The KRAS inhibitor scene has always been a bit braggadocious with Amgen and Mirati Therapeutics battling it out for the first-to-market advantage. But now, a new crop of scrappy KRAS upstarts has arrived on the medical conference circuit, trying to needle away at the leaders.
Large companies like Eli Lilly and Roche’s Genentech, alongside smaller biotechs like Frontier Medicines and Quanta Therapeutics, debuted data at the American Association for Cancer Research (AACR) meeting in Orlando in April.
What they all have in common is a goal to beat Amgen’s Lumakras (sotorasib) and Mirati’s Krazati (adagrasib) on side effects and combination regimens—two areas where MD Anderson’s David Hong, M.D., says the first two drugs in the class have struggled. Right now, both therapies are only approved for patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), but there are plenty of tumors that harbor a KRAS mutation that are still without a treatment option. RAS mutations are the most frequent oncogenic alterations in humans, with KRAS being the most frequent.
“The cat is now out of the bag, right?” Hong said of the approvals. He serves as deputy chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center in Houston. “I compare this to kinda like the four-minute mile.”
When the four-minute mile barrier was finally breached on May 1954 by athlete Roger Bannister, his feat was repeated a month later by someone else. Just like that, drugging the KRAS mutation was long thought impossible, but now myriad companies have candidates that are showing preclinical and early clinical success.
KRAS is a protein that, when mutated, is activated in an “on” position, causing cancer cells to grow and proliferate. A 2013 breakthrough from the University of California, San Francisco’s Kevan Shokat, Ph.D., showed an image of the protein, allowing scientists at Amgen to discover a pocket that a small-molecule drug could hang onto. It took almost 40 years of scientific exploration to even produce a drug for KRAS mutations, Hong said.
“We’ve come a long way, but now it’s kind of off to the races,” he added.
While there are two therapies on the market, they may not ultimately be the best therapies for the target. Researchers across biopharma are now trying to find the perfect molecule for the G12C target, but also for related ones like G12D and G13C.
Hong’s MD Anderson colleague Ferdinandos Skoulidis, M.D., Ph.D., has done research on which subset of patients may benefit from KRAS inhibitors and what drug combinations could boost response rates. Hong says that clearly patients with NSCLC can have some benefit, but oncologists believe that difficult cancers like colorectal or pancreatic could be important future indications for KRAS inhibitors.
Colorectal is one of the indications that Genentech is going after with RG6330, which was recently renamed divarasib and has also been referred to as GDC-6036. At the AACR meeting, the Roche unit revealed data from a small 29-patient phase 1b study showing that when combined with Eli Lilly’s Erbitux, divarasib led to a partial response in 66% of patients with a confirmed overall response rate of 62%.
Even with the small patient population, Genentech’s Charles Fuchs, head of oncology and hematology global product development, said the response rate is notable in an area of oncology that has long lacked new treatments.
“I will tell you as somebody who has spent decades investigating colorectal cancer and taking care of patients with colorectal cancer, that is a profoundly impressive response rate and activity,” Fuchs said in an interview.
Hong agreed that Genentech’s molecule seems to have high activity in colorectal cancer as a single agent based on the data he has seen—even if doctors don’t exactly know why. He said scientists have zeroed in on a “feedback loop” that occurs in colorectal cancer with the EGFR receptor, a target that has had a lot of clinical attention with BRAF inhibitors.
Adverse events did crop up for a large number of patients in the small trial for Genentech’s drug just as they have with others in the class, including 11 grade 3 to 4 treatment-emergent adverse events. But Fuchs said that the grade 3 events that did happen were moderate in nature, including rashes and diarrhea. Thirteen patients had to have their treatment modified due to adverse events, three had to have their dose reduced but no patients discontinued due to adverse events, according to the AACR abstract. Overall, there were 11 discontinuations, 10 of which dropped out because of disease progression and one at the doctor’s discretion.
But most importantly, divarasib paired well with Erbitux, which is the standard of care in this type of colorectal cancer.
“That’s a real litmus test, right? Can patients stay on it?” Fuchs said. “And the answer is, in this study, there were no patients who withdrew [divarasib] because of toxicity.” He also noted that the therapy seems to be five to 25 times more potent than other molecules and 10 to 50 times more selective than those that are already approved.
