Sotorasib With Carboplatin And Pemetrexed In KRAS G12C-Mutated Advanced NSCLC

Sotorasib is an oral KRAS^G12C inhibitor with better progression-free survival (PFS) than docetaxel in advanced NSCLC patients with a KRAS G12C mutation (HR=0.66; p=0.0017). When paired with carboplatin, its anti-tumor activity was amplified in mouse models.

This report is the first global study from the CodeBreaK 101 subprotocol F phase 1b trial that evaluates the safety and effectiveness of sotorasib in conjunction with carboplatin and pemetrexed.

This was a phase 1b study focused on dose exploration and expansion. Patients with KRAS -mutated advanced NSCLC received 960 mg daily sotorasib, 500 mg/m² IV Q3W pemetrexed, and carboplatin AUC 5 IV Q3W for up to four cycles. The treatment with pemetrexed and sotorasib was sustained until any signs of disease progression, medication intolerance, consent withdrawal, or study termination.

In the dose exploration phase (cohort A dose level 1), patients had prior exposure to anti-PD-(L)1 and/or platinum-based chemotherapy or had declined standard treatment. For dose expansion, cohort A1 included patients without prior anti-PD-(L)1 or platinum-based chemotherapy. In contrast, cohort A2 consisted of patients who had previous anti-PD1 monotherapy, platinum-based chemotherapy, or neoadjuvant/adjuvant chemotherapy. 

Primary outcomes were dose-limiting toxicities, treatment-emergent adverse events, and treatment-related adverse events (TRAEs). Secondary outcomes included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), PFS as per RECIST 1.1 guidelines, and overall survival (OS). 

Data were collated from both the dose exploration and expansion phases. They were analyzed based on prior treatments in the locally advanced or metastatic setting, separating patients into treatment-naïve and treatment-exposed subgroups.

As of February 3, 2023, the study included 30 patients with a median age of 67 years; 60% were male, and their ECOG performance status was 0/1 for 47%/53% of participants. They received a combination of sotorasib, carboplatin, and pemetrexed. Among them, 19 underwent their first treatment for locally advanced or metastatic NSCLC, while 11 had one prior treatment line in the same setting. Treatment-related adverse events (TRAEs) were experienced by 29 patients (97%), with 19 of them (63%) encountering grade 3-4 TRAEs (detailed in table). Neutropenia was the most prevalent grade 3-4 TRAE at 30%, followed by anemia and thrombocytopenia, each at 17%. There were no fatal adverse events. 

In patients new to treatment (1L), the objective response rate (ORR), both confirmed and unconfirmed, was 73% (95% CI: 45, 92), and the disease control rate (DCR) was 100% (detailed in table). For those in the second line (2L) setting, the ORR was 55% (95% CI: 23, 83). Median duration of response (DOR) couldn’t be estimated yet, and both progression-free survival (PFS) and overall survival (OS) data remain incomplete.

The regimen of sotorasib, pemetrexed, and carboplatin demonstrated favorable clinical outcomes for patients with KRAS G12C-mutated advanced NSCLC in both first and second-line treatment scenarios. The treatment was generally well-tolerated, and the rate of grade 3-4 TRAEs largely aligned with those of other platinum-based doublet therapies.

Source: https://cattendee.abstractsonline.com/meeting/10925/presentation/1015

Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT04185883

Clarke, J.M., Felip, E., Li, B.T., Ruffinelli, J.C., Garrido, P., Zugazagoitia, J., Goldberg, S.B., Ramalingam, S.S., Victoria, I., Puri, S., Gandara, D.R., Varrieur, T., Edmonds, S., Palmer, K., Snyder, W., Govindan, R., Rybkin, I. CodeBreaK 101: Safety and Efficacy of Sotorasib with Carboplatin and Pemetrexed in KRAS G12C-Mutated Advanced NSCLC.