The CodeBreaK 200 study data indicate that oral sotorasib has a greater efficacy, a better safety profile, and is associated with better quality-of-life (QoL), compared with intravenous docetaxel, in patients with previously treated advanced KRASG12C-mutated non-small cell lung cancer (NSCLC). In CodeBreaK 200, the randomised phase III study, sotorasib increased progression-free survival (PFS), compared with docetaxel, with a 34% reduction in relative risk of having disease progression or death. The overall response was significantly higher with sotorasib with a faster time to response and longer duration of response. PFS and overall response rate (ORR) favoured sotorasib across all subgroups. Sotorasib was well tolerated with fewer grade 3 or worse and serious treatment-related adverse events (TRAEs). Sotorasib also showed clinically meaningful improvement in patient-reported outcomes compared with docetaxel. The findings from the CodeBreaK 200 study are published by Prof. Luis Paz-Ares of the Medical Oncology, Hospital Universitario 12 de Octubre in Madrid, Spain and colleagues on 7 February 2023 in the Lancet.
Activating mutations in KRAS are present in 25–39% of non-squamous NSCLCs, with the KRASG12C mutation occurring in 13–16% of lung adenocarcinomas. The KRASG12C mutation is nearly mutually exclusive with known actionable driver genomic alterations (e.g. EGFR, ALK, ROS1, BRAF, MET, RET, NTRK, and HER2). For over 40 years, KRAS was considered undruggable. In 2013, a targetable regulatory pocket on the KRASG12C protein was discovered.
Sotorasib is a small molecule that specifically and irreversibly inhibits the KRASG12C protein. The phase II CodeBreaK 100 data previously showed that sotorasib has clinical efficacy when used as monotherapy in patients with previously treated advanced KRASG12C-mutated NSCLC, with an ORR of 37.1%, median PFS of 6.8 months, and a median overall survival (OS) of 12.5 months. TRAEs were generally mild and manageable, and patient-reported outcomes improved or remained stable.
The CodeBreaK 200 study investigators conducted this randomised, open-label phase III study at 148 centres in 22 countries. They recruited patients aged at least 18 years with advanced KRASG12C-mutated NSCLC, who progressed after previous platinum-based chemotherapy and a PD1 or PD-L1 inhibitor. Key exclusion criteria were new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (e.g. EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the treatment was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation.
The study team randomly assigned (1:1) patients to oral sotorasib, 960 mg once daily or intravenous docetaxel, 75 mg/m2 once every 3 weeks in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of treatment in advanced disease (1 versus 2 versus >2), ethnicity (Asian versus non-Asian), and history of centralnervous system metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer treatment, withdrawal of consent, or death, whichever occurred first. The primary endpoint was PFS, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients.
Between 4 June 2020 and 26 April 2021, 345 patients were randomly assigned, of whom 171 to sotorasib (50%) and 174 to docetaxel (50%). In total, 169 patients (99%) in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17.7 months, the study met its primary endpoint of a statistically significant increase in the PFS for sotorasib, with median PFS of 5.6 months (95% confidence interval [CI] 4.3–7.8) compared with 4.5 months (3.0–5.7) in docetaxel group (hazard ratio 0.66, CI 0.51–0.86; p = 0.0017).
Sotorasib was well tolerated, with fewer grade 3 or worse (33% versus 40%) and serious TRAEs compared with docetaxel (11% versus 23%). For sotorasib, the most common TRAEs of grade 3 or worse were diarrhoea (12%), alanine aminotransferase increase (8%), and aspartate aminotransferase increase (5%). For docetaxel, the most common TRAEs of grade 3 or worse were neutropenia (9%), fatigue (6%), and febrile neutropenia (5%).
The authors commented that upfront next-generation sequencing testing will allow for the identification of these patients at diagnosis. Combination studies are ongoing for sotorasib including in the front-line setting with chemotherapy or as a lead-in before immune checkpoint inhibitor (ICI), or in later lines with an SHP2 inhibitor as a mechanism to overcome resistance. Additional analyses will further investigate the effect of sotorasib on QoL and define biomarkers predictive of clinical response.
In an accompanied article, Dr. Sarah B. Goldberg and Prof. Roy S. Herbst of the Division of Thoracic Oncology, Center for Thoracic Cancers, Yale School of Medicine and Yale Cancer Center in New Haven, CT, US wrote that one of the most significant breakthroughs in oncology in recent years is the ability to target KRAS. They explored what might have contributed to the lack of OS benefit. The study was not powered to show a statistically significant improvement in survival, although it is unlikely that even a larger sample size would have led to different results. In this study, 34% of patients crossed over from docetaxel to sotorasib. The lack of survival benefit probably reflects the heterogeneity in outcomes in patients with KRASG12C-mutated NSCLC, with many patients not deriving benefit and others responding to treatment, but quickly acquiring resistance.
Many new questions emerge from data in this study. Some patients experience durable benefit, but with no ability to prospectively identify them. Exploratory analyses from previous studies show that co-mutations in STK11 and KEAP1 might predict outcomes with sotorasib, and an ongoing prospective LungMAP study will help to definitively answer this question. It seems unlikely that KRASG12C inhibitors will move to the front-line setting without better patient selection or effective combination strategies. As patients with KRAS mutations can have significant benefit from ICIs, replacing ICIs with targeted therapy at this point would be difficult. Combining KRASG12C inhibitors with ICIs is an attractive possibility, although toxicity might be a barrier.
Adagrasib is another KRASG12C inhibitor that had promising results and many other agents are also in development, including LY3537982 and GDC-6036. Whether these therapies will prove to be superior remains to be seen. Various mechanisms of resistance to KRASG12C inhibitors have been described, including acquired secondary KRAS alterations, activation of bypass signalling pathways, e.g. through MET amplification or BRAF mutation, and histologic transformation from adenocarcinoma to squamous cell carcinoma. Understanding of the biology of KRAS signalling and resistance has led to several clinical studies examining rational combinations, including with inhibitors of EGFR, SHP2, and SOS1.
The editorialists concluded that the results of this study pave the way for further exploration of KRAS inhibitors in patients with NSCLC. As the G12C mutation represents only a fraction of KRAS mutations in lung cancer, targeted agents against other mutant forms of KRAS are eagerly anticipated.
The study was funded by Amgen.
References
- De Langen AJ, Johnson ML, Mazieres J, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet; Published online 7 February 2023. DOI: https://doi.org/10.1016/S0140-6736(23)00221-0
- Goldberg SB, Herbst RS. The end of the beginning: progress and next steps in KRAS-mutant non-small-cell lung cancer. Lancet; Published 9 February 2023. DOI: https://doi.org/10.1016/S0140-6736(23)00288-X