Trial Surprise: Rigosertib May Benefit Some MDS Patients

Fran Lowry

March 16, 2016

Scientific advances are sometimes made from the stuff of failure. That may be the case in the blood cancers known as myelodysplastic syndromes (MDS).

The story starts with a clinical trial of an experimental therapy, rigosertib, which did not significantly improve overall survival compared with best supportive care in patients with MDS for whom standard treatment with the first-line hypomethylating drugs azacitidine (Vidaza, Celgene Corporation) or decitabine (Dacogen, Otsuka Pharmaceutical Co, Ltd) had failed.

But rigosertib did show promise in a subset of patients, according to the results of the randomized, controlled, phase 3 ONTIME study. This result has prompted a subsequent trial of rigosertib (NCT 02562443) in this subset of patients.

"If you look at the survival trends, there is a benefit in terms of survival, but it didn't reach significance,” lead author Guillermo Garcia-Manero, MD, professor, University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News.

"But when we looked at the survival according to the type of patient, we found that patients who initially responded to hypomethylating agents but later relapsed, categorized as secondary failure patients, did not benefit from rigosertib, but patients who never responded at all to the hypomethylating agents, deemed primary failure patients, showed what looked like a significant trend towards improved survival with rigosertib," Dr Garcia-Manero said.

The study was published online March 8 in the Lancet Oncology.

"Hypomethylating agents like azacitidine or decitabine have transformed the care of patients with MDS, but we are lacking second-line treatments, because when these patients stop responding or do not benefit from these agents, the outcome is very poor," Dr Garcia-Manero said.

"It is almost a universal phenomenon that most people with MDS at some point will be in need of a second-line agent, and it is not clear what strategies are effective in this context, so there was a very important need for this study," he said.

ONTIME was conducted from December 13, 2010, to August 15, 2013, at 74 hospitals and university medical centers in the United States and Europe.

It included 299 patients who had been diagnosed as having refractory anemia with excess blasts type 1 (RAEB-1), RAEB-2, RAEB in transformation, or chronic myelomonocytic leukemia. For all patients, treatment with a hypomethylating drug had failed during the past 2 years.

The patients were randomly assigned to receive either rigosertib 1800 mg per 24 hours via 72-hour continuous intravenous infusion administered every other week (n = 199 patients) or best supportive care, with or without low-dose cytarabine (n = 100 patients).

The primary outcome was overall survival in the intention-to-treat population.

The median follow-up was 19.5 months (interquartile range, 11.9 - 27.3 months).

As of February 1, 2014, the median overall survival was 8.2 months (95% confidence interval [CI], 6.1 - 10.1) in the rigosertib group and 5.9 months (95% CI, 4.1 - 9.3) in the best supportive care group (hazard ratio [HR], 0.87; 95% CI, 0.67 - 1.14; P = .33).

For the subset of patients for whom primary hypomethylating drug therapy had failed, the HR was 0.72 (99% CI, 0.46 - 1.13; P = .060).

"The primary failure patients, the ones who never responded to either azacitabine or decitabine, looked like the subset of patients who benefited the most. The secondary failure patients did not look as if they benefited from rigosertib. When we designed this trial, we were not aware of this, so we did not stratify for this criteria, and that is why we cannot make a conclusion that the study was positive or negative for this particular group of patients," Dr Garcia-Manero said.

Hence, the next phase 3 study, INSPIRE (NCT02562443), is studying the primary failure patients who appeared to benefit most from rigosertib therapy in ONTIME.

Failure Can Be a Great Teacher

The ONTIME trial has taught the investigators a great deal, Dr Garcia-Manero said.

"One is this issue of primary vs secondary failure patients. The second thing is, if this is correct, if the biology of these primary and secondary failures is different, we will need to have a therapy specifically for each category. This is the way we are now directing our research," he said.

"Perhaps there is something different about these two groups, and how do we exploit that from a therapeutic perspective? So we did learn something very important from this study," Dr Garcia- Manero said.

"Biomarkers will have a pivotal role in the selection of patients who will benefit most from a drug," Emilio P. Alessandrino, MD, and Matteo G. Della Porta, MD, from the Policlinico San Matteo and the University of Pavia Medical School, Italy, write in an accompanying editorial.

Dr Alessandrino and Dr Della Porto note that data from randomized trials such as ONTIME can be analyzed retrospectively to investigate specific biomarkers, such as in the INSPIRE trial.

The editorialists predict: "In the next generation of clinical trials, whole populations of people with myelodysplastic syndromes will undergo comprehensive analysis, and experimental treatment will be allocated according to the presence of specific predictive biomarkers."

The study was funded by Onconova Therapeutics and the Leukemia and Lymphoma Society. Dr Garcia-Manero, Dr Alessandrino, and Dr Della Porta report no relevant financial relationships.

Lancet Oncol. Published online March 8, 2016. Full text, Editorial

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