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Novel KRAS inhibitor induces disease control in 96% of treated patients with non-small cell lung cancer
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BARCELONA — AMG 510 appeared well-tolerated and showed promising antitumor activity among patients with locally advanced or metastatic non-small cell lung cancer, with 96% of patients achieving disease control, according to phase 1 study results presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.
The KRAS G12C mutation is one of the most common KRAS mutations in lung cancer, causing about 12% to 13% of lung adenocarcinomas. The mutation also can be found in about 3% of colorectal and appendix cancers and 1% to 3% of other solid tumor types.
“Lung adenocarcinoma is not one disease, it’s a collection of multiple diseases driven by various different alterations,” Ramaswamy Govindan, MD, medical oncologist at Siteman Cancer Center, and Anheuser Busch endowed chair in medical oncology and director of the section of medical oncology at Washington University School of Medicine, told HemOnc Today. “KRAS accounts for the largest proportion of patients with lung cancer — about 20% to 25%. Within the KRAS there are different alterations that occur when the glycine is replaced by cysteine, and G12C is the most common alteration that we see in KRAS-mutant lung cancer.”
AMG 510 (Amgen) irreversibly inhibits KRAS G12C by permanently blocking it in an inactive GDP-bound state.
“This particular group has been very difficult to target so far, and due to breakthroughs in chemistry and biology, AMG 510 represents a first-in-class novel small molecular inhibitor that specifically binds to a mutant protein in KRAS,” Govindan said during a press conference. “This is very specific and customized to the mutant protein, and therefore we expect fewer novel toxicities.”
Researchers assessed AMG 510 in a basket trial of 76 patients with locally advanced or metastatic KRAS G12C-mutant solid tumors who had progressed on standard therapy. The current analysis includes a subset of 34 patients with NSCLC, 23 of whom were evaluable for efficacy.
The study included four dose expansion cohorts of AMG 510: 180 mg, 360 mg, 720 mg and 960 mg.
Safety served as the study’s primary endpoint. Objective response rate, duration of response, PFS and pharmacokinetics served as secondary endpoints.
At a July data cutoff, about a year after the first patient was treated, results showed that 96% of patients achieved disease control, with a 48% ORR rate. Researchers observed responses across dose levels.
“More importantly, half of the patients achieved partial responses, which is the hallmark of activity of a drug,” Govindan said.
Researchers recommended 960 mg as the phase 2 dose. All 13 patients who received this dose in the phase 1 study achieved disease control, with a 54% ORR and a 46% rate of stable disease.
“One hundred percent of these patients achieved disease control; in other words, no patient had disease progression on the first scan and many of them had a decrease in tumor size,” Govindan said.
Eight of 11 patients with partial response, and eight of 11 patients with stable disease, remain on study. Median duration of treatment is 15.1 weeks (range, 4.1-42.3) for patients with partial response and 10 weeks (range, 4.1-35.1) for patients with stable disease.
“The partial responses happened very quickly, as you can expect with targeted therapies, and many of them are ongoing,” Govindan said. “One of our patients has a partial response going on for more than 8 months. This is clearly a very encouraging set of data.”
Toxicities with AMG 510 appeared minimal and were mostly grade 1 or grade 2. Treatment-related adverse events of any grade occurred among 35.3% of patients, 23.5% of which were grade 2 or higher. Three patients experienced grade 3 treatment-related adverse events, which included anemia and diarrhea.
No patient experienced a treatment-related grade 4 adverse event and there were no dose-limiting toxicities or adverse events leading to treatment discontinuation.
“These data show that the drug works in the way that it was intended to,” Govindan said.
Given that the first patient was treated on this study only about a year ago, the 100% response rate in the 960 mg group was a “pleasant surprise,” Govindan told HemOnc Today.
“We’ve enrolled more than 70 patients in the entire study and 34 patients for the lung cancer cohort,” he said. “For a disease group that was historically not targeted, this is absolutely a huge story [coming out of this meeting].”
Because this was a phase 1 study among a small group of patients, in the phase 2 study researchers seek to observe the durability of responses over time, whether new toxicities occur, and to assess the group of patients who aren’t responding, Govindan added.
“It’s always important to be cautious, but the important thing to keep in mind is that this is a group for which we had no targeted therapies before,” he said. “The chemotherapy and immunotherapy drugs that worked did so variably and nonspecifically. Now for this, one of the largest subgroups of patients with lung cancer, there is a very real possibility with near certainty that there will be a new therapy option available for them.” – by Alexandra Todak
Reference:
Govindan R, et al. Abstract OA02.02. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.
Disclosure: Govindan reports consultant or advisory roles with AbbVie, Adaptimmune, AstraZeneca, Celgene, Ignyta, Inivata, Merck, NEKTAR, Pfizer and Roche. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Charu Aggarwal, MD, MPH
KRAS G12C-mutant NSCLC represents about 13% of newly diagnosed NSCLC. There is no approved targeted therapy for this mutation. AMG 510, a small molecule inhibitor that is administered orally, irreversibly inhibits KRAS G12C by permanently locking it in an inactive GDP-bound state.
In an update of data reported at this year’s ASCO Annual Meeting, Govindan and colleagues reported response rates with AMG 510 of approximately 48%, which is unprecedented among patients with NSCLC, especially those who received prior therapies including immune checkpoint inhibitors. The majority of patients experienced partial response, observed as early at about 6 weeks.
Additionally, only one patient progressed and an additional 48% (n = 11) experienced disease stabilization, representing a disease control rate of 96%. These findings are early but promising.
The drug was well-tolerated, with no dose-limiting toxicities reported to date. No treatment-related serious or fatal adverse events were reported.
Although these are small numbers, the tolerability and efficacy make this a very promising agent. For a subset of patients with NSCLC that is not uncommon, this drug presents a viable option and represents one of the most exciting presentations coming out of this meeting. It is no surprise the FDA has granted fast track designation to AMG 510 for the treatment of patients with previously treated metastatic NSCLC harboring a KRAS G12C mutation.
Reference:
Fakih M, et al. Abstract 3003. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
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