FDA Issues Complete Response Letter to Sotorasib for KRAS G12C–Mutated NSCLC

The FDA has issued a complete response letter (CRL) to the supplemental new drug application seeking the full approval of sotorasib (Lumakras) for patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC).¹ The FDA also issued a new postmarketing requirement (PMR) for an additional confirmatory trial to support full approval of sotorasib for this patient population. This trial will be completed by February 2028 at the latest.

The CRL follows findings from the phase 3 CodeBreak 200 trial (NCT04303780) of sotorasib vs docetaxel in adult patients with previously treated locally advanced or metastatic KRAS G12C–mutated NSCLC.² At a median follow-up of 17.7 months (IQR, 16.4-20.1), patients who received sotorasib (n = 171) achieved a statistically significant increase in progression-free survival (PFS) compared with those who received docetaxel (n = 174). The median PFS in the sotorasib and docetaxel arms were 5.6 months (95% CI, 4.3-7.8) and 4.5 months (95% CI, 3.0-5.7), respectively (HR, 0.66; 95% CI, 0.51-0.86; P = .0017).

Sotorasib was the first KRAS G12C inhibitor to gain regulatory approval in the United States.

Data from the phase 2 CodeBreaK 100 trial (NCT03600883) supported the May 2021 FDA accelerated approval of sotorasib for adult patients with KRAS G12C–mutated NSCLC who have received at least 1 prior systemic therapy.³ In CodeBreaK 100, 36% of patients had an objective response, and 58% of patients experienced a duration of response of at least 6 months.

The CRL was announced in conjunction with confirmation that the dose-comparison PMR that was issued at the time of the May 2021 accelerated approval of sotorasib, to compare the safety and efficacy of sotorasib at 960 mg once daily vs a lower daily dose, has been fulfilled, and that once-daily dosing of 960 mg will remain the dose of sotorasib for patients with KRAS G12C–mutated NSCLC under the accelerated approval.¹

CodeBreak 200, which was conducted at 148 centers across 22 countries, enrolled patients at least 18 years of age with KRAS G12C–mutated advanced NSCLC who had progressed after prior treatment with platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.² Patients were excluded if they had new or progressing untreated brain lesions, symptomatic brain lesions, a previously identified oncogenic driver mutation other than KRAS G12C for which an approved therapy is available, previous treatment with docetaxel, previous treatment with a KRAS G12C inhibitor, systemic anticancer therapy within 28 days of the first day of CodeBreak 200, and palliative or therapeutic radiation within 2 weeks of beginning study treatment.

Patients were randomly assigned 1:1 to receive oral sotorasib at 960 mg once daily or intravenous docetaxel at 75 mg/m2 once every 3 weeks. Patients continued treatment until an independent central confirmation of disease progression, treatment intolerance, the start of another anticancer therapy, withdrawal of consent, or death.

Blinded independent central review–assessed PFS in the intention-to-treat population served as the primary end point of this trial.

Regarding safety, in CodeBreak 200, 33% and 11% of patients in the sotorasib arm experienced grade 3 or higher or serious treatment-related adverse effects (TRAEs), respectively, compared with 40% and 23% of those in the docetaxel arm, respectively. In the sotorasib arm, the most common grade 3 or higher TRAEs were diarrhea (12%), alanine aminotransferase increase (8%), and aspartate aminotransferase increase (5%). In the docetaxel arm, the most common grade 3 or higher TRAEs were neutropenia (9%), fatigue (6%), and febrile neutropenia (5%).

References

1. Amgen provides regulatory update on status of Lumakras (sotorasib). News release. Amgen. December 26, 2023. Accessed January 2, 2023. https://www.amgen.com/newsroom/press-releases/2023/12/amgen-provides-regulatory-update-on-status-of-lumakras-sotorasib
2. de Langen AJ, Johnson ML, Mazieres J, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401(10378):733-746. doi:10.1016/S0140-6736(23)00221-0
3. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. FDA. May 28, 2021. Accessed January 2, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug?utm_medium=email&utm_source=govdelivery