“The activity and tolerability of this molecule we think is not specific to colorectal cancer. We think it’s across all malignancies where KRAS G12C mutations occur,” Fuchs said. Therefore, Genentech is advancing it in NSCLC, colorectal and other settings, with different combinations to find the right fit.
Lilly similarly touted the safety and combination profile for LY3537982 at AACR, a candidate picked up from Loxo Oncology. In a phase 1 study combining the KRAS inhibitor with PD-1 inhibitors such as Merck & Co.’s Keytruda, LY3537982 showed preliminary efficacy across all dose levels in multiple tumor types. On safety, there were a few grade 3 events including diarrhea and one instance of elevated liver enzymes, but no high-grade liver toxicity.
“If this holds up, we’ll be in a position, I hope, to launch a suite of phase 3 randomized studies to explore the medicine in first-line lung cancer, and I think advance the field in a way that others haven’t yet been able to do,” said Jake Van Naarden, executive vice president at Lilly and CEO of Loxo@Lilly.
Lilly and Genentech both believe their candidates have a better safety profile than Amgen and Mirati’s candidates. MD Anderson’s Hong said there have been “relatively low numbers” of grade 3 or higher liver toxicity events for single agent use of the approved meds. He says the rate with Krazati was 5% to 6% and lower for Lumakras.
But when combined with multiple different checkpoint inhibitors, the liver toxicity rate climbed to over 30% for Lumakras, sometimes reaching as high as 60% depending on the combination, according to Hong. Clinicians found that staggering the dosing brought the rate down to 30%. That all means that Lumakras will be difficult to move up into the front-line setting in NSCLC, which includes highly successful checkpoint inhibitors like Keytruda, Bristol Myers Squibb’s Opdivo or Regeneron’s Libtayo.
“That may be a difficult problem to solve,” Hong said. “I know that Amgen is trying to find a way to move forward with that.” He does, however, believe the first-line setting isn’t out of the realm of possibility for KRAS-mutated cancers, and the clinical work is already happening now to facilitate the jump. The journey of checkpoint inhibitors from later-line to first choice took about 10 years, so KRAS is still early days, he explained.
Mirarti, on the other hand, has seen slightly better data not that far off the single agent profile, which helped bust the myth that the combo toxicity was a class effect.
“We know that KRAS can affect the immune microenvironment. [There’s] a lot of different ways it can do that,” Hong said. “But particularly there seems to be some differences between adagrasib and sotorasib here.”
And likely, the other candidates will be different in this way, too, whether it’s Lilly or Genentech’s offering, Novartis or any other, Hong noted.
Smaller companies are going after KRAS G12D and G13C, including Revolution Medicines, which has four candidates covering the KRAS spectrum in development. Hong is one of the investigators for some of Revolution’s studies. Immuneering, meanwhile, has a pan-RAS inhibitor for the entire mutation.
On the preclinical side, Frontier Medicines presented data of FMC-376 at AACR showing that the candidate exhibited potent inhibition of tumor cell viability across KRAS G12C mutant tumor cell lines. The early data also seemed to suggest that FMC-376 could evade resistance, whereas Lumakras and Krazati have a loss in activity.
“Although these inhibitors do seem to have temporary benefit, many of these cancers are developing resistance fairly quickly, and trying to find the next iteration either of a drug or combinations is going to be somewhat difficult,” Hong said.
Quanta Therapeutics also teased some early data for the multi-KRAS inhibitor QTX3034 in preclinical models, showing that the treatment suppressed KRAS-driven cancer cell growth. The data support Quanta’s plans to move into human testing, according to a release. Another treatment, QTX3046, demonstrated anti-tumor activity in colorectal, pancreatic and lung cancer xenograft models.
Where Genentech’s Fuchs really hopes KRAS inhibitors can make an impact is in pancreatic cancer. Hong says that Mirati has already seen response rates in the 20% to 50% range with Krazati as a single agent.
While it’s a small population, Hong would not be surprised if Genentech seeks accelerated approval in that indication. “Pancreatic has a lower bar to cross,” he said, given the unmet need.
For Fuchs, it’s personal after a long career as a gastrointestinal oncologist.
“That’s another cancer that I’ve spent a career on, and I can tell you, we absolutely need better therapies, and the vast majority of patients diagnosed with pancreatic cancer die from the malignancy because of the paucity of active therapies,” said Fuchs.
“So being able to target that malignancy based on what we know is clear biology—that is where the vast majority have a KRAS mutation—having that type of therapy could be potentially transformative.”