In most key prespecified molecularly defined subsets of patients with pretreated KRAS G12C–mutated non–small cell lung cancer, sotorasib continued to demonstrate consistent benefit vs docetaxel.
In the phase 3 CodeBreaK 200 trial (NCT04303780), a consistent benefit was seen with sotorasib (Lumakras) vs docetaxel in the majority of key prespecified molecularly defined subsets of patients with pretreated KRAS G12C–mutated non–small cell lung cancer (NSCLC), according to findings from an exploratory analysis which were presented at the 2023 ASCO Annual Meeting.1
Co-alterations in key genes included TP53, STK11, and KEAP1. In the overall population, these mutations were detected in 57% (sotorasib, 54%; docetaxel, 60%), 38% (37%; 39%), and 26% (28%; 23%) of patients, respectively. Seventeen percent of patients had both STK11 and KEAP1 mutations (20%; 15%).
Sotorasib retained progression-free survival (PFS) benefit over docetaxel across all key co-alteration subgroups, including those with STK11-altered (HR, 0.68; 95% CI, 0.45-1.05) and wild-type (HR, 0.65; 95% CI, 0.46-0.92) disease, those with KEAP1-altered (HR, 0.84; 95% CI, 0.48-1.47) and wild-type (HR, 0.62; 95% CI, 0.45-0.84) disease, and those with TP53-altered (HR, 0.83; 95% CI, 0.58-1.18) and wild-type (HR, 0.48; 95% CI, 0.30-0.75) disease.
Similar results were observed regarding overall response benefit, and this was broadly retained for sotorasib over docetaxel spanning all major co-alteration defined subgroups of patients.
Sotorasib was also found to improve PFS over docetaxel, independent of PD-L1 expression. In patients who had a PD-L1 protein expression of less than 1%, sotorasib (n = 57) resulted in a median PFS of 8.3 months (95% CI, 4.1-8.6) vs 5.9 months (95% CI, 3.5-7.2) with docetaxel (n = 55; HR, 0.66; 95% CI, 0.41-1.06; P = .06). In those with a PD-L1 protein expression 1% or higher but less than 50%, the median PFS with sotorasib (n = 46) and docetaxel (n = 70) was 4.6 months (95% CI, 3.4-7.8) and 3.0 months (95% CI, 2.1-4.5), respectively (HR, 0.61; 95% CI, 0.39-0.96; P = .03). Lastly, in those with a PD-L1 protein expression of at least 50%, the median PFS with sotorasib (n = 60) was 5.7 months (95% CI, 4.0-10.0) vs 5.4 months (95% CI, 2.0-10.2) with docetaxel (n = 40; HR, 0.75; 95% CI, 0.44-1.23; P = .14).
“In the first randomized, molecularly defined analysis of the KRAS G12C inhibitor vs docetaxel, sotorasib demonstrated consistent clinical benefit vs docetaxel across most co-alteration–defined subgroups,” said Ferdinandos Skoulidis, MD, PhD, MRCP, lead study author and associate professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, in a presentation of the data. “A number of novel hypothesis-generating findings were observed in this study. Specifically, patients harboring tumors with additional KRAS co-alterations were more refractory to either sotorasib or docetaxel. [Moreover,] in a small subset of patients harboring tumors with NOTCH1 co-mutations, sotorasib was associated with worse outcomes.”
For those who receive KRAS G12C inhibitors, clinical outcomes are heterogeneous, according to Skoulidis. As such, there is a major unmet need to evaluate efficacy of these agents in molecularly defined subgroups of patients to appropriately inform therapeutic decisions.
In May 2021, the FDA approved sotorasib for use in adult patients with KRAS G12C–mutated NSCLC who have previously received at least 1 systemic therapy, based on findings from the phase 2 CodeBreaK 100 trial (NCT03600883).2,3 At the time of the decision, sotorasib elicited an objective response rate (ORR) of 36% (95% CI, 28%-45%) in this population. The median duration of response was 10 months, with 58% experiencing a response that lasted for at least 6 months. The disease control rate (DCR) was 81% (95% CI, 73%-87%).
CodeBreaK 200 enrolled patients with locally advanced/unresectable or metastatic KRAS G12C–mutated NSCLC who received 1 or more previous treatments, including platinum-based chemotherapy and a checkpoint inhibitor. Patients needed to have an ECOG performance status of 0 or 1, but they could not have active brain metastases.1
Study participants (n = 345) were randomly assigned 1:1 to receive oral sotorasib at a daily dose of 960 mg (n = 171) or intravenous docetaxel at 75 mg/m2 every 3 weeks (n = 174).
