Sotorasib: Subgroup Analysis of Phase II Trial Shows Activity With KRAS Inhibitor in Lung Cancer

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The KRAS-specific inhibitor sotorasib achieved responses in patients with KRAS G12C–mutated non–small lung cancer (NSCLC) who had experienced disease progression on platinum-based chemotherapy, immunotherapy, or both treatments. The objective response rate was 37.1%, and responses extended to all subgroups, according to an analysis of the phase II CodeBreaK 100 trial presented at the 2021 ASCO Annual Meeting by lead study author Ferdinandos Skoulidis, MD, PhD, Assistant Professor of Thoracic Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.1 A confirmatory phase III CodeBreaK 200 trial is designed to compare sotorasib vs docetaxel.

The first report from the study suggested that patients with co-mutations in STK11, a driver of poor outcomes with standard care, derived benefit from sotorasib.2 The extended subgroup analysis presented at the ASCO meeting showed a numerically higher response rate and longer progression-free and overall survival in patients with STK11 co-mutated but KEAP1 wild-type disease. Due to the small number of patients, further study is needed to determine which subgroups—if any—have more robust responses to sotorasib.

Ferdinandos Skoulidis, MD, PhD

Ferdinandos Skoulidis, MD, PhD

Vamsidhar Velcheti, MD

Vamsidhar Velcheti, MD

“Extensive efforts are underway to understand the molecular determinants of response to sotorasib and to characterize the full spectrum of possible mechanisms of resistance,” Dr. Skoulidis said. “The CodeBreaK 100 results represent a pivotal step in our progress against KRAS-mutant tumors and will likely be a stepping stone for even more effective and tailored combination regimens. The future looks promising.”

For the moment, the news is focused on the success of the first drug to target KRAS—formerly considered a nondruggable mutation in NSCLC. The study was published in The New England Journal of Medicine3 to coincide with the presentation at the ASCO meeting.

Senior author of the study, Vamsidhar Velcheti, MD, Director of Thoracic Medical Oncology, NYU Langone Health, Perlmutter Cancer Center, New York, was most enthusiastic about the promise of sotorasib. “The phase II CodeBreaK 100 study is an important landmark study. Sotorasib is the first KRAS tumor-selective drug to be approved for any tumor type. Patients with KRAS G12C–positive lung adenocarcinoma have limited systemic treatment options after experiencing disease progression on standard chemotherapy and immunotherapy. Sotorasib is now a great treatment option for these patients after disease progression on front-line chemotherapy and immunotherapy,” said Dr. Velcheti. [Editor’s Note: On May 28, 2021, the U.S. Food and Drug Administration granted accelerated approval to sotorasib for the first treatment of adults with NSCLC containing the KRAS G12C mutation and who had at least one prior systemic therapy.]

“Most importantly, sotorasib is very well tolerated with fewer side effects than salvage chemotherapy options like docetaxel for these patients,” he continued.

“Sotorasib is a highly selective oral drug specifically designed to target tumors with a KRAS G12C mutation, which accounts for about 13% to 15% of all newly diagnosed patients with lung cancer. This is the most common KRAS mutation in lung cancer, although it can be seen in other tumor types as well,” Dr. Velcheti said.

“The data for the subgroup analysis are based on small numbers of patients. The subgroup with STK11 mutations may benefit more from the drug, but this is preliminary. We need to study subgroups further to try to understand which ones may benefit more from the drug. A small subset of patients with KEAP1 alterations appear to be less responsive to sotorasib, and there are several efforts ongoing to study combination-based approaches for this population,” he added. “Sotorasib is obviously a significant advance in developing targeted therapy for patients with NSCLC and KRAS mutations. There are a lot of ongoing efforts currently to develop innovative combination approaches with sotorasib to overcome primary and acquired resistance to sotorasib.”

Study Details

CodeBreaK 100 assigned 126 patients with locally advanced or metastatic KRAS G12C–mutated NSCLC that had progressed on prior standard therapies to receive sotorasib at 960 mg/d until disease progression. Radiographic scans were conducted every 6 weeks up to week 48 and every 12 weeks thereafter. The primary endpoint was objective response rate according to the Response Evaluation Criteria in Solid Tumors by independent central review. Key secondary endpoints were duration of response, disease control rate, time to recurrence, progression-free survival, overall survival, and safety. Evaluation of biomarkers was an exploratory endpoint.

