After decades of failures laid waste to R&D outfits looking to solve the KRAS G12C puzzle, Amgen is as close as anyone ever has been to an approval with sotorasib. For Amgen R&D head David Reese, the drug’s looming review date is a point of reflection for his own career and a big milestone for Amgen’s blooming — if controversial — next-gen oncology pipeline.
Amgen filed its FDA application for sotorasib in December to treat metastatic non-small cell lung cancer with the KRAS mutation — once thought to be “undruggable” — months after the agency offered its breakthrough designation based on pivotal Phase I data showing previously unheard of response rates.
Reese, who has had a first-row seat to the many failures to target KRAS since it was identified in the early 1980s, told Endpoints News that sotorasib’s fast development — it took just 28 months for the drug to go from the first patient dosed to registration — was particularly remarkable given the weight of history Amgen had to overcome. During his tenure in Dennis Slamon’s groundbreaking lab at the National Cancer Institute, Reese recalls the slim research on oncogenes like KRAS and the simplistic thinking that led multiple players to run into a brick wall against the mutation.
“One of the first things I did (when I arrived at the lab) was buy a little book called Oncogenes — in those days you could memorize them all — and about a third of the book was devoted to the RAS family,” Reese said. “We thought, “fine, we’ll get an inhibitor, problem solved.’ But it was a little more tricky than that.”
Sotorasib broke through on that front in 2018 with Amgen revealing Phase I data in June of that year and following it up at ESMO 2020 with expanded data showing a 32.3% response rate in 59 patients. Amgen is planning to uncork more data from a Phase II trial in NSCLC at the virtual World Lung Cancer Conference later this month and has 10 combination trials and a global trial involving 600 patients underway. The company revealed cryptic topline results from that Phase II study in October, saying only that sotorasib hit overall response rates in the study “consistent” with its Phase I results.
All that success — obviously with regulatory approval withstanding — is one of a few accomplishments that Reese will keep as a feather in his cap after decades in biopharma.
“Personally for me, as an oncologist, having the privilege of being part of the team to bring the first KRAS inhibitor to market is one of those less than a handful of things you put right at the top of the list when you’re reflecting back on a career,” he said.
But even as sotorasib prepares to set the stage for even more KRAS applications, the drug hasn’t done much to instill confidence in other tumor types where the prevalence of the mutation is far lower and the response rates are more meager.
Amgen expects to read out Phase II results for sotorasib in colorectal cancer at some point in the first half of year, but early results in that indication and in solid tumors haven’t been so impressive. In a Phase I trial in colorectal, sotorasib posted just a 7.1% response rate with the majority of the 42 patients in the trial having received at least three prior lines of therapy — a testament to how hard the mutation is to dose.
In other tumors outside of NSCLC and colorectal, the drug fared even more poorly, with just three of 22 patients showing partial responses seven weeks after treatment. Reese predicted the Phase II readout in colorectal cancer would provide a meaningful guidepost as to whether sotorasib has a likely path forward as a monotherapy.
“I think those data will be fairly definitive as to whether we think there’s a further path or utility of monotherapy in colorectal or whether that’s a combination therapy,” Reese said.
Meanwhile, Reese highlighted the promise of sotorasib’s combo therapy pipeline in colorectal cancer and other solid tumors, with a group of trials running as part of a “master protocol” with independent arms eligible for advancement into the equivalent of a Phase II study.
“For many of these instances, combination therapy probably will be the ultimate solution, but we’re pretty well poised with the program as it unfolds right now to answer both the monotherapy and combination therapy questions,” he said.
Meanwhile, with its KRAS application in a holding pattern, 2021 will likely prove to be a pivotal year for Amgen’s bispecific T cell engager (or BiTE) candidates with nine separate molecules in the clinic and data expected to read out this year. As opposed to CAR-Ts, which require a lengthy and expensive manufacturing process, BiTE molecules come off the shelf and could provide a rapid-scale alternative.
The two most advanced molecules, targeting prostate cancer and the DLL3 ligand in small cell lung cancer could help provide Amgen a clue on the promise its aggressive pipeline play holds.
“The question there is do we generate data in the coming months where we say, ‘OK, there’s really a drug here and now we’re moving into a registration phase of those programs,'” he said.