Sotorasib Significantly Improves PFS Vs Docetaxel for KRAS G12C–Mutated NSCLC

The KRAS G12C inhibitor sotorasib (Lumakras) doubled the rate of progression-free survival (PFS) at 12 months and reduced the risk of progression or death by 34% compared with docetaxel for patients with previously treated non–small cell lung cancer (NSCLC) with KRAS G12C mutations, according to findings from the phase 3 CodeBreaK 200 trial (NCT04303780) presented at the ESMO Congress 2022.¹

At a median follow-up of 17.7 months, the 12-month PFS rate was 24.8% with sotorasib compared with 10.1% with docetaxel. Median PFS was 5.6 months (95% CI, 4.3-7.8) with sotorasib vs 4.5 months (95% CI, 3.0-5.7) with docetaxel (HR, 0.66; 95% CI, 0.51-0.86; P = .002). There were fewer grade 3 or greater treatment-related adverse effects (TRAEs) with the KRAS G12C inhibitor compared with chemotherapy (33.1% vs 40.4%, respectively). Additionally, serious adverse events were less common with sotorasib vs docetaxel (10.7% vs 22.5%).

“The PFS rate doubled and the PFS benefit was seen across all subgroups tested. Likewise, the secondary end points of objective response rate [ORR], disease control rate [DCR], time to response, and duration of response were all significantly improved in favor of sotorasib,” said study author Melissa L. Johnson, MD, director, Lung Cancer Research Program, Sarah Cannon Research Institute. “In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C–mutated NSCLC.”

Based on findings from the earlier phase 1/2 CodeBreaK 100 trial (NCT03600883), the FDA granted sotorasib an accelerated approval in May 2021 for patients with KRAS G12C–mutated locally advanced or metastatic NSCLC. In this study, the ORR was 36% (95% CI, 28%-45%) for a median duration of 10 months.²

The global phase 3 CodeBreaK 200 study enrolled 345 patients with locally advanced, unresectable, or metastatic KRAS G12C–mutated NSCLC. The study was originally designed to enroll 650 participants but was reduced to approximately 330, based on guidance from the FDA. The agency requested that patients on the docetaxel arm be able to crossover to receive sotorasib following disease progression. This shift maintained the statistical power for the primary end point of PFS but underpowered the trial to show a statistical difference in overall survival (OS), which was a secondary end point.

The median OS was 10.6 months (95% CI, 8.9-14.0) with sotorasib compared with 11.3 months (95% CI, 9.0-14.9) with docetaxel (HR, 1.01; 95% CI, 0.77-1.33; P = .53). Thirty-six percent of patients in the sotorasib arm received a subsequent therapy at crossover compared with 42% in the docetaxel arm. A subsequent KRAS G12C inhibitor was received by 34% of patients in the docetaxel arm. The most common treatment at crossover for those in the sotorasib arm was chemotherapy (21%).

“The trial was initially twice as big and when the CodeBreaK 100 data read out the FDA suggested strongly that the trial be amended to reduce the number of patients enrolled by half, so it would decrease the number of patients randomized to docetaxel,” Johnson said.

For the study, patients were randomized to receive either oral sotorasib at 960 mg per day (n = 171) or intravenous (IV) docetaxel at 75 mg/m² every 3 weeks (n = 174). All patients had received prior platinum-based chemotherapy and a checkpoint inhibitor either concurrently or sequentially. Patients with active brain metastases were excluded from the study, although a history of brain metastases was allowed, Johnson noted.

Patient characteristics were balanced across groups. In the sotorasib arm, the median age was 64 years, and most were enrolled in Europe (73.7%). Most patients were current or former smokers (97.1%) and a third had a history of CNS involvement (33.9%). Nearly half of patients had received 1 prior line of therapy (45%) and 17% had received more than 2.

