One of the more promising agents for advanced NSCLC in the last few years has been the oral Met inhibitor tivantinib, also known as ARQ-197.  I've described it in some detail in a couple of prior posts, and I was definitely encouraged by the results of the randomized phase II trial of tivantinib with Tarceva (erlotinib) compared with Tarceva alone in Tarceva-naive patients with advanced NSCL which indicated a potentially real survival benefit with the combination for non-squamous patients, and perhaps a particular value for this combination over Tarceva alone for KRAS mutation-positive patients (although this provisional conclusion about KRAS mutation-positive NSCLC was based on a very small number of patients in the phase II trial).

This phase II work led to a large phase III trial called MARQUEE, an approximately 1000-patient global study that I participated in.  Unfortunately, we just received word that the Data Monitoring Committee has reviewed the interim analysis results and recommended that the trial be stopped early, since their analysis led them to conclude that it would not demonstrate a significant difference in overall survival, though it did show a significant improvement in progression-free survival.  This analysis also led to no new safety concerns. 

While this is clearly unwelcome news, I suppose there is still a chance that if the trial demonstrates a survival benefit for patients with KRAS mutation-positive advanced NSCLC for the combination of tivantinib/Tarceva over Tarceva alone, the drug could still have a chance of being further developed for that large subset of NSCLC patients, in whom Tarceva alone is rarely especially effective.   That's probably wishful thinking, but we'll see.

One other question that has come up is whether these results suggest that "MetMAb", or onartuzumab, an antibody against Met, will suffer the same fate.  Onartuzumab has looked very promising for patients with high expression of the Met protein on their tumor cells, and the phase III trial with that agent in combination with Tarceva and compared with Tarceva alone is ongoing.  I don't think the absence of a survival benefit for tivantinib suggest any failure of onartuzumab is more likely: we already know that EGFR tyrosine kinase inhibitors and monoclonal antibodies against EGFR have very different behavior and activity in NSCLC and other cancer types. I wouldn't generalize these negative results and look forward to the completion of the trial with onartuzumab. Let's hope for better results and a new treatment based on that work.

If you were offered participation on a different trial with a Met inhibitor, would you be dissuaded by the findings from the MARQUEE trial?