Approximately one-third of patients with non-small-cell lung cancer (NSCLC) who were treated with the targeted therapy sotorasib survived for at least two years after enrolling in a large clinical trial that evaluated the drug — significantly longer than what can be expected from patients treated with standard chemotherapy.

The promising data from that clinical trial, called CodeBreak 100, are shared in “Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated KRAS G12C mutated non-small-cell lung cancer: a 2-year analysis of CodeBreak 100,” published in the Journal of Clinical Oncology. The publication highlights detailed analysis updated since the results of the phase 1/2 trial were presented at the 2022 annual meeting of the American Association for Cancer Research (AACR).

“The two-year survival is a landmark observation,” says Grace Dy, MD, Director of Thoracic Medicine Translational Research at Roswell Park Comprehensive Cancer Center and first author of the paper. “We also found that there were long-term benefits in nearly a quarter of patients, meaning these patients had progression-free survival greater than 12 months. That is much higher than we anticipate with traditional chemotherapy.”

Contributors to the collaborative study included co-senior author Bob Li, MD, PhD, MPH, Physician Ambassador to China and Asia-Pacific, Memorial-Sloan Kettering Cancer Center.

Approved by the U.S. Food & Drug Administration (FDA) in 2021 after primary analysis of the phase 2 portion of the CodeBreak 100 clinical trial, sotorasib is designed to treat advanced-stage NSCLC tumors with the G12C mutation of the KRAS gene when earlier treatment has failed to control the disease. The KRAS gene produces a protein called K-Ras, which regulates cell growth.

But a KRAS gene mutation called G12C, which represents 13% of NSCLC mutations, can cause cells to grow rapidly and uncontrollably, leading to tumour formation. Sotorasib, which blocks G12C, is the first FDA-approved therapy for a malignancy targeted specifically against K-RAS mutation.

The analysis of the multi-institutional clinical trial CodeBreak 100 included 174 patients combined from both the phase 2 and phase 1 portions. Most had previously undergone an average of two lines of platinum-based chemotherapy or immunotherapy. All patients in the analysis received 960 mg of sotorasib daily. The overall survival rate (OS) was 50.8% after one year and 32.5% after two years. The median OS was 12.5 months.

Partial or complete response was experienced by 40.7% of patients, with median duration of response at 12.3 months. The extended response was unaffected by PD-L1 protein levels or STK11 co-mutation, which means sotorasib may be a treatment option for patients whose tumours are unlikely to respond to immunotherapy.

While median progression-free survival (PFS) was 6.3 months, 40 patients (23%) experienced long-term clinical benefit — PFS of at least 12 months.

“Before this drug was available, these patients received chemotherapy — usually docetaxel (brand name Taxotere) with or without ramucirumab (brand name Cyramza), which is more toxic,” notes Dr. Dy, adding that PFS also is shorter in patients treated with docetaxel. And unlike chemotherapy, sotorasib produced generally manageable low-grade toxicity and was not associated with severe or cumulative late-onset side effects, she says.

The Journal of Clinical Oncology article represents the longest follow-up report to date on patients treated with any KRAS G12C inhibitor.

Dr. Dy says the findings from this analysis anticipated and complemented the recently reported results from the global phase 3 CodeBreak 200, which confirmed that sotorasib improved PFS as primary endpoint compared to standard chemotherapy with docetaxel in patients who were treated previously for advanced NSCLC with the KRAS G12C mutation. Conclusions from the long-term safety and efficacy analysis of CodeBreak 100 support additional studies that are evaluating the therapeutic role of sotorasib in earlier lines of therapy for patients with KRAS G12C mutated NSCLC.

Source: Roswell Park Comprehensive Cancer Center