Avapritinib Demonstrates Potentially Practice Changing Results in GIST

Michael C. Heinrich, MD

Avapritinib (BLU-285) showed substantial clinical activity in patients with gastrointestinal stromal tumors (GIST) withKITandPDGFRAmutations, according to findings from the phase I NAVIGATOR trial presented at the 2018 CTOS Annual Meeting. To date, patients with GIST who harbor these mutations have typically been resistant to all available therapies.

"Avapritinib has the potential to change GIST treatment paradigms. Avapritinib represents a therapeutic advance in GIST, a rare cancer with high medical needs across lines of treatment. In particular, the updated data demonstrate the broad clinical impact of avapritinib for patients withPDGFRAD842V-driven GIST and fourth-line GIST, where there are currently no effective therapies," said lead study author Michael C. Heinrich, MD.  

The updated data presented at CTOS from the ongoing phase I NAVIGATOR trial (NCT02508532) support the new drug application (NDA) planned for submission to the FDA in the first half of 2019 by the drug developer, Blueprint Medicines, for the treatment of both patients withPDGFRA exon 18 mutant GIST and fourth-line GIST. The former patient population mostly included patients with a D842V mutation, and for patients with GIST being treated in the fourth-line, there are currently no approved or effective therapies.

“Although imatinib [Gleevec] is an effective first-line treatment for patients with advanced gastrointestinal stromal tumours, most patients inevitably relapse or progress. Sunitinib [Sutent] and regorafenib [Stivarga] are approved second- and third-line agents, but they have shown limited activity and/or tolerability, defining an unmet need for patients with imatinib-resistant GIST,” said Heinrich, a professor of medicine at the Oregon Health & Science University School of Medicine.

“Avapritinib is a highly potent and selective oral kinase inhibitor that targets mutant forms ofKITandPDGFRA, including those that confer resistance to approved tyrosine kinase inhibitors.”

The open-label study evaluated the efficacy and safety of avapritinib in 231 patients who were treated with avapritinib during the dose escalation and expansion portions of the phase I clinical trial at 8 dose levels, ranging from 30 to 600 mg once daily. This population comprised 167 patients withKIT-driven GIST, 56 withPDGFRAD842V-driven GIST, and 8 with otherPDGFRAmutations.

The key objectives included determination of the maximum-tolerated dose (MTD), recommended phase II dose, safety, pharmacokinetics, and clinical activity by line of therapy and mutational status, as well as objective response rate (ORR) and radiological assessment according to modified RECIST criteria version 1.1 (mRECIST v1.1) for planned NDA and marketing authorization application regulatory filings.

Heinrich presented findings from 4 efficacy populations:PDGFRAD842V mutation—positive patients, avapritinib administered in the fourth-line setting or beyond, avapritinib administered as third or fourth line in regorafenib-naïve patients, and avapritinib administered in the second-line setting.

As of the October 15, 2018, data cutoff date, 56 patients withPDGFRAD842V-driven GIST, 109 patients receiving avapritinib for fourth-line or later GIST, 23 patients receiving avapritinib for third- or fourth-line GIST who were regorafenib naïve and did not have thePDGFRAD842V mutation, and 20 patients with second-line GIST who did not harbor thePDGFRAD842V mutation were evaluable. These patients had received ≥1 centrally

reviewed radiographic scan according to mRECIST 1.1 criteria for GIST. The evaluation of clinical benefit rate (CBR) was done in patients having ≥2 radiographic scans.

Avapritinib demonstrated important clinical activity in patients withPDGFRA- driven GIST at all dose levels. The ORR was 84% (95% CI, 71.7%-92.47%) in these patients; 9% had a complete response (CR) and 75% showed partial responses (PRs), while 4 PRs are awaiting confirmation. Sixteen percent of patients achieved stable disease (SD), yielding a CBR at 4 months of 96% (95% CI, 87.7%-89.6%). The best response by central radiology showed that 98% of these patients had tumor reduction. The 12-month duration of response (DOR) was 76%, and the 12-month progression-free survival (PFS) rate was 81.2%.

In heavily pretreated patients receiving avapritinib at doses of 300 or 400 mg in the fourth line or later, the ORR was 20% (95% CI, 13.1%-29.0%); 1 (1%) patient achieved a CR, 19% had a PR, and 1 PR is pending confirmation; 40% of patients showed SD for a CBR of 40% (95% CI, 31.1%-50.2%). The median DOR was 7.3 months, and 78% of patients in this cohort demonstrated tumor reduction. Median PFS by central review was 3.7 months and 5.4 months by investigator review.

The cohort of regorafenib-naïve patients with third- or fourth-line GIST who were treated with avapritinib at doses of300 or 400 mg demonstrated an ORR of 26% (95% CI, 10.0%-48.4%). There were no CRs achieved but 26% of patients achieved a PR and 57% had SD for a CBR of 70%. The median DOR was 10.2 months. Tumor reductions were demonstrated in 78% of patients. Median PFS was 8.6 months by central and 10.2 months by investigator review.

Heinrich noted that preliminary data showed robust clinical activity in patients with regorafenib-naïve third- and fourth-line GIST.

“In contrast, historical data shows a 5% ORR and median PFS of 4.8 months with regorafenib, the current standard-of-care treatment in third-line GIST,” he commented.

In the cohort of patients with second-line GIST but without thePDGFRAD842V mutation, the ORR was 25% in patients receiving avapritinib at doses up to and including 300 or 400 mg; 3 PRs are pending confirmation. The DOR and CBR at 4 months were not reached. Median PFS in this cohort was 8.6 months by central review and 10.2 months by investigator review.

"With an increased understanding of molecular drivers of GIST over the last decade, it is encouraging to see an investigational drug like avapritinib bring a precision therapy approach to GIST," Heinrich remarked. “Mutational profiling analysis and promising second-line data provide a strong rationale for genotype-selected second-line study.”

Regarding safety, avapritinib was well tolerated, with mostly grade 1 or 2 adverse events (AEs) reported. The most common any-grade treatment-emergent AEs (TEAEs) reported in ≥20% of patients included nausea (61%), fatigue (55%), anemia (46%), periorbital edema (40%), diarrhea (39%), vomiting (38%), decreased appetite (35%), peripheral edema (33%), increased lacrimation (31%), memory impairment (26%), constipation (23%), facial edema (23%), hair color change (21%), and dizziness (20%). Grade 3 or 4 treatment-related AEs (TRAEs) occurring in ≥2% included anemia, fatigue, hypophosphatemia, increased bilirubin, decreased white blood count/neutropenia, and diarrhea. Avapritinib treatment was discontinued by 20 patients (8.7%) due to TRAEs.

Reference:

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. Presented at: 2018 CTOS Annual Meeting; November 14-17, 2018; Rome, Italy. Paper 012.