Glembatumumab vedotin is a fully-human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB). gpNMB is a protein overexpressed by multiple tumor types, including breast cancer and melanoma. gpNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize and to correlate with reduced time to progression and survival in breast cancer. The gpNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream, but to release MMAE upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect. Glembatumumab vedotin is in development for the treatment of locally advanced or metastatic breast cancer—with an initial focus in triple negative disease. This program is also in development for the treatment of Stage III and IV melanoma.

CR011

Breast Cancers Expressing gpNMB

In late 2012, Celldex completed the Phase 2 EMERGE study in metastatic breast cancer. This exploratory study was prospectively designed to enable the Company to analyze if potential clinical benefit could be linked back to gpNMB expression levels. Final data from the study were published in the Journal of Clinical Oncology (Yardley 2015) and supported a clinical benefit in heavily pre-treated breast cancer patients with tumors that over-express gpNMB, quantified as expression in greater than 25% of tumor cells.

EMERGE Study in Metastatic Breast Cancer: Efficacy Measures (Intent-to-Treat Population)

EMERGE Data

The METRIC Study in Triple Negative Breast Cancer

METRIC Triple Negative Breast Cancer Logo

In December 2013, Celldex initiated a randomized study, called METRIC, evaluating glembatumumab vedotin in patients with gpNMB overexpressing triple negative breast cancer. Enrollment in METRIC has been completed with 327 patients on study. Patients with metastatic triple negative breast cancers that overexpress gpNMB and who had received standard therapies, including anthracycline, if clinically indicated, and taxane treatments, were randomized (2 to 1) at sites in the United States, European Union, Canada and Australia. The study is a direct comparison of glembatumumab vedotin versus capecitabine, also known by the trade name Xeloda®. The primary endpoint for this study is progression free survival, which is defined as the time from randomization to the earlier of disease progression or death due to any cause. The study calls for 203 progression events for evaluation of the primary endpoint, which will be assessed based on an independent, central reading of patient scans. The sum of the data, including the secondary endpoints of response rate, overall survival, duration of response and safety, will be important in assessing clinical benefit. The Company projects that topline primary endpoint data should be available in the second quarter of 2018, but it could occur earlier or later based on the rate of events in the study. Please visit clinicaltrials.gov for more information on this trial.

Xeloda is a registered trademark of Genentech, Inc., a member of the Roche Group.

Melanomas Expressing gpNMB

Overview of Single-Agent and Combination Cohorts

More than 85% of patients with metastatic melanoma express gpNMB, making it an attractive target for study of glembatumumab vedotin. In December 2014, the Company initiated an open-label Phase 2 study of glembatumumab vedotin in patients with unresectable Stage III or IV melanoma, and enrollment has been completed. In May 2016, we amended the protocol to add a second cohort of patients to a glembatumumab vedotin and varlilumab combination arm to assess the potential clinical benefit of the combination and to explore varlilumab’s potential biologic and immunologic effect when combined with an ADC, and enrollment has been completed. In November 2016, we amended the protocol to add a third cohort of patients evaluating glembatumumab vedotin in combination with an approved checkpoint inhibitor (i.e., nivolumab or pembrolizumab) following progression on the checkpoint inhibitor alone, and enrollment is ongoing. In September 2017, Celldex amended the study protocol to add a fourth cohort evaluating glembatumumab vedotin in combination with CDX-301 to assess the safety, tolerability and biologic activity of the combination. CDX-301 promotes the production and maturation of dendritic cells. Following completion of this cohort and evaluation of available data, the protocol amendment also allows for the exploration of additional cohorts. The primary endpoint for each cohort is ORR, except the fourth cohort which is assessing safety and tolerability. Secondary endpoints include analyses of PFS, duration of response, OS, retrospective investigation of whether the anti-cancer activity of glembatumumab vedotin is dependent upon the degree of gpNMB expression in tumor tissue and safety of both the monotherapy and combination regimens.

Single-Agent Cohort

We presented mature data from the single-agent cohort in an oral presentation at the American Society of Clinical Oncology Annual Meeting in June 2017. The cohort enrolled 62 evaluable patients with unresectable stage IV melanoma. All patients had been heavily pre-treated (median prior therapies = 3; range 1-8) and had progressed during or after checkpoint inhibitor therapy, and almost all patients had received both ipilimumab (n=58; 94%) and anti-PD-1/anti-PD-L1 (n=58; 94%) therapy. Twelve patients presented with BRAF mutation, and fifteen had prior treatment with BRAF or BRAF/MEK targeted agents. Median overall survival (OS) for all patients was 9.0 months (95% CI: 6.1, 13.0). The primary endpoint of the cohort (threshold of 6 or more objective responses in 52 evaluable patients) was exceeded. 7 of 62 (11%) patients experienced a confirmed response, and an additional three patients also experienced single timepoint partial responses. One patient experienced a confirmed complete response. The median duration of response was 6.0 months. A 52% disease control rate (patients without progression for greater than three months) was demonstrated, and median progression free survival (PFS) for all patients was 4.4 months. The safety profile was consistent with prior studies of glembatumumab vedotin with rash, neutropenia and neuropathy experienced as the most significant adverse events.

Combination with Varlilumab

Data from the second cohort, combining glembatumumab vedotin and varlilumab, were accepted for presentation at the Society for Immunotherapy of Cancer's (SITC) 32nd Annual Meeting in November 2017. The cohort enrolled 34 patients with unresectable stage IV melanoma. All patients had been heavily pre-treated (median prior therapies = 3; range 1-8) and had progressed during or after checkpoint inhibitor (CPI) therapy (median prior CPI therapies = 2; range 1-4). Almost all patients had received ipilimumab (n=26; 76%) and/or anti-PD-1/anti-PD-L1 (n=34; 100%) therapy. Nine patients presented with BRAF mutation, and eleven had prior treatment with BRAF or BRAF/MEK targeted agents. Median PFS for all patients was 2.6 months (95% CI: 1.4, 2.8), and median overall survival (OS) for all patients was 6.4 months (95% CI: 3.2, 8.3). One of 31 patients eligible for response evaluation experienced a confirmed partial response (3%) and an additional two patients also experienced single timepoint partial responses. 52% of patients experienced stable disease (minimum of six or more weeks). A 19% disease control rate (patients without progression for greater than three months) was demonstrated. The safety profile was consistent with prior studies of glembatumumab vedotin and there was no evidence of additive toxicity associated with the combination. Biological effects of varlilumab were consistent with prior observations and did not appear to be impacted by the addition of an ADC.

Modest clinical benefit in the combination could be due to multiple factors, including varying sensitivity to immunotherapy in patients with checkpoint refractory disease, many of whom progressed so rapidly that they experienced a very short duration of varlilumab treatment (median 2 doses); a possible dearth of antigen presenting cells in tumors; and the potential for immune checkpoint molecules to remain unblocked without checkpoint inhibitor therapy. Planned future cohorts are designed to address some of these potential factors. No significant correlation between rash and outcome was observed, but will continue to be monitored in future cohorts.

Additional Indications

In addition to triple negative breast cancer and metastatic melanoma, glembatumumab vedotin is being evaluated in other indications in which gpNMB is highly expressed, including squamous cell lung cancer and uveal melanoma, through third-party sponsored studies.

For more information on the glembatumumab vedotin program, view recent scientific presentations and publications.