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KRAS G12C Mutated NSCLC
KRAS G12C–Mutated NSCLC: Addressing Unmet Needs and Emerging Therapeutic Insights

Released: June 26, 2026

Christine Bestvina
Christine Bestvina, MD
Luis Paz-Ares
Luis Paz-Ares, MD, PhD
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Key Takeaways
  • Next-generation KRAS G12C inhibitors are showing encouraging improvements in response rates and durability, with agents such as divarasib, olomorasib, and elisrasib demonstrating promising activity in both previously treated and frontline settings.
  • Combination approaches with next-generation KRAS G12C inhibitors and immunotherapy may expand treatment possibilities, potentially enabling chemotherapy-free frontline strategies for some patients regardless of PD-L1 expression, although careful toxicity management remains essential.

KRAS is one of the most frequently mutated oncogenes in solid tumors and is present in >90% of pancreatic cancers and approximately 30% of non-small-cell lung cancer (NSCLC). Among the various KRAS alterations, G12C accounts for roughly 40% to 45% of KRAS mutations in NSCLC. Although KRAS has long been considered a difficult therapeutic target, recent advances have led to the development of selective KRAS G12C inhibitors, such as sotorasib and adagrasib, that are now available in clinical practice. Despite these advances, resistance remains a major challenge, limiting the durability of response for many patients. Next-generation KRAS inhibitors and combination approaches, particularly those incorporating immunotherapy with or without chemotherapy, have demonstrated encouraging activity in early studies.

Unmet Need in KRAS G12C–Mutated NSCLC

Christine Bestvina, MD
Currently, we have 2 approved KRAS G12C inhibitors for patients with locally advanced or metastatic NSCLC: sotorasib and adagrasib. Although these agents have expanded our treatment options, most patients eventually experience disease progression, and the durability of benefit remains limited in the second-line setting. In randomized phase III trials (CodeBreaK-200 and KRYSTAL-12), sotorasib demonstrated a median progression-free survival (PFS) of 5.6 months, and adagrasib demonstrated a median PFS of 5.6 months when compared to docetaxel. This highlights a significant unmet need.  Next-generation KRAS G12C inhibitors can achieve more durable responses, higher response rates, and better compatibility with immunotherapy. Ultimately, these advances could help move KRAS-targeted therapies into the frontline setting and allow more patients to benefit from these treatments.

Luis Paz-Ares, MD, PhD
The emergence of resistance is a major limitation of first-generation KRAS G12C inhibitors. Resistance can arise through secondary KRAS mutations, alterations in other KRAS alleles, RAS amplification, activation of alternative signaling pathways, or the development of novel gene fusions. In addition, KRAS G12C–mutated tumors are often associated with comutations such as LKB1 and KEAP1, which can negatively affect prognosis and may diminish the benefit of immunotherapy. We need some novel therapies to address this population of patients.

Raising Expectations for KRAS G12C Treatment

Christine Bestvina, MD
What I find most exciting about the emerging data in KRAS G12C–mutated NSCLC is that several next-generation inhibitors are demonstrating impressive response rates and durability. In addition, these therapies appear to be safe in combination with immunotherapy, opening the door to chemotherapy-free frontline treatment approaches for some patients. Like the first-generation agents, these drugs target the inactive, GDP-bound form of KRAS G12C, but they are designed to achieve more potent and sustained target inhibition with the goal of improving response rates, prolonging PFS, and overcoming resistance.

As an example, divarasib has generated encouraging results. In a phase I study involving largely pretreated patients with KRAS G12C–mutated NSCLC, divarasib achieved an objective response rate of 56% and a median PFS of 13.8 months. The safety profile was favorable, with relatively low rates of grade 3 or higher treatment-related adverse events (AEs) and less hepatic toxicity than has been reported with some earlier-generation inhibitors. Similarly, olomorasib has demonstrated promising activity. In a first-in-human phase I study, the objective response rate was approximately 33%, including patients who had previously received a KRAS G12C inhibitor. Treatment was generally well tolerated, with low rates of hepatic enzyme elevations and manageable gastrointestinal toxicities.

