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Apatorsen plus chemotherapy combination may provide survival benefit for bladder cancer
CHICAGO — The addition of apatorsen to first-line gemcitabine and cisplatin may benefit patients with advanced bladder cancer, according to results from an international phase 2 trial presented at the ASCO annual meeting.
Apatorsen (OGX-427, OncoGenex) is an investigational agent that is administered intravenously weekly to inhibit the production of heat shock protein 27 (Hsp27), an intracellular protein that protects cancer cells and helps them survive. Using this antisense oligonucleotide may also enhance the efficacy of chemotherapy, according to study background.
Joaquim Bellmunt, MD, PhD, director of the bladder cancer center at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School in Boston, and colleagues conducted this study to evaluate the safety and efficacy of apatorsen in combination with gemcitabine and cisplatin in patients with advanced bladder cancer.
The researchers randomly assigned 179 chemotherapy-naive patients with advanced bladder cancer to one of three treatment arms: gemcitabine and cisplatin plus 600 mg apatorsen; gemcitabine and cisplatin plus 1,000 mg apatorsen; or gemcitabine and cisplatin plus placebo.
OS served as the study’s primary endpoint.
Researchers also planned a post-hoc analysis to determine if Hsp27 inhibition might be relevant to OS in patients with a poor prognosis.
Median OS was 15.2 months in all patients.
Patients who received 600 mg apatorsen demonstrated improved OS (HR = 0.86) and improved PFS (HR = 0.83) compared with patients who received the combination plus placebo. Patients who received 1,000 mg apatorsen also demonstrated improved OS (HR = 0.90) and PFS (HR = 0.93) when compared with the placebo arm.
Post-hoc results demonstrated that Karnofsky performance status, liver metastases, alkaline phosphatase and hemoglobin were prognostic. Researchers stratified patients with a good prognosis vs. those with a poor prognosis — with 50% of the study population in each cohort — based on a median prognostic score.
Patients with a poor prognosis treated with 600 mg apatorsen demonstrated a greater reduction in risk for death (HR = 0.72) compared with patients who had a good prognosis (HR = 1.44).
Researchers noted the most significant prognostic factor was Karnofsky performance status less than or equal to 80%, which resulted in an HR of 0.5 in favor of the 600 mg apatorsen group.
Apatorsen proved to be well tolerated, according to the researchers. The most common grade 3 or grade 4 adverse events were neutropenia, thrombocytopenia, hypertension and anemia. The frequency of adverse events was 89% in the placebo group, 93% in the 600 mg apatorsen arm and 95% in the 1,000 mg apatorsen cohort.
“What we can conclude from this trial is that the 600-mg dose of apatorsen was more effective than the 1,000-mg dose,” Bellmunt said during his presentation. “Also, the durability was much better and the patients who benefitted most were those with poor prognostic features. The single most important poor prognostic feature was lower performance status, and lower Karnofsky performance status in the 600 mg apatorsen arm showed the most important survival benefit.”
Although apatorsen is a targeted agent aimed at the Hsp27 protein, Bellmunt was not able to present any data directly focusing on the impact of the drug on that protein. Researchers continue to study that data for presentation at a later date, he said.
“After decades with little progress in the treatment of metastatic bladder cancer, we are finally beginning to see exciting innovation in treatment approaches that may improve outcomes, even in patients with poor prognosis,” Bellmunt said in a press release. – by Anthony SanFilippo
Reference:
Bellmunt J, et al. Abstract 4503. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: Bellmunt reports consultant/advisory roles with Astellas, Pfizer and Pierre Fabre, research funding from Millennium and Sanofi and travel expenses from Merck Oncology and Pfizer. See the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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This was a study that was very similar to the SYNERGY trial, also presented at the ASCO Annual Meeting, and this drug — apatorsen — targets a similar pathway. SYNERGY was a randomized phase 3 study, whereas the current analysis was a 3-arm phase 2 study; but, it was not any better overall. In each study the investigators said, “Look, let’s go back and look at the poor prognostic population.” The first flaw in the logic is that it was a post-hoc analysis. It’s unfortunate, because people should be thinking about this ahead of time and should stratify for it and not do it backwards because this creates biases. So, when you look at it retrospectively, you see the poor prognostic patients benefit more from whatever drug you are studying, in this case apatorsen. We see that frequently in these post-hoc analyses.
It is food for thought, but whether it’s something that would support spending millions of dollars for a phase 3 study is unclear. What’s missing here and also in the SYNERGY study is a biomarker. If you say this targets something — like Hsp27 in this case — then enrich your population with what you want to target. Maybe it’s higher in poor-risk patients — let’s say 50%. If you give that 50% the drug and they do well, then it would be a home run. But that’s what’s missing here. If you have a drug with a target, let’s look at the target and see if the target is there. In the best-case scenario, you show you are hitting the target. We are seeing that in the immunological studies. It’s not 100%, but there certainly are discussions — some that were in the same session as this study — that suggest that if the target is there, you are probably going to get a better response rate or better durability.