Daver Investigates Combination Therapy in TP53-, FLT3-Mutated AML

Naval G. Daver, MD

Naval G. Daver, MD

Venetoclax (Venclexta) has revolutionized the treatment of elderly patients with acute myeloid leukemia (AML). The BCL-2 inhibitor has shown activity in this patient population as a single-agent with an acceptable toxicity profile, and researchers have since turned to look at combination approaches with venetoclax.

For example, venetoclax is being investigated in combination with the hypomethylating agents (HMAs) azacitidine (Vidaza) or decitabine (Dacogen), as well as with low-dose cytarabine. Venetoclax had received approval from the FDA for use in combination with each of these agents for the treatment of newly diagnosed patients with AML who are ≥75 years or who have comorbidities that preclude them from receiving intensive induction chemotherapy.

According to data presented at the 2019 ASCO Annual Meeting, patients with theTP53mutation treated with either azacitidine or decitabine plus venetoclax achieved an objective response rate (ORR) of 47% in the frontline and 24% in the relapsed setting. This trial compared the combination therapy to single-agent treatment with azacitidine or decitabine. Patients experienced similar ORRs to the monotherapy but achieved a higher rate of complete responses (CRs) with the combination regimen.

In addition, investigators are also looking at the role of FLT3 inhibitors in elderly patients with AML. Gilteritinib (Xospata) was approved by the FDA for adult patients with relapsed/refractory FLT3-mutant acute myeloid leukemia (AML), based on the results from the phase III ADMIRAL trial. Quizartinib, another FLT3 inhibitor, is under review by the FDA for this patient population.

The label forgilteritinib was also recently approved by the FDAfor an update with more recent overall survival (OS) data from the ADMIRAL study, which also demonstrated an improvement with gilteritinib over salvage chemotherapy (9.3 vs 5.6 months; HR, 0.637; 95% CI, 0.490-0.830; P = .007). The FDA is scheduled to make a decision on the quizartinib approval by August 25, 2019; however, theOncologic Drugs Advisory Committee panel recently voted8-3 against approval of the agent. The panel had found concerns with the generalizability of the trial data showing an improvement over salvage chemotherapy.

Quizartinib has also been investigated in combination with azacitidine, and newer trials are looking at combinations with venetoclax, too. Although data have shown that these combinations could further improve the response rate and survival in patients harboring theFLT3mutation, quizartinib should first be approved before finding combinations that could best improve the median OS.

“One of the nice things about these combinations is they are mutation-agnostic, so we don’t exclude people with FLT3, IDH, or any other mutations,” said Naval G. Daver, MD. “In the community, physicians love this because they are able to start treatment right away without having to necessarily wait for all the mutational data.”

In an interview withTargeted Oncology, Daver, associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, discussed the possibility of combination therapy in patients with AML. He highlights some of the most recent data to come out for this patient population, including for those harboring aTP53orFLT3mutation.

TARGETED ONCOLOGY: Can you discuss the activity of venetoclax-based therapy inTP53-mutated AML?Daver:There are some recent data that our group is presenting here at this ASCO meeting. For some background in AML, 1 of the major breakthroughs has been the development of combinations with venetoclax, specifically 2 combinations. One is with HMAs of either azacitidine or decitabine, and the other is low-dose cytarabine with venetoclax. Both of these were evaluated in 2 phase II studies that have been published recently and have actually resulted in the FDA approval of both combinations about 6 months ago. Both of these showed that in elderly patients with azacitidine or decitabine with venetoclax, we could get response rates of about 70% to 75% with a median overall survival (OS) of 18 to 20 months, which is about 2 to 3 times higher than we were getting with azacitidine or decitabine alone. This is a really major improvement, and even in 3-year follow-up, we were seeing about 45% alive, which in elderly AML has historically been 10% to 15%. This has really revolutionized the treatment of elderly AML, same with the low-dose cytarabine plus venetoclax, which is a little bit lower in response rates. However, compared to single-agent low-dose cytarabine, it’s about 4 or 5 times higher.

Because of this, we are frequently using them in the frontline setting. One of the nice things about these combinations is they are mutation-agnostic, so we don’t exclude people withFLT3,IDH, or any other mutations. In the community, physicians love this because they are able to start treatment right away without having to necessarily wait for all the mutational data; if they feel the patient is not a candidate for intensive chemotherapy or is elderly, the HMA or low-dose cytarabine with venetoclax combinations are quite effective.

TARGETED ONCOLOGY: What challenges have you come across with these combinations?Daver:The issue is, though, that while they work quite well in most patients, there are certain subsets where we are seeing survival has not improved dramatically. One of them is TP53-mutated patients, the other is patients who have complex or adverse cytogenetics. Both of these groups often overlap each other. With theTP53-mutated AML [population] in the frontline setting, although the response rates were quite high at about 55% to 60%, we see the median OS is about 6 to 9 months. In the relapsed setting with patients with TP53, it’s actually quite dismal with a survival of only 3 to 4 months. The bottom-line is that, I think, forTP53-mutated, complex cytogenetics, and potentially for patients with secondary AML, we still have not completely changed their outlook with the HMA/venetoclax [combination]. It’s a decent regimen, but we need to find other things to either add to it or that work independently. A lot of that research is being looked at with bispecific antibodies, immune therapies including PD-1 inhibitors and CTLA-4 inhibitors, and potentially CAR T cells.

TARGETED ONCOLOGY: Could you also discuss the current significance of FLT3 mutations in AML?Daver:FLT3 inhibitors have a lot of data. There are 2 major FLT3 inhibitors that are being evaluated in the relapsedFTL3-mutated AML space. These are quizartinib and gilteritinib. Both of these are extremely potent, second-generation, selective FLT3 inhibitors, and both of them in the last year completed phase III studies. The design of the phase III study was either quizartinib or gilteritinib in the individual study, randomized versus chemotherapy, which could be the investigator’s choice; they had 3 or 4 options including high-dose chemotherapy or low-dose chemotherapy.

TARGETED ONCOLOGY: What data have we seen so far for quizartinib?

Daver:The first study to report out was the quizartinib QuANTUM-R study in the relapsed population. They had about 400 patients, and they saw that the patients that got quizartinib had about double the response rate as those that got standard chemotherapy, which was quite striking because the chemotherapy was usually a 2- or 3-drug, high-dose, IV chemotherapy given in the hospital as compared to single-agent oral quizartinib. Even though this was a much easier, outpatient, tolerable oral therapy, it gave 2 times higher CR/CRi rates. The median OS, which was the primary endpoint of the study, was significantly improved with quizartinib. This was the first study in the relapsed setting that established that a single, oral, potent FLT3 inhibitor could overcome the high-dose multiple chemotherapy approach. This study is being reviewed by the FDA currently, and we hope the drug will become available.

We have also done a lot with combinations with quizartinib with azacitidine, and we’re looking at it with venetoclax. It seems like you can further improve the response rate and survival. Getting the drug approved is the first step, but then combining it would further improve the median OS outlook.

TARGETED ONCOLOGY: Could you also speak to the importance of gilteritinib in these patients?

Daver:Similarly with gilteritinib, which is actually already FDA approved, this study went out a few months after the quizartinib study, but also showed very similarly that you could double the ORR. One of the major advantages with gilteritinib is there was also better [hematologic] count recovery because it is myelosuppressive. There also seems to be better activity against theFLT3-TKD mutation. Based on this, gilteritinib is approved in the relapsed setting, and now we are doing a number of combinations with gilteritinib with venetoclax, with decitabine, and with immunotherapy. I think forFLT3