FDA Approves Sotorasib for KRAS G12C–Mutated NSCLC


The FDA has approved sotorasib as the first treatment for adult patients with non–small cell lung cancer whose tumors harbor KRAS G12C mutations and who have received at least 1 prior systemic therapy.



The FDA has approved sotorasib (Lumakras) as the first treatment for adult patients with non–small cell lung cancer whose tumors harbor KRAS G12C mutations and who have received at least 1 prior systemic therapy.1,2

The regulatory decision was based on data from the phase 2 CodeBreaK 100 trial (NCT03600883), which demonstrated that treatment with KRAS G12C inhibitor elicited an objective response rate of 36% (95% CI, 28%-45%) in patients with KRAS G12C–mutated NSCLC who had progressed following treatment with an immunotherapy and/or chemotherapy. The median duration of response (DOR) with the treatment was 10 months; 58% of patients experienced a DOR that was 6 months or longer. Notably, the disease control rate achieved with sotorasib was 81% (95% CI, 73%-87%).

KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need for patients with certain types of cancer,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release. “Today’s approval represents a significant step toward a future where more patients will have a personalized treatment approach.”

A total of 126 patients were enrolled to the phase 2 CodeBreaK 100 trial; 124 of these patients were determined to have centrally evaluable lesions per RECIST criteria at baseline.3 To be eligible for enrollment, they needed to have locally advanced or metastatic NSCLC with a KRAS G12C mutation assessed per central testing of tumor biopsies. Patients had to have progressed on prior standard therapies. Those who had active brain metastases were excluded.

In the trial, study participants received oral sotorasib at 960 mg until disease progression. Radiographic scans were done every 6 weeks up to week 48 and then once every 12 weeks thereafter.

The primary end point of the trial was ORR per RECIST v1.1 criteria by blinded independent central review, while key secondary end points included DOR, DCR, time to recovery, PFS, overall survival, and safety. The examination of biomarkers served as an exploratory end point.

Findings from exploratory biomarker analyses revealed that the clinical activity with sotorasib extended across a range of biomarker subsets, including those with PD-L1–negative or –low status, and those whose tumors harbored STK11 mutations.4 STK11 mutations have been known to be associated with poorer outcomes in patients with NSCLC who received prior treatment with checkpoint inhibitors and chemotherapy.

The approved dose is based on available clinical findings, and is supported by pharmacokinetic and pharmacodynamic modeling. As part of the evaluation for this accelerated approval, the FDA has required a post-marketing trial to investigate whether a lower dose will have a comparable clinical effect.

The most frequent toxicities experienced with sotorasib are diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough. According to the FDA, the agent should be withheld if patients develop symptoms of interstitial lung disease (ILD); if ILD is confirmed, the agent should be permanently discontinued. Liver function tests should be monitored prior to treatment initiation. If a patient develops liver damage, sotorasib should be withheld, dose reduced or permanently discontinued.


  1. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. May 28, 2021. Accessed May 28, 2021. https://bit.ly/3c172Ah
  2. FDA approves LUMAKRAS (sotorasib), the first and only targeted treatment for patients with KRAS G12C–mutated locally advanced or metastatic non-small cell lung cancer. News release. May 28, 2021. Accessed May 28, 2021. https://prn.to/3yLuxqY
  3. Li BT, Skoulidis F, Falchook G, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.
  4. Bauml JM, Li BT, Velcheti V, et al. Clinical validation of plasma cell-free DNA (cfDNA) sequencing in the phase 2 trial of sotorasib in patients (pts) with KRAS p.G12C mutated NSCLC. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Poster CT181.
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