The RET inhibitor Eli Lilly picked up in its Loxo Oncology buyout continues to deliver. On the heels of an encouraging performance in lung cancer, the drug shrank tumors in more than half of patients with a rare thyroid cancer who had already tried at least two kinase inhibitors.
The phase 1/2 data, presented Sunday at the annual meeting of the European Society for Medical Oncology, show that the drug shrank tumors in 56% of 55 patients with RET-mutant medullary thyroid cancer (MTC), who had been treated with Sanofi Genzyme’s Caprelsa (vandetanib) and/or Exelixis’ Cabometyx (cabozantinib).
As of the data cutoff date, the study had followed the patients for a median of 11 months, at which point, about one-third of the patients saw their disease worsen. But not enough had worsened to report a figure for median progression-free survival.
“We followed a pretty heavily pretreated group for close to a year. To be shy of 50% of progression events—we are pretty proud of that. It’s shaping up to be pretty good,” Jake Van Naarden, COO of Loxo Oncology, told FierceBiotech.
Unlike thyroid cancer patients with other mutations such as BRAF or NTRK, patients with RET mutations haven’t benefited from a specifically targeted treatment. Caprelsa and Cabometyx are the front-line treatments, but there's nothing approved for patients who relapse after taking one or both of them, Van Naarden said.
“There’s really not a lot for those patients today, so to demonstrate a 56% response rate is a meaningful advance for that patient population, particularly coupled with the safety profile,” Van Naarden said.
The safety data come from all 531 patients enrolled in the LIBRETTO-001 study, including patients with RET-altered non-small cell lung cancer, colon cancer and other types of thyroid cancer. Only nine of the 531 patients (1.7%) quit the study due to treatment-related side effects. The most common side effects were along the lines of dry mouth, headache, diarrhea, constipation, hypertension and an increase in liver enzymes.
Lilly also reported data from 76 patients with RET-mutant MTC who had not received any kind of cancer treatment and 26 “heavily pretreated” patients with RET fusion-positive thyroid cancer—selpercatinib shrank tumors in 59% of patients in the first group and 62% of patients in the second group. The study followed these patients for a shorter period of time, about six months, Van Naarden said. The “vast majority” of patients in both groups haven’t gotten worse, the company said in a statement.
While RET mutations happen in the majority of MTC cases, RET fusions occur in various types of thyroid cancers, including papillary, follicular and anaplastic thyroid cancers. RET-fusion thyroid cancers have a range of treatments, including radioactive iodine, surgery and kinase inhibitors, namely Eisai’s Lenvima (lenvatinib) and Bayer’s Nexavar (sorafenib), which tend to be toxic, too, Van Naarden said.
Selpercatinib would fit differently into care for these two buckets of thyroid cancers. MTC is relatively rare, accounting for about 4% of thyroid cancers, according to the American Cancer Society. RET mutations drive cancer in the majority of MTC cases, so a RET-targeted treatment would de facto be a treatment for all patients with this rare, but difficult-to-treat cancer.
It’s a different conversation with non-medullary thyroid cancers: “They are more molecularly diverse in a way that is helpful to our story. Today, BRAF mutations account for a portion of thyroid cancers; there is a targeted treatment for those. NTRAK fusions account for another portion, and there are approved therapies targeting those. And RET accounts for a portion,” Van Naarden said. “While MTC is heavily RET-driven, other thyroid cancers are more of a pie chart.”
Lilly figures if it can fill out another piece of the pie chart with selpercatinib, more patients and their doctors will want their tumors to be tested to “triage” them to the right treatments, as opposed to what Van Naarden called the “scattershot approach” of the past.
“We’re putting all the datasets together for an NDA submission by the end of the year,” he said. Lilly has breakthrough status for both previously treated RET-fusion thyroid cancers and RET-mutant MTC, as well as in RET-fusion non-small cell lung cancer.