New RET Inhibitors Show Reduced Toxicities in Thyroid Cancer

Nancy A. Melville

October 15, 2018

WASHINGTON, DC — Two novel RET inhibitors, BLU-667 (Blueprint Medicines) and LOXO-292 (Loxo Oncology/Bayer), continue to show encouraging efficacy in the treatment of advanced RET-altered medullary and papillary thyroid cancers, with fewer side effects than current multikinase inhibitors (MKIs), according to updates from ongoing clinical trials presented here at the 2018 Annual Meeting of the American Thyroid Association.

"The results of these two promising phase 2 clinical trials demonstrate the importance of the RET oncogene in the biology of this disease; and that, when suppressed by potent RET inhibitors, may effectively control the disease," Mabel Ryder, MD, of the Mayo Clinic, in Rochester, Minnesota, and co-chair of the meeting program committee, told Medscape Medical News.

"These therapies may significantly improve therapeutic approaches for patients with advanced disease," she stressed.

Latest Data on BLU-667

While presenting the latest updates from the ARROW trial, the first in-human study of BLU-667, Mimi Hu, MD, of the University of Texas MD Anderson Cancer Center, Houston, highlighted progress among patients with advanced solid tumors in RET-altered MTC. The trial also includes patients with nonsmall-cell lung cancer (NSCLC).

Initial results from the ARROW study were presented at the American Association for Cancer Research (AACR) 2018 Annual Meeting in April, as reported by Medscape Medical News.

Hu reported that early results have shown a "durable and high" overall response rate (ORR) of 62% among 13 MTC patients treated at doses of 300/400 mg/day for 24 weeks, with an ORR of 49% across all doses and all cycles (n = 35). Doses in the first part of the study ranged from 30 to 600 mg/day, and 400 mg/day was found to be the maximum tolerated dose.

About 50% of patients with thyroid cancer in the trial were pretreated with MKIs, and the ORR of MTC in patients regardless of prior MKI treatment was approximately 50% (50% among 18 patients with no prior MKI; 47% among 17 patients with prior MKI treatment).

Overall, 83% (35 of 42) of the patients with thyroid cancer have remained on treatment, and all 14 patients who received 400 mg/day remain on treatment.

Of 48 patients treated with doses ranging from 30 to 400 mg/day, most of the adverse events were reversible grade 1 events, and there were no grade 4 to 5 adverse events.

In terms of the safety profile of all doses and in all patients in the study (including those with NSCLC; n = 69), most adverse events were grade 1 and there were only two discontinuations for related adverse events, both involving neutropenia.

Treatment-emergent adverse events occurring in more than 15% of patients included decreases in white blood cells (29%) and increases in aspartate aminotransferase (AST, 33%) and alanine aminotransferase levels (ALT, 25%).

Treatment-emergent grade 3 adverse events included decreases in levels of neutropenia/neutrophils (9%), anemia (9%), and hypertension (16%).

"BLU-667 is well-tolerated and demonstrates significant clinical activity in advanced, RET-altered MTC and papillary thyroid cancer regardless of RET-alteration or prior multikinase inhibitor therapy," Hu said.

"What's particularly remarkable is the durable response, with patients remaining on the therapy over 15 months," she noted. "All patients treated initially at the 400 mg/day dose have remained on treatment and responses have increased over time."

LOXO-292 Responses Also Encouraging

In the second study, Lori J. Wirth, MD, associate professor of medicine, Harvard Medical School, and Massachusetts General Hospital Cancer Center, Boston, Massachusetts, presented updated results from the LIBRETTO-001 study of LOXO-292, another highly selective RET inhibitor.

The drug was granted breakthrough therapy designation by the US Food and Drug Administration (FDA) in September.

Wirth reported that, to date, the study has included 38 RET-altered thyroid cancers, including 29 (76%) RET-mutant MTCs and 9 (24%) RET fusion-positive thyroid cancers.

With a 9-month follow-up, the ORR in RET-mutant MTC is 59% and the confirmed ORR is 56%. For RET fusion-positive thyroid cancer, the ORR is 78%.

Wirth noted that all responses initially reported at the American Society of Clinical Oncology (ASCO) 2018 annual meeting in June as being unconfirmed have indeed since been confirmed.

She added that 94% of MTC responses and 100% of fusion-positive thyroid cancer responses are ongoing, and two patients with MTC have shown a complete response.

Patients in the study were heavily pretreated, with the majority having received at least one prior therapy with cabozantinib or vandetanib, and the study included a diverse range of RET mutations.

Many patients responded soon after treatment, and the durability has been strong, Wirth noted.

"Many had responses early on at their first evaluation and we saw others catch-up quickly," she explained.

"Now, with median follow-up of 9 months, the majority of patients remain in response and remain on treatment."

Early declines were observed with carcinoembryonic antigen (CEA) and calcitonin levels, she added.

"There were dramatic early declines and many patients have had their calcitonin levels entirely normalized over time. And we've also seen that with a couple of patients in terms of their CEA levels."

In terms of safety, there were eight treatment-emergent adverse events, mostly grade 1 and deemed not related to LOXO-292, Wirth said.

There were four grade 4 treatment-related adverse events, including diarrhea, increased ALT/AST, thrombocytopenia, and tumor lysis syndrome; however, all were reversible with a dose interruption, Wirth said.

"LOXO-292 demonstrated robust anti-tumor activity in both RET-mutant MTC and RET fusion-positive thyroid cancer...We are seeing significant, long-lasting durability in terms of response with this drug," she emphasized.

Findings a Reminder That "It's an Exciting Time to Be in Medicine"

Although MTC is a rare cancer, there is much interest in the RET-inhibitors as patients seek alternatives to current therapies that are notorious for their toxicities, Gary Clayman, MD, of the Clayman Thyroid Center, Thyroid and Parathyroid Institute, Tampa General Hospital, Florida, told Medscape Medical News.

"Only about 3% of all thyroid cancers are medullary thyroid cancers, but the clinical trials are filling up because patients are waiting in the wings for the next best agent," he said.

"The problem with currently approved systemic therapies is they're all toxic, and there are no curative therapies — they're all maintenance therapies. Patients do have responses, but those are not durable unless you maintain therapy, so anyone who starts these drugs is essentially committed to life-long therapy, with occasional potential breaks — that's a pretty significant burden."

"But the new therapies are not nearly as toxic and the response rates are very exciting and very durable. So this is good news," he observed.

Although the RET inhibitors show great promise, Clayman said he is nevertheless looking forward to the agents that could ultimately prevent the need for surgery.

"We see that technology and informatics have greatly improved our ability to move things through and increase our understanding of these cancers, so it's an exciting time to be in medicine."

"But controlling the disease in the neck is of paramount importance. I look forward to the therapies that will respond so greatly that surgery will no longer play a role, and I think that eventually should happen, at least in MTC."

The ARROW study is sponsored by Blueprint Medicines. LIBRETTO-001 is sponsored by Loxo Oncology/Bayer. Hu has reported relationships with Blueprint Medicines, Eisai, and Genzyme. Wirth has reported relationships with Ayala, Bayer, Eisai, Loxo Oncology, and Merck. Clayman has reported no relevant financial relationships.

2018 Annual Meeting of the American Thyroid Association. October 5, 2018; Washington, DC. Abstracts Short Call Oral 5 and 6.

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