CHICAGO — Point mutations or gene rearrangements in the receptor tyrosine kinase proto-oncogene RET have been seen in several tumors, including medullary thyroid carcinoma (MTC) and non–small cell lung cancer (NSCLC). However, there are no approved targeted therapies against RET — as yet.
A new agent has now shown activity in a first-in-human study. The product, BLU-667 (from Blueprint Medicines), an oral RET-tyrosine kinase inhibitor, achieved objective response rates (ORR) in about 50% of patients with a variety of tumors.
The new results, which come from the ARROW study, were reported here at the American Association for Cancer Research (AACR) 2018 Annual Meeting and were simultaneously published online in Cancer Discovery.
“Current therapies for RET-altered cancers are restricted to multikinase inhibitors and chemotherapy, which are nonspecific and display significant off-target toxicity. In an effort to revolutionize treatment for these cancers, BLU-667 was designed to specifically target oncogenic RET fusions and activating mutations,” study presenter Vivek Subbiah, MD, said at a press conference.
“BLU-667 potently inhibits RET-driven tumors with subnanomolar potency compared with dirty multikinase inhibitors,” Subbiah said.
Subbiah is assistant professor in the department of investigational cancer therapies and is associate medical director of the Clinical Center for Targeted Therapy at the University of Texas MD Anderson Cancer Center in Houston.
Study Details
The clinical study was initiated after preclinical work had shown that BLU-667 potently inhibited RET in several RET-driven cancers. In addition, this activity was 100 times more selective for the RET kinase than it was for hundreds of other human kinases tested, he pointed out.
Noteworthy, it was a potent inhibitor of gatekeeper mutations, which were associated with resistance to multikinase tyrosine kinase inhibitor (TKI) therapies.
The ARROW study enrolled 49 patients with unresectable, advanced solid tumors ― 29 with MTC, 19 with NSCLC, and one with paraganglioma.
RET fusions were predominant ― seen in 63% of NSCLC patients and 72% of MTC patients. Patients were treated with BLU-667 in doses ranging between 30 mg/day to 400 mg/day. A maximally tolerated dose (MTD) has not been reached, and dose escalation continues. “Dose expansion is open and enrolling globally,” Subbiah said.
At doses ≥60 mg/day, BLU-667 showed broad antitumor activity across multiple RET tumors. Radiographic tumor reductions ranged between 2% to 70% in 83% of patients with RET-driven tumors.
Of 40 patients evaluable for response, complete response was seen in one patient (3%), partial responses were seen in 17 patients (43%), and stable disease was reported in 20 patients (50%). The objective response rate (ORR) was 46% in the overall patient group. ORR in RET-fusion NSCLC was 50%; in RET-mutant medullary thyroid cancers, it was 40%.
Most toxicities were of grade 1 and included constipation (23%), increases in liver enzyme level (16%), and diarrhea (14%). Fatigue, creatinine kinase increase, increases in white blood counts, and hypertension also occurred (12% each). Three dose-limiting toxicities were associated with a grade 3 increase in alanine transaminase increase level (one case), grade 3 tumor lysis syndrome (one case), and grade 3 hypertension (one case).
Ten patients discontinued treatment — six because of disease progression, two because of drug-related toxicities, and one because of death (not drug related).
Of 51 patients with RET-altered tumors, 41 remain on treatment. Clinical activity was seen in patients who had failed prior therapy with multikinase inhibitors.
“This ongoing phase 1 study has shown proof-of-concept of this selective RET inhibitor,” Subbiah said in an AACR statement. “Although it’s very early in clinical testing, we observed promising antitumor activity in NSCLC and MTC,” he said.
To make his point, he shared case studies of patients with RET-driven tumors who showed remarkable response to BLU-667. “This is what wakes up a phase 1 investigator in the morning,” he said.