These early studies have established an important foundation, but what is particularly exciting now is seeing these agents move into frontline clinical trials, often in combination with immunotherapy.

Key Clinical Updates from ASCO 2026

Christine Bestvina, MD
One of the most notable presentations at ASCO this year was the KRAScendo-170 study evaluating first-line divarasib plus pembrolizumab in advanced KRAS G12C–mutated NSCLC. Across both PD-L1–positive and PD-L1–negative cohorts, the efficacy signals were impressive. In the PD-L1-positive cohort, the response rate reached 73%, with an additional 19% of patients achieving stable disease. Median PFS was 19.3 months, and responses were observed regardless of level of PD-L1 expression or the presence of KEAP1 and STK11 comutations. Similarly encouraging activity was seen in the PD-L1–negative cohort, where the response rate approached 70%.

The efficacy data are compelling, particularly because this represents a chemotherapy-free strategy regardless of PD-L1 status. However, toxicity remains an important consideration. Grade 3 or higher treatment-related AEs occurred in 65% of patients, with frequent dose interruptions and reductions. Gastrointestinal AEs and liver enzyme elevations were among the most commonly reported toxicities. As these regimens move forward into larger studies such as the ongoing phase III KRAScendo-2 trial (NCT06793215), understanding how to optimize toxicity management will be critical.

Another exciting ASCO presentation was of elisrasib, a next-generation KRAS G12C inhibitor evaluated both as monotherapy and in combination with pembrolizumab in the frontline setting. In the phase I/II trial, elisrasib monotherapy achieved an objective response rate of 78% across PD-L1 subgroups, with a median PFS of 12.4 months. The safety profile was particularly encouraging, with few grade 3 or higher treatment-related AEs and no discontinuations due to toxicity.

When combined with pembrolizumab, the response rate increased to 81%, and median PFS had not yet been reached at the time of analysis. As expected, toxicity increased with combination therapy, highlighting the balance we continue to navigate between maximizing efficacy and managing cumulative treatment-related AEs. Nevertheless, the efficacy signals remain highly encouraging.

ASCO also provided valuable insights into clinical trial design. Data from the SUNRAY-01 and LOXO-RAS-20001 studies, which investigated olomorasib with pembrolizumab with or without chemotherapy in the 1first-line setting, suggested that patients who received a single cycle of standard-of-care therapy before enrolling on trial experienced outcomes similar to those who enrolled without prior treatment. I believe this is an important finding because it better reflects real-world practice, where patients often need to begin therapy quickly following diagnosis. Expanding eligibility criteria in this way may help improve trial access and enrollment while generating data that are more representative of the patients we treat every day.

Future Opportunities and Ongoing Questions

Christine Bestvina, MD
As we move through 2026, I expect we will continue to see exciting data on incorporating KRAS G12C therapies into frontline treatment for patients with metastatic NSCLC. I am particularly interested in whether these combinations can improve response rates, PFS, and, of most importance, overall survival by giving patients earlier access to more effective targeted approaches.

At the same time, we will need to carefully navigate cumulative toxicities, especially liver enzyme elevations such as AST and ALT. Optimizing management will be essential so that patients do not have immunotherapy held long term when these abnormalities may be driven by the KRAS inhibitor. I am also eager to see how these regimens perform in real-world populations as clinical trial design continues to evolve.

Luis Paz-Ares, MD, PhD
I am particularly excited about the newer generation of KRAS G12C inhibitors, which appear to provide higher activity, higher response rates, and more durable benefit, with a clearer impact on PFS. Trials such as KRAScendo-2, comparing divarasib with first-generation inhibitors in the second-line setting, will be especially informative.

Equally important, these agents appear more compatible with immunotherapy and are already being studied in earlier-stage disease, including perioperative approaches such as SUNRAY-01 with olomorasib plus chemoimmunotherapy in resectable NSCLC. I think the future with these therapies is promising.

Your Thoughts
What evidence would you like to see from ongoing phase III studies before considering chemotherapy-free KRAS-targeted regimens in the frontline setting?

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How often do you discuss clinical trials of next-generation KRAS G12C inhibitors with your patients with advanced NSCLC and KRAS G12C mutations?

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