by Kelly Davio  Published Online in Targeted Oncology: 9:33 PM, Fri November 16, 2018

Michael C. Heinrich, MD

The investigational agent avapritinib demonstrated encouraging response rates in patients with advanced gastrointestinal stromal tumors (GIST) and PDGFRα D842V-driven GIST, according to findings presented during the 2018 Annual Meeting of the Connective Tissue Oncology Society in Rome, Italy. 1

Findings from the phase I NAVIGATOR study (NCT02508532) showed an overall response rate (ORR) of 84% in patients with PDGFRα D842V-driven GIST and a 20% ORR fourth-line or later GIST. Additionally, 98% of patients with PDGFRα D842V GIST and 60% of patients in fourth-line or later experienced tumor reduction.

Lead study author Michael C. Heinrich, MD, of the Oregon Health and Science University’s Knight Cancer Institute in Portland, Oregon, presented the findings during the meeting.

In an interview with Targeted Oncology, Heinrich discussed the NAVIGATOR study, the next steps for Avapritinib’s development, and how this therapy could deliver on the promise of precision medicine for patients with this malignancy.

TARGETED ONCOLOGY:  What is the key finding from the NAVIGATOR study in patients with GIST?

Heinrich: The key finding is that it endorses our vision of precision medicine for all of oncology, but particularly in GIST, which is knowing particular types of mutations in different types of GIST and rationally designing drugs that would be most beneficial in terms of effectiveness and also safety.

That also builds upon existing drugs that have some benefit, particularly in the first-line, not so much in the second- and third-line, but we’ve come to learn that there are particular reasons for drugs not working.

Avapritinib builds upon all that 15 years of knowledge that there are particular mutations that existing drugs don’t work against, and making a better drug to target those secondary mutations will lead to better results. What the results show is that in patients with D842V-mutant GIST ­­– which is a less common type of GIST but a GIST that doesn’t respond to any available therapy – 98% of patients treated with avapritinib had tumor shrinkage. This is truly amazing for any disease, and any drug, let alone this disease where we’d expect a response rate of close to 0% for anything else we could do.

We also found that, consistent with how the drug was developed and what it was designed to do, in patients with 1 to 6 prior lines of therapy, that they also would respond to avapritinib.

Going forward, we can move from a static view of the patient’s tumor—which is their biopsy from 10 years ago of their original tumor—to understanding, at the time when we need to switch therapies, what’s going on with their tumors based on sampling their blood. We could select or deselect populations who would greatly or less greatly benefit from avapritinib. Moving forward, we’d like to explore that in a prospective study where patients are randomized based on what’s going on with their mutations in their blood.

TARGETED ONCOLOGY:  What are the next steps in development of avapritinib, and do you foresee an FDA submission on the horizon?

Heinrich: We believe that the results are very promising for PDGFRA D842V-mutant GIST, which has no effective treatment, and for patients with fourth-line or later-treated GIST, who have no treatment at all. Our data are compelling enough that a new drug application would be filed next year in those indications.

There’s an ongoing randomized phase III study of avapritinib versus the current standard third-line treatment, which is regorafenib. We hope in the next year to complete enrolment of that study to see the results, but based on our preliminary results from our phase I, we would be optimistic that avapritinib would be superior to regorafenib in that setting. More exciting—or less developed right now—is the idea of moving avapritinib into the second-line, but rather than basing it on line of therapy, selecting patients based on mutational status. If they have the type of circulating tumor DNA profile that predicts optimally for avapritinib response, they would be randomized versus sunitinib, which is the current therapy, to see the outcome.

We would predict that in the optimally selected or deselected population, that that would increase efficacy in the second-line. Conversely, we feel that sunitinib patients could also benefit, because patients who would benefit the most from sunitinib would be given sunitinib rather than enter this randomized study. We feel it has the potential to increase the second-line outcomes both for patients favored for avapritinib and for sunitinib.

TARGETED ONCOLOGY:  How well tolerated is avapritinib so far?

Heinrich: I think it’s generally well-tolerated. Less than 9% of people discontinued the drug due to adverse events, which is a low rate for many TKIs. We felt that the side effects were consistent with inhibiting KIT in PDGFRA, which is the target. If we hit the target, there are certain side effects that we’re going to expect, and we see them.

Compared to second- and third-line agents, I feel the side effect profile is much better. Many patients would endorse that. I’ve had patients say, “I haven’t felt this well in years,” which is partly because the drug is working, and partly because it has fewer side effects than what they were on previously.

TARGETED ONCOLOGY:  How might avapritinib change the treatment landscape for GIST?

Heinrich: We expect that for D842V-mutant GIST, it would be approved and would be the first-line therapy for those patients. We feel that in the fourth-line and later patients, there’s no therapy that has efficacy and has been approved. Avapritinib has strong activity for those patients.

As the third-line randomized studies go on, we predict it would eventually become the third-line agent and potentially the second-line agent for patients with certain genotypes. Optimistically, it probably would be the best agent for frontline therapy, but imatinib has really good results for efficacy and safety, so that would be a much bigger venture to try to move into frontline therapy.

Can you say a bit about the ongoing VOYAGER trial?

Heinrich: It’s a randomized study for patients in the third-line or fourth-line who have never received regorafenib, the standard treatment. Patients are randomized to regorafenib or avapritinib. If patients receive regorafenib first and get progression, then they can receive avapritinib, so everybody has the opportunity to get avapritinib either first or second.

TARGETED ONCOLOGY:  How do you characterize the treatment landscape for GIST, and what are some open research questions?

Heinrich: There’s another agent in development, DCC-2618, that had results presented at this meeting by Dr Suzanne George, which also shows promising activity. 2 Both were rationally designed. So, what is avapritinib going to be approved for? What could DCC-2618 be approved for?

A number of different studies here have looked at circulating tumor DNA, so there is some value to that: how do we use it, what type of decisions do we make based on the results, when should we even do it? These are open questions, but that’s exciting. Knowing what was wrong in a patient’s tumor, having a drug that would fix that which was wrong, and doing so is a much better approach than saying “We use this first, we use this second, we use this third, we don’t really care about your tumor, we don’t care about anything individual about you, these are the ways we do things.” In a disease that is heterogenous, diverse, and different patient have different mutations, that doesn’t make sense anymore.

The idea of precision oncology is to take an understanding of the biology of the disease—what’s broken—and apply, in the most precise way possible, the fix to it. We’re moving from the world of radiation and chemotherapy, which are effective for many cancers—but they’re kind of blunt instruments, they’re not individualized, they’re not precision, it’s the same for everybody.

We believe that, in the future, for any patient, rather than saying, “You have disease X,” it’d be better to say, “You have disease X with the following abnormalities, which would be sensitive to the following drugs,” and choose a therapy based on that.

References:

  1. Heinrich M, von Mehren M, Jones RL, et al. Avapritinib is highly active and well-tolerated in patients (PTS) with advanced GIST driven by diverse variety of oncogenic mutations in KIT and PDGFRA. Paper 012 #3027631. Presented at the 2018 Annual Meeting of the Connective Tissue Oncology Society, November 14-17, 2018; Rome, Italy.
  2. George S, Heinrich M, Chi P, et al. Initial results of phase 1 study of DCC-2618, a broad-spectrum KIT and PDGFRA inhibitor, in patients (PTS) with gastrointestinal stromal tumor (GIST) by number of prior regimens. Paper 013 #3033840. Presented at the 2018 Annual Meeting of the Connective Tissue Oncology Society, November 14-17, 2018; Rome, Italy.