Intracranial efficacy of sotorasib versus docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC): Practice-informing data from a global, phase 3, randomized, controlled trial (RCT).

Anne-Marie C. Dingemans Erasmus MC Cancer Institute, University Medical Center, Rotterdam, Netherlands info_outline Anne-Marie C. Dingemans, Konstantinos Syrigos, Lorenzo Livi, Astrid Paulus, Sang-We Kim, Yuanbin Chen, Enriqueta Felip, Frank Griesinger, Kadoaki Ohashi, Gerard Zalcman, Brett Gordon Maxwell Hughes, Jens Benn Sorensen, Normand Blais, Carlos G. M. Ferreira, Colin R Lindsay, Rafal Dziadziuszko, Patrick J. Ward, Cynthia Chinedu Obiozor, Yang Wang, Solange Peters

Authors Anne-Marie C. Dingemans Erasmus MC Cancer Institute, University Medical Center, Rotterdam, Netherlands info_outline Anne-Marie C. Dingemans, Konstantinos Syrigos, Lorenzo Livi, Astrid Paulus, Sang-We Kim, Yuanbin Chen, Enriqueta Felip, Frank Griesinger, Kadoaki Ohashi, Gerard Zalcman, Brett Gordon Maxwell Hughes, Jens Benn Sorensen, Normand Blais, Carlos G. M. Ferreira, Colin R Lindsay, Rafal Dziadziuszko, Patrick J. Ward, Cynthia Chinedu Obiozor, Yang Wang, Solange Peters Organizations Erasmus MC Cancer Institute, University Medical Center, Rotterdam, Netherlands, Sotiria General Hospital, Athens, Greece, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy, Centre Hospitalier Universitaire de Liège, Liège, Belgium, Asan Medical Center, Seoul, South Korea, Cancer & Hematology Centers of Western Michigan, Grand Rapids, MI, Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain, Pius-Hospital Oldenburg, Oldenburg, Germany, Okayama University Hospital, Okayama, Japan, Hospital Bichat Claude Bernard, Paris, France, The Prince Charles Hospital, Brisbane, Australia, Rigshospitalet, Copenhagen, Denmark, Department of Medicine, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada, Oncoclinicas, Rio De Janeiro, Brazil, Division of Cancer Sciences, University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom, Uniwersyteckie Centrum Kliniczne, Gdańsk, Poland, Oncology Hematology Care, Inc, Blue Ash, OH, Amgen Inc., Thousand Oaks, CA, Lausanne University Hospital, Lausanne, Switzerland Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Amgen Inc. Background: Brain metastases are common (~30%) in patients (pts) with KRAS G12C-mutated advanced NSCLC and have a negative impact on survival and quality of life (QOL). In the CodeBreaK 200 global, phase 3 RCT, sotorasib was the first oral KRAS G12C inhibitor to show improved progression-free survival (PFS) and overall response rate (ORR), with a better toxicity profile and QOL, compared with intravenous docetaxel in pretreated KRAS G12C-mutated advanced NSCLC. Here we describe the first RCT data evaluating the intracranial (IC) efficacy of sotorasib versus docetaxel from the CodeBreaK 200 study. Methods: Pts with KRAS G12C-mutated advanced NSCLC who progressed after platinum-based chemotherapy and a checkpoint inhibitor were randomized 1:1 to sotorasib (960 mg daily; n=171) or docetaxel (75 mg/m 2 every 3 weeks; n=174). Patients with treated, stable (non-progressing) brain metastases were eligible for study. Baseline brain imaging, by contrast enhanced MRI, was performed for all pts at screening. For pts with history of or brain metastasis at baseline, the brain MRI was repeated at every subsequent imaging assessment (every 6 weeks). A post-hoc analysis on IC efficacy (CNS PFS and time to CNS recurrence) was assessed by blinded independent central review (BICR) per modified Response Assessment in Neuro-Oncology Brain Metastases (mRANO-BM). Systemic response was also assessed by RECIST 1.1. Results: CNS metastases by imaging at baseline were present in 40 pts (23%) in the sotorasib arm and 29 pts (17%) in the docetaxel arm (full analysis set, FAS). With a median follow-up of 20.0 months, the median systemic PFS by RECIST 1.1 in the FAS was 6.1 months versus 4.5 months (HR 0.57 [95% CI: 0.30, 1.07], P=0.045) for sotorasib versus docetaxel, respectively. Time to CNS recurrence in the FAS was 9.6 months with sotorasib versus 5.4 months with docetaxel (HR 0.84 [95% CI: 0.32, 2.19], P=0.37). Treatment-related adverse events of any grade occurred in 77.5% of pts treated with sotorasib versus 89.7% of pts treated with docetaxel. Conclusions: In the first randomized evaluation of IC activity of any KRAS G12C inhibitor, sotorasib demonstrated a reduced risk of progression and trend towards delayed time to CNS recurrence versus docetaxel in patients with pretreated KRAS G12C-mutated advanced NSCLC who had treated, stable brain metastases. These results suggest IC activity with sotorasib to complement the overall PFS benefit observed with sotorasib versus docetaxel. Clinical trial information: NCT04303780.

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