Perspective from Louis M. Weiner, MD
April 15, 2018
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BLU-667 shows antitumor activity in RET-altered cancers

Perspective from Louis M. Weiner, MD
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Vivek Subbiah

CHICAGO — BLU-667, a next-generation oncogenic RET inhibitor, demonstrated antitumor activity among patients with RET-altered tumors, according to results from an ongoing study presented at American Association for Cancer Research Annual Meeting.

The agent also appeared well tolerated.

RET is a rare driver of multiple, diverse tumor types,” Vivek Subbiah, MD, assistant professor in the department of investigational cancer therapeutics and associate medical director of Clinical Center for Targeted Therapy at The University of Texas MD Anderson Cancer Center, said during a press conference.

RET mutations are present in more than 60% of medullary thyroid cancers, 10% to 20% of papillary thyroid cancers, 1% to 2% of non-small cell lung cancers, and less than 1% of other tumor types.

“Precision oncology has benefited patients with EGFR and ALK mutations,” Subbiah said. “Unfortunately, RET-altered cancers have not benefited from precision oncology kinase inhibitors. The current drugs that being used — which are repurposed multikinase inhibitors like cabozantinib [Cabometyx, Exelixis] and vandetanib [Zactima, AstraZeneca] — have decreased activity and increased off-target toxicities for patients with RET-altered tumors. So, there was a need to design a selective drug for this target.”

Subbiah and colleagues conducted an open-label, first-in-human study to assess BLU-667 (Blueprint Medicines), a potent and selective oral inhibitor that targets RET fusions, point mutations and resistance mutations.

At the time of presentation, researchers had enrolled 51 patients with unresectable advanced solid tumors. The population included:

  • 29 patients with RET-mutant medullary thyroid cancer;
  • 19 patients with non-small cell lung cancer with RET fusion;
  • two patients with papillary thyroid cancer; and
  • one patient with paraganglioma.

Patients had undergone a median one prior antineoplastic treatment (range, 0 to 8).

Researchers administered once-daily BLU-667 in doses ranging from 30 mg to 400 mg. The maximum tolerated dose was not reached.

Results showed a best overall response rate of 45% among 40 evaluable patients with RET-altered cancers who received a dose of at least 60 mg and had at least one response assessment after baseline.

One patient (3%) achieved complete response, 17 (42%) achieved partial response, 20 (50%) achieved stable disease and two (5%) experienced progressive disease.

Researchers reported a 50% ORR among patients with RET-fusion NSCLC and 40% among those with RET-mutant medullary thyroid cancer.

The majority (83%) of patients demonstrated radiographic tumor reductions (range, –2% to –70%).

“We don’t have long durations of response because our trial is less than 1 year old,” Subbiah said. “Almost 84% of patients had some regression. However, many of those patients came at the lower dose level,” Subbiah said. “We have only just now reached the recommended phase 2 dose. The phase 2 study will inform about how many patients will respond to this drug.”

Forty-one patients remained on study at the time of reporting.

The most common adverse events associated with BLU-667 included grade 1 constipation (23%), alanine aminotransferase increase (16%), aspartate aminotransferase increase (16%), diarrhea (14%), fatigue (12%), creatinine increase (12%), white blood cell decrease (12%) and hypertension (12%).

Sixteen percent of patients experienced treatment-related grade 3 adverse events. Researchers observed three dose-limiting toxicities, but no grade 4 or grade 5 adverse events.

“BLU-667 has broad antitumor activity in RET-altered cancers, regardless of the tumor type, regardless of the genomic alteration, regardless of prior therapies of immunotherapy that included multikinase inhibitor therapy, and regardless of the number of prior therapies,” Subbiah said. – by Cassie Homer

 

Reference:

Subbiah V, et al. Abstract CT043. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.

Disclosure: Subbiah reports research funding from AbbVie, Amgen, Bayer, Berg, Blueprint Medicines, Boston Biomedical, D3, Fujifilm, Genentech/Roche, GlaxoSmithKline, Incyte, Loxo, MultiVir, Nanocarrier, National Comprehensive Cancer Network, NCI Cancer Therapy Evaluation Program, Northwest Biotherapeutics, Novartis, PharmaMar, Pfizer and Vegenics.