For decades, scientists searched for a drug capable of shrinking tumors harboring one of the most common genetic mutations in cancer.
Those efforts consistently came up short until this June, when Amgen first showed that one of its experimental medicines could work in treating cancers positive for defects in the gene called KRAS. On Monday, early clinical data disclosed by San Diego biotech Mirati Therapeutics show Amgen's breakthrough might be replicated.
Mirati's KRAS-blocking drug spurred responses in one patient with Stage 4 lung cancer and another with metastatic colon cancer, according to results from a Phase 1 study presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Theraeputics.
The tumors of two other study participants with lung cancer also reduced in size following treatment, but those responses are still unconfirmed by a second imaging scan.
Monday's data are a first look at whether Mirati's therapy can follow the example set by Amgen's, which has proved effective in roughly half of patients with lung cancer treated to date. Investors will likely be quick to compare the two datasets, although, with results from so few patients available, it's difficult to judge the drugs against each other.
"Once more patients are enrolled in this study, as well as the Amgen study, I thank you can make comparisons," said Pasi Jänne, director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, on a call with reporters Monday afternoon.
"But I think it's encouraging that both agents are showing clinical activity for a disease where we have not had targeted therapies before," added Jänne, who is a paid consultant for Mirati and presented the data.
KRAS mutations are found in many lung, colorectal and pancreatic cancers, and the lack of an approved therapy designed to attack mutant KRAS signalling means tumors positive for the mutation are often difficult to treat.
Investor optimism that Amgen and Mirati can crack the KRAS code that's stumped drugmakers for years has fueled substantial increases in the share price of both companies. Entering Monday, Mirati's valuation stretched past $3 billion, more than twice what the company was valued at to begin 2019.
With three responses in lung cancer, and one in colon cancer, Mirati appears to have posted data similar to what Amgen first unveiled at the American Society of Clinical Oncology annual meeting in June. But that might disappoint some investors who had hoped for Mirati to better Amgen's numbers.
First data for Mirati show Amgen isn't the only one with an active KRAS inhibitor
Drug | Conference | Primary result |
---|---|---|
AMG 510 | ASCO | 50% ORR (5/10) in pts. w/lung cancer, 100% ORR (3/3) at high dose |
AMG 510 | WCLC | 48% ORR (11/23) in pts. w/lung cancer, 54% ORR (7/13) at high dose |
AMG 510 | ESMO | 3% ORR (1/29) in pts. w/colon cancer, 8% ORR (1/13) at high dose |
MRTX849 | AACR-NCI-EORTC | 50% ORR (3/6) in pts. w/lung cancer, 25% ORR (1/4) in pts. w/colon cancer |
*High-dose results included in first ORR listed SOURCE: Companies, conference presentations
All told, 17 patients have enrolled in Mirati's study, 12 of whom were evaluable for efficacy as of Oct. 11. In addition to the participants with lung and colon cancer, two patients with appendiceal cancers were included in the data Mirati presented Monday. Neither responded to treatment.
Side effects to treatment were generally mild, although two patients experienced Grade 3 adverse events of fatigue and decreased appetite. Investigators also reported one case of isolated enzyme elevations without pancreatitis, which was judged to be Grade 4.
While the results show Mirati's drug to be active, the early nature of the data limit what conclusions can be drawn about the treatment's ultimate efficacy. Scans to confirm responses were done after six weeks, meaning follow-up to initial responses is very limited.
Moreover, physicians and analysts usually wait for response rate data across several dozen patients, at least, before being confident in results.
Amgen and Mirati are the first in a wave of companies newly interested in targeting KRAS. Johnson & Johnson and Boehringer Ingelheim recently began Phase 1 studies of their own, while other efforts are underway at Moderna, BridgeBio and the National Cancer Institute.
Each of Amgen, Mirati and J&J's drugs target a specific type of KRAS mutation known as G12C, present in 13% of all lung cancers and between 1% and 3% of other solid tumors according to numbers cited by Amgen.
Research activity around KRAS G12C increased following a 2013 paper from researchers at the University of San Francisco, California, which described one approach to binding a drug to the mutant KRAS protein.
Both Amgen and Mirati designed their respective compounds to irreversibly lock onto to what Amgen's head of cancer development Greg Friberg calls a "hidden groove" on the KRAS protein. In scientific terms, the drugs are known as covalent inhibitors, a type of molecule that was once disfavored by large drugmakers.
"Historically, there was a period of time when covalent inhibitors got a bad reputation in the pharmaceutical industry for causing liver injury," said William Sellers, a member of the Broad Institute of MIT and Harvard as well as an advisor at Dana-Farber, on the Monday call with reporters.
"Ibrutinib was sort of a rebirth, which turned out to be a covalent inhibitor of BTK and ... ignited that field again," he added, referring to AbbVie and J&J's top-selling blood cancer drug Imbruvica. Other covalent inhibitors, such as AstraZeneca's Tagrisso and Boehringer's Gilotrif, are also approved.
In that respect, Amgen's and Mirati's work on KRAS inhibition is part of a broader revolution in targeted cancer therapies, one that's yielded dozens of approvals.
Such treatments aren't definitive, though. Tumors often respond and mutate, resulting in resistance that can lead to relapses and disease progression. For that reason, Amgen is planning combination studies with its drug in hopes of achieving greater efficacy and more durable responses.