BARCELONA-Mutations to the proto-oncogene KRAS are drivers in a number of malignancies. The KRASG12C mutation, in which the glycine present as the 12th residue in the wild-type protein is replaced by a cysteine, is present in roughly 13 percent of lung cancers, 3 percent of colorectal cancers, and 1-3 percent of other solid cancers. AMG 510 is a first-in-class selective irreversible KRASG12C inhibitor that is currently being evaluated in a first-in-human phase I/II study (NCT03600883) in patients with malignancies that have been confirmed to have KRASG12C-mutant disease.
Results from this study were recently presented at the 2019 World Conference on Lung Cancer (WCLC) by Ramaswamy Govindan, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, St. Louis, Mo.
"Historically, it was thought that KRAS was an 'undruggable' target, however, in this study, we did see some clinical activity, with partial responses achieved in seven out of 13 evaluable patients (two confirmed as of cutoff) with an objective response rate (ORR) of 54 percent in previously treated patients with non-small cell lung cancer (NSCLC).
"In addition, the investigational compound appears to show good selectivity for the KRASG12C mutant, as there were no serious or fatal treatment-associated adverse events (AEs); if broad-based binding to multiple Ras isoforms was occurring, one would expect to see serious toxicities."
In September 2019, the FDA granted Fast Track designation to AMG 510 for the treatment of adults with KRASG12C-mutant NSCLC who had received prior treatment. AMG 510 is an irreversible inhibitor of the mutant KRASG12C protein. Mechanistically, it undergoes a rapid reaction and forms a covalent bond with the thiol moiety of the cysteine-12 residue of guanosine diphosphate (GDP)-bound KRASG12C (ACS Med Chem Lett 2019;10(9):1302-1308).
"In doing so," Govindan explained, "the protein is locked in an inactive, GDP-bound state." When asked if this compound inhibited normal, wild-type (WT) KRAS, he noted, "Because the compound forms a covalent bond with the cysteine present in the mutant protein, this inhibitor displays remarkable selectivity, with no inhibition of the WT KRAS."
Study Details
The primary objectives of this clinical trial are to assess safety and tolerability of AMG 510 in adult patients having KRASG12C-mutant solid tumor malignancies. An additional objective in this trial is the assessment of dose-limiting toxicities to determine the maximum tolerated dose and/or the recommended phase II dose in these same patients. Key secondary study endpoints included the following: pharmacokinetic assessment, ORR, disease control rate (DCR), progression-free survival, duration of response, and duration of stable disease. Among the key inclusion criteria were locally advanced or metastatic, molecularly confirmed KRASG12C-mutant solid tumor malignancy, prior treatment with standard therapies, and no active brain/CNS metastases.
The phase I portion of the trial is an open-label, multicenter dose-escalation study. The phase II portion of the study is an expansion phase and uses the recommended phase II dose determined in the dose escalation part of the trial.
Results
First patient enrollment occurred on Aug. 27, 2018, while the date for data cutoff was July 17, 2019. The analyses presented by Govindan at WCLC included results from the 34 patients with NSCLC. Of these patients, 19 were included in the dose-escalation cohort at the following levels: 180 mg (3), 360 mg (2), 720 mg (6), and 960 mg (8). A total of 15 patients were included in the expansion cohort which was dosed at 960 mg/day. There was a total of 23 patients who were evaluable who had the first 6-week scan or early disease progression; of these, 13 received the recommended phase II dosage of 960 mg/day.
No dose-limiting toxicities were observed in the safety population of 34 patients. A total of 12 patients in this population experienced a treatment-related AE; however, the majority were minor (grade 1 or 2). There were only three incidents of grade 3 AEs (diarrhea-2 and anemia-1).
Pharmacokinetics analyses showed a maximum serum concentration (Cmax) of 7.5 [mu]g/mL and an AUC (area under the time-concentration curve) of 65.3 hr*[mu]g/mL. In addition, these analyses afforded a mean elimination half-life (t1/2) of 5.5 hours.
Among the 23 evaluable patients, 11 showed a partial response, 11 showed stable disease, while one showed progressive disease. These figures gave an ORR of 48 percent and a DCR of 96 percent. Among the 13 evaluable patients at the recommended phase II dosage of 960 mg/day, seven showed a partial response while six showed stable disease for an ORR and DCR of 54 percent and 100 percent, respectively.
Among the 11 patients that showed a partial response to therapy with AMG 510, the median duration of treatment was 15.1 weeks with a range of 4.1 to 42.3 weeks.
Discussion
When asked what he thought the major lesson was from this study, Govindan replied, "For the first time in humans, we have used AMG 510 against a target that was previously thought to be 'undruggable'; moreover, there was some efficacy in previously treated NSCLC patients with metastatic or locally advanced KRASG12C-mutant disease, as shown by the ORR of 54 percent and DCR of 100 percent in those evaluable patients receiving the recommended phase II dosage.
"AMG 510 displayed a favorable safety profile at all dose levels tested; importantly, no dose-limiting toxicities have been observed. In addition, no cumulative toxicities were noted, even with extended treatment."
When discussing the next steps for AMG 510, Govindan stated, "Currently, enrollment is ongoing for phase I studies evaluating AMG 510 in combinations with other drugs, as well as phase II monotherapy studies."
Richard Simoneaux is a contributing writer.