NEW YORK – At the American Society of Clinical Oncology's virtual annual meeting last week, Blueprint Medicines said that its RET-targeting drug pralsetinib continued to show encouraging activity across a range of RET fusion-positive solid tumors.
The presentation follows on the heels of the recent approval of Lilly's RET-targeting drug selpercatinib (Retevmo) by the US Food and Drug Administration for three types of cancers: RET fusion-positive non-small cell lung cancer, RET-mutant medullary thyroid cancer, and RET fusion-positive thyroid cancer. Selpercatinib is the first targeted drug approved for cancer patients with RET gene alterations.
Pralsetinib is a RET inhibitor that can target RET alterations, including both RET fusions and RET mutations, regardless of tissue of origin. In pre-clinical trials, the drug selectively targeted RET over other types of kinases.
Vivek Subbiah from MD Anderson Cancer Center presented data from a cohort of the Phase I/II ARROW study of pralsetinib involving patients with a variety of RET fusion-positive solid tumors. In this 27-patient cohort, 13 patients had RET fusion-positive thyroid cancer, and 14 patients had other types of RET fusion-positive tumors, including cholangiocarcinoma, and colon, pancreatic, ovarian, and thymus cancer. Most patients had received another line of therapy.
RET fusions occur in up to 20 percent of papillary thyroid cancers, in up to of 2 percent of non-small cell lung cancers, and less frequently in many other cancer subtypes. CCDC6 was the most common type of RET fusion partner in this cohort, occurring in 46 percent of the RET-fusion positive thyroid cancers, and 29 percent of the other cancer types.
In the study, 91 percent of 11 response-evaluable RET fusion-positive thyroid cancer patients on pralsetinib saw their tumors shrink. Patients started responding two to three months after starting treatment, and all patients achieved disease control in the form of a complete or partial response or stable disease.
In the subset of patients with other types of RET fusion-positive tumors, 12 were evaluable for response. Among them, the overall response rate on pralsetinib was 50 percent and the disease control rate was 92 percent, while 8 percent of patients experienced disease progression on therapy.
Subbiah noted that all patients with pancreatic adenocarcinoma and cholangiocarcinoma responded to the drug. Responses were also seen in patients with thymus tumors and neuroendocrine tumors, which Subbiah said were difficult to treat. "This shows that if the RET fusion is present, it is actionable across tumor types," he said. "When the patients responded, they had a prolonged response as well."
Pralsetinib was well-tolerated in the trial. No new safety signals were reported in this cohort, and no patients discontinued treatment due to adverse events.
The registration-enabling ARROW study is still ongoing and enrolling patients. However, two other cohorts of the ARROW study, one involving RET fusion-positive NSCLC patients and another involving RET-mutated medullary thyroid cancer patients, have already reported out high response rates. Around three fourths of treatment-naïve patients in both of these cohorts saw their tumors shrink on pralsetinib, while around 60 percent of previously treated patients did.
Subbiah said that after the data was submitted for primary analysis and presentation at ASCO in February, patients with other types of cancers outside of those documented in this dataset tested positive for RET fusions and were enrolled into the trial. Some patients had extremely rare cancers like microcystic adnexal cancer.
"We need to genomically test all patients with cancer and look for these RET alterations," Subbiah proposed.
Regulatory, market entry plans
Meanwhile, the emerging data from the different cohorts of the ARROW study is helping pralsetinib's sponsor Blueprint Medicines steadily advance the drug through regulatory channels in different indications.
Blueprint CEO Jeff Albers said during a call with investors last week that the company's new drug application for pralsetinib in RET fusion-positive NSCLC was accepted by the FDA, and the company is expecting a decision by Nov. 23. The European Medicines Agency also accepted the company's marketing authorization application in the same indication.
Blueprint CMO Andy Boral said that the firm found it particularly encouraging that there was a 33 percent complete response rate in the central nervous system metastases of these NSCLC patients. The responses were durable, and no patients with a CNS response experienced further CNS progression.
Additionally, the company plans to file a new drug application for pralsetinib in RET-mutant and RET fusion-positive thyroid cancers in June.
Outside of the ARROW trial, Blueprint is also running a Phase III trial in RET fusion-positive treatment-naïve NSCLC patients. The trial will randomize pralsetinib against platinum-based chemotherapy with or without pembrolizumab (Merck's Keytruda).
Then, in the second half of 2020, the company will initiate a randomized Phase III trial for patients with RET fusion-positive medullary thyroid cancer. The trial will compare pralsetinib against multikinase inhibitors cabozantinib or vandetinib.
Boral said during the call that pralsetinib could be an additional option for RET-altered patients who might not tolerate the recently approved selpercatinib. He noted Blueprint recently enrolled a patient who had come off selpercatinib due to an adverse event and progressive disease. At the first assessment after receiving pralsetinib, the patient appeared to already be responding.
Boral also presented examples highlighting pralsetinib's activity in patients with acquired resistance mutations. Boral said that in EGFR-driven lung cancer treated with osimertinib (AstraZeneca's Tagrisso) and other covalent inhibitors, resistance was found to mediated by a RET inhibitor.
"RET is a mechanism of resistance in osimertinib. In a few cases, we've shown that the combination of pralsetinib with osimertinib can be highly active in that setting and well tolerated," said Boral.
Chrissy Ross, CCO of Blueprint, said during the call that even though pralsetinib is projected to enter the market three months after Lilly's selpercatinib, she doesn't believe this will give Lilly a huge first-to-market advantage.
"This is still a very rare mutation in a common patient population. When you see first-to-market advantages play out is where physicians amass a ton of experience with a new agent quickly, and then it becomes embedded. That dynamic is just not at play here given the frequency of RET patients," said Ross. "We've gotten feedback that [physicians] intend to utilize both [pralsetinib and selpercatinib]. They will gain that clinical experience and see what they're comfortable with."
At ASCO, Turning Point Therapeutics also presented preclinical data on its RET and SRC kinase inhibitor TPX-0131. Turning Point stated that inhibition of the SRC family of kinases has the potential to reduce bypass resistance and increase the therapeutic effect of TPX-0046. Across in vivo and in vitro studies, TPX-0046 was active across a range of RET mutations and fusions, including selpercatinib resistance mutations in RET G810.
TPX-0131 is designed to be a next-generation RET inhibitor for RET-altered patients who have not been previously treated with a tyrosine kinase inhibitor and for patients who have become resistant to prior RET inhibitor treatment. The drug is being studied in an ongoing Phase I/II trial in patients with RET-altered solid tumors.