherapy and immune checkpoint inhibitors.

Acknowledgments

None.

Footnote

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2712/coif). The authors have no conflicts of interest to declare.

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