A study in SCARLET: investigating a new combination of therapies for KRAS G12C mutated non-small cell lung cancer

The development of KRAS G12C inhibitors marked a major advance in thoracic oncology after decades in which KRAS was considered largely “undruggable”. Building on the activity demonstrated with sotorasib and adagrasib in the second line setting (1,2), there is growing interest in moving KRAS G12C inhibitors into earlier lines of therapy and in rational combination strategies designed to deepen responses and delay resistance. Against this backdrop, the phase 2 SCARLET study explored the addition of carboplatin and pemetrexed to sotorasib in treatment-naïve advanced nonsquamous non-small cell lung cancer (NSCLC) with KRAS G12C mutation (3).

SCARLET (Japan Registry of Clinical Trials number 2051210086) should be viewed in the context of a rapidly evolving therapeutic landscape in NSCLC. Combination strategies pairing targeted therapy with chemotherapy have precedent in oncogene-driven lung cancer, most notably in EGFR-mutant disease with the Food and Drug Administration (FDA) approval of osimertinib with platinum-doublet chemotherapy (4,5). However, KRAS G12C-mutant NSCLC has distinct biologic and clinical considerations. Unlike classic “immune-cold” oncogene-driven subsets, KRAS G12C tumors may retain immunogenic features (6,7), making the role of immunotherapy particularly relevant in first-line treatment selection, especially in patients with a tumor programmed death-ligand 1 (PD-L1) expression ≥50%. This makes interpretation of SCARLET more nuanced and raises important questions about patient selection and trial design.

In that context, one notable aspect of SCARLET is the absence of immunotherapy in a population in which checkpoint inhibition remains a key component of standard first-line care. The SCARLET study explored the addition of carboplatin and pemetrexed to sotorasib in patients with previously untreated non-squamous NSCLC harboring a KRAS G12C mutation. It is worth noting that sotorasib is not currently approved for use in this setting. The recommended treatment for the population included in this study in most countries, including Japan, where this study was conducted, would be platinum-doublet chemotherapy combined with a programmed death-1 (PD-1) inhibitor (8). This is especially relevant given that half the enrolled patients had PD-L1 expression ≥50% and would have been eligible for single immune checkpoint inhibitor rather than the control arm offered. Rather than framing this solely as a question of control arm choice, the more substantive issue is how best to position KRAS G12C inhibitors relative to an established chemoimmunotherapy backbone. Relatedly, understanding post-protocol therapies, including subsequent use of PD-1 blockade, would help contextualize efficacy outcomes and inform interpretation.

The reported median progression-free survival of 6.6 months should also be interpreted cautiously given the small sample size. The authors note that patients whose disease had PD-L1 expression levels <1% seemed to have better outcomes with the combination of sotorasib and carboplatin and pemetrexed in this study. While this study was underpowered to draw any meaningful conclusions about individual sub-groups, this finding does raise the question about the distribution of somatic alterations (such as KEAP1, STK11, or SMARCA4) in this PD-L1 <1% population. These somatic alterations have been consistently shown to confer worse outcomes with immune checkpoint inhibitors (9-11), and this population in particular may benefit from the addition of a KRAS G12C inhibitor.

Perhaps the most important contribution of SCARLET are the questions it raises for ongoing drug development in this space. Several ongoing prospective clinical trials, such as CodeBreaK 202 (NCT05920356), KRYSTAL-4 (NCT06875310), KRAScendo-2 (NCT06793215), and SUNRAY-01 (NCT06119581) are being conducted that may better define the role of KRAS G12C inhibitors in the first line setting. In addition, these studies may clarify whether certain high-risk subsets (such as patients with KEAP1, STK11, or SMARCA4 alterations), may benefit from a dedicated combination strategy. Additionally, these studies will clarify any potential safety signals with the combination of KRAS G12C inhibitors and immune checkpoint inhibitors.

Taken together, SCARLET reflects both the promise and the complexity of developing frontline combination strategies for KRAS G12C mutant NSCLC. Given the complexities of KRAS biology, the lack of clear biomarkers to distinguish differential susceptibilities to immune checkpoint inhibitor versus KRAS G12C inhibitors, and the rapidly evolving therapeutic landscape, future success may depend more on thoughtful integration of KRAS G12C inhibition into biomarker-informed, multi-modality treatment strategies.

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