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BLU-667 active, safe in RET fusion-positive non-small cell lung cancer
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CHICAGO — BLU-667 induced durable antitumor responses with manageable toxicity among patients with advanced RET fusion-positive non-small cell lung cancer, according to updated results of the ongoing ARROW study presented at ASCO Annual Meeting.
“Genetic alternations in the RET receptor tyrosine kinase drive the pathogenesis of various solid tumors, including lung cancer, thyroid cancers and multiple other tumor types,” Justin F. Gainor, MD, director of targeted immunotherapy at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, said during the presentation. “RET rearrangements generate oncogenic RET fusion proteins that are found in approximately 1% to 2% of non-small cell lung cancers. There are currently no FDA-approved selective RET inhibitors.”
BLU-667 (Blueprint Medicines), a highly potent selective RET inhibitor, targets oncogenic RET alterations, including those that are resistant to multikinase inhibitors.
The registration-enabling ARROW study includes 79 patients with advanced RET fusion-positive NSCLC who received BLU-667 at 30 to 600 mg once or twice per day (n = 21) or at the recommended phase 2 dose of 400 mg per day (n = 58).
Patients underwent a median of two (range, 0-8) prior therapies, including chemotherapy (76%), immunotherapy (41%) and multikinase inhibition (27%). Thirty-nine percent of patients had brain metastases at baseline.
Overall response rate and safety served as the study’s primary endpoints.
Results among 57 response-evaluable patients with measurable disease and at least one follow-up disease assessment showed an ORR of 56% (95% CI, 49-62), including 32 partial responses, nine partial responses pending confirmation, 20 patients with stable disease and five patients with progressive disease.
Of the 32 patients who achieved a partial response, 29 (91%) remained on treatment and six achieved a response duration of 6 months or longer.
Researchers reported a disease control rate of 91%.
The ORR among 30 patients who received the recommended phase 2 dose of BLU-667 after prior treatment with platinum chemotherapy was 60%, including 18 partial responses, seven of which were pending confirmation.
Responses occurred regardless of prior treatment or RET fusion genotypes, and researchers observed intracranial activity with shrinkage of brain metastases.
Most patients (80%) with NSCLC who received the recommended phase 2 dose remained on treatment at the time of the update, with only 3% discontinuing because of treatment-related adverse events.
Treatment-related toxicities among patients with NSCLC were mostly low-grade and reversible, including increased aspartate aminotransferase (22%), hypertension (18%), increased alanine aminotransferase (17%), constipation (17%), fatigue (15%) and decreased neutrophils (15%).
“BLU-667 demonstrates broad and durable antitumor activity in patients with RET fusion-positive lung cancer,” Gainor said. “This drug has FDA breakthrough therapy designation in RET fusion-positive NSCLC that progressed following platinum-based chemotherapy. Data support expansion of ARROW trial in treatment-naive [patients with] NSCLC and continued enrollment of other RET-altered solid tumor groups.” – by John DeRosier
Reference:
Gainor JF, et al. Abstract 9008. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Gainor reports consultant/advisory roles with Agios, Amgen, Array BioPharma, Bristol-Myers Squibb, Genentech, Jounce Therapeutics, Loxo Oncology, Merck, Oncorus, Regeneron, Takeda and Theravance; honoraria from Ariad Pharmaceuticals, Incyte, Merck, Novartis, Pfizer and Takeda; and research funding from Adaptimmune, Alexo Therapeutics, Ariad Pharmaceuticals, Array BioPharma, AstraZeneca, Blueprint Medicines, Bristol-Myers Squibb, Genentech, Jounce Therapeutics, Merck, Moderna Therapeutics, Novartis and Tesaro. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Jorge Nieva, MD
The great thing about targeted agents is that they tend to work.
Whenever we compare targeted therapies with chemotherapies for patients with actionable mutations, we generally find that these drugs provide good responses. The RET population in lung cancer is a particularly difficult population. A number of multikinase inhibitors have been used for these patients in the past, and although a high proportion respond, those responses tend to be short-lived.
The BLU-667 data replicates this experience and demonstrates that although we are very good at achieving responses in RET-fusion lung cancer, the duration of response is often low. In the clinical abstract presented by Dr. Gainor, only six patients had responses that lasted more than 6 months.
We need to go back to the laboratory to understand the fundamental biology that leads to resistance for these difficult tumor types. It may require a second drug to make these responses more durable, and I suspect that someday we will find a combination of therapeutics that prevents the early onset of resistance to RET-driven cancers.
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