Regulatory Decision Summary for Lumakras

Lumakras (sotorasib) is a first-in-class and selective inhibitor of mutant Kirsten rat sarcoma viral oncogene homolog (KRAS)-G12C. In this New Drug Submission (NDS), the sponsor proposed the use of sotorasib for the treatment of patients with previously treated KRAS-G12C mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Advanced NSCLC (stage IIIB and IV) is a serious and life-threatening disease, with a 5-year overall survival (OS) rate of 5.2%. Advanced NSCLC patients (with no other driver mutations) currently have no curative treatment options. In metastatic subjects who have progressed on prior immunotherapy and platinum-doublet chemotherapy, palliative treatment options include single agent cytotoxic chemotherapy. An unmet medical need exists as responses to single agent chemotherapy are of short duration and have significant drug-related toxicity.

The benefit of sotorasib was evaluated in NSCLC subjects in the pivotal single arm, open-label, multi-centre Phase 2 study CodeBreak 100. The primary endpoint was Objective Response Rate (ORR), as confirmed by Blinded Independent Central review (BICR). Of the 123 patients assessed, the BICR-confirmed ORR was 37.4% (95% confidence interval [CI]: 28.8, 46.6). The complete response (CR) and partial response (PR) rates were 1.6% and 35.8% respectively. The responses were durable, with a median duration of response of 8.4 months (range: 1.3, 8.4) and was considered clinically meaningful. The observed ORR demonstrates an improvement compared to the current standard of care option docetaxel. The historical control ORR estimates for docetaxel ranged between 6-15%. A full cancer drug approval (NOC) is based on more direct evidence of clinical benefit, such as an improvement in survival (Progression-free survival, OS), an improvement in a patient’s quality of life, disease-related symptoms, etc. These clinical benefits may be reasonably predicted by the surrogate marker ORR, however, this correlation requires further verification from confirmatory studies.

The ORR was generally consistent across multiple pre-specified subgroups. There were a limited number of locally advanced NSCLC subjects enrolled to confirm clinical benefit. The efficacy in the locally advanced population was extrapolated from the metastatic population, given the similarity in disease biology, clinical treatment options and unmet medical need. Additionally, distant metastases were not observed in a majority of locally advanced subjects. As this subpopulation is at a high risk for progression to stage IV, the absence of distant metastases was considered promising evidence of efficacy for sotorasib. Based on non-clinical toxicology studies, sotorasib had no adverse effects on fertility. Sotorasib was not genotoxic or mutagenic, based on in vitro and in vivo studies. 

Harms: The majority of adverse reactions associated with sotorasib were manageable with supportive care and/or dose modifications. The key risks related to sotorasib were pneumonitis and hepatotoxicity. Severe or life-threatening cases of pneumonitis occurred in 1.5% of the NSCLC population, and serious hepatotoxic cases occurred in 3% of the NSCLC population. Grade ≥3 adverse events, which occurred at frequency of approximately 5% -10% included hepatotoxicity, diarrhea, musculoskeletal pain, and pneumonia. Adverse reactions that led to permanent discontinuation occurred in 9% of the population, indicating a good tolerability profile.

The reproductive toxicity animal studies demonstrates that a risk to the foetus from exposure to sotorasib during pregnancy cannot be excluded.

Drug-drug interactions have been adequately investigated and appropriate risk mitigation measures are labelled in the Product Monograph (PM).

Uncertainties: Although the proposed dosing regimen of 960 milligram (mg) once daily for sotorasib was considered acceptable (based on safety and efficacy data derived from study CodeBreak 100) in NSCLC patients, the optimal dosing regimen is still to be determined. Indeed, a similar ORR and safety profile was noted between the 180-960 mg once daily regimens of sotorasib in NSCLC patients during the dose escalation study. Additionally, inhibition of the mutant KRAS-G12C protein was likely achieved at all doses investigated for sotorasib. The non-linear pharmacokinetic (PK) profile of sotorasib was suspected to be the underlying cause for these observations. To address these limitations and determine the optimal dosing regimen for sotorasib, the sponsor will evaluate a lower dose through a randomized dose optimization study as a post-market commitment.

This NDS has been submitted under the Notice of Compliance with Conditions (NOC/c) policy. A limitation with the supporting data is the absence of a comparator arm and use of a surrogate marker (ORR) to evaluate the clinical benefit. To address these uncertainties, Amgen Canada Inc. will confirm the clinical benefits and risks of sotorasib through a randomized study evaluating sotorasib versus docetaxel in previously treated NSCLC using progression-free survival as the primary endpoint.

Overall, the benefit-risk-uncertainty profile for sotorasib, based on the ORR and duration of response observed in a patient population with a high unmet medical need, is considered favourable. Although sotorasib can cause serious and severe toxicities, the risks are mitigated through appropriate labelling. A NOC/c is recommended.

For more information on Health Canadas decision, please view the Summary Basis of Decision.