KRAS Inhibitor Very Active in NSCLC Subtype

Unprecedented Disease Control Rate

Pam Harrison

September 09, 2019

BARCELONA, Spain — A first-in-its-class novel drug that inhibits a specific mutation in the KRAS gene produced tumor shrinkage in nearly half of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the mutation and has a highly favorable toxicity profile, results from a phase 1 study indicate.

"The KRAS mutation we are treating [KRAS G12C] happens downstream to epidermal growth factor and other kinase mutations so there hasn't been any drug that specifically inhibited this KRAS protein until now," Ramaswamy Govindan, MD, Siteman Cancer Center at Washington University School of Medicine, St. Louis, Missouri, told Medscape Medical News.

"And so far, it worked very well — finally the science came through in the clinic, which is not always the case — and while it's still early data, results look very good so far," he said.

The study was presented here at the IASLC 2019 World Conference on Lung Cancer.

The phase 1 NSCLC component is part of a larger study that included 34 patients with locally advanced or metastatic lung adenocarcinoma.

Patients all had evidence of harboring the specific KRAS G12C mutation expressed in their tumors, as Govindan noted. The KRAS G12C mutation causes about 12% to 13% of lung adenocarcinoma.

A variety of dose levels were evaluated in the phase 1 trial and ranged from a low of 180 mg AMG 510 to a highest dose at 960 mg of the same drug. The drug was taken orally once daily for 21 days, which was followed up with radiographs and examinations.

"The very first patient went on this study just about 1 year ago," Govindan told a press briefing here, "and all the other patients have come into the study within a year of the research."

At the time of current analysis in July, 23 patients were evaluable out of the 34 who had already been treated.

Almost half of the group (48%) exposed to any dose of the drug achieved a partial response to treatment — "the hallmark of the activity of any drug," Govindan observed.

Disease stabilized in another 48% of patients, for a disease control rate of 96% in the group overall, he noted.

A total of 13 patients received the highest 960 mg dose of AMG 510.

In this treatment subset, "we saw a response rate of 54%," Govindan reported. "Strikingly, there was 100% disease control rate — in other words, nobody had disease progression on their first scan [post study enrollment] and many of them had a decrease in tumor size."

Responses to treatment also happened quite quickly, as has come to be expected with targeted therapies.

Responses also appear to be durable so far, in that 8 out of 11 patients who received any dose of the drug still continued on with the study, as did the same number of patients who achieved stable disease based on results of their first scan.

Minimal Toxicities

"As was expected by drug design, toxicities with AMG 510 were really minimal," Govindan continued.

One third of patients did experience some adverse events but most of them were grade 1 and 2; no grade 4 toxicities were seen in any patient.

There were also no dose-limiting toxicities, no serious adverse or fatal events, or any adverse event leading to discontinuation of therapy, Govindan added.

"So this drug works the way it was intended to," he observed. 

As Govindan noted, lung cancer is increasingly seen as a disease with multiple subtypes — including one of the most important subtypes, KRAS mutant lung cancer.

There are different kinds of alterations in the KRAS gene. One of the most common is the G12C alteration, in which the KRAS protein is overactivated, leading to excessive cancer cell proliferation.

The small molecule drug developed by Amgen specifically binds to this mutation and locks it into an inactive state so that KRAS activity is restrained.

This is why the toxicity of AMG 510 is so limited, Govindan explained, because it binds only with proteins that are abnormal in tumor cells — and none of the proteins present in normal tissue.

"KRAS G12C mutant lung adenocarcinoma is one of the largest subsets of NSCLC potentially amenable to targeted therapies," Govindan reiterated in a statement.

"I am pleased that we have a promising new oral therapy for this group of patients," he observed.

Asked by Medscape Medical News to comment on the findings, session co-chair Luis Paz-Ares, MD, PhD, Hospital Universitario Doce de Octubre, Madrid, Spain, cautioned that it will be important to see how long responses to AMG 510 last and what impact responses may have on overall survival.

Nevertheless, Paz-Ares felt the results from the current phase 1 trial were "fantastic news."

"After over 40 years of having discovered this oncogene and trying to get a reasonable drug or strategy that works in this space, it seems we have finally got something and the toxicity profile is very reasonable," he said.

The 100% disease control rate, especially in this patient population, is also unprecedented, Paz-Ares added.

The phase 1 study is continuing, and investigators are planning to take AMG 510 into phase 2 studies in the near future, with 960 mg a day as the target phase 2 study dose.

The study was funded by Amgen. Govindan has served on the advisory board for AbbVie, AstraZeneca, BMS, Celgene, Genentech, Merck, and Nektar. Paz-Ares has received speakers bureau fees from MSD, Roche, AstraZeneca, Lilly, and Bristol-Myers Squibb.

IASLC 2019 World Conference on Lung Cancer. Presented September 8, 2019.

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