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PANVAC plus docetaxel may have clinical benefit for metastatic breast cancer
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The addition of a poxviral-based cancer vaccine, or PANVAC, to docetaxel may confer a clinical benefit for patients with metastatic breast cancer, according to the results of a randomized phase 2 study.
“Despite improvements in treatment, an overwhelming majority of patients diagnosed with metastatic breast cancer will die as a result of their disease,” James L. Gulley, MD, PhD, chief of the genitourinary malignancies branch and director of medical oncology service at NCI’s Center for Cancer Research at NIH, and colleagues wrote. “Standard chemotherapy agents are capable of shrinking tumors, but treatment usually needs to be stopped owing to tumor progression or toxic effects.”
Previous phase 1 and 2 studies have suggested that PANVAC (Therion Biologics) has immunologic activity and clinical efficacy for breast, ovarian and colorectal cancers. Further, preclinical data have shown that docetaxel can modify tumor phenotype and make tumor cells more amenable to T cell-mediated killing, according to the researchers.
Gulley and colleagues conducted a randomized, open-label phase 2 trial to evaluate the addition of PANVAC to docetaxel. The study included data from 48 patients with metastatic breast cancer, treated at the NCI or The University of Texas MD Anderson Cancer Center between May 2006 and February 2012.
The researchers randomly assigned 25 patients (median age at enrollment, 55 years; 100% women) to PANVAC plus docetaxel and 23 patients (median age at enrollment, 52 years; 96% women) to docetaxel alone. Thirty-two percent of patients in the combination arm and 35% of patients in control arm had received three or more prior lines of treatment.
PFS — with the intent of identifying a trend toward benefit (P ≤ .1) — served as the primary endpoint. Secondary endpoints included safety and immunologic correlative studies.
In the final data analysis, patients who received PANVAC demonstrated a trend toward improved PFS (7.9 months vs. 3.9 months; HR = 0.65; 95% CI, 0.34-1.14).
No patients remained on the study at the time of final analysis. Patients in the combination arm received a median of five docetaxel cycles (range, 0-17) and patients in the control arm received a median number of three cycles (range, 1-15).
Little difference in adverse events occurred between the treatment arms. No grade 4 adverse events occurred in either study arm.
More patients in combination arm experienced grades 1 and 2 edema (P = .02) and injection-site reactions (P < .001). However, the researchers noted that the increased incidence of edema may be related to a greater median number of docetaxel cycles in the study arm.
The researchers acknowledged the small patient population and disease heterogeneity among the patients enrolled may be limitations to these findings. Further, they noted that patients at the NCI received granulocyte-macrophage colony–stimulating factor but patients at MD Anderson did not.
“The clear separation of the treatment arm curves indicates potential benefit, which meets the prespecified parameters of the trial design, but the difference was not statistically significant, likely owing to the small number of participants enrolled,” the researchers wrote. “However, the intriguing findings in this hypothesis-generating study provide both rationale and statistical assumptions on which to base a larger, appropriately powered and designed definitive randomized clinical trial in a more uniform patient population, such as patients with ER-positive/PR-positive tumors who have not previously received cytotoxic chemotherapy.”
Leisha Ann Emens
Careful consideration of the interactions between chemotherapies and immunotherapies will be important to future clinical trial designs, according to Leisha Ann Emens, MD, PhD, associate professor of oncology and member of the tumor immunology research program at The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, in an accompanying editorial.
“It seems natural to test cancer vaccines and immune checkpoint antagonists with standard chemotherapies, but the effect of distinct chemotherapies on the immune system must be considered,” Emens wrote. “Chemotherapy is generally thought to suppress the immune system, and blindly adding immunotherapies to standard chemotherapy may be destined to fail. However, chemotherapy can also promote tumor immunity when used at the proper dose and schedule. Rational trial designs that strategically harness the ability of distinct chemotherapies to potentiate tumor immunity in different ways will be required to realize the full potential of cancer immunotherapy when it is combined with chemotherapy.”
However, the findings of this trial will likely contribute to the growing understanding of immunotherapy in the cancer treatment arena, Emens wrote.
“Like this trial, multisite basket trials designed to quickly vet immunotherapy approaches in patients with diverse tumor types have been successful in driving definitive clinical testing in larger numbers of patients, thus accelerating clinical development,” Emens wrote. “It is clear that combinations are the future of cancer immunotherapy, and the strategic use of chemotherapy with cancer immunotherapy will likely play an important role in further improving patient outcomes.” – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures. Emens reports research funding from Amplimmune, EMD Serono, Genentech/Roche, Maxcyte and Merck, as well as consultant roles with Aduro Biotech, AstraZeneca, Aveo, Bristol-Myers Squibb, Celgene and Vaccinex. Further, Emens reports that she is entitled to milestone payments and royalties on the sales of the vaccine described in this study under a licensing agreement between Aduro Biotech and her employer, Johns Hopkins University.
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