SAN DIEGO—Targeting metabolic pathways in cancer is an emerging field, even though a link between dysregulated cellular metabolism and cancer was described as early as 1926 by Nobel laureate Otto Heinrich Warburg in the eponymous Warburg effect. Now, data presented here at the American Association for Cancer Research Annual Meeting from a Phase I trial are showing that key elements in the metabolic pathway, isocitrate dehydrogenase 1 and 2 (IDH1/2), are valid therapeutic targets in hematologic malignancies (Abstract CT103).
IDH is a critical metabolic enzyme in the citric acid cycle, explained the researcher who reported the data, Eytan M. Stein, MD, Assistant Attending Physician in the Leukemia Service at Memorial Sloan Kettering Cancer Center. Mutated IDH blocks normal cellular differentiation and IDH1 and IDH2 have been identified in a wide v
Somatic point mutations in IDH2 are found in approximately 25 percent of patients with angio-immunoblastic non-Hodgkin lymphoma, 15 percent of patients with acute myeloblastic leukemia (AML) patients, and five percent of patients with myelodysplastic syndromes (MDS). Mutated IDH1 is found in 70 percent of cases of low-grade glioma, at least 50 percent of patients with chondrosarcoma, and five percent of cases of MDS.
Stein described the Phase I trial of a potent, reversible, and selective inhibitor of mutated IDH2, the first-in-class oral agent AG-221. The study included 22 patients with relapsed or refractory AML, elderly patients with untreated AML, or MDS.
Among the 10 AML patients, he said, in the first two dose-escalation cohorts there have been three complete responses (CRs), two pathologic complete responses, one partial response, one stable disease, and three patients who were not evaluable. One patient with a complete remission left the study to undergo allogeneic bone marrow transplantation.
Stein reported that therapy has been well tolerated among all 22 patients evaluable for toxicity and that no dose-limiting toxicities were seen. The maximum tolerated dose has not been reached.
Possible drug-related severe adverse events were one case of grade 2 hyperleukocytosis and differentiation syndrome, and one of grade 3 confusion in a patient with respiratory failure and sepsis.
There were four deaths within 30 days of study drug termination, which Stein said were due to complications of disease-related sepsis.
“Although the primary goal of this Phase I study was to determine the safety and tolerability of AG-221, we were pleased to find promising clinical activity even at the lowest drug dose we tested in patients with AML IDH2 mutations,” he said.
AG221 as ‘Next Big Targeted AML Therapy’?
The Discussant for this paper, John C. Byrd, MD, Chair of Leukemia Research, Director of the Division of Hematology, and Professor of Medicine and Medical Chemistry at Ohio State University Comprehensive Cancer Center, introduced his comments with the question, “Is AG221 the Next Big Targeted AML Therapy?”
The challenge is great, Byrd said, because AML is a difficult target to reach for several reasons: First, there are multiple AML subtypes based on mutations and cytogenetic aberrations, but there is no known uniform genomic aberration or dominant driving pathway to pathogenesis as in CML or other leukemia subtypes.
“The current understanding of the origin of AML is that there are two or more driving mechanisms—mechanisms that block differentiation and mechanisms that enhance survival and proliferation,” Byrd said. “The question is, do we have to target both?”
The answer to that is still unknown, he said.
Drug development for AML is complicated by the fact that the initial introduction of therapeutics is done in relapsed disease where secondary aberrations often predominate—meaning that there is a lower likelihood of seeing benefit.
Also, AML is often proliferative, which makes it difficult to observe patients on an ineffective dose or therapy for 30 days, a typical requirement of a Phase I study. And virtually all patients with AML have cytopenias, often with associated infections, which makes interpretation of disease versus drug-related events difficult.
“We need a clean agent,” Byrd said.
The trial was well planned, he said, and importantly, it included patients with advanced disease as well as elderly patients, who would not be expected to do well.
Sixteen of the 23 patients enrolled to date remain on study, Byrd noted. “This is very impressive for an AML study, even though the follow-up is short. And the fact that there are five CRs already, with two beyond two months, is very encouraging, given the dose levels and that there were no dose-limiting toxicities.
“We can conclude from this trial that AML with associated IDH2 mutations and associated onco-metabolites can be therapeutically targeted by AG221. What is most impressive to me is that AG221 thus far represents a patient-friendly therapy with a favorable therapeutic index, which really justifies moving it into early combination studies with AML. I've seen enough that I would have no problems putting an elderly patient on AG221,” Byrd said.
Some questions, though, he said, will need answers before the “Next Big Targeted Therapy” title can be bestowed:
- How durable are remissions in AML patients who have relapsed/refractory disease or are previously untreated elderly patients?
- How well does AG221 work for the more aggressive IDH2R172 mutation that is associated with older age, resistance to induction chemotherapy, and shorter survival?
- Do late side effects show up?
- How best to combine the drug with hypomethylating agents, chemotherapy, or targeted agents?
- How to sequence with other therapies?
Byrd concluded his discussion by saying that for AG221 to be the next big targeted AML therapy it will have to do better than FLT3 inhibitors and ibrutinib. “We've been working with the FLT3 inhibitiors for a long time now and at best, remission times are a few months,” and ibrutinib gives patients a few years, he said.
Whether AG221 reaches the remission levels of imatinib or all-trans retinoic acid in other hematologic malignancies remains to be seen, he said, “but the future does look interesting at this time.”
In an interview with reporters discussing new drugs described at the meeting, AACR president Carlos L. Arteaga, MD, Professor of Medicine and Cancer Biology and Professor of Breast Cancer Research at Vanderbilt-Ingram Cancer Center, noted the high complete-response rate in the Phase I AG221 study: “When we see that kind of response, we know we're dealing with a really formidable drug,” he said.