Amgen Presents Updated KRAS Inhibitor Data: Modest Disappointment but Strong Project Outlook Maintained

Compiled | newborn

At the conference, Amgen’s latest data revealed more encouraging signals for AMG 510 in lung cancer. However, given the industry’s exceedingly high expectations, these results may disappoint some stakeholders...

The 20th World Conference on Lung Cancer (WCLC), hosted by the International Association for the Study of Lung Cancer (IASLC) in 2019, was held in Barcelona, Spain, from September 7 to 10. At this conference, Amgen announced the latest research data on AMG 510, a KRAS inhibitor that has attracted close attention from the industry.

The data presented at the conference were derived from an ongoing first-in-human, open-label Phase I study conducted in patients with KRAS G12C-mutated solid tumors who had previously received at least two prior lines of therapy. Patients were randomized into four dose cohorts: 180 mg, 360 mg, 720 mg, and 960 mg, administered orally once daily. The primary endpoint was safety, and key secondary endpoints included pharmacokinetics, objective response rate (ORR, assessed every six weeks), duration of response (DOR), and progression-free survival.

Preliminary data from the study were presented at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) held in June this year. The results presented at the World Conference on Lung Cancer (WCLC) included additional follow-up data from a larger patient cohort. Among the 34 patients with non-small cell lung cancer (NSCLC) who received treatment, efficacy was evaluable in 23 patients: 11 patients (48%) achieved partial response (PR), 11 patients (48%) had stable disease (SD), and 1 patient (4%) experienced disease progression (PD), resulting in an objective response rate (ORR) of 48% and a disease control rate (DCR) of 96%. Furthermore, among the 13 efficacy-evaluable patients who received the highest dose of 960 mg, 7 patients (54%) achieved PR and 6 patients (46%) had SD, yielding an ORR of 54% and a DCR of 100%.

Regarding safety, no dose-limiting toxicities were observed among the 34 patients with non-small cell lung cancer (NSCLC), and no adverse events led to treatment discontinuation; 27 patients remained on treatment. Among the 34 patients, only 9 (26.5%) reported grade 1 or 2 treatment-related adverse events (TRAEs). Three patients reported grade 3 TRAEs (anemia and diarrhea). No grade 4 or higher TRAEs occurred.

Based on the aforementioned data, Amgen has selected a once-daily 960 mg dose as the dosing regimen for AMG 510 in the expansion cohort study and Phase II study.

Ramaswamy Govindan, MD, Professor at the Siteman Cancer Center, Washington University School of Medicine, and principal investigator of the study, highly praised the findings: “KRAS G12C-mutant lung adenocarcinoma represents one of the largest subgroups of non-small cell lung cancer (NSCLC) with potential for targeted therapy. The data presented at the conference continue to demonstrate that AMG 510 exhibits encouraging antitumor activity, offering a promising oral therapeutic option for this patient population.”

Currently, Amgen is rapidly advancing the clinical program for AMG 510. Patient enrollment in the 960 mg dose expansion cohort has been completed, and the company will present the next clinical update, including data from patients with colorectal cancer, at the European Society for Medical Oncology (ESMO) Congress held in late September.

Although Phase I trials focused on AMG 510 monotherapy, combination therapies will be a key component of Amgen’s development program, given the potential for tumors to develop treatment resistance. Currently, Amgen is enrolling patients with non-small cell lung cancer (NSCLC) in studies evaluating AMG 510 in combination with anti-PD-1 inhibitors, while another pivotal Phase II monotherapy study is also actively enrolling patients.

Industry Reaction: Somewhat Disappointing, but Data Still Sufficient to Maintain Positive Outlook for AMG 510 as a High-Value Asset

Last week, Evercore ISI analysts speculated that the objective response rate (ORR) of AMG 510 in the treatment of lung cancer could reach 70-80%. Some other analysts expect the overall response rate at a 960mg dose to be between 50%-70%. However, these individuals also acknowledged that this is a very high threshold.

