FDA Rejects sNDA for Sotorasib in KRAS G12C-Mutated NSCLC


The FDA did not fully approve sotorasib for the treatment of patients with KRAS G12C-mutated non–small cell lung cancer.

KRAS G12C mutation in non-small cell lung cancer: © Aiden - stock.adobe.com

KRAS G12C mutation in non-small cell lung cancer: © Aiden - stock.adobe.com

  • The FDA has rejected the supplemental new drug application (sNDA) for sotorasib (Lumakras) for patients with previously treated locally advanced or metastatic KRAS G12C-mutated non–small cell lung cancer (NSCLC).1 The drug's accelerated approval status remains in place.
  • In October 2023, the FDA’s Oncologic Drugs Advisory Committee (ODAC) found that the progression-free survival (PFS) data from the CodeBreaK 200 trial (NCT04303780) could not be reliably interpreted.
  • Accelerated approval was granted in May 2021 to sotorasib in this intent-to-treat (ITT) population, along with 2 companion diagnostic devices.2

Sotorasib’s sNDA has been rejected by the FDA for the treatment of locally advanced or metastatic KRAS G12C-mutated NSCLC that has been treated with at least 1 prior line of therapy. The FDA issued a complete response letter and issued a new postmarketing requirement study to be completed no later than February 2028.1

The NDA was supported by findings from the confirmatory phase 3 CodeBreaK 200 trial. The sNDA sought full approval of sotorasib. At an ODAC meeting in October 2023, the committee found in a 10-2 vote that the primary end point of PFS per blinded independent central review could not be reliably interpreted. The ODAC concluded that the difference in PFS between the sotorasib and docetaxel arms was small, and there was no difference in overall survival (OS).

The FDA also expressed concern about the study’s integrity, as there was greater patient dropout observed in the docetaxel arm, as well as patient crossover from the docetaxel arm to the sotorasib arm prior to assessment of disease-progression.

About CodeBreaK 200

CodeBreaK 200 is a multicenter, randomized, open-label, active-controlled, confirmatory, phase 3 study of sotorasib vs docetaxel in the ITT population. To be eligible for enrollment, patients must have received 1 or moreprevious treatments, including platinum-based chemotherapy and a checkpoint inhibitor, and have an ECOG performance status of 0 or 1.3

Overall, 345 patients were enrolled and randomly assigned in a 1:1 manner to receive oral sotorasib 960 mg (n = 171) or intravenous docetaxel 75 mg/m2 every 3 weeks (n = 174).

At a median follow-up of 17.7 months (interquartile range, 16.4-20.1), there was a 34% reduction in the risk of disease progression or death in the sotorasib arm compared with docetaxel (HR, 0.66; 95% CI, 0.51-0.86; P =.0017). This met the trial’s primary end point. The median PFS was 5.6 months (95% CI, 4.3-7.8) in the sotorasib arm vs 4.5 months (95% CI, 3.0-5.7) in the docetaxel arm. The 12-month PFS rates were 24.8% with sotorasib and 10.1% with docetaxel.4

Furthermore, the PFS benefit with sotorasib was improved independent of PD-L1 expression. No significant differences were observed in OS rates. The sotorasib arm had a 10.6-month OS (95% CI, 8.9-14.0), and the OS in the docetaxel arm was 11.3 months (95% CI, 9.0-14.9).

The safety profile of sotorasib was consistent with the known profile, and no new safety signals were identified.

1. Amgen provides regulatory update on status on Lumakras (sotorasib). News release. Amgen. December 26, 2023. Accessed January 2, 2023. http://tinyurl.com/yv559hb2
2. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. News release. U.S. Food and Drug Administration. May 28, 2021. Accessed November 17, 2023. http://tinyurl.com/55575fmk
3. Study to compare AMG 510 “proposed INN sotorasib” with docetaxel in non small cell lung cancer (NSCLC) (CodeBreak 200). ClinicalTrials.gov. Updated October 23, 2023. Accessed November 17, 2023. https://clinicaltrials.gov/study/NCT04303780 
4. Skoulidis F, De Langen A, Paz-Ares LG, et al. Biomarker subgroup analyses of CodeBreaK 200, a phase 3 trial of sotorasib versus (vs) docetaxel in patients (pts) with pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl 16):9008. doi:10.1200/JCO.2023.41.16_suppl.9008
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