Recently Approved Targeted Therapy for Fourth-Line GIST

Shreyaskumar, Patel, MD: So lately I think as you already alluded to a few minutes ago, we do have approval of ripretinib in the specific PDGFR [platelet-derived growth factor receptor] alpha D842 subset of patients. But more importantly, the resistant KIT mutant patients who don't have any other option, we now have a recent approval of ripretinib in the fourth-line setting. Can you tell us a little bit about the clinical trial, the mechanism of action, and some of the data that led to the approval of this agent as a standard of care in fourth line therapy?

Andrew Wagner, MD: Sure. Ripretinib is another kinase inhibitor, although it does have different mechanism of action than some of the other kinase inhibitors that we've discussed already. Notably it binds to a different region in KIT called the switch pocket. Making it different than the other three drugs which bind in the binding domain. The ripretinib binds to a different area on KIT. The importance of that is probably that the resistance mutations that can occur that prevent, strictly prevent imatinib or sunitinib or regorafenib from binding may be overcome by ripretinib.

And similarly, that the way the activation loop moves and can also be resistance and some of these drugs may still be inhibited by ripretinib. It does have a different mechanism of action, at least preclinically in that led to its study in a variety of different clinical trials to explore its efficacy and safety in patients with advanced gastrointestinal stromal tumor. The goal, of course being to try to find a new treatment after the other drugs no longer were working.

And this was first of course studied in a phase 1 study, it was quite large. It had had many different cohorts. It included patients in different lines of therapy, second, third, fourth line and more than fourth-line therapy. I think overall there were about 180 patients who were treated at doses over 100 milligrams a day, and ultimately defined the recommended dose to be 150 milligrams a day. And most of the patients in the study had KIT mutant tumors although there were a few also that had PGFR [platelet growth factor receptor] mutant tumors or wild type tumors.

And what was important in the phase 1 study aside from establishing the dose and the safety profile, the responses were seen. With about 30% of patients in the second line, about 20 to 25% of patients in the third line and about 11% of patients in the fourth line. And those numbers are granted, many of these, these cohorts were relatively small except for the fourth or greater line which was a large cohort. But these numbers are significantly higher than what we would see with sunitinib or Regorafenib in terms of response rate.

So those data were encouraging as was the disease control rate for a second line therapy that ran about 30% at the year, which was an impressive duration of disease control. With progression, median progression-free survivals that were about 40 weeks in the second and third line setting and about 24 weeks in the fourth or greater line setting. So, importantly from this study we learned that there was activity of ripretinib in GIST in multiple lines of - after multiple lines of therapy and the safety profile was was established. And this was explored further in the Phase 3 study called INVICTUS. This was in fourth line.

This was after prior imatinib, sunitinib, and Regorafenib. And patients were randomized in this study in a two-to-one fashion to ripretinib at 150 milligrams a day or to placebo in a blinded fashion. 129 patients were enrolled, and crossover was permitted at the time of progression, similar to the GRID study that you mentioned before. The outcomes were impressive. The progression free survival was just over 6 months for ripretinib and only a month for placebo with a hazard ratio of 0.15. The response rate of ripretinib was 9%, and there was a difference in survival that was about 15 months for ripretinib versus 6.6 months for placebo.

But this was not able to be classified statistically because of a hierarchical determination that required significance of PFS then response rate before this could be analyzed. And although there was 9% response compared to 0, that did not meet statistical significance, and therefore significance could not be claimed for the overall survival.

Although I think we're all impressed by the difference in the median numbers that are reported there. In this phase 3 study, especially compared to placebo. The toxicity profile was better able to be defined then than what you would see in a phase 1 trial. And most of the toxicity was as well, easy to manage or it wasn't so significant. More than 20% of patients had a number of different toxicities, including some hair loss, fatigue, nausea and some other GI [gastrointestinal] symptoms. The palmar plantar erythrodysesthesia that we mentioned before and hand-foot syndrome.

There was also less frequently but of note were some primary cutaneous malignancies, hypertension and cardiac dysfunction was seen in the study. The other important features of the study was a good look at quality of life and other patient reported outcomes. There really were 5 different measures that were assessed and all of them showed improvement on ripretinib compared to placebo.

And so that in addition to the certainly important tumor response, disease control metrics, perhaps more important was how the patients were feeling, and as reported in the PR data. These were the data that led to FDA approval just a few weeks ago, but I think well supported by the study design and results.

Shreyaskumar, Patel, MD: Absolutely. I think that was a very nice summary of a longer experience. I think if I remember right the first time, we heard about this drug was ASCO 2011. So here we are almost about 9 years later that we have the drug approved and it has gone through a fairly long process. I think a different way for our audiences to picture and why we are excited about this drug and why we think it's an important advance. We sort of talked about median PFS [progression-free survival] and we all agreed that amongst various endpoints I think PFS [progression-free survival] may be one that's the more relevant one, if not the most relevant one for comparison's sake.

And if we sort of look at a bar graph with imatinib, it's 24 months, sunitinib drops down to 6 months, Regorafenib drops down below 4.8 and on that same bar graph if we put the Korean randomized trial of rechallenged with imatinib versus best supportive care, the rechallenge with imatinib goes down to 1.9 months or 2 months to round it off. It is a matter of diminishing returns as we go from one line to another. And in that context now we have an agent that actually has turned the corner around with the PFS [progression-free survival] of 6 plus months, right.

It's almost back to a comparable second line. Recognizing we're not comparing one study to another. But the whole idea was to can we really turn this whole downward process around? And I think statistical significance and hierarchical analysis aside I think in a large enough experience a 6 plus months median PFS [progression-free survival] is clearly of interest. And especially so when it is coupled with quality of life improvements like you talked about, and a median overall survival of 15 plus months.

I think that clearly tells us that in this late line setting, it has less to do with the composite of the endpoint and other things that happened to patients beyond. But more so what this particular drug does to this patient population at this time.

Transcript edited for clarity.

Andrew Wagner, MD, reports the following disclosures: Consulting with Deciphera, Daiichi-Sankyo, NanoCarrier. He also reports research funding to his institution with Daiichi-Sankyo, Eli Lilly, Karyopharm, Plexxikon, Aadi Biosciences.