New data emerging from the closely watched field of targeted KRAS therapeutics offer hope that researchers are finally making headway against the most commonly mutated oncogene. But even as early data suggest that a new class of drugs called KRAS G12C inhibitors can shrink some tumors, scientists are scrambling to figure out how to make them work better, longer, and for more cancer patients.
Oncology researchers at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics this week saw the first swath of data on Mirati Therapeutics’ MRTX849, a small molecule that blocks KRAS G12C, one of several KRAS mutants.
Dana Farber Cancer Institute thoracic oncologist Pasi A. Jänne presented very early data from 12 people with various solid tumors at the AACR meeting. Of those, 3 out of 6 evaluable lung cancer patients and 1 out of 4 colon cancer patients saw their tumors shrink. In all other people in the study, the cancers remained stable.
Industry watchers are scouring that limited data set for signs that Mirati’s drug was demonstrably different than AMG 510, a similarly acting drug in development by Amgen. When asked if it’s possible to compare the performance of the Mirati and Amgen drugs, Jänne cautioned that it is too early to tell. But, he added, “it’s encouraging that both agents are showing clinical activity for a disease where we have not had targeted therapies before.”
That tiny data set was also parsed for signs that MRTX849’s benefits will last. KRAS is a central node in a complex network providing many opportunities for feedback loops that allow cancer to survive.
To that end, companies developing KRAS G12C inhibitors are exploring how to prolong and expand the benefits of their drugs. This week Amgen provided new preclinical evidence that supports combining cancer immunotherapy and targeted KRAS inhibitors.
In a Nature paper (DOI: 10.1038/s41586-019-1694-1), Amgen researchers showed that AMG 510 and an anti-PD-1 drug together caused tumors to disappear in 9 out of 10 mice tested. The benefits lasted for more than two months after treatment was stopped. And when researchers analyzed the environment around the tumors, they found many more immune cells had infiltrated the cancer cells than cells treated with either drug on its own.
These new data, while in mice, are “exciting,” says University of Chicago lung cancer specialist Jyoti D. Patel, and provide clues about how to make KRAS drugs more effective over a longer period of time. “A fair number of patients are responding, but we don’t know how long they’ll respond or what progression will look like,” she says. “So combination strategies are absolutely important.”
As part of its ongoing Phase I study of AMG 510, Amgen is testing the small molecule in combination with Merck & Co.’s anti-PD-1 inhibitor Keytruda, and this year the firm will add study arms that specifically look at the addition of MEK inhibitors and anti-PD1 inhibitors in people with colorectal cancer. Meanwhile, AMG 510 is swiftly moving through the development pipeline and toward consideration by regulatory authorities.
“The potential registration-enabling Phase II study is rapidly enrolling,” an Amgen spokesperson says.
Beyond combinations, companies are also looking to develop new flavors of KRAS inhibitors that could address a broader patient population and the concern over feedback loops.
That work is greatly needed, according to Patel. KRAS G12C inhibitors have “captured our imagination, certainly, but at the same time there’s also a lot of humility about the target based on how prevalent this mutation is and how little success we’ve had in really unraveling all the bypass tracks and mechanisms of resistance,” she says.
At the AACR meeting, Boehringer Ingelheim provided details on a new clinical candidate that it hopes will address some of those bypass mechanisms: a small molecule that blocks the interface between KRAS and a protein called SOS1.
If KRAS is “the beating heart of cancer”—pumping through a process controlled by two nucleotides, guanosine diphosphate (GDP) and guanosine triphosphate (GTP)—then SOS1 is the pacemaker, explains Darryl McConnell, research head for Boehringer’s site in Vienna. SOS1 binds to KRAS to force GDP out, allowing GTP to flood in and turn the protein on.
During that nucleotide exchange, KRAS is briefly left empty—an opportunity for chemists to sneak a small molecule into the interface between SOS1 and KRAS. But, disrupting a protein-protein interaction is no easy feat. While Mother Nature has come up with big, complex molecules to wedge into such gaps, chemists have struggled to design compounds that can fill them.
Moreover, while some proteins might greet each other with a fist bump, SOS1 and KRAS meet with a full-on bear hug. “That interaction is actually huge—thousands of angstroms,” McConnell says, noting that it is one of the largest protein-protein interaction surfaces known in biology.
Boehringer researchers wanted to take advantage of a pocket on SOS1 that was identified several years ago. It turned out that the first hit to emerge from their high-throughput screening efforts was a compound left over from a 1990s project to inhibit EGFR, another well known cancer target.
“It wasn’t a clinical candidate, it was missing some decorations,” McConnell notes, but that hit made them realize that the pocket on SOS1 is astonishingly similar to the pocket on EGFR.
While that old key fit a new lock, the molecules bind the two pockets in completely different ways, McConnell explains. Chemists then carefully built out the small molecule to prevent the two proteins from coming together.
This month, Boehringer began a Phase I study of the resultant SOS1 inhibitor, BI 1701963, in people with KRAS-mutated tumors. The drug is being tested alone and in combination with trametinib, which blocks MEK, another key protein in the KRAS signaling pathway.