On 28 May 2021, the US Food and Drug Administration (FDA) granted accelerated approval to sotorasib (Lumakras™, Amgen, Inc.), a RAS GTPase family inhibitor, for adult patients with KRAS G12C ‑mutated 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 also approved the QIAGEN therascreen® KRAS RGQ PCR kit (tissue) and the Guardant360® CDx (plasma) as companion diagnostics for Lumakras. If no mutation is detected in a plasma specimen, the tumour tissue should be tested.
Approval was based on CodeBreaK 100, a multicentre, single-arm, open label, clinical study (NCT03600883) which 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 disease progression or unacceptable toxicity.
The main efficacy outcome measures were objective response rate (ORR) according to RECIST v1.1, as evaluated by blinded independent central review and response duration.
The ORR was 36% (95% confidence interval 28%, 45%) with a median response duration of 10 months (range, 1.3+, 11.1).
The most common adverse reactions (≥ 20%) were diarrhoea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased haemoglobin, 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 with or without food.
The approved 960 mg dose is based on available clinical data, as well as pharmacokinetic and pharmacodynamic modelling that support the approved dose. As part of the evaluation for this accelerated approval, FDA is requiring a postmarketing study to investigate whether a lower dose will have a similar clinical effect.
Full prescribing information for Lumakras is available here.
This indication is approved under accelerated approval based on ORR and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this 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.
This review used the Real-Time Oncology Review pilot programme, which streamlined data submission prior to the filing of the entire clinical application, the Assessment Aid, and the Product Quality Assessment Aid, voluntary submissions from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 10 weeks ahead of the FDA goal date.
This application was granted priority review, fast-track, breakthrough therapy and orphan drug designation.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.
For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA’s OCE Project Facilitate.