On May 28, 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to sotorasib (Lumakras™), a RAS GTPase family inhibitor, for adult patients with KRAS G12Cmutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA approved test, who have received at least one prior systemic therapy.

FDA Grants Accelerated Approval to Sotorasib for KRAS G12C-Mutated NSCLC

FDA also approved the QIAGEN therascreen® KRAS RGQ PCR kit (tissue) and the Guardant360® CDx (plasma) as companion diagnostics for sotorasib. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Approval was based on a multicenter, single-arm, open-label clinical trial (NCT03600883, CodeBreaK 100) that included patients with locally advanced or metastatic NSCLC with KRAS G12C mutations. Efficacy was evaluated in 124 patients whose disease had progressed on or after at least one prior systemic therapy. Patients received sotorasib 960 mg orally daily until they experienced disease progression or unacceptable toxicity. 

The main efficacy outcome measures were objective response rate (ORR) according to response evaluation in solid tumors 1.1, as evaluated by blinded independent central review and response duration. ORR was 36% (95% CI = 28%, 45%) with a median response duration of 10 months (range = 1.3+, 11.1). 

The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium. 

The recommended sotorasib dose is 960 mg orally once daily, an approval based on available clinical data and pharmacokinetic and pharmacodynamic modeling. As part of the evaluation for the accelerated approval, FDA is requiring a postmarketing trial to investigate whether a lower dose would have a similar clinical effect. 

View the full prescribing information for sotorasib

FDA approved the indication under accelerated approval based on ORR and duration of response. Continued approval for the indication is contingent on verification and description of clinical benefit in a confirmatory trial. 

The review was conducted under Project Orbis, an initiative of FDA’s Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For the review, FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, and the United Kingdom Medicines and Healthcare products Regulatory Agency. The application reviews are ongoing at the other regulatory agencies. 

The review used the Real Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, Assessment Aid, and the Product Quality Assessment Aid, voluntary submissions from the applicant to facilitate FDA’s assessment. FDA approved the application approximately 10 weeks ahead of its goal date. 

FDA granted the application priority review, fast-track, breakthrough therapy, and orphan drug designations. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics.  

Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine or device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088. 

For assistance with single-patient oncology investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov