Summary Basis of Decision for Lumakras

 

Clinical Pharmacology

Sotorasib, the medicinal ingredient in Lumakras, is an oral, potent and highly selective inhibitor of a Kirsten rat sarcoma virus (KRAS) protein containing a point mutation in codon 12 that results in a glycine-to-cysteine substitution (KRAS-G12C), a tumour-restricted, mutant-oncogenic form of the rat sarcoma virus (RAS) guanosine triphosphate hydrolase (GTPase), KRAS. The mutated KRAS-G12C protein is present in approximately 13% of lung adenocarcinomas and has been identified as a putative oncogenic driver in this tumour type. Sotorasib forms an irreversible, covalent bond with the unique cysteine of KRAS-G12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS.

The pharmacokinetics of sotorasib was characterized in patients with KRAS-G12C-mutated solid tumours, including NSCLC, and in healthy subjects. The median time to achieve peak plasma concentration was one hour following single-dose or multiple-dose administration of sotorasib. At steady state, the mean volume of distribution of sotorasib was 211 L. Sotorasib is metabolized primarily through glutathione conjugation and oxidative metabolism. The mean plasma terminal elimination half-life (± standard deviation) is 5 ± 2 hours. The mean oral clearance (CL/F) (coefficient of variation [CV%]) was 12.7 L/hour (75%) following a single oral dose of sotorasib 960 mg, and increased to 26.2 L/hour (76%) at Day 8 following multiple-dose administration. After a single dose of radiolabeled sotorasib, approximately 74% (53% unchanged) of the dose was recovered in the feces and 6% (1% unchanged) was recovered in the urine.

The pharmacokinetics of sotorasib in patients with NSCLC was evaluated in the pivotal Phase I/II study, CodeBreaK 100 (described in the Clinical Efficacy section). Sotorasib exhibited non-linear, time-dependent pharmacokinetics over the dose range of 180 mg to 960 mg, administered once daily. The observed systemic exposure levels were similar across doses at steady state, as measured by the area under the plasma concentration-time curve from time 0 to 24 hours after administration (AUC_0-24h) and the peak plasma concentration (C_max). The similarities in systemic exposure levels have been attributed to the low solubility of sotorasib. Steady state was reached within 22 days, and no accumulation was observed with multiple dosing.

The overall safety, tolerability, and efficacy data in patients with NSCLC and the results from exposure-response modelling indicate that the proposed dosing regimen of 960 mg sotorasib once daily is acceptable. However, further optimization of the dosage regimen is expected as part of the post-market commitments by the sponsor. Similar efficacy was observed when lower daily doses (180 mg to 720 mg once daily) were administered to patients, although the number of patients that received lower doses was not considered sufficient to draw conclusions from the data. Additionally, similar steady state exposures were observed across the 180 mg to 960 mg dosing regimens, likely due to poor solubility. No significant trends were identified from exposure-response modelling for efficacy or safety endpoints, with the exception of a slightly higher frequency of Grade 3 or higher gastrointestinal toxicities. However, the exposure-safety modelling was confounded by worse baseline disease status (as determined by Eastern Cooperative Oncology Group [ECOG] score and tumour size at baseline). Based on these observations, a randomized dose-optimization study was requested to determine whether a lower daily dose of sotorasib may provide similar efficacy and decrease the pill burden for patients.

No clinically meaningful differences were identified in the pharmacokinetics of sotorasib based on age, sex, race, body weight, prior lines of therapy, or Eastern Cooperative Oncology Group performance status.

Based on the excretion profile and the results of the population pharmacokinetic analysis of sotorasib, dose adjustment is not recommended for patients with mild to moderate renal impairment. As post-market commitments, the sponsor is expected to conduct a hepatic impairment study in subjects with moderate to severe hepatic impairment.

The co-administration of Lumakras with acid-reducing agents (proton pump inhibitors or H2 receptor antagonists) and strong CYP3A4 inducers should be avoided. When co-administered in clinical studies, changes were observed in the exposure levels of Lumakras or the co-administered drug, which may reduce the efficacy of Lumakras. Lumakras is also a moderate CYP3A4 inducer. Co-administration of Lumakras with CYP3A4 substrates should therefore be avoided, as this decreases the concentration of CYP3A4 substrates and may result in therapeutic failure of these substrates. Additionally, co-administration of Lumakras and a P-glycoprotein (P-gp) substrate led to an increase in P-gp substrates, and should be avoided as changes in the concentration of P-gp substrates with a narrow therapeutic index may result in an increase in adverse reactions.

For further details, please refer to the Lumakras Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Evidence of the clinical efficacy of Lumakras was provided through the pivotal Phase II study, CodeBreaK 100. Patients enrolled in the study had locally advanced or metastatic NSCLC with a KRAS-G12C-mutation, and had disease progression after receiving at least one prior line of systemic therapy. Out of 126 patients initially enrolled in the study, 123 patients had at least one measurable lesion at baseline according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, evaluated by blinded independent central review (BICR). A 960 mg oral dose was administered to these 123 patients once daily, until disease progression or unacceptable toxicity. The median duration of treatment was 5.5 months (range: 0, 12) with 48% of patients treated for at least 6 months and 29% of patients treated for at least 9 months.

