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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)

 

ARQ 197: Novel c-MET inhibitor shows promise in early clinical trial results with Tarceva

Please Note: New Treatments Have Emerged Since this Original Post
Author
Howard (Jack) West, MD

Earlier this week, the Boston (Woburn, actually)-based company Arqule announced preliminary results from a trial of their investigational oral c-MET inhibitor ARQ 197 combined with the EGFR inhibitor Tarceva (erlotinib), which sent their stock soaring. Although I and other investigators dislike learning about potentially important cancer trial outcomes from the business news outlets, this was again following that pattern. Unlike some other press releases describing preliminary outcomes, however, this one truly does impress me. We'll certainly need to learn a lot more, but I believe that this drug may represent a meaningful improvement, at least for a subset of patients with advanced NSCLC. c-Met is a receptor tyrosine kinase implicated in tumor cell migration, invasiveness, and proliferation, and it is abnormal in many human cancers. Importantly, about 20% of patients with an epidermal growth factor receptor (EGFR) mutation who initially respond well to an oral EGFR inhibitor are found to have a c-MET mutation, and it is currently believed that this mutation contributes to "acquired resistance" to these agents when patients progress over time. The drug ARQ 197 inhibits c-Met and inhibitrs cancers in preclinical models, which is great, but the real test is how well a drug works in real patients, who are far more complex than test tube or animal models of cancer. The results highlighted in the press release strongly suggest what I would consider to be a potentially clinically meaningful benefit. So let's dig deeper.

The clinical trial ARQ 209 enrolled 167 patients with advanced NSCLC of any histology who were previously treated with a single line of chemotherapy who were then randomized to receive either standard second line Tarceva (erlotinib) alone at the typical 150 mg daily dose, or the same drug and dose with ARQ 197, an oral agent given twice daily (360 mg each dose): arq-209-trial-design (click on image to enlarge) Importantly, the trial did require availability of tumor tissue for analysis of EGFR, K-RAS, and c-MET mutation status. The primary endpoint of the trial was progression-free survival (PFS), and the preliminary report this week noted that this was 66% longer in patients who received ARQ 197 with Tarceva (median 16.1 weeks), compared to patients who received second line Tarceva alone (median 9.7 weeks). This wasn't a statistically significant difference, but a pre-specified analysis of the difference of PFS in patients with non-squamous histology (117 patients) showed a 94% longer PFS in recipients of Tarceva + ARQ 197 (median 18.9 weeks) vs. Tarceva alone (9.7 weeks) was statistically significant with a hazard ratio of 0.61 (corresponding to an overall 39% improvement in PFS for patients who received ARQ197 over the course of treatment). The press release also noted an absence of any real differences in side effects, which were overall dominated byt he known side effects of Tarceva: rash, diarrhea, and some fatigue. Of course, there's still plenty that we don't yet know about, most notably a survival difference, though if there is a two month difference in PFS among patients with non-squamous NSCLC, I would suspect that it may well be more than a month and would be a promising signal, though it almost certainly wouldn't amount to a statistically significant difference. Regardless, that's not really what you're looking for from a phase II trial, which is primarily to clarify whether the results look encouraging enough to move forward with a phase III randomized trial. I certainly imagine that these results will lead to a subsequent trial with a goal of FDA approval, and I think that they should. There is a lot more very interesting information yet to be presented, including the molecular marker work. I hope that, along with the histology results, molecular marker studies inform us which patients do or don't receive some incremental benefit from a c-MET inhibitor. If these types of variables are used to further narrow the population of patients for the subsequent phase III trial, we hope to demonstrate highly significant benefits for the exact patients who stand to gain from receiving this class of agents rather than diluting it with a broad population that includes patients who wouldn't be likely to experience improved outcomes. This work is also looking only at patients who haven't received an EGFR inhibitor before. It may be that ARQ 197 and/or another c-MET inhibitor could restore activity and clinical benefit for patients who previously responded to an EGFR inhibitor and then progressed from acquired resistance. That concept remains to be demonstrated, but the concept is certainly appealing. I look forward to learning more about this trial and providing details later.

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