The KRASG12C inhibitor sotorasib continues to impress in non-small cell lung cancer: In the phase II CodeBreak 100 trial, the agent elicited responses in more than a third of patients and led to a median progression-free survival of almost 7 months. Based on these results, Amgen has filed for the drug's approval with the FDA and the European Medicines Agency.
The KRASG12C inhibitor sotorasib (AMG 510; Amgen) continues to yield strong results in previously treated non–small cell lung cancer (NSCLC): In the phase II CodeBreak 100 trial, the agent elicited responses in more than a third of patients, and yielded a median progression-free survival (PFS) of almost 7 months. Based on these results, Amgen has filed for the drug's approval with the FDA and the European Medicines Agency.
“KRAS is the most frequently mutated oncogene in human cancers, and despite its discovery nearly 40 years ago, there is to date no KRAS-targeted therapy approved,” said Bob Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center in New York, NY, who presented the results at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer, held virtually January 28–31, 2021.
Sotorasib and Mirati's adagrasib both target KRASG12C, a mutation associated with poor outcomes present in approximately 13% of lung cancers. The agents trap the protein in an inactive state, shutting down oncogenic signaling and tumorigenesis.
In phase I of the CodeBreak 100 trial, 19 of 59 patients with previously treated NSCLC and KRASG12C mutations responded to sotorasib, and 33 more experienced stable disease. Patients had a median PFS of 6.3 months and median duration of response (DoR) of 10.9 months. Side effects were generally manageable, occurring in 66.1% of patients. These results led researchers to select the highest dose, 960 mg, for phase II testing (N Engl J Med 2020;388:1207–17).
In phase II of the trial, researchers enrolled 126 patients with locally advanced or metastatic NSCLC and KRASG12C mutations whose cancer had worsened on other therapies. Ninety percent of them had been treated with platinum-based chemotherapy or a PD-1–PD-L1 inhibitor, and 81% had received both.
Of 124 evaluable patients, 46 responded to sotorasib, and 54 more had stable disease. The drug demonstrated durable responses, with a median PFS of 6.8 months and median DoR of 10 months. An exploratory biomarker analysis revealed that patients responded regardless of PD-L1 status or the presence of STK11 or KEAP1 mutations. Side effects—most commonly diarrhea and nausea—occurred in 69.8% of patients; 19.8% of patients experienced grade 3 adverse events.
Adagrasib has achieved similar early success. Most recently, researchers reported that in the phase I/II KRYSTAL-1 trial, the agent elicited responses in 23 of 51 patients with advanced NSCLC and KRASG12C mutations.
“The findings to date are encouraging … KRASG12C inhibitors are finally here,” said Pasi Jänne, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, who provided commentary on sotorasib and is involved in clinical trials of adagrasib. “Collectively, these agents are very well tolerated” due to their selectivity, he added. Both drugs are now being tested against standard docetaxel.
Whether certain patients will benefit more than others from KRASG12C inhibitors needs to be studied, Jänne added. For example, preliminary evidence suggests that patients with concurrent STK11 mutations might fare particularly well.
Jänne also noted “tremendous interest” in combination therapies. Ongoing trials are combining adagrasib or sotorasib with agents such as the PD-1 inhibitor pembrolizumab (Keytruda; Merck) and the EGFR inhibitor afatinib (Gilotrif; Boehringer Ingelheim Pharmaceuticals), among others. This research will help oncologists determine which patients may benefit from single-agent therapy and which should receive combinations, he said— “an important consideration for the field.” –Catherine Caruso