At baseline, the median patient age was 63.5 years; all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1; 92.9% were current or former smokers. Patients had up to three prior lines of therapy; 89.7% had platinum-based chemotherapy; 91.3% had checkpoint inhibitor therapy; and 81% had both.


  • For the first time, a KRAS inhibitor—sotorasib—has shown disease control in advanced, pretreated non–small cell lung cancer.
  • The confirmed objective response rate with sotorasib was 37.1%, the median duration of response was 11.1 months, the median progression-free survival was 6.8 months, and the median overall survival was 12.5 months.
  • 'Based on an exploratory analysis of the CodeBreaK 100 trial, efficacy was extended to all subgroups assessed, including patients whose tumors harbored co-mutations in STK11, KEAP1, and TP53.

Key Findings

At a median follow-up of 15.3 months, the rate of complete response was 3.2%; the partial response rate was 33.9%; stable disease rate was 43.5%, for a disease control rate of 80.6% in this advanced, pretreated population. The median duration of response was 11.1 months, and the median time to response was 1.35 months.

On the 960-mg dose—the FDA-approved dose—median progression-free survival was 6.8 months, and median overall survival was 12.5 months.

Most treatment-related adverse events were grade 1 and 2 and were generally manageable. No fatal treatment-related adverse events were reported as of data cutoff on March 15, 2021. Treatment-related adverse events led to dose modification in 28 patients (22.2%) and treatment discontinuation in 9 patients (7.1%). Any-grade treatment-related adverse event was reported in 69.8%, and grade 3 events were reported in 19.8%. The most commonly occurring adverse events were diarrhea, nausea, and increases in liver enzymes.

In the exploratory biomarker analysis, response to sotorasib was consistently observed among patient subgroups. One standout subgroup included patients treated with prior anti–PD-L1 but no platinum-based chemotherapy; this group had an objective response rate of 69.2% and a median overall survival of 17.7 months.

The efficacy of sotorasib was observed in molecular subgroups associated with suboptimal outcomes with the standard of care, including TP53, STK11, and KEAP1. However, again, it is important to note the small number of patients and the need for further study to determine which subgroups may benefit.

Question of Dose Optimization

Patients enrolled in CodeBreaK 100 were treated with sotorasib at 960 mg/d, although evidence from a phase I trial of the drug showed no dose-response relationship. In fact, a small number of patients (n = 3) benefited from a daily dose of 180 mg, raising the question of whether lower doses of the drug might be equally efficacious or even more so if given with food. A commentary in The ASCO Post delved more deeply into optimal doses of anticancer drugs, including sotorasib in NSCLC. 

DISCLOSURE: Dr. Skoulidis has held stock ownership in BioNTech SE and Moderna Inc; has received honoraria from Bristol Myers Squibb and RV Mais Promocao Eventos LTDS; has received institutional research funding from Amgen, Mirati Therapeutics, Boehringer Ingelheim, Merck & Co, Novartis, and Pfizer; has an immediate family member who has received research funding from AImmune Therapeutics; and has been reimbursed for travel, accommodations, or other expenses by Tango Therapeutics, Amgen, and AstraZeneca Pharmaceuticals. Dr. Velcheti has served as a consultant or advisor to Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, EMD Serono, Foundation Medicine, GSK, Lilly, Merck, Novartis, and Novocure; and has received institutional research funding from Alkermes, Altor BioScience, Atreca, Bristol Myers Squibb, Eisai, Genentech, Genoptix, GlaxoSmithKline, Heat Biologics, Leap Therapeutics, Merck, NantOmics, OncoPlex Diagnostics, RSIP Vision, and Trovagene.


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. 2021 ASCO Annual Meeting. Abstract 9003. Presented June 4, 2021.

2. Li BT, Skoulidis F, Falchook G, et al: CodeBreaK 100: Registrational phase 2 trial of sotorasib in KRAS p.G12C mutated non-small cell lung cancer. 2020 World Conference on Lung Cancer. Abstract PS01.07. Presented January 30, 2021.

3. Skoulidis F, Li BT, Dy GK, et al: Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 384:2371-2381, 2021.

4. Ratain MJ, Lichter AS: Empowering the FDA to require dose optimization of all new oncology drugs. The ASCO Post. January 25, 2021.


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