A highly anticipated presentation at the 2022 World Conference on Lung Cancer will be the first report of efficacy and safety from the phase 1b/2 CodeBreak 101 clinical trial and will provide updated results from the phase 2 CodeBreak 100 study.
Updated results on sotorasib (Lumakras) for the treatment of advanced KRAS G12C–positive non–small cell lung cancer (NSCLC) and sotorasib combined with other targeted therapies will be presented in August at the IASLC 2022 World Conference on Lung Cancer in Vienna, Austria.1
“Our goal is to see if we can move this ultimately to first line, and we hope to combine with a checkpoint inhibitor in that setting. Right now, it’s not sure if sotorasib will be better than chemoimmunotherapy in the front-line setting, as seen in KEYNOTE-189 [NCT02578680],” Alexander I. Spira, MD, PhD, FACP, a co-investigator of CodeBreak 100/101 and medical oncologist at Virginia Cancer Specialists, told Targeted OncologyTM.
The presentation will be given by Bob T. Li, MD, PhD, MPH, a physician ambassador to China and Asia-Pacific, at Bobst International Center, co-director, Thoracic Liquid Biopsy Program, and chief scientific officer, MSK Direct, at Memorial Sloan Kettering Cancer Center. The highly anticipated presentation will be the first report of efficacy and safety from the phase 1b/2 CodeBreak 101 clinical trial (NCT04185883) and will provide updated results from the phase 2 CodeBreak 100 study (NCT03600883).
The data read-out comes more than a year after the FDA granted accelerated approval to sotorasib for patients with KRAS G12C–mutated locally advanced or metastatic NSCLC, who have received at least 1 prior systemic therapy. The approval was supported by initial findings from CodeBreak 100. At the time, the study showed that sotorasib induced durable objective responses in the advanced KRAS G12C–mutant NSCLC patient population.2
CodeBreak 100 is a first-in-human, open-label, multicenter study of 793 patients. From the NSCLC cohort, 124 patients were assessed during the primary analysis. All patients in the cohort were treated with 960-mg oral sotorasib once daily. Eighty-one percent of patients had progressed on both platinum-based chemotherapy and PD-1/L1 inhibitors before enrolling in the study.
In the study, sotorasib achieved an objective response rate (ORR) of 36% (95% CI, 28%-45%), with a disease control rate (DCR) of 81% (95% CI, 73%-87%). At the 2020 World Conference on Lung Cancer, it was also reported that among all responders, the median best reduction in tumor size with sotorasib was 60%. The median time to objective response was 1.4 months and the median duration of response (DOR) was 10 months.3
At a median follow-up of 12.2 months, sotorasib also showed a median progression-free survival (PFS) of 6.8 months in the study.2
In terms of safety, treatment-related adverse events (TRAEs) in CodeBreak 100 were mostly grade 1 or 2. No treatment-related deaths were reported in the study. Grade 3 TRAEs occurred in 25 patients (19.8%) and 1 patient (0.8%) reported a grade 4 TRAE. The most frequently reported TRAEs of any grade were diarrhea (31.0%), nausea (19.0%), increased alanine aminotransferase (15.1%), and increased aspartate aminotransferase (15.1%). Due to TRAEs, 7.1% of patients in the study discontinued treatment.
“Sotorasib has changed how we treat patients with KRAS G12C–mutant lung cancer. However, we need to find ways to extend the DOR and increase the number of respondents to KRAS G12C targeted therapies. Pre-clinical evidence supports the combination of immune checkpoint blockade with sotorasib. These clinical trials are incredibly important to improve the outcomes of patients with lung cancer,” CodeBreak 100/101 co-investigator, Ramaswamy Govindan, MD, professor of medicine, the Anheuser Busch chair in Medical Oncology, and director, Section of Medical Oncology, Division of Oncology at Washington University School of Medicine, stated to Targeted Oncology™.
The FDA’s accelerated approval of sotorasib was contingent upon positive results verifying the clinical benefit of the agent in confirmatory trials. CodeBreak 101, for example, might demonstrate sotorasib’s ability to improve the efficacy of other standard targeted therapies and chemotherapy.2
CodeBreak 101 includes 1054 patients with KRAS G12C–mutant NSCLC who are enrolled in 1 of 15 possible treatment arms. The sotorasib combinations in the first 10 arms include sotorasib plus either trametinib (Mekinist); AMG 404; RMC-4630; afatinib (Gilotrif); pembrolizumab (Keytruda); atezolizumab (Tecentriq); panitumumab (Vectibix) with or without folinic acid, fluorouracil, and irinotecan (FOLFIRI); the combination of carboplatin, pemetrexed, docetaxel, and pembrolizumab; palbociclib (Ibrance); and everolimus (Afinitor).4
In the remaining arms, sotorasib is used alone or in combination with either trametinib plus panitumumab; bevacizumab-awwb (Mvasi) plus either FOLFIRI or folinic acid, fluorouracil, and oxaliplatin (FOLFOX); TNO155; or afatinib plus loperamide.
The phase 1b coprimary end points include the number of patients with dose-limiting toxicities, treatment-emergent AEs, TRAEs, and clinically significant changes in vital signs, ECG measurements, and laboratory test values. The phase 2 primary end point is ORR.
As secondary end points, the study is assessing maximum plasma concentration, time to maximum plasma concentration, the area under the plasma concentration-time curve, ORR, DCR, DOR, PFS, duration of stable disease, time to response, overall survival, and intracranial responses.
Results from the CodeBreak 100/101 studies will be presented on August 7, 2022, at 3:00 PM Central European Time.
“These results will hopefully drive oncologists to try this combination for front-line patients,” Spira added.
1. Session Information. IASLC.org. Accessed July 14, 2022.
2. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. News release. FDA. May 28, 2021. Accessed July 14, 2022. https://bit.ly/3yEIIiq
3. 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. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.
4. Sotorasib activity in subjects with advanced solid tumors with KRAS p.G12C mutation (CodeBreak 101). Clinicaltrials.gov. Update July 8, 2022. Accessed July 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04185883