-- Study met its primary endpoint with a 38% objective response rate
“Constitutive activation of receptor tyrosine kinases by mutation or rearrangement is an oncogenic event in a substantial proportion of patients with non-small cell lung cancer (NSCLC), and includes the activation of RET by gene rearrangement in about 1-2% of patients with adenocarcinoma histology,” said Dr. Drilon, the study’s principal investigator. “Cabozantinib is an active therapy in RET-rearranged lung cancers, as demonstrated by the durable objective responses observed in the first stage of this study. While this trial continues to accrue patients to complete its second stage, it has already met its primary endpoint. Further investigation is clearly warranted.”
This single-institution, open-label phase 2 trial evaluates cabozantinib in patients with advanced RET-rearranged NSCLC, including the KIF5B-RET fusion, the most common rearrangement. Eligible patients must have stage IV lung cancer (with RET rearrangement confirmed by break apart fluorescence in situ hybridization and/or next generation sequencing), Karnofsky Performance Status greater than 70 percent, and measurable disease per RECIST 1.1. Patients receive 60 mg daily cabozantinib in 28-day cycles until disease progression or unacceptable toxicity.
The trial is designed to enroll a maximum of 25 patients in two stages. The first stage of the trial, the subject of today’s data presentation, enrolled 16 patients, and one partial response was required to expand the trial into its second stage that will enroll an additional nine patients.
The primary endpoint of the trial is ORR, with five partial responses (PRs) required to meet the endpoint. Secondary endpoints include response rate at 12 weeks, progression-free survival (PFS), overall survival (OS), and toxicity.
At the time of data cut-off, 20 patients had been treated and 18 were evaluable. Data were presented for the 16 patients enrolled in the first stage of the trial. The median age for patients in the first stage of the trial was 59 (range 38-80 years), and 62 percent (10/16) of these were female. All patients in the first stage had adenocarcinoma, the median number of prior lines of chemotherapy was 1, and 31% of patients had received ≥ 2 lines of prior chemotherapy.
Sixteen patients from the first stage of the trial were evaluable for tumor response. ORR, the primary endpoint of the trial, was 38%, with six confirmed PRs recorded. The median duration of response was 8 months (range 5.5-26 months) including one patient with a confirmed partial response who remained on treatment more than 25 months. One patient with a best response of stable disease remained on cabozantinib treatment for more than 21 months. ORR at 12 weeks, a secondary endpoint, was 36%, with five confirmed PRs recorded among the 14 patients evaluable at 12 weeks.
PFS and OS are secondary endpoints. The median PFS was 7 months (95% CI 5-NA). The median OS was 10 months (95% CI 8-NA) with a median follow-up of 24 months.
Grade 3 adverse events deemed related to study drug by the investigators were thrombocytopenia (19%), increased lipase (13%), increased AST, hypophosphatemia, fatigue, oral mucositis, palmar plantar erthrodysesthesia, hypertension, and retroperitoneal hematoma (all 6%). Half of the patients (8/16) experienced one dose reduction to 40 mg during the course of therapy, with 19% (3/16) reducing to 20 mg daily. One patient discontinued therapy secondary to a grade 3 retroperitoneal hemorrhage, and there was one death unrelated to drug (grade 5 respiratory failure [post-thoracentesis]).
Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGFRs and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.
COMETRIQ® (cabozantinib) is currently approved by the
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WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE
Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.
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This press release contains forward-looking statements, including,
without limitation, statements related to: future data presentations for
the phase 2 IST evaluating cabozantinib in patients with advanced
RET-rearranged lung cancers; potential future evaluation of cabozantinib
in NSCLC; the continued development and clinical, therapeutic and
commercial potential of, and opportunities for, cabozantinib in a
variety of disease settings; and Exelixis’ commitment to working with
independent investigators and collaborators at the National Cancer
Institute’s Cancer Therapy Evaluation Program to evaluate such potential
and discuss the potential next steps for cabozantinib in NSCLC. Words
such as “will,” “continues,” “further,” “committed,” “potential,” “look
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projections. Forward-looking statements involve risks and uncertainties.
Exelixis’ actual results and the timing of events could differ
materially from those anticipated in the forward-looking statements as a
result of these risks and uncertainties, which include, without
limitation: the availability of data at the expected times; risks
related to the potential failure of cabozantinib to demonstrate safety
and efficacy in clinical testing; the clinical, therapeutic and
commercial value of cabozantinib; the uncertain timing and level of
expenses associated with the development of cabozantinib; Exelixis’
ability and the ability of its collaborators to conduct clinical trials
of cabozantinib sufficient to achieve a positive completion; market
competition; changes in economic and business conditions; and other
factors discussed under the caption “Risk Factors” in Exelixis’
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Susan Hubbard, 650-837-8194
Investor Relations and Corporate Communications
For Exelixis, Inc.
Hal Mackins, 415-994-0040