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Expert Highlights Durable Responses Induced by BLU-667 in RET+ Thyroid Cancers

Danielle Ternyila
Published Online:9:00 PM, Mon July 29, 2019
Vivek Subbiah, MD
Vivek Subbiah, MD
BLU-667, a potent RET inhibitor, induced durable responses in patients with advanced thyroid cancers with a RETalteration, according to findings from the phase I/II ARROW study (NCT03037385) presented at the 2019 ASCO Annual Meeting. This drug was granted a breakthrough therapy designation by the FDA for patients with RET-mutant medullary thyroid cancer (MTC) and previously treated RET fusion–positive non–small cell lung cancer (NSCLC).

Patients were enrolled in the dose-escalation phase of the ARROW study and received varying doses of BLU-667 between 30 mg and 600 mg once daily or twice daily. The 400 mg daily dose was moved to the second part of the trial.

Part 2 is currently ongoing, accruing patients with RET-positive MTC, papillary thyroid cancer (PTC), and NSCLC. As of the data cutoff of December 19, 2018, 60 patients with advanced RET-altered MTC and 5 patients with RET-altered PTC were treated. Responses from 49 patients in this cohort were evaluable and presented at this year’s meeting.1

The objective response rate (ORR), 1 of the coprimary endpoints of the study, was 47%; 2 patients had a complete response (CR) while 21 had partial responses (PRs). The disease-control rate (DCR) in this cohort was 98%, while the median duration of response had not yet been reached.

Of the patients with MTC who had prior treatment with a RET inhibitor, either cabozantinib (Cabometyx) or vandetanib (Caprelsa), the ORR was 63%, and 16 patients had a CR. The DCR in these patients was 94%. For the 9 patients with RET-altered PTC, the ORR was 83%; responses are pending for 2 patients, and 8 patients are still receiving treatment.

In terms of safety, a coprimary endpoint, the most common treatment-emergent adverse events (AEs) included hypertension, constipation, and neutropenia in patients with RET-mutant MTC. The investigators noted that treatment-related AEs were generally low grade and reversible, including hypertension, neutropenia, constipation, and leukopenia. No patients with MTC discontinued treatment due to treatment-related toxicity.

The clinical trial sponsor intends to submit BLU-667 to the FDA for accelerated approval in 2020 for patients with RET-altered MTC who had previously been treated with either cabozantinib or vandetanib.

In an interview with Targeted Oncology, Vivek Subbiah, MD, assistant professor in the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed the activity and tolerability of BLU-667 in patients with advanced RET-altered MTC and PTC. He also discussed the next steps planned for this ongoing trial and how this agent can impact the treatment landscape of patients with RET-altered thyroid cancers.

TARGETED ONCOLOGY: How frequently are RET-altered thyroid cancers seen? What sort of challenges currently exist in the treatment of these patients?

SubbiahRET alterations are targetable oncogenic drivers in about 90% of advanced MTC and about 20% of PTC. To date, the FDA-approved options for MTC have included multikinase inhibitors that have been repurposed to treat patients with RETalterations. These drugs, like vandetanib and cabozantinib, were originally designed to target other kinases, such as VEGFR2.  This leads to significant adverse-effect profiles—diarrhea, rash, and hypertension—that limit use in certain patients or limit the dose that patients can tolerate.

TARGETED ONCOLOGY: What was the rationale for investigating BLU-667 in this patient population?
SubbiahBLU-667 is a next-generation small-molecule RET inhibitor specifically designed for highly potent and selective targeting of oncogenic RETalterations, including the most prevalent RET fusions (eg, KIF5B–RETand CCDC6–RET) and RET-activating mutations (eg, C634W, M918T). BLU-667 was also designed to inhibit predicted resistance mutations (eg, V804L/M) with the goal of providing durable benefit. BLU-667 demonstrated increased RETpotency and selectivity relative to multikinase inhibitors both in vitro and in in vivo models of RET-driven thyroid, lung, and colorectal cancers. 

TARGETED ONCOLOGY: Could you go into the methods of design for this trial?

SubbiahARROW is a phase I/II clinical trial designed to evaluate the safety, tolerability, and efficacy of BLU-667 in multiple ascending doses in adults with RET-altered cancers, including MTC. The trial consists of 2 parts: a dose-escalation portion, which is now complete, and an expansion portion, in which enrollment is ongoing.

