FDA Delays PDUFA Date for Sotorasib Plus Panitumumab in KRAS G12C+ mCRC

FDA

The FDA has pushed back the Prescription Drug User Fee Act (PDUFA) target action date for the application seeking the approval of sotorasib (Lumakras) in combination with panitumumab (Vectibix) for the treatment of patients with metastatic colorectal cancer (mCRC) harboring KRAS G12C mutations.¹

The PDUFA date, which was originally October 17, 2024, was extended to allow the regulatory agency to review recently submitted supplemental data. The updated target action date is January 17, 2025.

The sotorasib/panitumumab application in KRAS G12C–mutated mCRC was supported by data from the phase 3 CodeBreaK 300 trial (NCT05198934), which demonstrated that at a median follow-up of 7.8 months (range, 0.1-13.9), patients treated with sotorasib at 960 mg plus panitumumab (n = 53) achieved a median progression-free survival (PFS) of 5.6 months (95% CI, 4.2-6.3) compared with 2.2 months (95% CI, 1.9-3.9) for those given investigator’s choice of therapy (n = 54; HR, 0.49; 95% CI, 0.30-0.80; P = .006).² The median PFS was 3.9 months (95% CI, 3.7-5.8) in patients treated with sotorasib at 240 mg plus panitumumab (n = 53; HR vs control arm, 0.58; 95% CI, 0.36-0.93; P = .03).

CodeBreaK 300 is a multicenter, open-label, randomized, active-controlled trial that enrolled adult patients with mCRC harboring KRAS G12C mutations who had received at least 1 prior line of therapy in the metastatic setting; had progressed on or following fluoropyrimidine, irinotecan, and oxaliplatin; and who had no prior exposure to a KRAS G12C inhibitor. They needed to have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 to 2, and adequate organ function.

Patients were randomly assigned 1:1:1 to receive sotorasib at 960 mg once per day plus panitumumab at 6 mg/kg once every 2 weeks; sotorasib at 240 mg once per day plus panitumumab at 6 mg/kg once every 2 weeks; or the investigator’s choice of standard-care therapy with trifluridine/tipiracil (TAS-102; Lonsurf) or regorafenib (Stivarga).

Stratification factors included prior receipt of antiangiogenic therapy (yes vs no), time from initial diagnosis of metastatic disease to randomization (≥18 months vs <18 months), and ECOG performance status (0 or 1 vs 2).

Blinded independent central review–assessed PFS per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included overall survival (OS), objective response rate (ORR), duration of response (DOR), time to response, disease control, safety, and quality of life.

Updated data shared during the 2024 ASCO Annual Meeting showed that at a data cutoff date of December 18, 2023, the median PFS in the sotorasib 960-mg group and control group was 5.8 months (95% CI, 4.2-7.5) vs 2.0 months (95% CI, 1.9-3.9), respectively (HR, 0.46; 95% CI, 0.29-0.72).³ The median PFS in the 240-mg group was 4.0 months (95% CI, 3.7-5.9; HR vs control, 0.57; 95% CI, 0.37-0.88).

The ORRs achieved in the sotorasib 960-mg group, sotorasib 240-mg group, and the control group were 30% (95% CI, 18.3%-44.3%), 8% (95% CI, 2.1%-18.2%), 2% (95% CI, 0%-9.9%), respectively. The median DOR was 10.1 months (95% CI, 3.1 to 12.9+).

Moreover, the median OS in the 960-mg sotorasib group was not evaluable (NE; 95% CI, 8.6-NE) vs 10.3 months (95% CI, 7.0-NE) in the control group (HR, 0.70; 95% CI, 0.41-1.18; P = .20). The median OS in the 240-mg sotorasib group was 11.9 months (95% CI, 7.5-NE; HR vs control arm, 0.83; 95% CI, 0.49-1.39); P = .50).

Regarding safety, the rates of any-grade treatment-related adverse effects (TRAEs) were 94.3% in the 960-mg sotorasib cohort, 96.2% in the 240-mg sotorasib cohort, and 82.4% in the control arm.² The rates of grade 3 or higher TRAEs were 35.8%, 30.2%, and 43.1%, respectively.

In the sotorasib arms, the most common any-grade TRAEs included hypomagnesemia (960-mg cohort, 28.3%; 240-mg cohort, 30.2%), rash (28.3%; 24.5%), and dermatitis acneiform (22.6%; 37.7%).

In May 2021, the FDA granted accelerated approval to sotorasib for the treatment of adult patients with KRAS G12C–mutated non–small cell lung cancer who have received at least 1 prior systemic therapy.⁴ However, in December 2023, the regulatory agency issued a complete response letter to the supplemental new drug application seeking the full approval of sotorasib for this population, and a post-marketing requirement for an additional confirmatory trial to support the agent’s full approval was added.⁵

References

1. Amgen reports third quarter 2024 financial results. News release. Amgen. October 30, 2024. Accessed October 30, 2024. https://investors.amgen.com/news-releases/news-release-details/amgen-reports-third-quarter-2024-financial-results
2. Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023;389(23):2125-2139. doi:10.1056/NEJMoa2308795
3. Fakih MG, Salvatore L, Esaki T, et al. Overall survival (OS) of phase 3 CodeBreaK 300 study of sotorasib plus panitumumab (soto+pani) versus investigator’s choice of therapy for KRAS G12C-mutated metastatic colorectal cancer (mCRC). J Clin Oncol. 2024;42(suppl 17):LBA3510. doi:10.1200/JCO.2024.42.17_suppl.LBA3510
4. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. FDA. May 28, 2021. Accessed October 30, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug
5. Amgen provides regulatory update on status of Lumakras (sotorasib). News release. Amgen. December 26, 2023. Accessed October 30, 2024. https://www.amgen.com/newsroom/press-releases/2023/12/amgen-provides-regulatory-update-on-status-of-lumakras-sotorasib