May 2015, Vol. 2, No. 3
PROSTVAC plus Immune Checkpoint Inhibitors: Evidence of Improved Overall Survival in Prostate Cancer
The combination of active immunotherapy and immune checkpoint inhibitors shows signs of improved overall survival (OS) in patients with prostate cancer, according to data presented at the 2015 Genitourinary Cancers Symposium.
“The comparison of 3 independent trials of PROSTVAC active immunotherapy provides hypothesis-generating data that the addition of an immune checkpoint inhibitor may have a positive effect on OS through a potential synergy in mechanism of action,” said Harpreet Singh, MD, a clinical research fellow at the National Cancer Institute, Bethesda, MD. “The updated long-term survival data are further evidence of improved OS with PROSTVAC.”
As Singh explained, the results of recent clinical trials have escalated interest in immunotherapy in oncology; a number of cancer immunotherapies have been approved recently, and others are in late-stage clinical development.
PROSTVAC, a poxvirus-based active immunotherapy, is currently under evaluation in a global, phase 3, randomized, placebo-controlled trial. Generally well tolerated, the vaccine expresses prostate-specific antigen (PSA) and 3 T-cell costimulatory molecules and has demonstrated evidence of clinical benefit in phase 1 and phase 2 studies. It is ready to use with minimal preparation and does not require blood cell collection from individual patients.
Ipilimumab, an approved immune checkpoint inhibitor in melanoma, is also being evaluated in a phase 3 trial in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC).
For this study, Singh compared the results of 2 phase 2 trials in men with mCRPC treated with PROSTVAC alone with results from a phase 1 combination study in mCRPC patients treated with PROSTVAC plus escalating doses of ipilimumab.
“In a multicenter phase 2 trial, 125 men were randomized 2:1 to receive PROSTVAC or placebo,” said Singh. “Patients treated with PROSTVAC had improved OS compared to placebo (25.1 vs 16.6 months; hazard ratio, 0.56; 95% CI, 0.37-0.85).”
Similar data were seen in a second phase 2 trial of PROSTVAC.
“Thirty-two patients with mCRPC had a median OS of 26.6 months,” said Singh, “when the predicted median OS by the Halabi nomogram was only 17.4 months.”
Combining Vaccines and Immune Checkpoint Inhibitors
In the phase 1 combination study conducted at the National Institutes of Health, 30 patients with mCRPC and similar baseline characteristics were treated with PROSTVAC plus escalating doses of ipilimumab. This study also produced encouraging results.
“The observed median OS was 31.3 months for all dose cohorts and 37.2 months for patients treated at 10 mg/kg based on updated overall survival data,” said Singh. “Again, treatment outperformed the predicted median OS of 18.5 months. Furthermore, there appears to be a tail on the curve with approximately 20% of patients at 10 mg/kg alive at 80 months.”
At this dosage, 73.3% of the patients were alive at 24 months. Fourteen of 24 patients (58%) who were chemotherapy-naive had a decline in their PSA, 6 of whom (25%) had a PSA decline >50%.
“The combination was well tolerated with not a lot of overlapping toxicity,” Singh concluded.
According to Singh, these data suggest that therapeutic vaccines may make T-cell–poor tumors into T-cell–inflamed tumors that are responsive to immune checkpoint inhibition. Future randomized trials are in development to prospectively evaluate this hypothesis.
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A new class of cancer therapies has set its sights on immune checkpoints. A trio of studies presented at the 2015 Genitourinary Cancers Symposium offered a glimpse into the evolving landscape of treatment for metastatic renal cell carcinoma (mRCC), and the programmed death ligand 1 (PD-L1) and its receptor, programmed [ Read More ]