Sotorasib Demonstrates Efficacy in CodeBreaK 100 Phase 2 Study Results

One of the leading causes of cancer-related death is lung cancer. Approximately 230,000 cases of lung cancer are diagnosed each year in the United States, with more than 135,000 patient deaths occurring each year.¹ Worldwide, it is the leading cause of death in men and the second leading cause of death in women.¹ The majority of lung cancer cases (80%-85%) are non–small-cell lung cancer (NSCLC), with adenocarcinoma being the most common subtype.² KRAS^G12C mutations occur in approximately 13% of lung adenocarcinoma cases, making the disease aggressive and difficult to treat.³

In patients with advanced NSCLC who have previously received therapy, <20% experience a favorable outcome and progression-free survival (PFS) is <4 months.⁴ Sotorasib, a first-in-class small molecule, selectively targets the KRAS^G12C mutation to irreversibly bind to the mutated protein to turn off cell signaling that triggers cell division and cancer growth.³

The phase 1 CodeBreaK 100 trial of sotorasib demonstrated the drug was well tolerated, with a 32% response rate in NSCLC patients who were heavily pretreated prior to treatment.⁴ Building on the phase 1 trial, the phase 2 single-arm CodeBreaK 100 trial evaluated the safety and efficacy of sotorasib in 126 patients with locally advanced or metastatic NSCLC with a KRAS^G12C mutation. In addition to confirmed KRAS^G12C mutation, trial enrollees also had previous treatment with anti–PD-1/PD-L1 and/or platinum-based combination chemotherapy with progressing disease and targeted therapy if ALK, EGFR, and ROS1 molecular alterations were identified, and ≤3 prior therapy line treatments. Patients with brain metastases were excluded from the trial. Confirmed objective response rate (ORR) was the primary end point. Secondary end points were PFS, median duration of response (DOR), disease control rate (DCR), and safety.

The primary analysis of the phase 2 study was presented at the 2020 World Conference on Lung Cancer in Singapore in January 2021. Study participants received 960 mg of sotorasib orally once a day.⁴ All patients received at least 1 dose of sotorasib. The majority of enrollees (117) were current or former smokers and 123 had at least 1 measurable lesion at baseline. The median age of study participants was 63.5 years. ORR was 37.4% with 46 patients experiencing a confirmed response.⁴ Median follow-up was 6.9 months for DOR with 52.2% of responders remaining on treatment without disease progression.⁴ The median PFS was 6.7 months.⁴ The DCR was 80.5%.⁴

Sotorasib therapy appeared to be well tolerated. Treatment-related adverse events (AEs) were reported in 69.8% of patients. In 9 patients, AEs led to treatment discontinuation. Grade ≥3 AEs occurred in 20.6% of patients, with 6.3% of patients experiencing an increase in alanine aminotransferase, 5.6% experiencing an aspartate aminotransferase increase, and 4% experiencing diarrhea.⁴ No fatal adverse events were reported during the study.

Sotorasib therapy in patients with heavily pretreated NSCLC possessing the KRAS^G12C mutation was found to be safe, effective, and well tolerated in this patient population.

References

1. Clark SB, Alsubait S. Non-small cell lung cancer. StatPearls. Treasure Island, FL: StatPearls Publishing; October 1, 2020.
2. American Cancer Society. Cancer Facts & Figures 2021. www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2021.html. Accessed May 22, 2021.
3. Hong DS, Fakih MG, Strickler JH, et al. KRAS^G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383:1207-1217.
4. Li BT, Skoulidis F, Falchook G, et al. CodeBreaK 100: registrational phase 2 trial of sotorasib in KRASp.G12C mutated non-small cell lung cancer. Presented at: 2020 World Conference on Lung Cancer, January 30, 2021. Abstract PS01.07.