Sotorasib Approaches EU Approval for KRAS G12C–Mutated Advanced NSCLC


The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion recommending the conditional marketing authorization of sotorasib for the treatment of adult patients with advanced non–small cell lung cancer whose tumors harbor a KRAS G12C mutation and who have progressed after at least 1 prior line of systemic therapy.

David M. Reese, MD

David M. Reese, MD

The European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending the conditional marketing authorization of sotorasib (Lumykras) for the treatment of adult patients with advanced non–small cell lung cancer (NSCLC) whose tumors harbor a KRAS G12C mutation and who have progressed after at least 1 prior line of systemic therapy.1

The recommendation is supported by findings from the phase 2 CodeBreak 100 trial (NCT03600833), which showed that the agent elicited an objective response rate (ORR) of 37.1% (95% CI, 28.6%-46.2%), which was comprised of a complete response rate of 3.2% and a partial response rate of 33.9%.2,3

Moreover, at a median follow-up of 15.3 months, sotorasib resulted in a median overall survival (OS) of 12.5 months (95% CI, 10.0–not evaluable [NE]) and a median progression-free survival (PFS) of 6.8 months (95% CI, 5.1-8.2). The median time to response (TTR) was 1.35 months, and the median duration of response (DOR) was 11.1 months (95% CI, 6.9–NE). The disease control rate (DCR) with sotorasib was 80.6% (95% CI, 72.6%-87.2%).

The recommendation will be reviewed by the European Commission. The regulatory agency is anticipated to decide on the application by mid-January 2022.

“After 40 years of cancer research to target the KRAS mutation, many in the scientific community believed that KRAS was ‘undruggable,’ leaving patients with this mutation with limited treatment options,” David M. Reese, MD, executive vice president of Research and Development at Amgen, stated in a press release. “The [sotorasib] development program was designed to bring this targeted therapy to patients with KRAS G12C–mutated NSCLC as quickly as possible. The EMA CHMP positive opinion brings patients in the European Union [EU] closer to this transformative therapy and highlights our commitment to improving patient outcomes in difficult-to-treat cancers.”

CodeBreaK 100 enrolled a total of 126 patients with locally advanced or metastatic NSCLC harboring a KRAS p.G12C mutation, as assessed by central testing of tumor biopsies. To be eligible for participation, patients needed to have progressed on previous standard therapies.

Study participants received oral sotorasib at a once-daily dose of 960 mg until disease progression. They 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 by RECIST v1.1 criteria and independent central review, and key secondary end points comprised DOR, DCR, TTR, PFS, OS, and safety.

The median age of patients enrolled to the trial was 63.5 years (range, 37-80), and 30.2% had an ECOG performance status of 0. The majority of patients (92.9%) were either current or former smokers. Moreover, 42.9% of patients received 1 prior line of therapy, 34.9% received 2 prior lines, and 22.2% received 3 prior lines. Previous treatments included platinum-based chemotherapy (89.7%), PD-1/PD-L1 inhibition (91.3%), or both (81.0%).

Efficacy of sotorasib was examined in exploratory analyses of molecularly defined subsets of patients. Tumor mutational burden (TMB) was not found to be a predictive factor of response to the agent. The ORR achieved with sotorasib was 40.0% in those determined to have TMB-high disease, defined as ≥ 10 mutations/mb; this rate was 42.0% in those with TMB-low disease, defined as < 10 mutations/mb.

Responses were observed in those with co-occurring mutations in TP53 (wild-type, 40%; mutant, 39%), STK11 (wild-type, 39%; mutant, 40%), and KEAP1 (wild-type, 44%; mutant, 20%).

Moreover, in the 22 patients with STK11-mutant, KEAP1 wild-type disease, sotorasib elicited an ORR of 50%, a median PFS of 11.0 months, and a median OS of 15.3 months. In those with STK11-mutant, KEAP1-mutated disease, the ORR was 23%. In those with STK11 wild-type, KEAP1-mutant disease, the ORR was 14%, and it was 42% in those with STK11 wild-type, KEAP1 wild-type disease. The median PFS in these subsets was 2.6 months, 5.5 months, and 6.8 months, respectively. The median OS was 4.8 months, 7.5 months, and NE, respectively.

The most frequent treatment-related adverse effects experienced with sotorasib included diarrhea (32%), nausea (19%), increased alanine aminotransferase level (ALT; 15%) and increased aspartate aminotransferase level (AST; 15%). The most common severe, grade 3 or higher, TRAEs included increased ALT (6%), increased AST (6%), and diarrhea (4%). Seven percent of patients discontinued treatment because of a TRAE.

“Patients with KRAS G12C–mutated NSCLC face poor prognosis and usually do not respond to currently available treatments,” Professor Fabrice Barlesi, general director of Gustave Roussy, stated in a press release. “The introduction of sotorasib in the EU as a novel treatment option would be a welcome development as a potentially new standard of care for the tens of thousands of patients with NSCLC living with this common mutation.”

Previously, in May 2021, the FDA approved sotorasib (Lumakras) as the first treatment for adult patients with NSCLC whose tumors harbor KRAS G12C mutations and who have received at least 1 prior systemic therapy.4 The decision was supported by earlier data from CodeBreaK 100.


  1. LUMYKRAS (sotorasib) receives positive opinion from EMA CHMP for patients with KRAS G12C-mutated advanced non-small cell lung cancer. News release. Amgen. November 12, 2021. Accessed November 12, 2021.
  2. 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
  3. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371-2381. doi:10.1056/NEJMoa2103695
  4. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. Accessed November 11, 2021.
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