The primary efficacy endpoint was the objective response rate (ORR) according to RECIST version 1.1, evaluated by BICR. The ORR was determined to be 37.4% (95% confidence interval [CI]: 28.8, 46.6). The complete response and partial response rates were 1.6% and 35.8%, respectively. Noting the limitations of cross-trial comparisons, the ORR for Lumakras observed in this study (including the lower bounds for the 95% CI) is an improvement over docetaxel, the current standard of care. Based on historical data, the ORR for docetaxel is between 6% and 15%. The median duration of response (DOR) of sotorasib was confirmed by the BICR as 8.4 months (range: 1.3, 8.4) as of the data cut-off in September 2020. The lower bounds for the 95% CI of the DOR were 6.9 and 8.4 months. The responses were durable and considered clinically meaningful.

The ORR was generally consistent across several prespecified subgroups. The subgroups evaluated were age (less than 65 years or more than 65 years), sex, number of prior lines of therapy, Eastern Cooperative Oncology Group status (0-1), types of prior therapies, prior sequential immunotherapy and chemotherapy versus (vs.) combination immunotherapy and chemotherapy, and tissue biopsy vs. blood sample.

Differences in the efficacy of sotorasib between subjects with locally advanced NSCLC and metastatic NSCLC could not be identified from the study data, as only 4 out of 123 patients had locally advanced NSCLC. However, these patients represent a population with an unmet medical need. Therefore, the efficacy of Lumakras in patients with locally advanced NSCLC was extrapolated from the overall population based on the similarities in disease biology and clinical treatment options. No distant metastases were observed in a majority of patients with locally advanced NSCLC treated with Lumakras. As this subpopulation is at a high risk for progression to stage IV disease, the absence of distant metastases is considered promising evidence of the efficacy of Lumakras.

Indication

Sponsor’s proposed indication	Health Canada-approved indication
Lumakras (sotorasib) is indicated for the treatment of patients with previously treated Kirsten rat sarcoma viral oncogene homolog (KRAS)-G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC).	Lumakras (sotorasib) is indicated for the treatment of adult patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C-mutated locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior systemic therapy.

For more information, refer to the Lumakras Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Lumakras was determined based on data from the overall safety population of 357 patients with any type of locally advanced or metastatic solid tumour with a KRAS-G12C-mutation who received a dose of 960 mg once daily. Within the overall safety population, 204 patients with KRAS-G12C-mutated locally advanced or metastatic NSCLC (hereafter referred to as the NSCLC population) were enrolled in the pivotal study, CodeBreaK 100 (described in the Clinical Efficacy section). In the NSCLC population, the median duration of exposure to Lumakras was 19.5 weeks (range: 1.0 to 74.1), with 38.7% of patients exposed for at least 6 months, 22.1% of patients exposed for at least 9 months, and 2.9% of patients exposed for at least one year. 

The majority of patients with NSCLC treated with Lumakras (99%) reported a treatment-emergent adverse event (TEAE). The most common adverse events (reported in at least 10% of patients, and listed in order of decreasing frequency) were diarrhea, musculoskeletal pain, fatigue, nausea, hepatotoxicity, cough, vomiting, constipation, dyspnea, abdominal pain, edema, decreased appetite, pneumonia, arthralgia and rash. The majority of these adverse events were Grade 1 or 2 in severity. Grade 3 or higher adverse events occurred at a frequency of approximately 5% to 10%, and included hepatotoxicity, diarrhea, musculoskeletal pain, and pneumonia. Although a dedicated QT/corrected QT (QTc) study was not conducted, no significant prolongation of the QT interval was detected in the pivotal study.

The most frequently reported serious adverse drug reactions were pneumonia (8%), musculoskeletal pain (5%), hepatotoxicity (3%) and diarrhea (2%). Deaths due to adverse events occurred in 16% of patients and were mostly associated with disease progression and/or complications. Fatal cases of treatment-related pneumonia occurred in 0.5% of the 204 patients in the NSCLC population.

Permanent discontinuation due to adverse events occurred in 9% of patients, indicating a favourable tolerability profile. The most common adverse reactions leading to discontinuation were hepatotoxicity (4%), pneumonitis (1%), increased blood alkaline phosphatase (1%), pneumonia (0.5%), dyspnea (0.5%) and vomiting (0.5%). The most common adverse drug reactions leading to dosage interruption and/or reduction were hepatotoxicity (11%), diarrhea (9%), musculoskeletal pain (4%), increased blood alkaline phosphatase (3.4%), nausea (3%) and pneumonia (3%).

Interstitial lung disease (ILD)/pneumonitis and hepatotoxicity are considered the primary risks with Lumakras, and are described in the Warnings and Precautions section of the Lumakras Product Monograph. Severe or life-threatening ILD/pneumonitis was observed in 1.5% of patients in the NSCLC population. Pneumonitis may be confounded by prior immunotherapy or radiotherapy, and/or by NSCLC disease progression, as pneumonitis was not observed in patients with other solid tumour types. Hepatotoxicity was identified most commonly as increases in aspartate aminotransferase (AST) or alanine aminotransferase (ALT), with 3% of hepatotoxic cases reported as serious. The majority of AST/ALT increases were asymptomatic, not serious, and did not lead to liver failure. The observed incidence of AST/ALT increases was approximately two times more frequent in NSCLC tumours compared to other solid tumours (20% and approximately 10%, respectively). The incidence, types, and severities of other adverse events were generally similar between NSCLC tumours and other tumour types.

Overall, considering the available data in the context of treatment for a life-threatening disease, the toxicity profile of Lumakras was determined to be favourable.

For more information, refer to the Lumakras Product Monograph, approved by Health Canada and available through the Drug Product Database.