To the editor:
Despite the introduction of proteasome inhibitors and immunomodulatory drugs followed by autologous stem cell transplant, most patients with multiple myeloma (MM) will have disease recurrence after primary therapy. Thus, agents with different mechanisms of action and different targets need to be explored. We conducted a phase 1B study of cabozantinib in patients with relapsed and/or refractory MM (NCT01866293). Cabozantinib is a small-molecule inhibitor of multiple receptor tyrosine kinases implicated in tumor growth and neoangiogenesis. The primary targets of cabozantinib are hepatocyte growth factor (HGF) receptor protein, vascular endothelial growth factor receptor 2, and RET.1 HGF and HGF receptor protein (MET) have been implicated in myeloma pathogenesis based on the observation that elevated HGF levels are associated with worse prognosis2-4 and lack of response to chemotherapy.5,6 In addition, MM cells express HGF, creating a putative autocrine HGF/MET loop.7-9 In vitro models demonstrated myeloma cell growth inhibition through MET or HGF inhibition.10,11
Here, we report our experience with single-agent cabozantinib. Two phase 1 studies were conducted, one at Memorial Sloan-Kettering Cancer Center (MSK; NCT01866293) and one at Massachusetts General Hospital Cancer Center (MGH; NCT01582295). The design of the studies was the same, as was the starting dose. The research studies were approved by the MSK and MGH institutional review boards, and all participants gave written informed consent. Eligible patients received cabozantinib orally as a tablet daily on a 28-day cycle. The trials had a standard 3-by-3 dose-escalation design, with 3 daily dose levels (dose level −1, 20 mg; dose level 1, 40 mg; and dose level 2, 60 mg). Patients were assessed for safety every 2 weeks during the first 3 cycles at MSK and weekly at MGH. Myeloma response was assessed by International Myeloma Working Group criteria after each cycle. The dose-limiting toxicity (DLT) evaluation period was 6 and 4 weeks at MSK and MGH, respectively. Major eligibility criteria included MM that was relapsed or refractory after therapy with at least 1 immunomodulatory drug and at least 1 proteasome inhibitor, as well as adequate bone marrow reserve (defined as ANC ≥1500/mm3 [MSK] or ≥1000 [MGH], platelets ≥50 000/mm3, bilirubin ≤1.5 times the upper limit of normal, and serum creatinine ≤ 1.5 times the upper limit of normal or calculated creatinine clearance ≥50 mL/min [MSK] or ≥ 45 mL/min [MGH]). Patients requiring therapeutic anticoagulation or with a recent history of pulmonary or gastrointestinal bleed or with cavitating pulmonary lesions or major surgery were excluded.
Nine patients received treatment with cabozantinib at MSK and 3 at MGH. Patient characteristics are as shown in Table 1. The initial starting dose was 40 mg daily. In the initial cohort of 3 patients at MSK, 1 DLT was observed (congestive heart failure in a patient with a history of congestive heart failure). Therefore, 3 additional patients were treated at the 40 mg dose level. Because no further DLT was observed at the 40 mg dose level, 3 patients were treated at dose level II (60 mg daily). Three patients were treated at the initial dose level of 40 mg at MGH. No DLTs were observed.
Table 1.
Patient characteristics (n = 12)
| n (%) | |
|---|---|
| Median age (range), y | 64 (53-76) |
| Female | 7 (58%) |
| High-risk cytogenetics | 6 (50%) |
| Median prior lines of therapy (range) | 3 (1-7) |
| Prior proteasome inhibitor | 12 (100%) |
| Prior carfilzomib | 6 (50%) |
| Prior IMiD | 12 (100%) |
| Prior pomalidomide | 2 (17%) |
| Double refractory (to PI and IMiD) | 7 (58%) |
| Prior high-dose melphalan with stem cell rescue | 9 (75%) |
IMiD, immunomodulatory drug; PI, proteasome inhibitor.
The median time on therapy was 61 days (range, 14-128). Best responses for all patients were 1 minimal response, 8 stable disease, and 2 progression of disease. One patient was inevaluable for response, having experienced a DLT prior to completing the first cycle of therapy. There were 2 serious adverse events (AEs; 1 grade 2 congestive heart failure and 1 grade 3 PNA) felt to be possibly cabozantinib related. Most other nonhematologic AEs were primarily gastrointestinal and were mostly grade 1 or 2 and included diarrhea (67%, grade 3 in 1 patient), abdominal pain/bloating (25%), nausea/anorexia (50%), dysgeusia (17%), alanine aminotransferase/aspartate aminotransferase elevation (89% and 58%, respectively), and lipase/amylase elevation (42% and 25%, respectively). Hyperglycemia (75%, grade 3 in 2 patients), hypocalcemia (42%), hypomagnesemia (33%), and hypophosphatemia (33%, grade 3 in 1 patient) were also commonly noted. Less frequently seen grade 1/2 treatment-emergent AEs thought to be possibly due to cabozantinib included dyspnea (42%), hoarseness (25%), palmar-plantar erythrodysesthesia syndrome (17%), hypopigmentation (17%), and grade 2 neuropathy in 1 patient. Grade 3 hematologic AEs were anemia (2 patients), lymphopenia (4 patients), neutropenia (2 patients, grade 4 in 1 patient).
The reasons for discontinuation of therapy were DLT in 1 patient, progression of disease in 7 patients, and withdrawal of consent in 4 patients. MTD was not reached. However, given the lack of activity, the fact that 4 patients withdrew consent due to toxicities, and considering the impact of the grade 1-2 toxicities on our patients’ quality of life, it was thought that exploring higher dose levels was not warranted.
We conclude that cabozantinib does not have significant single-agent activity in patients with relapsed and/or refractory MM. HGF levels at the time of study entry were not available in these patients; therefore, this study does not exclude the possibility that cabozantinib may have activity in myeloma patients with higher levels of HGF or where disease is driven by HGF.
Authorship
Acknowledgments: This study was supported by research funding from Exelixis (S.G.).
Contribution: S. G., N.L., S.M.D., A.J.Y., and N.S.R. designed the studies; I.T. and A.A. collected the data; N.L, A.J.Y., H.H., N.K., A.M.L., H.L., S.M., G.K., D.J.C., O.L., N.S.R., and S.G. participated in the clinical care of the patients and critically read the manuscript; and N.L. and A.J.Y. wrote the manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Sergio Giralt,1275 York Ave, Box 235, New York, NY 10065; e-mail: giralts@mskcc.org.
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