Roche has shed more light on its investigational KRAS G12C inhibitor's phase 3 victory over Amgen’s Lumakras and Bristol Myers Squibb’s Krazati.
The open-label Krascendo 1 trial enrolled 338 people with previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC). Patients who had already received a KRAS G12C inhibitor or pan-KRAS/RAS inhibitor were excluded from the trial. Participants received either divarasib once daily, Lumakras once daily or Krazati twice daily.
Roche announced back in July that divarasib had demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS), meeting the trial’s primary and key secondary endpoints. But the Swiss pharma had been holding back the detailed data until now.
At the European Society for Medical Oncology (ESMO) Congress in Madrid, Roche revealed that median OS for the 167 patients who received divarasib was 17.7 months, compared to 12 months for the 171 patients who received Lumakras or Krazati.
The benefit was similarly clear when it came to median PFS, which stood at 9.8 months versus 5.7 months, respectively. A total of 44% of patients receiving divarasib were alive without disease progression at one year, compared to 24% of the control group, according to Roche’s presentation.
It was a similar story for the objective response rate, which came in at 58% for divarasib versus 32% for the control group, while median duration of response was 11.9 months versus 6.9 months.
Stefan Frings, M.D., Ph.D., deputy chief medical officer at Roche Pharma, told Fierce that the data made for a “very comprehensive, strong package, which should be convincing to health authorities.”
“It’s an important advance for patients with lung cancer,” Frings said in an interview at a Madrid hotel during the conference.
“It's a second-line setting, and patients who receive divarasib benefit compared to the current first-generation KRAS G12C inhibitors by having far longer overall survival,” he continued.
“They live longer. They have better progression-free survival, better response rates, and with a safety profile which is—if [anything]—even better,” he said.
According to Roche, 4.8% of patients receiving divarasib discontinued treatment due to treatment-related adverse events, compared to 11.7% in the control group. Serious treatment-related adverse events were also less common with divarasib, at 7.8% versus 15.2%.
Roche’s confidence in divarasib had been building even before this phase 3 success. The candidate had already shown better potency and selectivity than the incumbent KRAS G12C inhibitors Krazati and Lumakras in preclinical tests. After cross-trial comparisons suggested that the edge translated into better clinical outcomes, Roche axed a study comparing divarasib to the chemotherapy docetaxel and went toe-to-toe with Lumakras and Krazati.
“We designed the drug on purpose with higher potency and better selectivity,” Frings explained. “So, based on preclinical models, we clearly knew it would be superior to the first generation.”
“It’s honestly not so frequent that pharma companies go head-to-head,” he added. “But if you want to make a point, if you want to convince payers, prescribers and patients … then a head-to-head win is rather rewarding.”
While Amgen and BMS reached the regulatory finish line first for KRAS G12C-mutated, locally advanced or metastatic NSCLC in 2021 and 2022, respectively, they have struggled to capitalize on their head start. Krazati brought in $55 million for BMS in the second quarter, while Lumakras delivered $111 million to Amgen.
For its part, Roche is aiming for peak divarasib sales of 1 billion to 2 billion Swiss francs ($1.2 billion to $2.5 billion), according to Frings.
The Big Pharma is currently recruiting patients into a phase 3 trial comparing divarasib plus Keytruda against Keytruda plus chemotherapy in previously untreated advanced or metastatic nonsquamous KRAS G12C-mutated NSCLC. Roche has previously suggested that sales in metastatic disease would account for most of the forecast.
Frings was tight-lipped on the exact timeline for a regulatory filing but said the Swiss pharma is “certainly keen to get this to as many patients as possible around the world.”
Roche has more RAS drugs coming up behind divarasib. The pharma has already launched phase 1 trials of a pan-RAS inhibitor called RG6505 and a KRAS G12D inhibitor dubbed RG6620 in solid tumors. Roche’s partner Chugai Pharmaceutical is also testing a pan-KRAS inhibitor called AUBE00.
Roche has made a “deliberate effort” to test a range of RAS drugs, Frings said. “If you have many rare mutations and you are scrambling to find sufficient patients, a pan-RAS inhibitor makes a lot of sense,” he explained.