Phase III Nelipepimut-S Study in Breast Cancer Halted After Futility Review

Mark W. Schwartz, PhD

A phase III trial investigating the first-in-class immunotherapy vaccine nelipepimut-S (NeuVax) for the prevention of recurrence in early-stage breast cancer has been stopped due to futility, announced Galena Biopharma, Inc., the biopharmaceutical company manufacturing the drug.

The halting of the trial—known as PRESENT (NCT01479244)—followed a recommendation from the Independent Data Monitoring Committee (IDMC) based on a planned safety and futility interim analysis that was triggered after 70 qualifying disease-free survival (DFS) events were reached.

“We are extremely disappointed with the outcome of the PRESENT futility analysis,” said Mark W. Schwartz, PhD, president and chief executive officer of Galena Biopharma, in a statement. “To date, the trial has not been unblinded other than by the IDMC, and we need to evaluate the data. We expect to host a conference call next week to provide a preliminary review of the PRESENT trial and an update on all of our immunotherapy and hematology clinical development programs.”

The PRESENT trial was a multicenter, international, prospective, randomized, double-blind, controlled study investigating 758 women with early-stage node-positive breast cancer with low-to-intermediate HER2 expression (HER2 1+ by IHC or HER2 2+ by IHC/FISH) at over 140 sites.

Patients were randomized 1:1 to receive either nelipepimut-S plus sargramostim or the GM-CSF agent with a water-based placebo for 6 consecutive months followed by vaccine boosters every 6 months for a total of 36 months. The primary endpoint was DFS upon reaching 141 events with 3 years of minimum follow-up.

Patients were required to have undergone either total mastectomy or lumpectomy and all those with a positive sentinel lymph node must have undergone a completion axillary dissection level I/II except for those who had a lumpectomy and had clinically node negative T1 or T2 tumors and fewer than 3 involved lymph nodes.

Additionally, patients must have completed neoadjuvant chemotherapy, adjuvant chemotherapy, or both, or have received radiation therapy, and have no evidence of disease to be included in the trial. Patients with bilateral breast malignancy or suspicious mass in the opposite breast, inflammatory breast malignancy, or prior treatment with trastuzumab (Herceptin) were excluded from the trial, which was run under a Special Protocol Assessment (SPA) granted by the FDA.

Nelipepimut-S had previously demonstrated a statistically significant increase in DFS in node-positive, HER2 1+ and 2+ patients with early-stage breast cancer in preliminary phase I and II trials. The vaccine in combination with sargramostim and GM-CSF appeared to be well tolerated and effective at raising HER2 immunity.

In addition to PRESENT, the vaccine is also being studied in several other breast cancer trials. A phase IIb study is investigating nelipepimut-S in combination with trastuzumab in node-positive and HER2 IHC 1+/2+ disease. A second phase II study is also looking at the vaccine in high-risk, node-positive or node-negative negative HER2 IHC 3+ patients.

Nelipepimut-S is also being explored in patients with ductal carcinoma in situ (DCIS). A randomized phase II trial is looking at nelipepimut-S plus GMCSF vaccine therapy versus sargramostim alone in this patient population. Additionally, there are trials planned in gastric cancer.

Nelipepimut-S is an immunodominant peptide derived from the extracellular domain of the HER2 protein, which stimulates specific CD8-positive cytotoxic T-lymphocytes (CTLs) following binding to specific HLA molecules on antigen presenting cells (APC). These activated specific CTLs recognize, neutralize, and destroy—through cell lysis—HER2-expressing cancer cells, including occult cancer cells and micrometastatic foci.

The nelipepimut-S immune response can also generate CTLs to other immunogenic peptides through inter- and intra-antigenic epitope spreading.