The KRAS G12C inhibitor sotorasib doubled the rate of progression-free survival at 12 months and reduced the risk of disease progression or death by 34% compared with standard second-line docetaxel for patients with previously treated non–small cell lung cancer (NSCLC) and KRAS G12C mutations. These findings from the phase III CodeBreak 200 trial were presented at the European Society for Medical Oncology (ESMO) Congress 2022.¹ Sotorasib was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in May 2021 for patients with KRAS G12C–mutated locally advanced or metastatic NSCLC, based on findings from the earlier phase I/II CodeBreaK 100 trial.

CodeBreaK 200 is the first phase III trial of a KRAS G12C inhibitor in NSCLC. Other KRAS G12C inhibitors are in various stages of development.

In CodeBreaK 200, at a median follow-up of 17.7 months, the 12-month rate of progression-free survival was 24.8% with sotorasib vs 10.1% with docetaxel. ­Median ­progression-free survival was 5.6 months with sotorasib vs 4.5 months (95%) with docetaxel (P = .002).

Melissa L. Johnson, MD

“[With sotorasib], the progression-free survival rate doubled, and benefit was seen across all subgroups tested. Likewise, the secondary endpoints of objective response rate, disease control rate, time to response, and duration of response were all significantly improved in favor of sotorasib,” said lead 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. These findings support sotorasib as an important treatment option in this setting and reinforce the role of next-generation sequencing testing for KRAS G12C,” she emphasized.

Study Details 

The global 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 that number was reduced to approximately 330, based on a request from the FDA that patients on the docetaxel arm be able to cross over to receive sotorasib after disease progression. This amendment maintained statistical power for the primary endpoint of progression-free survival but was underpowered for statistical significance for overall survival.

A total of 36% of patients in the sotorasib arm received subsequent therapy at crossover, compared with 42% in the docetaxel arm. A total of 34% of patients in the docetaxel arm received a subsequent KRAS G12C inhibitor. Chemotherapy was the most common treatment at crossover for those in the sotorasib arm who experienced disease progression (21%).

Patients were randomly assigned to receive either oral sotorasib at 960 mg/d (n = 171) or intravenous (IV) docetaxel at 75 mg/m² every 3 weeks (n = 174). All patients had been previously treated with 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.

At baseline, patient characteristics were balanced in both arms. In the sotorasib arm, the median patient age was 64, and most patients (73.7%) were enrolled in Europe. Most patients were current or former smokers (97.1%), and one-third had a history of central nervous system involvement (33.9%). Nearly half of patients had received one prior line of therapy (45%), and 17% had received more than two prior lines of therapy.

Main Results

Median overall survival was 10.6 months with sotorasib vs 11.3 months with docetaxel, an almost 1-month absolute difference that was not statistically significant. The objective response rate with sotorasib was 28.1% vs 13.2% with docetaxel (P < .001). The overall rate of disease control (ie, complete response, partial response, stable disease) was 82.5% with sotorasib and 60.3% with docetaxel. About 80% of sotorasib-treated patients had any degree of tumor shrinkage, compared with 62.8% of the docetaxel-treated patients.

Among responders, the median percent change in tumor size was 58.8% with sotorasib vs 48.5% with docetaxel. Median time to response was 1.4 months vs 2.8 months, respectively. Median duration of response was 8.6 months with sotorasib vs 6.8 months with docetaxel.

“Secondary endpoints were all significantly improved in favor of sotorasib,” Dr. Johnson noted. “Response, disease control, time to response, and duration were all positive in favor of sotorasib.”

Improved Safety and Quality of Life

Safety and quality-of-life domains were improved with sotorasib, the study authors said. Treatment-related adverse events were reported in 9.5% of patients on the sotorasib arm vs 11.3% on the docetaxel arm. The most common treatment-related adverse events of any grade were diarrhea (33.7% with sotorasib vs 18.5% with docetaxel), 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%).

Sotorasib was associated with fewer grade 3 or higher treatment-related adverse events than docetaxel (33.1% vs 40.4%). Serious adverse events were less common with sotorasib than with docetaxel: 10.7% vs 22.5%. The most common grade 3 or higher treatment-related adverse events with sotorasib were diarrhea, ALT increase, and AST increase; with docetaxel, they were neutropenia, fatigue, and febrile neutropenia.

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

Patient-reported outcomes were improved with sotorasib vs docetaxel, including the 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, for a 31% reduction in the risk of quality-of-life deterioration with the targeted therapy (P = .005). Sotorasib also delayed the deterioration of physical functioning by 31% vs docetaxel (9.4 vs 15.1; P = .007).

Furthermore, sotorasib delayed the worsening of key cancer-related symptoms compared with docetaxel. There was a 37% reduction in the risk of dyspnea (P < .001), and the risk of cough worsening was delayed by 45% with sotorasib (P < .001). A numerical trend showed a delay in the deterioration of chest pain with sotorasib, but this was not statistically significant.

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

Next Steps

The phase I/II CodeBreaK 101 trial is ongoing and is evaluating potential sotorasib combination therapies for solid tumors with KRAS G12C mutations. There are also several phase I/II studies exploring various sotorasib combinations across settings. Additionally, the phase III CodeBreaK 300 trial is evaluating sotorasib in combination with panitumumab for patients with KRAS G12C–mutant colorectal cancer.

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

REFERENCE

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. ESMO Congress 2022. Abstract LBA10. Presented September 12, 2022.

DISCLOSURE: Amgen funded the CodeBreaK 200 trial. Dr. Johnson reported institutional financial relationships with AbbVie, Acerta Pharma, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Carisma Therapeutics, Crovus Pharmaceuticals, CURIS, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax Technologies, Elicio Therapeutics, EMD Serono, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon Therapeutics, Helsinn Healthcare, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immnocore, Incyte, Janssen, Kadmon Pharmaceuticals, Lilly, Loxo Oncology, Lycera, Memorial Sloan Kettering, Merck, Merus, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, and Y-mAbs Therapeutics for research grants in which she served as PI for a study; has institutional financial relationships with Abbvie, Amgen, Astellas Pharma, AstraZeneca, Axelia Oncology, Black Diamond Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Checkpoint Therapeutics, CytomX, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Lilly, Merck, Mirati Therapeutics, Novartis, Oncorus, Regeneron, Revolution Medicines, Ribon Therapeutics, Sanofi, Turning Point, and WindMIL Therapeutics.