Revolution Medicines’ much-heralded FDA approval for Rasonque this summer marked a breakthrough for a devastating type of pancreatic cancer. It also set a new bar for other drugmakers working on the next wave of KRAS contenders.
The success of Revolution’s RAS(ON) inhibitor pill, which nearly doubled median overall survival compared with chemotherapy, also provided further evidence that the mutations in RAS genes, including KRAS, found in about 30% of cancers are no longer the untouchable foe they once were.
Even so, the drug class still faces a slew of challenges. Revolution’s new treatment can cause side effects including rash, diarrhea and mouth inflammation.
And a new crop of second-generation drugs is being developed to succeed in other areas where first-generation treatments, including Amgen’s Lumakras and Bristol Myers Squibb’s Krazati, fell short. In particular, later-stage options moving through the pipeline could fill existing gaps by targeting specific KRAS mutations like G12D, which occurs most frequently in pancreatic and colorectal cancers. If successful, the up-and-coming treatments could overcome drug resistance while tackling new types of tumors.
Here’s a look at three of pharma’s leading contenders.
Another Revolution drug takes aim at a uniquely challenging cancer subtype
Revolution wants to build on the success of Rasonque with its investigational zoldonrasib, which takes aim at a particularly challenging tumor subtype with RAS G12D mutations.
Some 90% of pancreatic cancers have RAS mutations, but the KRAS G12D variety, present in around 40%, has been associated with poorer outcomes than tumors without KRAS mutations. The company is testing zoldonrasib alone and in combination with other treatments, including Rasonque, in multiple cancers, including lung, pancreatic and other solid tumors.
The drug has seen some favorable results. In a phase 1 lung cancer trial, 52% of 27 previously treated patients with KRAS G12D-mutated non-small cell lung cancer saw their tumors shrink, and estimated overall survival at 12 months was 73%.
The drug also showed activity in a phase 1/2 trial in pancreatic cancer. Among previously-untreated patients, response rates were 82% with modified folfirinox and 61% with gemcitabine plus nab-paclitaxel — two different types of chemotherapy. If these results hold in ongoing phase 3 trials in pancreatic and lung cancer, it could mark a promising advance for patients and another triumph for Revolution.
Astellas’ unique mechanism for targeting KRAS mutations
Astellas Pharma is also zeroing in on the G12D mutation with its drug setidegrasib — but through a different mechanism.
As a first-in-class KRAS G12D-targeted protein degrader, setidegrasib doesn’t just block mutant proteins; it exploits the cell’s natural waste disposal system to eliminate them. The drug is now in phase 3 in pancreatic cancer and non-small cell lung cancer.
In phase 1, the drug showed “antitumor activity” alongside a low side-effect-related discontinuation rate in lung and pancreatic cancer. At the recommended dose, estimated one-year survival was 59% among 45 previously treated lung cancer patients. Among 21 previously treated pancreatic cancer patients, 24% responded and median survival was 10.3 months.
Genentech’s next-generation option with best-in-class potential
Genentech’s divarasib is also potentially on a favorable course. The investigational KRAS G12C inhibitor seemingly outperformed first-generation drugs in the same class in a phase 3 head-to-head lung cancer trial.
The drug, which targets a mutation found in some 14% of non-small cell lung cancer cases, hit its primary and key secondary endpoints in previously-treated patients, improving both progression-free and overall survival. The trial compared divarasib with the approved KRAS G12C inhibitors Lumakras or Krazati. If the results hold, they could establish divarasib as a new standard of care for previously-treated lung cancer patients with this subtype, according to the company.
The drug is also in phase 3 as a first-line lung cancer treatment and for those who have undergone surgery, chemotherapy and immunotherapy.
