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ARQ 197: Novel c-MET inhibitor shows promise in early clinical trial results with Tarceva
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):
(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.
6 Responses to ARQ 197: Novel c-MET inhibitor shows promise in early clinical trial results with Tarceva
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Thanks Dr West. Another great analysis of a news story with unknown significance. Keep it up. You stated that 20% of EGFR+ pts have c-Met and that ARQ197 seems to have some potential to benefit for these patients once they develop resistance.
Can you list the mutations that make up the remaining 80% of acquired resistance to tarceva? And you can you run through a list of drugs that may be designed to address those mutations?
My wife is a 40 y/o never smoker, egfr+, tarceva for 6 months. I am hoping to get a little more info about what mutations we can expect and what drugs (clinical trial or on the market) we should be thinking about as we plan the next steps.
Thanks in advance,
Joe Caridi
Dr. West -
It’s great to read of hopeful results from this trial.
The operative words here are “Importantly, the trial did require availability of tumor tissue for analysis of EGFR, K-RAS, and c-MET mutation status.” That is so very important, as I’ve learned just today.
I’ve been taking steps to join the Lung Cancer Mutation Consortium study underway at University of Colorado and other sites around the country. Unfortunately, I just learned from my HMO’s Pathology Dept. that there’s not enough tissue from my original biopsy (October 2008) to provide the sample required to qualify for that study. They used fine needle aspiration (FNA) for the biopsy and there was not much left after the HMO confirmed the diagnosis. Pathology Dept. is now looking at the remainder of the biopsy tissue to see if there’s sufficient tissue for ALK testing. Bless them for not giving up. I’m keeping fingers crossed. Needless to say, I am disappointed.
As mutation testing and the associated potential treatments become increasingly valid and prominent, I hope that our medical personnel can strike a balance between safety of the biopsy procedure and obtaining sufficient tissue to allow mutation testing down the line. In my case, the FNA was probably preferable due to the proximity of the tumor to heart and main arteries. It’s right in the middle of my chest. Plus, I presume there is less risk of “seeding” new tumors with FNA. As it was, the procedure caused a partial lung collapse.
That said, I wish the doc had grabbed some more while he was in there. The tumor has shrunk via chemo (hooray!). Given its location and current size (2.4 x 2.0 cm), I would hesitate to risk another biopsy and doubt my oncologist/HMO would go for it. So, my candidacy for mutation testing is pretty much on hold for now.
About 50% of patients of patients have a mutation called T790M, but we don’t know much more. Among drugs that may possibly inhibit this mutation are HKI-272 (neratinib, Wyeth), BIBW2992 (Boehringer-Ingelheim), XL647 (Exelixis),and PF00299804 (Pfizer). Additionally, heat shock protein-90 (HSP-90) are being looked at as a potential way to address this. may be effective in this setting. As for c-MET, XL 184 and also XL-880 (Exelixis for both)can inhibit c-MET, as does AMG 208 (Amgen). However, I should caution that some of these agents have been in clinical trials and haven’t been staggeringly impressive. For instance, trials of Wyeth’s HKI-272 were done years ago and, to my knowledge, have never been reported: this isn’t a sign of a hugely successful agent; meanwhile, Boehringer-Ingelheim seems to be testing their agent primarily in the setting of patients with EGFR mutations, which effectively loads the dice to maximize the chance of having it BIBW2992 looking favorable even if it provides no incremental benefit beyond what we can already get with Tarceva or Iressa. Other agents are just coming up through the ranks.
The latest news on ARQ 197 (again from the business news outlets) is that they’re getting “closer” to a phase III trial:
http://www.masshightech.com/stories/2010/08/02/daily20-ArQule-lung-cancer-treatment-one-step-closer-to-market.html
Here’s a related question: if c-MET is so important, why isn’t the Lung Cancer Mutation Consortium testing for it (we volunteered, as UCH already has tissue from Bobbye’s cancer, but as she’d already been tested for KRAS, EGFR and ALK they said there wasn’t more to learn)?
Thanks,
Joe S.
Is the c-Met mutation test available commercially?
The next part of the post-ASCO webinar discussion I did with Dr. Pennell and will post here is on the presentation of the data with ARQ-197 with Tarceva, so look for that here in the next few days. I just had a meeting with some of the folks coordinating the phase III trial with ARQ-197: it’ll be second or third line therapy, Tarceva with ARQ-197 or placebo, no crossover. The final version of the protocol is still being done, but they’re projecting having the trial start in the next few months so should have the final version done in a matter of weeks. I’m looking forward to offering this trial to patients at my center in the fall (perhaps late fall), provided all the regulatory hurdles are managed in a timely way.
Testing for c-MET isn’t commercially available to my knowledge, and I think the jury is still out on how important it really is. It’s not very clear that the provocative results with ARQ-197 were largely related to results on c-MET testing. Right now, we don’t have any commercially available agent for which c-MET testing would be important in clinical decision-making, so it isn’t the highest priority in current clinical practice. As for the question of it not being included in the Lung Cancer Mutation Consortium project, I believe Dr. Camidge fielded a question about it after his presentation and noted that while investigators would love to study far more, they were forced to accept some limits in the scope of what they could feasibly address. It wasn’t that c-MET isn’t interesting, but rather that other molecular marker questions were considered to be more immediately relevant and promising.