Guillermo Garcia-Manero, MD, discusses the potential impact of harnessing immunotherapeutics in MDS.
Guillermo Garcia-Manero, MD
Immunotherapies have begun to garner interest among researchers in the field of myelodysplastic syndromes (MDS). With early-phase studies of agents such as OPN-305 and pembrolizumab (Keytruda) showing promiseparticularly in patients who have failed on hypomethylating agents—investigators are now looking to move forward with these therapies.
Guillermo Garcia-Manero, MD, lead investigator on both the OPN-305 and pembrolizumab studies in patients with MDS, discussed the potential impact of harnessing these immunotherapeutics in his presentation during the 2017 SOHO Annual Meeting.
OPN-305 is a toll-like receptor 2 antibody (TLR2). TLR2 is commonly overexpressed in MDS and, as a fully humanized antagonistic IgG4 kappa monoclonal antibody to TLR2, OPN-305 significantly increases the formation of erythroid colonies in the bone marrow CD34-positive cells, which were isolated from patients with lower-risk MDS in vitro for the purposes of this study.1
The results of the phase I/II trial showed that treatment with OPN-305 was associated with an overall response rate (ORR) of 50% and was well tolerated, with no effect on the cytokine profile nor linked with significant toxicities. Investigators are continuing to dose escalate and evaluate the drug’s activity in the frontline setting.
“We saw a very normal toxicity profile,” said Garcia-Manero. “This is very important, because it is potentially possible that if you block this pathway these patients may develop all sorts of complications, and we have not seen that.”
Expression of PD-1, PD-L1, PD-L2, and CTLA-4 have also been observed in this patient population.
In a phase Ib study, the safety of the antiPD-1 agent pembrolizumab was evaluated in patients with MDS after failure on hypomethylating agents. Pembrolizumab was given at a dose of 10 mg/kg every 2 weeks for up to 2 years. The primary endpoints were safety and ORR.
Among the 28 patients, there was 1 partial response and 3 bone marrow complete responses (11%), for an ORR of 4% (90% CI, 0.2-0.16).2 Additionally, 14 patients had stable disease (52%) and 9 had progressive disease (33%), with no treatment-related deaths.
A high expression of CTLA-4 was observed in patients treated with pembrolizumab. Garcia- Manero suggests that this is a call for a combination regimen of a PD-1, a CTLA-4, and a hypomethylating agent.
Based on the manageable safety profile and clinical activity observed in this study, investigators noted that there are plans for future studies with pembrolizumab and azacitidine in patients with MDS who failed first-line treatment with a hypomethylating agent.
Overall, survival trends have been longer than expected with immunotherapeutic agents, though clinical activity with monotherapy remains modest. Doublets and newer combinations are promising, but larger randomized trials are needed, Garcia-Manero said.
Additionally, nivolumab (Opdivo) is being investigated in this space, but the use of it is still not established and requires further study before being widely used in this patient population.
“The main point is: don’t go home and start giving nivolumab in your clinic,” Garcia-Manero emphasized. “It needs a little bit more experience and understanding.”
Currently, an ongoing trial is evaluating nivolumab and ipilimumab (Yervoy) with 5-azacitidine in patients with MDS (NCT02530463). There are 6 cohorts: nivolumab monotherapy, ipilimumab monotherapy, nivolumab plus ipilimumab, 5-azacitidine plus nivolumab, 5-azacitidine plus ipilimumab, and 5-azacitidine plus nivolumab/ipilimumab. The primary endpoints are overall response in participants with hypomethylating agent failure and hematologic improvement.
The estimated enrollment is 120 patients and results are expected in late 2021.