One of the first patients to enroll in the ARROW study was a 27-year-old male patient with sporadic highly invasive MTC harboring multiple RET mutations. Prior to starting BLU-667, the patient was naive to treatment with TKIs. The highly invasive disease required emergency tracheostomy and extensive surgery. The postoperative course was complicated by chylothorax. The multidisciplinary team decided against radiotherapy to the neck. Restaging showed extensive disease as well as lung and liver metastases. Treatment with vandetanib and cabozantinib was not considered appropriate, owing to a risk for impaired wound healing and risk for hemorrhage. The patient was enrolled on the BLU-667 clinical trial and began treatment at the second dose level (60 mg QD). After only 28 days of BLU-667 therapy, there was a >90% reduction in the serum tumor marker, calcitonin. After 8 weeks, target lesions were reduced by 19%. After successive dose escalations of BLU-667 to 200 mg QD, the patient achieved partial response with >30% tumor reduction. Dose was escalated to 300 mg QD, and the patient achieved a partial response at 10 months. Carcinoembryonic antigen levels decreased by 57%. Improved health status allowed for removal of the tracheostomy tube and a return to baseline body weight after weight loss of several kilograms prior to treatment. BLU-667 has been well tolerated throughout 11 months of continuous treatment. There has been only drug-related adverse event, a transient grade 1 decrease in white blood cells, which resolved without druginterruption or dose modification. This patient remains on therapy with BLU-667, Subbiah noted.
Another case that Subbiah recounted was that of a 74-year-old man with KIF5B–RET NSCLC, who presented in a wheelchair. The patient had experienced disease progression with two lines of chemotherapy. He proceeded to receive therapy with vandetinib and everolimus, but disease progressed at 8 months. He enrolled in ARROW and started on BLU-667 at 300 mg. The dose was then escalated to 400 mg. Within 3 months, the patient was up and walking. “Now he can walk the stretch of the Altlanta airport,” Subbiah said. At 5 months, he has achieved a partial response (pending confirmation).
Subbiah concluded that BLU-667 showed a broad activity regardless of tumor type, genotype, prior treatment history, and number of prior therapies.
Subbiah also noted that precision targeted therapy with RET inhibition can have a powerful impact for patients whose cancer is induced by these oncogenic drivers, even in early clinical trial testing. “I encourage all cancer patients to undergo genomic testing, as tumors with rare genomic aberrations may have effective drugs that are in clinical trials that could be beneficial to them,” he said.
Commenting on the study, Alexander Drilon, MD, clinical director of early drug development at the Memorial Sloan Kettering Cancer Center, New York City, asked whether older drugs “should now RETire in light of data from the ARROW study.”
He noted that therapies against RET-driven tumors have centered around repurposing multikinase TKIs, such as cabozantinib (Carbometyx, Exelixis), vandetanib (Caprelsa, Sanofi Genzyme), lenvatinib (Lenvima, Eisai), and alectinib (Alecensa, Genentech).
“Currently, only LOXO-292 and BLU-667 are rationally designed to more optimally inhibit RET,” Drilon said.
Drilon commented that the responses seen with BLU-667 in patients with NSCLC and thyroid cancers are similar to those previously seen with cabozantinib and vandetinib, but these “older drugs can result in toxicity. BLU-667 is more tolerable, with only 16% of patients showing grade 3 or 4 toxicity.”
He noted that 1 of 49 patients reported a tumor lysis syndrome. “This is possibly due to the exquisite sensitivity of the drug,” Drilon said.
It is important to learn why some patients did not respond and also to learn about the the mechanism of resistance that emerges with BLU-667.
It will also be interesting to see progression-free survival results and to explore the central nervous system activity with BLU-667, he said. That will help to provide a better picture of how the new drug compares with the older multikinase inhibitors.
However, in terms of toxicity, BLU-667 is already a winner, he noted.
The study is sponsored and managed by Blueprint Medicines. Dr Subbiah receives research funding for clinical trials from Blueprint Medicines, Novartis, Bayer, GSK, Nanocarrier, Vegenics, Northwest Biotherapeutics, Boston Biomedical, Berghealth, Incyte, Fujifilm, PharmaMar, D3, Pfizer, Multivir, Amgen, AbbVie, LOXO, Roche/Genentech, NCCN, and NCI-CTEP. Dr Drilon reports associations with TP Therapeutics, Ignyta, Loxo, Roche, and Astra-Zeneca.
American Association for Cancer Research (AACR) 2018 Annual Meeting: Abstract CT043, presented April 15, 2018.
Cancer Discov. Published online April 15, 2018. Abstract
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