Early promising responses seen with immune checkpoint inhibitors for patients with ovarian cancer still need to be validated in larger randomized trials before a conclusion is made regarding their true efficacy, according to a presentation by Maurie Markman at the 33rd Annual Chemotherapy Foundation Symposium, a meeting of over 1,000 physicians and other oncology professionals in New York City.
“The checkpoint inhibitors are not ready for prime time yet in ovarian cancer. It's not because there's evidence that they don't work — it's just that there's no evidence at all,” said Markman, president of Medicine and Science at the Cancer Treatment Centers of America. “You could not think of a more appropriate tumor type to explore the concept of immunotherapy than ovarian cancer. Unfortunately, as we've all learned, it's much more complicated.”
Early studies have suggested that ovarian cancer might be highly susceptible to immunotherapy; however, despite this clear rationale, large trials investigating numerous agents have not panned out. In most situations, Markman noted, the agents showed a consistent response rate of 10 percent to 20 percent in phase 2 studies and then failed to improve outcomes in confirmatory trials.
"The 10 percent to 20 percent response rate is basically seen in all phase 2 studies for patients with ovarian cancer. Clearly, some of those responses are ultimately turned into results that are positive in phase III trials, but you have a lot of 20 percent responses that turn out to be nothing," Markman said. "We have to be very cautious when we look at objective responses, based on our historical data."
Findings were presented earlier this year for the PD-1 inhibitor Keytruda (pembrolizumab) at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago. Additionally, findings from a study exploring the PD-1 inhibitor Opdivo (nivolumab) were recently published in the Journal of Clinical Oncology.
In the pembrolizumab study, 26 evaluable patients were treated with pembrolizumab, with a confirmed response rate of 11.5 percent. Additionally, six patients (23.1 percent) had stable disease, for a disease control rate of 34.6 percent.
"PD-1 blockade with pembrolizumab is well tolerated and has antitumor activity in patients with advanced ovarian cancer," Markman said. "But clearly, this response rate is not a home run."
For the nivolumab study, 20 patients with platinum-resistant ovarian cancer were treated with the agent at 1 mg/kg (10 patients) or 3 mg/kg (10 patients) every two weeks for up to six cycles. The response rate for the overall study population was 15 percent and the disease control rate was 45 percent.
Median progression-free survival (PFS) was 3.5 and 3.0 months in the 1-mg/kg and 3-mg/kg cohorts, respectively. Median overall survival (OS) was 16.1 months in the low-dose arm. OS data were not yet mature for those treated with the higher dose. The median OS for the full population was 20 months.
"The PFS was short overall. The median survival was 20 months, although the time of the report was 2014 and some of the responses were continuing," Markman noted.
Results from larger phase 3 studies are still needed to validate early findings for checkpoint inhibition, particularly with regard to the duration of response seen with these agents, said Markman. Moreover, work is needed to uncover a biomarker of response and effective combination strategies.
"We have to look for clinically validated biomarkers," Markman said. "For the one patient who responds for four years, wouldn't it be wonderful today to know if there was something unique in her tumor or in her normal genetic makeup that allowed that to happen."
In addition to checkpoint inhibition, other immunotherapy approaches explored included interferon, interleuken-2, and a variety of tumor antigen specific vaccines. Despite the lack of success for these many approaches, Markman does not anticipate a stall in research.
"Vaccine studies will likely continue, because there is tremendous interest in vaccines," Markman said. "I have to conclude that utility, based on existing experience, is questionable. I would not look at an immune response as any indication that there will be any kind of benefit."