John Heymach, an oncologist at The University of Texas MD Anderson Cancer Center, stated in response to a question from the industry website BioPharma Dive: “These data provide clear evidence that this drug has significant antitumor activity in the G12C population, making it the first targeted therapy for which I believe such a claim can be made.”

However, John Heymach warned that it remains unclear how long the therapeutic response to AMG 510 will ultimately last. He also pointed out that among patients with KRAS G12C mutations, the response rates for chemotherapy and immunotherapy are only 10–20%. In contrast, the response rate for AMG 510 reached 48%, rising to 54% in the high-dose group, with some patients treated early in the trial maintaining their response after 6–10 months.

Due to the small number of patients in the study, definitive conclusions regarding response rates and durability of response cannot yet be drawn. However, the data presented at the conference appear likely to prompt industry analysts to reassess their expectations for AMG 510 to some extent. Nevertheless, EvaluatePharma, a pharmaceutical market research firm, stated that although the results suggest AMG 510 will not be effective in all KRAS-mutant patients, the latest data are still sufficient to maintain favorable expectations for this high-value asset.

KRAS: The Epitome of an “Undruggable” Target in Oncology, the “Mount Everest” of the Pharmaceutical Industry, Remaining Unconquered for Three Decades

KRAS is one of the first oncogenes discovered, with over three decades of research. Its mutations are present in approximately one-quarter of human tumors, making it one of the most well-defined targets in the field of oncology drug development.

However, regrettably, despite its promising prospects, KRAS has long remained virtually undruggable. This is because the KRAS protein adopts an unstructured, nearly spherical conformation with no obvious binding pockets, making it extremely difficult to develop compounds that can selectively bind to and inhibit its activity. Currently, KRAS has become synonymous with “undruggable” targets in the field of oncology drug development.

AMG510 is one of the first small-molecule inhibitors to successfully target KRAS and enter human clinical development. It inhibits the KRAS protein harboring the G12C mutation, which is present in approximately 13% of non-small cell lung cancers, 3–5% of colorectal cancers, and 1–2% of other types of solid tumors. Currently, no drugs targeting this mutation have been approved.

AMG510 specifically and irreversibly inhibits the pro-proliferative activity of G12C mutant KRAS protein by locking it in an inactive GDP-bound state. AMG510 is the most closely watched early-stage asset in the industry, with the potential to enable Amgen to achieve a breakthrough in targeting KRAS.

KRAS: Other Competitors

In the KRAS space, Amgen may face competition from Mirati Therapeutics, which also has a candidate drug targeting the KRAS G12C mutation, MRTX849, and has obtained excellent data in preclinical studies, with Phase I study results expected to be announced later this year. In July this year, Novartis reached a clinical collaboration agreement with Mirati to evaluate the combination therapy of MRTX849 and Novartis’ SHP2 inhibitor TN0155 for treating patients with advanced solid tumors carrying the KRAS G12C mutation.

SHP2 is a critical mediator of cellular signaling through the RAS/MAP kinase pathway and is frequently hyperactive in various types of cancer. Preclinical data demonstrate that combining a KRAS G12C inhibitor with an SHP2 inhibitor enhances antitumor activity, based on their complementary mechanisms of action.

Furthermore, earlier this month, Boehringer Ingelheim reached a licensing agreement with Rubicon Therapeutics, with a total transaction value exceeding $700 million, to develop Rubicon’s MEK inhibitor in combination with Boehringer Ingelheim’s innovative KRAS inhibitor for the treatment of gastrointestinal and lung cancers harboring a broad range of oncogenic KRAS mutations. Preclinical data indicate that combining KRAS and MEK inhibitors can enhance anti-tumor activity, leveraging their complementary mechanisms of action in suppressing KRAS-driven cancers.

Reference Source:

1、World Lung 2019 – Amgen tries to keep the pace in Kras chase

2、Amgen update shows promise, limits of KRAS cancer drug

3、AMGEN AT WCLC 2019