Sotorasib Maintains Durable Clinical Benefit in KRAS p.G12C-Mutant NSCLC

Updated results from the phase 2 CodeBreaK100 trial were presented by Ferdinandos Skoulidis, MD, PhD during the 2021 ASCO Annual Meeting.

Ferdinandos Skoulidis, MD, PhD

Ferdinandos Skoulidis, MD, PhD

Updated results from the phase 2 CodeBreaK100 trial (NCT03600883) show that sotorasib (Lumakras) provided continued durable clinical benefit in patients with pretreated KRAS p.G12C–mutated non–small cell lung cancer (NSCLC), according to a presentation given during the 2021 ASCO Annual Meeting.1,2

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%-46.2%), which included 4 complete responses (CRs). 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 an OS benefit in a registrational phase 2 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 in a presentation during the meeting. “The efficacy of sotorasib was observed across various patient subgroups prespecified by baseline patient characteristics.”

Additionally, sotorasib had activity in molecularly-defined subgroups from exploratory analyses within the study, including in those with STK11-mutated tumors.

Generally, outcomes for patients with KRAS-mutant tumors remain poor, and novel therapies are needed for those who progress on frontline therapy with checkpoint inhibition alone or with platinum-doublet chemotherapy, Skoulidis said.

Sotorasib is a first-in-class, irreversible, and selective KRAS G12C inhibitor that has demonstrated durable clinical benefit in previously treated patients with KRAS p.G12C-mutant NSCLC. Based on earlier findings of CodeBreaK, 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 prior systemic therapy.3

With the longer follow-up of the phase 2 CodeBreaK100 trial, investigators presented updated efficacy and safety data, including mature OS, with a data cutoff date of March 15, 2021. The findings 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 as assessed by central testing of tumor biopsies to receive sotorasib orally at 960 mg once daily until disease progression. Patients with stable brain metastases were permitted.

Patients underwent radiographic scans every 6 weeks up to week 48 and once every 12 weeks thereafter. The primary end point of the trial was ORR via RECIST v1.1 criteria by independent central review; key secondary end points 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 patients had an ECOG performance status of 0. Most patients (92.9%) were current or former smokers, and patients either had 1 (42.9%), 2 (34.9%), or 3 (22.2%) prior lines of systemic therapy. The types of prior treatment were platinum-based chemotherapy (89.7%), PD-1/PD-L1 inhibition (91.3%), or platinum-based chemotherapy plus PD-1/PD-L1 inhibition (81.0%).

The 37.1% ORR was comprised of a 3.2% (n = 4) CR rate and a 33.9% (n = 42) partial response rate; the stable disease rate was 43.5% (n = 54), and 16.1% (n = 20) of patients had progressive disease. Four patients could not be evaluated or were missing scans. 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 prespecified subgroups, including age, ECOG performance status, number of prior lines of treatment, and prior PD-1/PD-L1–directed therapy alone or in combination with platinum-based chemotherapy. Notably, for patients who received a prior 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–NE).

Efficacy was also evaluated in exploratory analyses of molecularly defined subgroups. Skoulidis noted that the likelihood of response to sotorasib was independent of whether patients had a KRAS p.G12C mutant allele frequency. Tumor mutational burden (TMB) was also not a predictive factor of response; the ORR was 40% in those with TMB-high disease (≥10 mutations/megabase [mb]) and 42% in patients with TMB-low disease (<10 mutations/mb). Moreover, responses occurred in patients with co-occurring mutations in TP53 (wild-type, 40%; mutant, 39%), STK11 (wild-type, 39%; mutant, 40%), and KEAP1 (wild-type, 44%; mutant, 20%).

“This is important because inactivating somatic mutations in STK11 and KEAP1 have been previously associated with worse clinical outcomes with standard-of-care systemic therapies, including chemoimmunotherapy, platinum-doublet chemotherapy, checkpoint inhibitor monotherapy, as well as chemotherapy with docetaxel,” Skoulidis said.

Additionally, investigators 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 with STK11 wild-type, KEAP1 wild-type disease. Also in these subgroups, 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.

“Although, it should be noted that objective responses to sotorasib were observed in 20% of KEAP1-mutant tumors,” Skoulidis added.

Regarding safety, mostly grade 1/2 treatment-related adverse events (TRAEs) were observed. All-grade TRAEs occurred in 69.8% of patients and grade 3 events in 19.8% of patients. The most common grade 3 TRAEs included diarrhea (4.0%), increased alanine aminotransferase (ALT; 6.3%), increased aspartate aminotransferase (AST; 5.6%), increased blood alkaline phosphatase (0.8%).

TRAEs that led to dose modifications occurred in 22.2% (n = 28) of patients, and treatment discontinuations due to TRAEs occurred in 7.1% (n = 9) of patients. The latter included drug-induced liver injury (n = 3), liver function test increase (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 confirmatory phase 3 CodeBreak200 trial (NCT04303780), which is evaluating sotorasib vs docetaxel in patients with pretreated KRAS p.G12C-mutated NSCLC, is currently ongoing.


1. Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated 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

2. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. Published online June 4, 2021. doi:10.1056/NEJMoa2103695

3. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. Accessed June 4, 2021.

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