The expansion portion consists of 7 defined cohorts of patients treated with BLU-667 at the recommended phase II dose of 400 mg once daily: (1) Patients with RET-fusion NSCLC who were previously treated with a platinum-based chemotherapy, (2) those with RET-fusion NSCLC who have not previously received a platinum-based chemotherapy, (3) those with RET-mutant MTC who were previously treated with cabozantinib or vandetanib, (4) patients with RET-mutant MTC who have not previously received cabozantinib or vandetanib, (5) patients with other RET-fusion tumors, (6) patients with other RET-mutant tumors, and (7) those with RET-altered solid tumors who were previously treated with a selective RET inhibitor.

Trial objectives include assessing response, pharmacokinetics, pharmacodynamics and safety. The trial is enrolling patients at multiple sites in the United States, European Union, and Asia.

TARGETED ONCOLOGY: What were the results that were presented at ASCO this year?

SubbiahUpdated safety and efficacy data were presented at ASCO this year.As of the data cutoff date, 32 patients with RET-mutant MTC who initiated treatment at the recommended phase II dose of 400 mg once daily were evaluable for response assessment, including 16 patients previously treated with the multikinase inhibitors cabozantinib or vandetanib. The ORR was 63% (9 confirmed PRs, 1 PR pending confirmation) and the DCR was 94% in patients with RET-mutant MTC who were previously treated with cabozantinib or vandetanib. Across all patientswith RET-mutant MTC, the median duration of response was not reached, and all responders remained on treatment as of the data cutoff date, with treatment durations up to 15.6 months for patients receiving a starting dose of 400 mg once daily. 

TARGETED ONCOLOGY: What are the most significant findings to come from these data? And what is the impact of these findings?

SubbiahRET is an established oncogene found in a wide range of cancers including NSCLC, MTC, and other tumor types. RET has now been shown to be an actionable target and that selective RET inhibitors are here to stay. In addition, based on the data generated to date, the trial sponsor has announced plans to seek FDA approval of BLU-667 next year.

TARGETED ONCOLOGY: Could you also speak to the efficacy and toxicity profile that has been associated with this drug so far?

SubbiahAs of the data cutoff date, 226 patients received a starting dose of 400 mg once daily and were evaluable for safety. Across all patients, BLU-667 was well-tolerated and most adverse events reported by investigators were grade 1 (mild) or 2 (moderate). There were no patients with MTC that discontinued treatment due to treatment-related adverse events, and only 4% discontinued due to treatment-related adverse events across the entire study.

In addition to MTC, 6 patients with papillary thyroid cancer were evaluable for response assessment by RECIST version 1.1. In these patients, the ORR was 83% (3 confirmed PRs, 2 PRs pending confirmation). 

TARGETED ONCOLOGY: What are the next steps for this agent?

SubbiahThe FDA has granted a breakthrough therapy designation to BLU-667 for the treatment of patients with RET-fusion positive NSCLC that has progressed following platinum-based chemotherapy, and RET-mutation positive MTC that requires systemic treatment and for which there are no acceptable alternative treatments. The clinical trial sponsor plans to submit a new drug approval application for accelerated approval to the FDA in the first half of 2020 for patients with RET-mutant MTC previously treated with cabozantinib or vandetanib. 

TARGETED ONCOLOGY: How do you see this agent potentially impacting patients with RET-altered thyroid cancers?

SubbiahI think the selective RET kinase inhibitors will supersede the multikinase inhibitors based on adverse effects alone. We will wait for the duration of response and progression-free survival data from the trials. 

TARGETED ONCOLOGY: Is there anything else that is important to note about BLU-667 or RET-altered thyroid cancer?

SubbiahWe have a highly potent and targeted drug in our hands. Key is to sequence all thyroid cancer patients for RETaberration and enroll them on selective RET trials. 
Taylor MH, Gainor JF, Hu MI-N, et al. Activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-altered thyroid cancers. J Clin Oncol.2019;37(suppl 15; abstr 6018). doi: 10.1200/JCO.2019.37.15_suppl.6018.

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