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Amgen Turning to Combination Strategies After Limited Lumakras Efficacy in KRAS-Mutated Colon Cancer

NEW YORK – After Amgen's sotorasib (Lumakras) demonstrated modest efficacy in patients with KRAS G12C-mutated advanced colorectal cancer, the company is hoping for better results in this setting with combination strategies.

According to data published from the CodeBreak-100 trial on Tuesday in Lancet Oncology, as of a March 1 data cutoff, six out of 62 KRAS G12C-mutated colorectal cancer patients, or 9.7 percent, responded to single-agent sotorasib. Ten percent of patients experienced treatment-related adverse events, and two patients had serious adverse events due to the drug.

"Although the 9.7 percent overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumor activity and manageable safety in these heavily pretreated chemorefractory patients," study authors led by Marwan Fakih, co-director of the gastrointestinal cancer program at City of Hope, wrote in the paper. They added that sotorasib is being evaluated with other drugs in the hopes of increasing its activity and overcoming resistance mechanisms.

The six patients who responded in the trial had partial tumor shrinkage on sotorasib. Most patients, 82 percent, achieved disease control, which is an endpoint comprising complete responders, partial responders, and those who achieved stable disease on treatment. Median progression-free survival was four months and median overall survival was around 11 months in the study.

Around 4 percent of colorectal cancer patients harbor KRAS G12C mutations. Patients with these mutations tend to have worse overall survival and tend to be resistant to EGFR inhibitors, which are commonly prescribed to prevent colorectal cancer cell growth. In the CodeBreak-100 trial, colorectal cancer patients were heavily pretreated, with nearly three-fourths receiving at least three prior treatments before receiving sotorasib.

In a statement, Amgen highlighted that the outcomes seen in the heavily pretreated colorectal cancer population in CodeBreak-100 is better than how they would be expected to fare on current standard treatments. According to Fakih, between 1 percent and 4 percent of recurrent, metastatic colorectal cancer patients respond to currently available options such as trifluridine and regorafenib (Bayer's Stivarga). The median progression-free survival on these therapies is between two and three months, and the median overall survival is between six and nine months.

David Reese, executive VP of R&D at Amgen, said in a statement that the company is still committed to bringing new treatments to colorectal cancer patients who harbor KRAS G12C mutations. "We believe the path forward is combination therapy," Reese said, noting that the company will study sotorasib in combination with the EGFR-inhibiting monoclonal antibody panitumumab (Amgen's Vectibix) as a third-line regimen in a Phase III trial.

"We are looking forward to the launch and completion of a randomized Phase III clinical trial to test and potentially confirm the superiority of sotorasib and panitumumab over standard of care and to enable the approval of this combination in this patient population with unmet needs," said Fakih.

In the Phase Ib/II CodeBreak-101 trial, Amgen considered the sotorasib-panitumumab combination in KRAS G12C-mutated advanced colorectal cancer patients. Researchers reported earlier this year that the objective response rate was 27 percent among 26 patients, including five patients who had progressed on sotorasib monotherapy. In patients who had not received prior sotorasib treatment, the objective response rate was 33 percent.

Meanwhile, data from the multi-cohort CodeBreak-100 trial earlier this year served as the basis for sotorasib's accelerated approval in the US for KRAS G12C-mutated previously treated, advanced non-small cell lung cancer patients. In that cohort of 124 NSCLC patients, the objective response rate was 36 percent, and the disease control rate was 81 percent.