KRAS-Mutant Lung Cancer: Unmet Needs Persist Beyond G12C, Expert Says

In an interview with Targeted Oncology^TM, Benjamin Herzberg, MD, of the Division of Hematology/Oncology at Columbia University Irving Medical Center, outlined the most pressing unmet needs in KRAS-mutant non–small cell lung cancer (NSCLC), discussed how he sequences KRAS G12C inhibitors with immunotherapy, and offered guidance on when community oncologists should refer patients to academic centers.

Addressing Unmet Needs Beyond KRAS G12C

Herzberg said the field's clearest gap is the absence of an approved targeted therapy for any KRAS mutation other than G12C, which occurs in approximately 11% to 14% of NSCLC cases.^1,2 KRAS G12D accounts for roughly 15% of KRAS-mutant NSCLC and about 5% of NSCLC overall—a prevalence similar to MET exon 14 skipping mutations or EGFR exon 20 insertions—yet has no approved inhibitor.

Herzberg pointed to setidegrasib (ASP3082), a first-in-class KRAS G12D-targeted protein degrader, as one of the agents now entering the clinic. In a phase 1 trial (NCT05382559) that included Herzberg as a coauthor, 45 patients with previously treated KRAS G12D-mutant NSCLC received setidegrasib at the recommended phase 2 dose of 600 mg weekly; 36% (95% CI, 22%-51%) had a partial response, median progression-free survival was 8.3 months (95% CI, 4.1 months-not estimable), and estimated 12-month overall survival was 59% (95% CI, 40%-74%).³

Beyond the G12D gap, Herzberg said durability remains a broader problem: even approved and emerging KRAS therapies generally produce shorter-lived responses than targeted therapies for other oncogene-driven NSCLC subsets.

“All of our KRAS therapies, the ones that are approved and the ones that are emerging, they all work, but most of them don't seem to work as long as targeted therapies for other subsets of non–small cell lung cancer,” Herzberg said. “There might be trivial explanations for this, like a lot of those patients are never smokers with very genomically simple tumors, and KRAS tumors might be a little bit more complex and have a higher rate of smoking, but I don't know that that's a sufficient explanation. From a patient perspective, what we need is better therapies and better regimens for all of those patients regardless.”

Sequencing KRAS Inhibitors With Immunotherapy

The only approved KRAS-directed therapies remain sotorasib (Lumakras) and adagrasib (Krazati), both indicated for previously treated KRAS G12C-mutant NSCLC—sotorasib based on progression-free and overall survival superiority over docetaxel in CodeBreaK 200 (NCT04303780), and adagrasib based on a progression-free survival benefit over docetaxel and intracranial activity in KRYSTAL-12 (NCT04685135).¹ Because G12C is a smoking-associated mutation and most patients have some smoking history, Herzberg said these patients respond to immunotherapy, and that continues to anchor frontline treatment.

"Since immunotherapy has the best chance in lung cancer for long-term disease control, we're still using immunotherapy first line for all of these patients,” Herzberg said.

He noted that combining next-generation G12C inhibitors with immunotherapy is showing promise where the regimens are tolerable together. Data from LOXO-RAS-20001 (NCT04956640), a phase 1/2 trial of olomorasib (LY3537982) plus pembrolizumab (Keytruda), showed an objective response rate of 73.9% (95% CI, 58.9%-85.7%) in first-line patients across PD-L1 levels and 90% (95% CI, 68.3%-98.8%) in first-line patients with PD-L1 expression of 50% or greater.⁴ The combination is now being tested against chemoimmunotherapy in the registrational, first-line SUNRAY-01 trial (NCT06119581).⁴ Divarasib, another next-generation covalent G12C inhibitor, is also in active clinical development.¹

Guidance on Referral to Academic Centers

Asked when community oncologists without easy access to academic centers should refer patients, Herzberg pointed to 2 windows. The first is at diagnosis, for patients who might be candidates for first-line clinical trials combining G12C inhibitors with pembrolizumab. Outside of a trial, he said sotorasib and adagrasib are straightforward enough that most patients can be managed locally after progression on chemoimmunotherapy.

The second window is later in the disease course. “The other time where I'm frequently seeing patients is after progression on sotorasib or adagrasib, so they've exhausted chemoimmunotherapy... That's a good time also to refer,” Herzberg said.

REFERENCES

1. Rosas D, Barad P, Wright J, Raez L. KRAS G12C-targeted therapy in non-small cell lung cancer: from resistant salvage to potential first-line backbone. Int J Mol Sci. 2026;27(14). doi:10.3390/ijms27146455

2. Andrade A, Mureb M, Karaman N, et al. Evaluating the efficacy of G12C inhibitors in conjunction with Gamma Knife radiosurgery for KRAS-mutant non-small cell lung cancer brain metastases. J Neurooncol. 2026;177(3). doi:10.1007/s11060-026-05547-x

3. Park W, Kasi A, Spira AI, et al. Setidegrasib in advanced non-small-cell lung cancer and pancreatic cancer. N Engl J Med. 2026;394(14):1409-1420. doi:10.1056/NEJMoa2600752

4. Burns TF, Ammakkanavar NR, Hollebecque A, et al. Efficacy and safety of olomorasib in combination with pembrolizumab in treatment of patients with KRAS G12C-mutant advanced NSCLC. J Thorac Oncol. 2025;21(4):103528. doi:10.1016/j.jtho.2025.11.018