The primary end point of the trial was PFS by blinded independent central review (BICR) by RECIST v1.1 criteria in the intention-to-treat (ITT) population. Key secondary end points included overall survival, ORR, duration of response, DCR, time to response, safety, patient-reported outcomes, and pharmacokinetics. Genomic co-alterations and PD-L1 protein levels served as exploratory end points.4,1
At a median follow-up of 17.7 months (interquartile range, 16.4-20.1), sotorasib resulted in a 34% reduction in the risk of disease progression or death over docetaxel (HR, 0.66; 95% CI, 0.51-0.86; P = .0017), meeting the primary end point of the trial. The median PFS with sotorasib was 5.6 months (95% CI, 4.3-7.8) vs 4.5 months (95% CI, 3.0-5.7) with docetaxel. The 12-month PFS rates were 24.8% and 10.1%, respectively.4
The BICR-assessed ORR was 28.1% (95%, 21.5%-35.4%) with sotorasib vs 13.2% (95% CI, 8.6%-19.2%) with docetaxel (P < .001). The DCRs in the investigative and control arms were 82.5% (95% CI, 75.9%-87.8%) and 60.3% (95% CI, 52.7%-67.7%), respectively. Overall survival was not significantly different between the sotorasib and docetaxel arms at 10.6 months (95% CI, 8.9-14.0) and 11.3 months (95% CI, 9.0-14.9), respectively (HR, 1.01; 95% CI, 0.77-1.33).
For the prespecified subgroup analyses, investigators analyzed tissue and/or plasma samples at baseline for key genomic alterations utilizing central targeted next-generation sequencing (NGS) with the Tempus xT assay and Resolution ctDx lung assay, respectively.1 Investigators evaluated PD-L1 protein level by local standard-of-care testing.
Of the 345 patients in the ITT population, 226 had tissue NGS data and 294 had plasma NGS data. A total of 318 patients comprised the biomarker-evaluable population. Baseline co-alterations were well balanced across the treatment arms.
Beyond TP53, STK11, and KEAP1, other additional co-alterations of interest included EGFR (21%); NTRK1, NTRK2, and NTRK3 (19%); MET (12%), ALK (11%); RET (7%); ROS1 (5%); and BRAF (5%). “The first conclusion is that these alterations were quite frequent. However, the prevalence of clinically actionable co-alterations in oncogenic drivers was considerably lower,” Skoulidis said.
Investigators also evaluated the impact of having additional alterations in KRAS, beyond the qualifying KRAS G12C mutation, on clinical outcomes with sotorasib and docetaxel. Twenty patients had copy number gains involving KRAS, and 8 patients had single nucleotide variants involving KRAS. Overall, 26 patients (sotorasib, n = 9; docetaxel, n = 17) had additional alterations in KRAS.
No objective responses to either agent was observed in those whose tumors harbored these additional KRAS alterations. “These findings keep with previously presented preclinical and clinical data that identified secondary alterations in KRAS as well as other isoforms as drivers of both primary and acquired resistance to sotorasib,” Skoulidis explained. The median PFS with sotorasib in these patients was 1.8 months (95% CI, 0.8-3.0) vs 2.5 months (95% CI, 1.4-3.1) with docetaxel (HR, 1.74; 95% CI, 0.84-3.58; P = .016).
Skoulidis and colleagues conducted an additional exploratory analysis in a subset of patients by using comprehensive tissue-based genomic profiling to identify genomic alterations that might be enriched in subgroups of patients with distinct clinical outcomes of either long-term benefit or early disease progression. Long-term benefit was defined as a PFS of at least 6 months, and early progression was defined as a PFS of less than 3 months with no complete or partial response, according to Skoulidis.
Most patients were found to have long-term benefit or early progression with sotorasib (n = 115) vs docetaxel (n = 96). In the sotorasib arm, 55% of those patients (n = 63) had long-term benefit and 45% (n = 52) had early progression. In the docetaxel arm, 38% of those patients (n = 36) had long-term benefit and 62% (n = 60) had early progression. Moreover, NOTCH1 was the most notable co-alteration linked with early progression or long-term benefit.
Based on these findings, investigators conducted a deeper analysis to evaluate the impact of NOTCH1 co-alterations on clinical outcomes with sotorasib or docetaxel. “This analysis identified an early progression signal for NOTCH1-mutated tumors in the sotorasib arm,” Skoulidis said. Seventy-eight percent of patients who had NOTCH1-mutated tumors (n = 7) experienced early progression. In contrast, 75% of patients with NOTCH1-mutated tumors who received docetaxel (n = 6) experienced long-term clinical benefit.
When looking at patients with KRAS G12C and NOTCH1 co-alterations, investigators observed a trend toward shorter PFS with sotorasib than docetaxel, at a median of 2.8 months (95% CI, 1.6-3.4) and 7.5 months (95% CI, 3.0–not evaluable), respectively.
Lastly, Skoulidis and colleagues set out to assess the link between inferred baseline tumor burden, based on analysis of plasma circulating tumor DNA, and clinical outcomes with sotorasib and docetaxel. “A higher baseline plasma tumor burden was associated with greater odds of early disease progression and a lower likelihood of long-term clinical benefit with either sotorasib or docetaxel,” Skoulidis said. “We conclude that baseline blood plasma tumor burden is negatively prognostic, independent of the treatment arm.”