Updated data from the phase 1/2 CodeBreaK 100 trial of sotorasib provide the longest follow-up of a KRAS G12C inhibitor in non–small cell lung cancer.
Close to one-third of patients with KRAS G12C–mutant non–small cell lung cancer (NSCLC) who were treated with sotorasib (Lumakras) on the phase 1/2 CodeBreaK 100 trial (NCT03600883) were alive at the 2-year timepoint, according to follow-up data presented during the American Association for Cancer Research (AACR) 2022 Annual Meeting.
Sotorasib resulted in a 2-year overall survival (OS) rate of 32.5% (95% CI, 25.0%-40.2%). Additionally, the overall response rate (ORR) achieved with sotorasib was 40.7% (95% CI, 33.3%-48.4%) and the disease control rate (DCR) was 83.7% (95% CI, 77.3%-88.9%). Moreover, the median duration of response (DOR) was 12.3 months (95% CI, 7.1-15.0), and 50.6% (95% CI, 37.4%-62.4%) of responders were in response for at least 12 months.
The median progression-free survival (PFS) was 6.3 months (95% CI, 5.3-8.2) and the median OS was 12.5 months (95% CI, 10.0-17.8). At 1-year, the OS rate was 50.8% (95% CI, 42.8%-58.2%).
“In this longest follow-up of patients on any KRAS G12C inhibitor, sotorasib demonstrated very meaningful and durable efficacy, as well as a safety profile [that was] consistent with what had been [previously] reported,” Grace K. Dy, MD, chief of thoracic oncology and professor of oncology at Roswell Park Comprehensive Cancer Center, said in a press conference during the meeting. “We also reported a 2-year [OS rate] of [approximately] 33% in [patients with] pretreated KRAS G12C–mutated NSCLC, which compares favorably with what we would expect with historical treatment using docetaxel in this setting.”
In May 2021, the FDA approved sotorasib for the treatment of patients with locally advanced or metastatic KRAS G12C–mutant NSCLC who have not received prior therapy. The regulatory decision was based on earlier findings from the CodeBreaK 100 trial.3
The pooled phase 1/2 CodeBreak 100 trial enrolled a total of 174 patients with locally advanced or metastatic KRAS G12C–mutant solid tumors. Patients had received at least 1 prior systemic therapy or were ineligible or intolerant for treatment. Those with stable brain metastases were permitted.
In the trial, study participants received oral sotorasib at the FDA-approved dose, which was 960 mg once daily, until disease progression. Radiographic scans were done every 6 weeks up to week 48 and then once every 12 weeks thereafter.
In the phase 1 portion of the research (n = 48), the primary end point was safety and tolerability; key secondary end points were pharmacokinetics, ORR, DOR, PFS, and duration of stable disease. In the phase 2 part of the trial (n = 126), the primary outcome measure was ORR by RECIST v1.1 criteria by blinded independent central review. Key secondary end points were DOR, DCR, PFS, OS, time to response, and safety.
For the updated analysis, the data cutoff was February 22, 2022. The median follow-up time for OS was 24.9 months.
In the updated analysis, investigators analyzed data from the 174 patients who were treated with sotorasib in the combined phase 1 and 2 portions of CodeBreaK 100; these patients received the FDA-approved dose of sotorasib at 960 mg daily. Notably, 82.8% of patients had previously received both platinum-based chemotherapy and anti–PD-1/PD-L1 treatment.
Additional findings showed that the clinical activity with sotorasib was observed regardless of PD-L1 expression and was seen in those with low PD-L1 levels. “Our findings also provide rationale for studies that investigate the incorporation of sotorasib earlier in the treatment course to improve the outcomes for patients [with] NSCLC who are less likely to benefit from immunotherapy,” Dy stated in a press release.
Further analyses were conducted on both tumor and plasma samples to identify biomarker profiles linked with durable clinical benefit. These studies showed that prolonged clinical benefit was observed regardless of tumor mutation burden, PD-L1 expression, and STK11 co-mutation status.
In patients with a PD-L1 expression of less than 1% (n = 31), the PFS benefit with sotorasib lasted at least 12 months in 51.6% of patients; in those whose PD-L1 expression was between 1% and 49% (n = 21), this rate was 28.6%. In patients who had PD-L1 expression of at least 50% (n = 4), 25.0% of patients had a PFS benefit of at least 12 months.
In patients with STK11-mutant/KEAP1 wild-type status (n = 13), the long-term PFS benefit was at least 12 months in 46.2%; this was true for 45.5% of those with STK11 wild-type/KEAP1 wild-type disease (n = 33). In those with STK11-mutant/KEAP1-mutant disease (n = 12), a PFS benefit of at least 12 months was experienced by 16.7% of patients; this was also true for 14.3% of those with STK11 wild-type/KEAP1-mutant disease (n = 7).
“Longer-term follow-up data are important to better define the safety and efficacy of sotorasib, since it is the first-in-class KRAS G12C inhibitor therapy to be approved for this patient population,” Dy added in the press release. “For this particular analysis, we also sought to determine whether there are potential biomarkers that can identify patients who will derive long-term benefit from sotorasib treatment.”
No new safety concerns were observed with long-term treatment with sotorasib. Grade 3/4 treatment-related adverse effects (TRAEs) occurred in 21% of patients, and 1 patient had a new onset grade 3 TRAE of hemolytic anemia after 1 year. Notably, no TRAE-related deaths occurred, nor did any TRAEs lead to discontinuation after 1 year of therapy.
“[Overall], most toxicities were grade 1/2 in severity; major AEs were [gastrointestinal] in nature [with] nausea, diarrhea, [liver function test] abnormalities, and 22% of patients required dose modifications or dose interruptions; about 6% required dose discontinuation,” Ly said in the presentation, adding that approximately one-quarter of patients remain on treatment after 1 year.
CodeBreaK 100 is a single-arm, non-randomized trial, which investigators noted as a limitation. The randomized, global phase 3 trial CodeBreaK 200 study (NCT04303780) is ongoing and includes a comparator arm of docetaxel in patients with KRAS G12C–mutant NSCLC.
“We eagerly await the results of the phase 3 study, which likely will be available later this year, and expect that they will confirm our findings from CodeBreaK 100,” Dy stated in the press release.