By ADAM FEUERSTEIN @adamfeuerstein

Scientists have long known that a mutant form of the cell-signaling protein called KRAS causes cancer, but discovering drugs capable of blocking KRAS has proven difficult. The protein is spherical and nearly featureless — its structure has been compared to a tennisball —  leaving potential drugs with few, if any, effective attachment points.

On Wednesday, Amgen (AMGN) is reporting early but potential progress in an effort to block mutant KRAS and kill cancer cells. The Amgendrug, a small molecule pill called AMG 510, caused tumors to partially shrink in 30% of patients with lung tumors that tested positive for a particular kind of KRAS mutation.

The new AMG 510 data — the first efficacy results reported in cancer patients — come from an early-stage clinical trial involving patients with different types of solid tumors.

Amgen included the preliminary results in a research abstract for the upcoming American Society of Clinical Oncology (ASCO) annual meeting. Research abstracts for the ASCO meeting, which starts May 31, were posted publicly on Wednesday night.

The absolute numbers reported Wednesday were small: Ten cancer patients — six with non-small cell lung cancer and four with colorectal cancer — were evaluable for response.

AMG 510 is one of the most important drugs in Amgen’s pipeline. The drug’s development is being closely followed given the benefit to patients and commercial success seen with other cancer drugs like Pfizer’s Xalkori or Loxo Oncology’s Vitrakvi, that target highly specific genetic mutations.

What sets AMG 510 apart even among the crop of genetically driven cancer drugs is the elusiveness of the target: KRAS mutations are implicated in about 25% of all human cancers but were thought to be “undruggable” until recently.

AMG 510 is designed to treat cancers that contain a particular alteration of KRAS called a cysteine mutation, or KRAS G12C. This mutation, currently untreatable, is found in approximately 14% of non-small cell lung cancer adenocarcinomas, 4% of colorectal cancer, and 2% of pancreatic cancer, said David Reese, Amgen’s executive vice president of research and development.

Building on some previously published discoveries about KRAS, Amgen scientists were able to exploit a structural weakness that creates a shallow pocket in the mutated protein when in an inactive state. Reese likened the pocket to a dimple on a golf ball. AMG 510 then uses this dimple as a binding site and locks onto the protein by interacting with the residue created by the cysteine mutation.

“There is some very elegant medicinal chemistry and structural biology behind this molecule,” said Reese, referring to AMG 510.

The ongoing Phase 1 clinical trial enrolled 22 patients, including six with lung cancer, 15 with colon cancer, and 1 patient with another type of solid tumor. A majority of the patients were no longer responding to three or more currently approved drugs. All of the tumors in these patients were genetically sequenced and found to contain KRAS G12C mutations. Escalating doses of AMG 510 were used to treat the enrolled patients.

Ten of the 22 enrolled patients were evaluable for response at the time of the abstract submission. Two of the six lung cancer patients showed a partial response to AMG 510 that was ongoing, another two lung cancer patients had stable disease, and the remaining two progressed. All four of the colon cancer patients had stable disease following AMG 510 treatment. Half of the patients reported side effects but all were mild to moderate in severity.

Reese declined to comment on the AMG 510 data contained in the abstract but noted that Amgen was able to select an effective target dose based on the outcome of the clinical trial and that additional clinical trials, including a combination with a checkpoint inhibitor, are moving forward.

Wednesday’s AMG 510 abstract is only a preview of a complete data presentation covering all the treated patients scheduled for the ASCO meeting on Monday, June 3.

Mirati Therapeutics (MRTX) is also developing a KRAS G12C inhibitor with first patient data expected in the second half of the year.

About the Author

Adam Feuerstein

Senior Writer, Biotech

Adam is STAT’s national biotech columnist, reporting on the intersection of biotech and Wall [email protected]@adamfeuerstein