General Information

Lumakras (sotorasib) is an inhibitor of the RAS GTPase family.

Lumakras is specifically indicated for the treatment of 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.

Lumakras is supplied as a tablet for oral administration. The recommended dosage is 960 mg (eight 120 mg tablets) orally once daily until disease progression or unacceptable toxicity. Take Lumakras at the same time each day with or without food. Swallow tablets whole. Do not chew, crush or split tablets. If a dose of Lumakras is missed by more than 6 hours, take the next dose as prescribed the next day. Do not take 2 doses at the same time to make up for the missed dose. If vomiting occurs after taking Lumakras, do not take an additional dose. Take the next dose as prescribed the next day.

Mechanism of Action

Lumakras (sotorasib) is an inhibitor of KRASG12C, a tumor-restricted, mutant-oncogenic form of the RAS GTPase, KRAS. Sotorasib forms an irreversible, covalent bond with the unique cysteine of KRASG12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS. Sotorasib blocked KRAS signaling, inhibited cell growth, and promoted apoptosis only in KRAS G12C tumor cell lines. Sotorasib inhibited KRASG12C in vitro and in vivo with minimal detectable off-target activity. In mouse tumor xenograft models, sotorasib-treatment led to tumor regressions and prolonged survival, and was associated with anti-tumor immunity in KRAS G12C models.

Side Effects

Adverse effects associated with the use of Lumakras may include, but are not limited to, the following:

• diarrhea
• musculoskeletal pain
• nausea
• fatigue
• hepatotoxicity
• cough
• laboratory abnormalities, including decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

Clinical Trial Results

This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

The FDA approval of Lumakras was based on results from a subset of patients in CodeBreaK 100, a phase 1/2 open-label, multicenter study, in patients with KRAS G12C-mutant solid tumors. Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The trial demonstrated favorable efficacy and tolerability in 124 patients with KRAS G12C mutation-positive NSCLC who had disease progression after receiving an immunotherapy and/or chemotherapy. In the trial, 960 mg of LUMAKRAS administered orally once-daily demonstrated an ORR (a proportion of patients with ≥ 30% decrease in tumor) of 36% with 81% of patients achieving disease control (percentage of patients who have achieved complete response, partial response and stable disease for more than three months). The median DoR was 10 months.