Munich, Germany, 22 October 2018. A groundbreaking report was presented today at ESMO 2018 titled, “Pre-specified interim analysis of a randomized phase 2b trial of trastuzumab + nelipepimut-S (NPS; NeuVax) vs trastuzumab for the prevention of recurrence demonstrates benefit in triple negative (HER2 low-expressing) breast cancer patients.” The oral presentation conveyed data from a prespecified interim analysis from a prospective, randomized, single-blinded, controlled, Phase 2b clinical trial of trastuzumab (Herceptin®; Genentech/Roche) ± nelipepimut-S (NPS) (administered with sargramostim [GM-CSF] as NeuVaxTM HER2-targeting vaccine; Sellas Life Sciences Group, Inc.) in patients with triple-negative breast cancer (TNBC). According to Col. (ret) George E. Peoples, MD, FACS, Director, Cancer Vaccine Development Program, The Metis Foundation, who participated in the trial, “Mortality associated with TNBC accounts for about half of breast cancer deaths in the US. We need a novel approach to this disease that we can incorporate into clinical practice.” This study was designed to determine the safety and efficacy of the combination of NPS + trastuzumab compared with trastuzumab alone in the adjuvant (or maintenance) setting in preventing recurrent disease in women with early-stage breast cancer with HER2 low-expressing tumors (defined as HER2 expression levels of 1+ or 2+ by immunohistochemistry [IHC]) who were at high risk for recurrence following completion of front-line surgery and neoadjuvant -or adjuvant- chemotherapy ± radiation. Both full safety and efficacy data from a prespecified interim analysis (with a median follow up of 19 months), as well as top-line data from the final analysis of the trial results (with a median follow-up of 26 months) were presented.
A total of 275 women were enrolled and 261 women were treated in the study, in which the primary endpoint was disease-free survival (DFS) rate (%) at 24 months (by landmark analysis); secondary endpoints included DFS rate at 36 months, safety, and immunologic response (by in vivo cutaneous delayed type hypersensitivity [DTH] and antigen (HER2)-specific T-lymphocyte (CD8) frequency in peripheral blood). In women with TNBC (n=98), and with a median follow-up of 19.3 months (interim analysis), there was a meaningful and statistically significant difference in 24-month DFS rate in favor of the NPS + trastuzumab arm over trastuzumab alone (91.1% vs. 69.9%; P=0.023). This benefit was further strengthened in the final analysis (with a more than 6-month additional follow-up time), showing a 24-month DFS rate of 92.6% vs. 70.2% (P=0.013) in favor of the combination. The benefit of the combination therapy was numerically maintained at the 36-month timepoint. Disease recurrences in the TNBC population also favored the combination arm (7.5% for NPS + trastuzumab vs. 26.7% for trastuzumab alone; log-rank P=0.023). No differences in the distribution or severity of treatment-related adverse events (TRAEs) were observed between patients receiving NPS + trastuzumab vs. trastuzumab alone, with most TRAEs being grade 1 or 2 local injection site reactions, which are expected given the mechanism of action of NPS as an intradermally administered peptide vaccine. Importantly, there were also no significant differences in the rates of cardiac-related adverse events or serially measured left ventricular ejection fraction measurements over time between the treatment arms.
The results of this interim analysis demonstrate that the combination of NPS + trastuzumab is safe and may provide clinically meaningful benefit to women with HER2 low-expressing breast cancer, with a particularly marked benefit in the subgroup with TNBC, which represents an underserved population with a high risk of disease recurrence and death. Moreover, the combination is potentially broadly applicable, as NPS is immunogenic in the context of a set of specific human leukocyte antigen (HLA) type A haplotypes that are highly prevalent in North American, European, as well as Asian populations. According to Dr. Peoples, “Ironically, despite TNBC being the most ‘visible’ subset of breast cancer to the immune system, mainly due its significantly higher tumor mutation burden compared to other subtypes of breast cancer, it becomes a disease with one of the worst biological behaviors, because the cancer can evade the immune system at a very early stage and distort the host immunity-tumor balance in favor of tumor growth. With the combination of NPS and trastuzumab, we are using active immunotherapy for TNBC in the adjuvant setting, that is immediately after completion of standard front-line therapy, to flip the balance back to the immune system so that it is able to recognize and eventually destroy the cancer.”
Finally, Elizabeth A. Mittendorf, MD, PhD, Director, Breast Immuno-Oncology Program Dana-Farber/Brigham and Women’s Cancer Center, and the Principal Investigator of the Phase 2b study mentioned “it is encouraging to see that the final analysis of the NPS ± trastuzumab Phase 2b trial for the TNBC cohort not only confirms the previously reported positive data presented in full today, but also provides evidence for a significant clinically positive outcome with the combination. In many early stage TNBC patients, the benefit of initial treatment with neoadjuvant chemotherapy is incomplete, leaving room for improvement, especially in the adjuvant or maintenance setting. To-date, targeted therapies have not proven effective for TNBC. Putting HER2 in the crosshairs of an immunotherapeutic combination, in this case NPS plus trastuzumab in triple-negative (HER2 IHC 1+/2+; hormone receptor negative) breast cancer makes sense biologically considering preexisting activated cellular immunity in most patients with these tumors and the pharmacodynamic synergy between these two agents.”