Abstract P6-10-01: A randomized phase 2 study of the antibody-drug conjugate CDX-011 in advanced GPNMB-overexpressing breast cancer: The EMERGE study

Abstract

Background: GPNMB is an internalizable transmembrane glycoprotein overexpressed in multiple tumor types, including breast cancer (BC). GPNMB promotes BC metastases in a murine model and is a poor prognostic marker in patients (pts) (Rose 2010). CDX-011 (glembatumumab vedotin) is a fully human GPNMB-specific monoclonal antibody conjugated to the potent cellular toxin MMAE via a protease-sensitive peptide linker, designed to cleave upon cellular internalization. In Phase I/II studies of CDX-011 in BC (n = 42), an objective response rate (ORR) (including confirmed and unconfirmed response) of 12% overall and 20% for “triple-negative” (ER/PR/HER2−; TN) pts was observed (Saleh, ASCO 2010). Methods: The Phase II EMERGE study examined the efficacy of CDX-011 by level of GPNMB expression. Refractory BC (2–7 prior cytotoxic regimens in metastatic setting), GPNMB expression in ≥ 5% of tumor or stroma cells (as centrally determined on archival tumor), and no persistent treatment-related toxicity (including neuropathy) of ≥ Grade 2 severity were required for enrollment. Pts were stratified by GPNMB expression pattern (any tumor, low stromal or high stromal) and randomized 2:1 to CDX-011 (1.88 mg/kg IV q 21 days) or “investigator's choice” (IC) single-agent chemotherapy, and treated until progression (PD) or intolerance with IC pt crossover permitted to CDX-011 at PD. Endpoints: ORR (primary), progression-free survival (PFS), safety, pharmacokinetics, pharmacodynamics. Results: 99% of screened tumor samples expressed GPNMB. 122 treated pts (81 CDX-011 vs. 41 IC) had median age = 56 vs. 56 years; median # prior anticancer regimens = 6 vs. 5; visceral disease (liver/lung) = 83% vs. 80%; TN = 33% vs 27%, respectively. To date, 15 IC pts have crossed over to CDX-011, and 14 pts (8 CDX-011, 6 IC) continue on treatment. CDX-011 was well tolerated with less hematologic toxicity than IC; CDX-011-related toxicity included rash (overall = 38%; Grade 1 = 20%; Grade 2 = 15%; Grade 3 = 3%) and neuropathy (overall = 18%; Grade 1 = 8%; Grade 2 = 7%; Grade 3 = 2%). Conclusions: CDX-011 was a well-tolerated and active agent in this heavily pre-treated BC pt population. Preliminary analysis of the EMERGE study demonstrates enhanced activity of CDX-011 in TN as well as high GPNMB expressing BC tumors, confirming that CDX-011 is a targeted agent. This noted promising activity in advanced TN and hGPNMB enriched pt populations warrants further evaluation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-01.

Glycoprotein non-metastatic b (GPNMB): A metastatic mediator and emerging therapeutic target in cancer

“…In these studies, development of a skin rash was one of the most common side effects experienced by melanoma (57%) and breast cancer patients treated with CDX-011 (48%, 47%) 103,104,107. This finding was of great interest, given that GPNMB is expressed in the skin 65,67.…”

“…Interestingly, melanoma patients who experienced rash within their first cycle of treatment also had significantly longer PFS than CDX-011-treated patients who didn’t develop rash (4.8 versus 1.2 months; P < 0.001), suggesting that rash may be an early indicator of a patient’s ability to tolerate and respond to the drug 103. Additional side effects in the EMERGE study that were worsened in patients treated with CDX-011 compared to IC include other dermatological conditions such as alopecia (hair loss) and pruritus (itch) as well as peripheral neuropathy and vomiting 107. However, patients undergoing CDX-011 therapy witnessed a reduction in hematologic side effects such as neutropenia, leucopenia, and thrombocytopenia.…”

“…The final results from this trial were presented at the 2012 San Antonio Breast Cancer Symposium and showed promise for CDX-011 treatment of patients with GPNMB-expressing and triple negative breast cancer 107. The trial enrolled 122 patients and was carried out in a 2:1 randomized fashion where 81 patients received CDX-011 and 41 received investigator’s choice of therapy (IC).…”

New targets in breast cancer

“…A phase IIb study showed that in patients with high GPNMB expression, CDX-011 therapy was associated with median OS was 10.0 months compared with 5.5 months with chemotherapy (p = 0.003). Fatigue, rash, nausea, peripheral sensory neuropathy, and neutropenia were the most frequent adverse events [45]. CDX-011 is now being compared with capecitabine monotherapy in a randomized clinical trial for patients with metastatic TNBC.…”

Targeting Glycoprotein NMB With Antibody‐Drug Conjugate, Glembatumumab Vedotin, for the Treatment of Osteosarcoma

“…Upon binding to GPNMB and internalization of the antibody‐drug conjugate, the drug is cleaved, and microtubule inhibition leads to cell cycle arrest and apoptosis . Glembatumumab vedotin, in early phase clinical trials, has led to increased progression free survival in patients with melanoma and breast cancer …”