Ipilimumab

Abstract

Immunotherapy has garnered an important place in the therapeutic landscape of treatment in prostate cancer since approval of sipuleucel-T. Ipilimumab is a checkpoint inhibitor that is currently approved for the treatment of advanced melanoma. In the June issue of Lancet Oncology, Kwon and colleagues report the phase III trial using ipilimumab in a post-docetaxel metastatic castration-resistant prostate cancer population. While the primary endpoint of overall survival was not met, several lessons are learned from the analysis of this trial. Perhaps better refinement of a more favorable group of patients who may potentially benefit from an immunologic treatment should be advocated.

Keywords: :

• ipilimumab
• prostate cancer

This article refers to:

Metastatic castration-resistant prostate cancer (mCRPC) up until recently had a limited number of effective agents for use in its treatment. In 2010, a novel autologous dendritic cell vaccine called sipuleucel-T showed a survival benefit in asymptomatic or minimally symptomatic patients with mCRPC in the phase III IMPACT trial.¹ While an improvement in overall survival (OS) was seen, no corresponding improvement in progression-free survival (PFS) or prostate-specific antigen (PSA) response was seen, but the treatment was approved by the FDA as an alternative therapy for patients with mCRPC. Given the promising results of an immunologic approach as a therapeutic target in prostate cancer, the use of immune checkpoint inhibitors was conceived.

Ipilimumab is a humanized monoclonal antibody that inhibits cytotoxic T-lymphocyte antigen 4 (CTLA-4) and has been studied in a population of men post-docetaxel in the CA184–043 trial reported in the Lancet Oncology by Kwon and colleagues.² CTLA-4 is an inhibitor of T cells, and thus by inhibiting CTLA-4, T-cell production and response is heightened. However, the effect of ipilimumab is non-specific, since T cells are one of the primary immune system regulators, increasing their potency lead to autoimmune side effects. Currently, it is approved in the use of metastatic or surgically unresectable melanoma, as it has been shown to prolong OS in this setting.³ Given the success of immune-modulating vaccines in prostate cancer and the use of ipilimumab in melanoma, phase I and II trials of ipilimumab for prostate cancer were begun. Subsequently, phase III trials in both post-docetaxel and pre-docetaxel were initiated.

CA184–043 was a phase III trial that compared ipilimumab vs. placebo in patients with mCRPC after progression on docetaxel. It was a large, double-blind, multi-center prospective trial that enrolled 799 patients across 191 centers in 26 countries. The primary endpoint was OS and the secondary endpoints were PFS (which was a composite endpoint consistent of either radiographic progression, death or PSA increment of 25% or more from nadir), pain response, and safety profile. All randomized patients were pre-treated with bone-directed radiotherapy with the rationale of increasing priming and enhancing anti-tumor immune responses. Both groups were equally well balanced although the trial did enroll close to a third of patients with visceral metastases, a known poor prognostic indicator of disease. Of note, over 40% were greater than 70 years of age, had alkaline phosphatase levels above 1.5 times the upper limit of normal, and had Gleason scores over 7. Patients were followed for less than 10 months (mo) in both ipilimumab and placebo arms in which the authors observed 268 deaths and 205 deaths, respectively, with an overall survival rate of 11.2 mo in the ipilimumab group and 10 mo in the placebo group (HR = 0.85, P = 0.053),which was deemed not statistically significant. Despite the insignificant finding in the primary outcome, secondary endpoints such as PFS (3.1 mo for the placebo group and 4 mo for the ipilimumab group) and prostate-specific antigen (PSA) level reductions (5.2% in the placebo group and 13.1% for the ipilimumab group) were observed although pain response was no different between the two arms. Of interest, after subjecting the data to post-hoc analysis, the study showed that ipilimumab may be of benefit in a selected group of patients with favorable prognostic indicators, such as alkaline phosphatase level less than 1.5 times the upper limit of normal, hemoglobin concentration over 11 g/dL, and absence of visceral metastases. OS in this favorable group of patients was 22.7 mo vs. 15.8 mo (P = 0.0038) favoring ipilimumab. However, some adverse events also deserve mention. Immune-related adverse events were increased in the ipilimumab group compared with placebo, the most common being diarrhea (39% vs 14%), pruritus (20% vs 4%), and rash (17% vs 4%), although majority (89%) of these events resolved after the initial 4 doses of ipilimumab were given. While majority of deaths were attributable to disease progression, about 30% in the ipilimumab vs. 20% from the placebo group had deaths occurring within 70 d on-study, with grade 5 or fatal events reported in 14% in the ipilimumab vs. 10% in the placebo group.

While the primary endpoint of this study was not met, several key findings of the trial may help inform the conduct of future trials. Perhaps not surprisingly, ipilimumab did not extend OS in this patient population of mCRPC who have progressed after receiving docetaxel since a heavily pre-treated chemotherapy population may not have harnessed optimal benefit from an immune-modulating response expected from a checkpoint inhibitor. It should be noted that only half of patients assigned to ipilimumab actually received all 4 doses of the study drug. It is likely that the pre-chemotherapy population CA184–095 trial,⁴ which has already fully accrued and awaiting analysis, may yield promising survival results especially since immunotherapy is found to work best in earlier states of disease when tumor burden is less.⁵ In addition, while earlier studies using immune-modulating vaccines showed improvements in OS, without improvements in PFS, this study showed just the opposite, a benefit in PFS without a benefit in OS, albeit the margins were small. Yet, when the authors used a piecewise hazard model, they observed OS improvements over time when compared with placebo. This finding is concordant with the original hypotheses of more protracted beneficial effects of immune-modulating therapies where OS improvements are seen over time. While comparison across other contemporary phase III post-docetaxel trials could not be reliably made, OS in the interventional group and the placebo group in this trial appears to be inferior to that of previously reported trials. This perhaps alludes to a sicker cohort of patients who may have more advanced disease as suggested in the post-hoc analysis, which while should be interpreted with caution, did show a benefit in patients who had better prognostic indicators.

In summary, CA184–043 was a large, well-executed, phase III trial that utilized a novel agent in the setting of mCRPC. Although the benefits of ipilimumab in a post-docetaxel population was limited, meaningful use in mCRPC may not necessarily be precluded until better refinement of the treatment population or in the much-awaited chemotherapy-naïve population, can be established.

Abbreviations:
IMPACT	=	Immunotherapy for Prostate Adenocarcinoma Treatment
FDA	=	Food and Drug Administration

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

10.4161/cbt.29928