Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of pazopanib (GW786034)

To the editor:

Vascular endothelial growth factor (VEGF) stimulates plasma cell proliferation and migration in vitro, and preclinical studies have demonstrated that these effects can be blocked by inhibition of VEGF receptors (VEGFRs) in multiple myeloma (MM) cell lines.¹  Pazopanib (GW786034), an oral angiogenesis inhibitor targeting VEGFR, platelet-derived growth factor receptor (PDGFR), and c-Kit, has demonstrated antitumor activity in clinical studies in patients with renal cell carcinoma (RCC), ovarian and related cancers, and soft tissue sarcoma (STS).^2-5  In preclinical models, the in vivo activity of pazopanib was dependent on achievement of a steady-state concentration of at least 40 μM (∼ 17 500 ng/mL).⁶  A similar steady-state trough plasma concentration (15 000 ng/mL) was associated with biologic and clinical effects after administration of pazopanib in a phase 1 study in patients with solid tumors.² 

This phase 2 study was conducted to evaluate the safety and efficacy of pazopanib (800 mg daily) in adult patients with relapsed and refractory MM. Eligible patients had measurable levels of M-protein (urine or serum). The primary objectives of the study were clinical efficacy (tumor response rate [RR]), safety, and tolerability. Secondary objectives included time to tumor progression (TTP), time to response, duration of response, pharmacokinetic (PK) profile, and effects of pazopanib on biomarkers of angiogenesis. Approval for these studies was received from each institution's Institutional Review Board and informed consent was obtained in accordance with the Declaration of Helsinki.

Twenty-one patients received at least 1 dose of pazopanib, with duration of treatment ranging from 1 to 279 days and a median exposure of 64 days. Two patients were excluded from the efficacy analysis: 1 patient violated study eligibility criteria and was withdrawn after receiving 1 dose of pazopanib; a second patient experienced an adverse event (AE) and was withdrawn before the first scheduled disease assessment. All patients had received extensive prior systemic therapy (see Table 1 for patient characteristics).

Sixteen (76%) patients received pazopanib 800 mg throughout the study; median exposure of these patients to treatment was 64 days (range, 1-279 days). Nausea, fatigue, and hypertension were the most frequently reported drug-related AEs. Hypertension was reported as an AE for 6 (29%) patients (grade 1 /2); 5 were considered drug-related. Patients were considered evaluable for efficacy if they completed 6 weeks of treatment and had at least 2 clinical assessments or, if they experienced disease progression, within the first 6 weeks. Nineteen patients were evaluable for efficacy. No patients achieved a partial or complete remission. At the time of the first response assessment at week 6, 9 patients had no change, and 10 patients had progressive disease at or before week 6. Median TTP was 52 days (range, 14-274 days in 15 patients for whom progression data were available). Because no clinical responses were observed, the study was terminated per protocol design.

Plasma pazopanib C₂₄ values in 7 of the 11 patients with available PK data were similar to the target concentration (17 500 ng/mL) that has demonstrated anti-VEGF effects in preclinical models.¹⁹ The lack of efficacy observed in patients with MM in this study is therefore unlikely to be attributed to low plasma pazopanib concentrations. Moreover, in this study, patients demonstrated “clinical pharmacodynamic effects” of effective tyrosine kinase targeting as evidenced by hair depigmentation and hypertension.^7,8  The lack of activity of pazopanib in patients with MM may therefore be attributed to the intrinsic biology of the disease. It is noteworthy that the preclinical evaluation of pazopanib in MM demonstrated cytotoxicity only in xenograft models lacking human cytokines. The results of this trial are consistent with data from earlier trials of VEGFR inhibitors (SU5416 and ZD6474) in MM, which also failed to produce any meaningful clinical responses with single-agent regimens.^9,10  Thus, further attempts at VEGF inhibition in MM patients should be approached with caution and need to be based on a strong rationale.