The ORR with sotorasib was 28.1% (95% CI, 21.5%-35.4%) compared with 13.2% (95% CI, 8.6%-19.2%) with docetaxel (P <.001). When also considering patients with stable disease, the overall DCR was 82.5% for sotorasib compared with 60.3% with docetaxel. Any degree of tumor shrinkage was seen in 80.4% of patients treated with sotorasib compared with 62.8% in those treated with docetaxel.

The median percent change in tumor size for responders was 58.8% with sotorasib vs 48.5% with docetaxel. Median time to response was 1.4 (95% CI, 1.2-8.3) months vs 2.8 (95% CI, 1.3-11.3) for sotorasib and docetaxel, respectively. Median duration of response was 8.6 months with sotorasib (95% CI, 7.1-18.0) compared with 6.8 months for docetaxel (95% CI, 4.3-8.3).

“Secondary end points were all significantly improved in favor of sotorasib,” said Johnson. “Response, disease control, time to response, and duration were all positive in favor of sotorasib.”

TRAEs leading to discontinuation were experienced by 9.5% of patients in the sotorasib arm compared with 11.3% with docetaxel. The most common any-grade TRAEs between sotorasib and docetaxel, respectively, were diarrhea (33.7% vs 18.5%), nausea (14.2% vs 19.9%), alanine aminotransferase (ALT) increase (10.1% vs 0%), aspartate aminotransferase (AST) increase (10.1% vs 0%), and fatigue (6.5% vs 25.2%). The most common grade 3 or greater TRAEs with sotorasib were diarrhea (11.8%), ALT increase (7.7%), and AST increase (5.3%).

“In CodeBreaK 100 as well as 200, the safety signals are pretty similar,” Johnson said. “There were 10% to 20% of patients who hit grade 3 [liver toxicity] but it was amenable to dose reduction and dose hold followed by restarting.”

Patient-reported outcomes were improved with sotorasib vs docetaxel, including time to deterioration in global health status, physical function, and cancer-related symptoms. For quality of life, global health status ratings were 6.6 with docetaxel vs 9.3 with sotorasib, representing a 31% reduction in the risk of quality-of-life deterioration with the targeted therapy (HR, 0.69; 95% CI, 0.53-0.91; P = .005). Sotorasib also delayed physical functioning deterioration by 31% vs docetaxel (9.4 vs 15.1; HR, 0.69; 95% CI, 0.52-0.92; P = .007).

The worsening of key cancer-related symptoms were also delayed significantly with sotorasib vs docetaxel. There was a 37% reduction in the risk of dyspnea (HR, 0.63; 95% CI, 0.48-0.83; P <.001) and the risk of cough worsening was delayed by 45% with sotorasib (HR, 0.55; 95% CI, 0.38-0.80; P <.001). Chest pain deterioration was numerically delayed with sotorasib, with lower scores seen with docetaxel (27.3 vs 34.9); however, this finding was not statistically significant (HR, 0.84; 95% CI, 0.60-1.18; P = .17).

“Sotorasib is oral daily vs IV for docetaxel every 3 weeks. You lose your hair with docetaxel. Patients don’t lose their hair with sotorasib, for example,” Johnson said. “There are a lot of subtle ways this data shows how much better quality of life is for patients [with sotorasib vs docetaxel] and the patient-reported outcomes also show that.”

The phase 1/2 CodeBreaK 101 trial (NCT04185883) continues to enroll patients to explore potential sotorasib combination therapies for solid tumors with KRAS G12C mutations. There are also several phase 1/2 studies exploring various sotorasib combinations across settings. Additionally, the phase 3 CodeBreaK 300 trial (NCT05198934) is exploring sotorasib with panitumumab (Vectibix) for patients with KRAS G12C–mutant colorectal cancer.

“We look at [CodeBreaK 200] as the first step. There are more studies ongoing adding other drugs to it,” Johnson said. “It is well tolerated, so it will pair nicely with other drugs inhibiting MAP kinase, EGFR, even PD-L1.”

References

1. Johnson ML, de Langen AJ, Waterhouse DM, et al. Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/j.annonc.2022.08.051
2. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. May 28, 2021. Accessed September 12, 2022. https://bit.ly/3De4CwM