Sotorasib Shows Durable Antitumor Activity in KRAS G12C–Mutant Advanced NSCLC

October 6, 2020

Sotorasib demonstrated durable responses in patients with KRAS G12C–mutated advanced non–small cell lung cancer who had progressed on a median of 2 previous lines of treatment.

Sotorasib (formerly AMG 510) demonstrated durable responses in patients with KRAS G12C–mutated advanced non–small cell lung cancer (NSCLC) who had progressed on a median of 2 previous lines of treatment, according to topline results from the phase 2 CodeBreaK 100 trial.1

The KRAS G12C small molecule inhibitor showed an objective response rate (ORR) that proved consistent with prior data observed in an earlier phase 1 trial that had been conducted in patients with advanced NSCLC who received the agent at a daily dose of 960 mg.

Moreover, the duration of response (DOR) achieved with sotorasib also proved to be encouraging, according to Amgen. Over half of those who responded to treatment continued to respond and were still on the agent, as of the data cutoff date. The safety and tolerability of sotorasib also proved to be comparable with what had previously been reported in the phase 1 trial.

Detailed data from the phase 2 trial will be submitted for presentation at the IASCLC World Congress on Lung Cancer, according to Amgen.

“Targeting KRAS has been a 40-year quest that has left patients with limited options. These topline data underscore our belief in the potential for sotorasib to become the standard of care for [patients with] NSCLC [who have a] KRAS G12Cmutation and remain in need of new treatment options,” David M. Reese, MD, executive vice president of Research and Development at Amgen, stated in a press release.

Results from a subgroup of 59 heavily pretreated patients with KRAS G12C–positive NSCLC enrolled in the phase 1 trial were presented during the 2020 ESMO Virtual Congress. In these patients, sotorasib resulted in a confirmed objective response rate (ORR) of 32.2% and a disease control rate (DCR) of 88.1%.2

A total of 129 patients were enrolled on the CodeBreaK 100 trial; 59 patients had NSCLC, 42 had colorectal cancer, and 28 had any of 11 other solid tumor types. Within the subgroup of patients with NSCLC, 4 cohorts received a different daily dose of the agent: 180 mg (n = 3), 360 mg (n = 16), 720 mg (n = 6), and 960 mg (n = 34). A reduction in tumor size was observed across all dose levels, although the 960-mg dose was deemed to be the most effective with acceptable tolerability. As such, 960 mg of sotorasib was examined in the expansion phase of the trial.

The primary end point of the trial was safety, while key secondary end points included ORR, DOR, DCR, and progression-free survival (PFS). A total of 14 patients were still receiving treatment with the agent at a median follow-up of 11.7 months. The majority of the 45 participants who discontinued treatment did so because of progressive disease.

The median age of participants was 68 years and just over half, or 59.8%, were female. The majority of patients, or 89.8%, were either current or former smokers. All participants received prior platinum-based chemotherapy, and most had received previous treatment with immunotherapy. All but 2 patients had ECOG performance scores of either 0 or 1. Patients with brain metastases were not permitted for inclusion, although 18 went on to develop the condition. Notably, 1 of these patients achieved a central nervous system (CNS) response with the agent.

At the time of the first series of scans, which were conducted every 6 weeks, tumor shrinkage of any magnitude was reported in 71.2% of patients (n = 42). In the cohort of patients who received the 960-mg dose (n = 19), the ORR with sotorasib was 35.3%, and the median DOR was 10.9 months. Ten of 19 responders were still in response at the June 1, 2020 data cutoff. Moreover, the DCR with the agent was 91.2%, with a 4.0-month median duration of stable disease.

No complete responses were observed with sotorasib. In both the 960-mg cohort and across the entire study population (n = 33), the stable disease rate was 55.9%. Moreover, the median PFS for the NSCLC subgroup was 6.3 months.

With regard to safety, no dose-limiting toxicities were reported. Additionally, no deaths associated with treatment occurred. Treatment-related adverse effects (AEs) that were grade 3 or higher were experienced by 18.6% of patients; however, only 1 grade 4 event of alanine transaminase (ALT) was observed. The most commonly reported grade 3 toxicities included increased ALT (n = 6), diarrhea (n = 3), and increased aspartate aminotransferase (AST; n = 3). The most frequently reported any-grade AEs included diarrhea (n = 15), increased ALT (n = 12), and increased AST (n = 12).

In the global, active-controlled phase 3 confirmatory CodeBreaK 200 trial (NCT04303780), investigators will compare the safety and efficacy of sotorasib versus docetaxel in patients with previously treated, locally advanced and unresectable, or metastatic KRAS G12C­–mutant NSCLC.3 The primary end point of the trial is PFS, while secondary end points include OS, objective response, DOR, time to response, safety, and pharmacokinetic parameters.

To be eligible for participation, patients must be 18 years of age or older; have an ECOG performance status of 0 or 1; and have histologically documented, locally advanced, and unresectable or metastatic NSCLC. Patients also need to have a centrally confirmed KRAS G12C mutation and have experienced disease progression or recurrence on or following at least 1 prior systemic treatment, which must have included either a platinum-based chemotherapy doublet and a checkpoint inhibitor or either given as 1 line or individual lines of treatment.

If patients received previous treatment with docetaxel in the unresectable or metastatic setting, they were not permitted; however, patients who received docetaxel in the neoadjuvant or adjuvant settings and did not progress within 6 months following the completion of treatment, could still participate. Patients who received previous treatment with sotorasib or other KRAS G12C inhibitors, had previously identified targetable mutations beyond KRAS G12C, or active brain metastases, will not be included in the analysis.

In the trial, patients will go through a 28-day screening period followed by randomization in a 1:1 fashion to either 21-day cycles of oral sotorasib at a daily dose of 960 mg (n = 325) or 21-day cycles of intravenous docetaxel at a dose of 75 mg/m2 every 3 weeks (n = 325). Patients will be stratified based on the number of previous lines of treatment they received (1 vs 2 vs more than 2), race (Asian vs non-Asian), and history of CNS involvement (present vs absent).

Treatment will continue until either progressive disease, unacceptable toxicity, initiation of another anticancer treatment, or withdrawn consent. Thirty days following the end of treatment, a safety follow-up will be performed. Twelve weeks after the safety follow-up, long-term follow-up will be done for up to 5 years.

The planned sample size is 650 patients, and the first participant was enrolled to the trial on June 4, 2020. Approximately 300 global sites are anticipated to participate in the effort, and enrollment is ongoing at sites in the following countries: United States, Australia, Belgium, France, Germany, Greece, Italy, Japan, South Korea, Netherlands, Poland, Russia, Spain, Switzerland, and Taiwan.


  1. Amgen announces positive topline phase 2 results for investigational KRAS G12C inhibitor sotorasib in advanced non-small cell lung cancer. News release. October 5, 2020. Accessed October 6, 2020.
  2. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 1257O.
  3. Reck M, Spira A, Besse B, et al. CodeBreaK 200: a phase 3, multicenter study of sotorasib, a KRASG12C inhibitor, versus docetaxel in patients with previously treated advanced non–small-cell lung cancer harboring KRAS p.G12C mutation. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Poster 1416TiP.