Jay Yang, MD, explains that drug development is not as simple as identifying a molecular target and matching inhibitor.
Jay Yang, MD
The treatment paradigm of acute myeloid leukemia (AML) has seen 5 FDA approvals in the past 1.5 years, but could be strengthened by novel second-generation FLT3 inhibitors as well as BCL-2 inhibitors, explained Jay Yang, MD.
“It has been really exciting and refreshing as a leukemia physician,” said Yang. “It's always good to have new and better therapies that give us more options for our patients.”
Following the FDA approval of midostaurin (Rydapt), enasidenib (Idhifa), CPX-351 (Vyxeos), gemtuzumab ozogamicin (Mylotarg), and ivosidenib (Tibsovo), the FDA received a supplemental new drug application (sNDA) for venetoclax (Venclexta) in combination with a hypomethylating agent or low-dose cytarabine.
The sNDA was submitted for the frontline treatment of patients with AML who are ineligible for intensive chemotherapy based on 2 phase Ib/II trials that demonstrated complete remissions (CRs) in more than 60% of patients.1
Though venetoclax may be nearing regulatory approval, Yang noted that quizartinib has also made an impact in clinical studies. In August, the FDA granted a breakthrough therapy designation to the FLT3 inhibitor for adult patients with relapsed/refractory FLT3-ITD—positive AML. The designation was announced following the results of the phase III QuANTUM-R study, in which there was a 24% reduction in the risk of disease progression or death compared with salvage chemotherapy following frontline treatment.2
Hedgehog inhibitors and spliceosome inhibitors are also under investigation, but in an interview during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Yang explained that drug development is not as simple as identifying a molecular target and matching inhibitor. With better understanding of the genetic mutations that present in this disease, he said physicians will be able to further enhance the treatment landscape.Yang: AML is an aggressive hematopoietic malignancy. It is one that has been notoriously difficult to treat. For many decades now, we've been struggling to find better and novel therapies for patients with this disease. Over the past 5 to 15 years, there has been a lot of development in understanding the genetic mutations that are seen in this disease. The discovery of these mutations means that sometimes we can find targeted therapies. We have targeted FDA-approved therapies for some of these mutations, and that can be extremely relevant for our patient population. There are a large number of mutations that are found in AML. There are currently more than 70 mutated genes in the AML genome. All of these could potentially be targets for drug therapies. However, only a few of them have been successful so far. The main ones are FLT3, which comes in 2 forms—–TKD and ITD mutations—– and IDH1/2 mutations. As of now, all 3 of those are targetable. For many years, we have been looking at our colleagues who treat multiple myeloma, Hodgkin lymphoma, B-cell lymphoma, and also chronic myeloid leukemia and chronic lymphocytic leukemia. [All those malignancies have] new drugs for patients. In the past 18 months, there have been 5 drug approvals in AML.There are a couple of drugs that could be nearing regulatory approval. One of them is venetoclax, which is an antiapoptotic protein. It's a BCL-2 inhibitor that has shown some activity in relapsed/refractory AML as a single agent. We've been most impressed by venetoclax in newly diagnosed, treatment-naïve patients who are not fit for intensive chemotherapy. The combination of venetoclax with either low-dose cytarabine or hypomethylating agents has been very impressive, perhaps more than anyone would have expected. It's probably one of the biggest developments in the past year or so. For this reason, there is a lot of interest in it. It very well could become available in the clinic in the near future.
The other potential drug that I could see reaching the clinic might be quizartinib. Of course, we have midostaurin, but it's a first-generation multikinase FLT3 inhibitor. It doesn’t have much activity for relapsed/refractory patients, but for newly diagnosed patients it is approved in combination with standard chemotherapy.
Quizartinib is a second-generation FLT3 inhibitor. It is much more potent against FLT3-ITD— mutated AML. In the relapsed/refractory setting, data have recently been presented showing that it is better, to some degree, than standard chemotherapy. Statistically speaking, it showed an improvement in overall survival. Some would say the results are a little bit modest, but there is a fairly good chance that it will be approved based on those results. That is an interesting drug. It is completely different than anything else that's in the pipeline. It's a hedgehog pathway inhibitor. As a single agent, it has not shown much activity in AML. However, in combination with chemotherapy and in combination with hypomethylating drugs, it has shown some additional activity. In randomized phase II trials, very promising results were presented. There is a randomized phase III trial looking at chemotherapy with or without this hedgehog inhibitor. Time will tell whether this will be fruitful or not.Despite all the drug approvals, there are still a lot of challenges. Targeting molecular mutations like FLT3 and IDH1/2 you might consider [to be] the lowest hanging fruit. These are common mutations, and they were able to rapidly develop drugs that specifically target those mutations. Going forward, it's going to be a little bit tougher. There are a lot of mutations out there, but AML is a very tricky and difficult disease to treat. Just because you have a drug that can target a mutation, doesn't mean that it's going to be effective.The one that is interesting to me is the spliceosome modulator; there is a class of mutations called spliceosome mutations. There are 4 of them—–SF3B1, SRSF2, and ZRSR2, and U2AF1. They are fairly common, especially in myelodysplastic syndrome (MDS). More than 50% of patients with MDS will carry one of these mutations, and perhaps 20% to 30% of patients with AML will also carry this mutation. H3B-8800 is a spliceosome modulator and is currently being evaluated in a phase I/II study in the clinic. We're participating in that clinical trial as well. One important topic is minimal residual disease (MRD). We've known about this for a long time. We know that patients, even if they're in morphologic or cytogenetic remission (CR), many times we can still measure MRD by more specific techniques—whether it be flow cytometry or polymerase chain reaction-based techniques. Patients who are in remission but who are MRD-positive have a much higher relapse rate than those who are MRD-negative. If a patient is MRD-positive, despite reaching a complete response, they might benefit from having an allogeneic stem cell transplant. That's important. The problem is, there's no standardized testing for MRD. That really should be a priority moving forward for investigators.