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.”
Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis, commented on the results: “Exelixis is committed to working with independent investigators, and with our collaborators at the National Cancer Institute’s Cancer Therapy Evaluation Program, to fully evaluate cabozantinib’s potential in a variety of disease settings beyond our company-sponsored pivotal trials in renal and liver cancers. The data in RET-rearranged NSCLC are compelling, and we look forward to discussing with our collaborators potential next steps for cabozantinib in this setting.”
Study Design
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.
Study Results
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]).
About Cabozantinib
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 U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).
The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.
Important Safety Information, including Boxed WARNINGS
WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE
- Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.
- Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.
- COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.
- Wound complications have been reported with COMETRIQ.
- COMETRIQ treatment results in an increase in hypertension.
- Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.
- Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.
- The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.
- Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.
- Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.
- COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.
- COMETRIQ can cause fetal harm when administered to a pregnant woman.
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.
Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf. Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted.
About Exelixis
Exelixis, Inc. is a biopharmaceutical company committed to developing small molecule therapies for the treatment of cancer. Exelixis is focusing its development and commercialization efforts primarily on COMETRIQ® (cabozantinib), its wholly-owned inhibitor of multiple receptor tyrosine kinases. Another Exelixis-discovered compound, cobimetinib, a highly selective inhibitor of MEK, is being evaluated by Roche and Genentech (a member of the Roche Group) in a broad development program under a collaboration with Exelixis. For more information, please visit the company’s web site at www.exelixis.com.
SOURCE: Exelixis
