Sotorasib impresses with long-lasting clinical benefits in NSCLC KRAS p.G12C +
At a median follow-up of 15.3 months, sotorasib was associated with a median overall survival (OS) of 12.5 months (95% CI, 10.0 – not evaluable [NE]), a median progression-free survival (PFS) of 6.8 months (95% CI, 5.1-8.2) and an objective response rate (ORR) of 37.1% (95% CI, 28 , 6% to 46.2%), which included 4 complete responses (CR). The median duration of response (DOR) was 11.1 months (95% CI, 6.9 – NE).
“This makes sotorasib the first KRAS G12C inhibitor to demonstrate a benefit for OS in a phase 2 registration clinical trial”, Ferdinandos Skoulidis, MD, PhD, lead study author and assistant professor in the Department of Thoracic and head and neck medical oncology at the University of Texas MD Anderson Cancer Center, said during a presentation at the meeting. “The efficacy of sotorasib has been observed in various subgroups of patients predefined by the baseline characteristics of the patients. “
In addition, sotorasib had activity in molecularly defined subgroups from exploratory analyzes within the study, including in those with STK11– mutated tumors.
In general, results for patients with KRAS-Mutant tumors remain poor and new therapies are needed for those who progress with first-line treatment with checkpoint inhibition alone or with platinum doublet chemotherapy, Skoulidis said.
Sotorasib is a first-class, irreversible and selective KRAS G12C inhibitor that has demonstrated lasting clinical benefit in patients previously treated with KRAS NSCLC p.G12C-mutant. Based on previous CodeBreaK results, the FDA approved sotorasib in May 2021 as the first treatment for adult patients with non-small cell lung cancer whose tumors harbor KRAS G12C mutations and who have received at least 1 previous systemic treatment.3
With the longer follow-up to the Phase 2 CodeBreaK100 trial, investigators presented updated efficacy and safety data, including mature OS, with a data deadline of March 15, 2021. The results also incorporated data from biomarker subgroups and baseline characteristics.
In the Phase 2 CodeBreaK100 trial, investigators enrolled 126 patients with locally advanced or metastatic NSCLC with a KRAS P.G12C mutation assessed by central tumor biopsy testing to receive oral sotorasib 960 mg once daily until disease progression. Patients with stable brain metastases were allowed.
Patients underwent radiographic examinations every 6 weeks through week 48 and once every 12 weeks thereafter. The primary endpoint of the trial was ORR via RECIST v1.1 criteria from an independent central review; the main secondary endpoints include DOR, disease control rate (DCR), time to response, PFS, OS, and safety.
The median age was 63.5 years (range: 37-80) and 30.2% of the patients had an ECOG performance index of 0. Most of the patients (92.9%) were current or former smokers, and patients had (34.9%) or 3 (22.2%) prior lines of systemic treatment. Previous treatment types were platinum-based chemotherapy (89.7%), PD-1 / PD-L1 inhibition (91.3%), or platinum-based chemotherapy plus PD-1 / PD inhibition -L1 (81.0%).
The ORR of 37.1% consisted of a CR rate of 3.2% (n = 4) and a partial response rate of 33.9% (n = 42); the stable disease rate was 43.5% (n = 54) and 16.1% (n = 20) of patients had progressive disease. Four patients could not be assessed or were missing tests. The DCR was 80.6% (95% CI, 72.6% -87.2%) and the median time to response was 1.35 months.
The clinical activity observed with sotorasib was consistent across all predefined subgroups, including age, ECOG performance index, number of prior treatment lines, and prior treatment against PD-1 / PD- L1 alone or in combination with platinum-based chemotherapy. Notably, for patients who received a PD-1 / PD-L1 inhibitor but not chemotherapy, the ORR was 69.2% (95% CI, 38.6% -90.9%) and the Median OS was 17.7 months (95% CI, 11.7 to NE).
Efficacy was also assessed in exploratory analyzes of molecularly defined subgroups. Skoulidis noted that the likelihood of responding to sotorasib was independent of whether or not patients had KRAS Frequency of the mutant p.G12C allele. Tumor mutational burden (TMB) was also not a predictor of response; the ORR was 40% in people with disease with a high rate of TMB (≥ 10 mutations / megabase [mb]) and 42% in patients with low TMB disease (TP53 (wild type, 40%; mutant, 39%), STK11 (wild type, 39%; mutant, 40%) and KEAP1 (wild type, 44%; mutant, 20%).
“This is important because the inactivation of somatic mutations in STK11 and KEAP1 have previously been associated with worse clinical outcomes with standard systemic therapies, including chemoimmunotherapy, platinum doublet chemotherapy, checkpoint inhibitor monotherapy, as well as chemotherapy with docetaxel, ”Skoulidis said.
In addition, the researchers noted that in patients with STK11-mutant, KEAP1 wild-type disease (n = 22), the ORR with sotorasib was 50%, the median PFS was 11.0 months, and the median OS was 15.3 months. The ORR was 23% in patients with STK11-mutant, KEAP1-mutant disease; 14% in STK11 wild type, KEAP1-mutant disease; and 42% in patients STK11 wild type, KEAP1 wild type disease. In these subgroups as well, the median PFS was 2.6 months, 5.5 months and 6.8 months, respectively; the median OS was 4.8 months, 7.5 months and not evaluable, respectively.
“However, it should be noted that objective responses to sotorasib were observed in 20% of KEAP1-mutant tumors, ”added Skoulidis.
Regarding safety, most grade 1/2 treatment-related adverse events (TRAE) were observed. RTEs of all grades occurred in 69.8% of patients and grade 3 events in 19.8% of patients. The most common grade 3 adverse reactions included diarrhea (4.0%), an increase in alanine aminotransferase (ALT; 6.3%), an increase in aspartate aminotransferase (AST; 5.6%) , an increase in blood alkaline phosphatase (0.8%).
TRAE resulting in dose changes occurred in 22.2% (n = 28) of patients, and treatment discontinuations due to TRAE occurred in 7.1% (n = 9) of patients. These included drug-induced liver damage (n = 3), increased liver function tests (n = 1), increased ALT (n = 2), increased AST (n = 2), increased alkaline phosphatase (n = 1), increased transaminases (n = 1), pneumonitis (n = 2) and dyspnea (n = 1).
The CodeBreak200 Phase 3 confirmatory trial (NCT04303780), which evaluates sotorasib versus docetaxel in patients with KRAS NSCLC, mutated by p.G12C, is currently underway.
- Skoulidis F, Li BT, Govindan R, et al. Overall Survival and Exploratory Subgroup Analyzes of the Phase 2 CodeBreaK 100 Trial of Sotorasib in Previously Treated Patients KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021; 39 (suppl 15): 9003. doi: 10.1200 / JCO.2021.39.15_suppl.9003
- Skoulidis F, Li BT, Dy GK et al. Sotorasib for lung cancer with KRAS p.G12C mutation. N English J Med. Published online June 4, 2021. doi: 10.1056 / NEJMoa2103695
- The FDA approves the first targeted therapy for the lung cancer mutation, previously considered resistant to drug therapy. Press release. FDA. May 28, 2021. Accessed June 4, 2021. https://bit.ly/3c172Ah