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Nivolumab, ipilimumab yield mixed results in myelodysplastic syndrome
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SAN DIEGO — Patients with myelodysplastic syndrome responded favorably to ipilimumab and to nivolumab when they were administered in combination with azacitidine for first-line therapy, according to findings of a phase 2 trial presented at the ASH Annual Meeting and Exposition.
Single-agent ipilimumab (Yervoy, Bristol-Myers Squibb) also yield responses in previously treated patients, but nivolumab (Opdivo, Bristol-Myers Squibb) monotherapy did not improve outcomes.
Because nivolumab has shown activity against PD-1 and ipilimumab has shown activity against CTLA-4 in solid tumors, Guillermo Garcia-Manero, MD, professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues evaluated whether use of these drugs after failure with hypomethylating agents or in combination with azacitidine (Vidaza, Celgene) in the first-line setting may show activity in myelodysplastic syndrome.
“Previous data have shown that immune checkpoint inhibitors have demonstrated significant activity in multiple malignancies,” Garcia-Manero said.
The analysis included 21 previously untreated patients and 33 patients who had failed on hypomethylating agents therapy.
Patients who had previously been treated with hypomethylating agents received:
- 3mg/kg IV nivolumab on days 1 and 15 of a 28-day cycle;
- 3mg/kg IV ipilimumab on day 1 of a 21-day cycle; or
- 3 mg/kg IV nivolumab on days 1 and 15 plus 3 mg/kg IV ipilimumab on day 1 of a 28-day cycle.
After six cycles of therapy, azacitidine could be added back to the regimen if there was no response or progression. In these cases, patients received 75 mg/m2 IV azacitidine on days 1 through 5 of a 28-day cycle.
Patients who were treatment naive received 75mg/m2 IV azacitidine on days 1 through 5 of a 28-day cycle with:
- 3 mg/kg IV nivolumab on days 6 and 20;
- 3 mg/kg IV ipilimumab on day 6; or
- 3 mg/kg IV nivolumab on days 6 and 20 plus 3 mg/kg IV ipilimumab on day 6.
- Garcia-Manero presented data from cohorts 1, 2 and 4.
The safety of the two drugs as single agents or in combination with azacitidine served as the primary outcome measure. Secondary endpoints included ORR and assessment of biological activity.
Thirty-five patients (95%) were evaluable for toxicity and 33 (89%) for response at the time of analysis.
Among 15 patients treated with only nivolumab, the complete response rate, marrow complete response and overall response rate were each 0%. Criteria for the stopping rule were met in this arm, and enrollment was stopped.
For the 18 patients receiving ipilimumab, the complete response rate was 6%, the marrow complete response rate was 12%, the ORR was 30% and 56% had no response. Among 20 patients treated with azacitidine and nivolumab, the complete response and marrow complete response rates were 35%, the ORR was 80% and 11% had no response.
“The patients who did not respond had higher rates of cytogenetic mutations,” Garcia-Manero said. “But there were not enough patients in this group, so the result is not statistically significant.”
Median OS was 13.1 months for nivolumab and 11.8 months for azacitidine and nivolumab. The OS endpoint was not reached in the ipilimumab group.
“As this is an interim analysis, we can’t really give a clear estimate,” Garcia-Manero said.
Median EFS was 3.6 months for nivolumab. Patients in both the ipilimumab and azacitidine plus nivolumab arms achieved a median EFS of 3.7 months.
Toxicity results indicated that rash, adrenal insufficiency, colitis, thyroiditis, pneumonitis and nephritis occurred, but grade 3 or higher events were infrequent.
“There was not a lot of significant morbidity with this therapy,” Garcia-Manero said.
“It is fair to say that treatment with immune checkpoint inhibitors alone or in combination with azacitidine is safe,” Garcia-Manero said. “With nivolumab, we didn’t see any evidence of clinical activity, but it was interesting to see that hypomethylating agents failure was not associated with OS at 13 months.”
He added that the survival outcome with ipilimumab was better than expected.
“The combination of azacitidine and nivolumab had an encouraging ORR that was higher than we expected,” he said. – by Rob Volansky
For more information:
Garcia-Manero G, et al. Abstract 344. Presented at: The ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure : Garcia-Manero reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
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Henry Chi Hang Fung, MD, FACP, FRCPE
This is the first time we have seen a checkpoint inhibitor used in myelodysplastic syndrome. They showed a response with the anti– CTLA-4 therapy, but not with anti– PD-1. I did not expect this response, so it was very surprising.
However, we still don’t really know how to use these drugs. It was particularly interesting that there was a minimal response from nivolumab but with a very nice survival benefit with a small number of patients. It’s my opinion that the nivolumab arm was stopped prematurely because of this.
I see these results as very encouraging but, again, we are still learning how to combine these drugs with hypomethylating agents as the standard of care. When we look at the patients even with hypomethylating agent failure, these patients only live for about 4 to 6 months, so any response is encouraging.
Myelodysplastic syndrome and leukemia are the same group of diseases, so there is reason to believe that this may work in leukemia, as well.
Overall, this is a good study with a good response, and I look forward to more data on this regimen.
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