Although hypomethylating agents previously appeared to be a promising treatment option for patients with bladder cancer refractory to immunotherapy, researchers were forced to halt a recent phase II clinical trial after patients experienced either no response to treatment or rapid tumor progression, according to a new study published by Jang et al in Clinical Cancer Research. The investigators hope that the new findings will give them insights into why some patients with solid tumors become resistant to immunotherapy and could help them develop alternative treatment strategies in the future.
Background
Immunotherapy has become a powerful tool to fight many cancer types; however, the treatment is still only effective in some patients, and researchers are looking for new options to help patients who become resistant.
Methylation is a process that works like an “on-off” switch for DNA. Researchers hypothesized that by blocking methylation, they could turn off two DNA pathways. One pathway would help the immune system recognize and target tumor cells. The second would reinvigorate “killer” immune cells—giving them more energy to fight the tumors.
“I’m incredibly grateful to the patients who were willing to enroll in this trial and try this novel approach,” emphasized senior study author Elizabeth Plimack, MD, MS, Professor of Hematology/Oncology, Director of Genitourinary Clinical Research, and Deputy Director at the Fox Chase Cancer Center. “Sometimes, what we think will happen doesn’t, and that was the case here. But we are going to learn something from this, and the legacy of the patients who had the courage to enroll in this trial will move forward with future work,” she added.
Study Methods and Results
In the new study, the researchers enrolled six patients with metastatic bladder cancer in the phase I portion of the trial, which examined the efficacy of the hypomethylating agent guadecitabine in combination with the immunotherapy drug atezolizumab. While the patients’ tumors didn’t shrink, they experienced stable disease with no unexpected side effects.
“They actually did quite well. We started off with a lot of enthusiasm,” Dr. Plimack explained.
For the phase II portion of the trial, the researchers expanded to 15 patients. However, they found that while most of the patients again had no response to the therapy, four of them saw their tumors start growing faster than expected—forcing the researchers to close the trial.
Conclusions
“It’s never a good feeling to have a study that doesn’t meet its endpoint,” Dr. Plimack stated. Nonetheless, the study has some important findings, including the researchers’ earlier findings regarding hypomethylation therapy.
The researchers underscored that although hypomethylation therapy had been used with some success in hematologic cancers such as leukemia, the treatment may be unlikely to offer similar benefits in solid tumors. They noted that the new study is only the latest of many solid tumor studies to see disappointing results.
“I think if we were going to see activity in solid tumors, we would have by now. I’m pessimistic that we’ll see meaningful results with currently available hypomethylating agents,” Dr. Plimack stressed.
The researchers hope that analyzing data gathered during the recent trial could yield new insights into why certain patients respond differently to treatment. They plan to further analyze the four cases of tumor progression for clues in the tumor tissue, blood, or other characteristics that could explain the negative response. The researchers concluded that this could lead to the development of more personalized treatments in the future that may yield more positive results.
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.
