Combination Therapies Showed Improved Efficacy Against FLT3- and RAS-Mutant AML

Eytan M. Stein, MD

Treatment regimens that target mutated proteins and aberrant protein interactions have improved survival in patients with relapsed and refractory acute myeloid leukemia (AML). In a presentation at the 26th Annual International Congress on Hematologic Malignancies, Eytan M. Stein, MD, a hematologic oncologist from Memorial Sloan Kettering Cancer Center, New York, NY, reported on single agent inhibitors followed by methods to overcome resistance using combination therapy.¹

FLT3 mutations are found in 30% of patients with AML. Twenty-three percent of those mutations are FLT3 internal-tandem duplications (ITD), and the remaining 7% of those are FLT3 tyrosine kinase domain (TKD) mutations.

Stein discussed the single agent, midostaurin (Rydapt), and its poor effectiveness as a monotherapy, “In the relapsed and refractory setting, midostaurin, which is a weak FLT3 inhibitor, really has very, very little, if any, significant clinical activity.” He then compared midostaurin to quizartinib (Vanflyta), a stronger FLT3 inhibitor. In the QuANTUM-R study (NCT02039726), a randomized, phase 3 study, investigators compared quizartinib vs salvage chemotherapy in patients with relapsed or refractory AML. Median overall survival (OS) was 6.2 months (range, 5.3-7.2) in the quizartinib group and 4.7 months (4.0-5.5) in the chemotherapy group (HR = 0.76; 95% CI, 0.58-0.98; P = .02).²

A different, more efficient FLT3 inhibitor, gilteritinib (Xospata), showed an even stronger separation in survival curves between FLT3 inhibitor treatment and chemotherapy alone. The investigators of the ADMIRAL study (NCT02421939) randomized patients with relapsed or refractory FLT3-mutated AML 2:1 to receive gilteritinib or salvage chemotherapy, similar to the QuANTUM-R study.³ Results showed that the median OS was 9.3 months vs 5.6 months in the gilteritinib and chemotherapy arms, respectively (HR = .665; 95% CI, P = .0013).

The challenge, however, is that patients who received these FLT3 inhibitor treatments without following up with allogeneic stem cell transplant were likely to relapse within a year. Stein elaborated on 2 mutations that commonly show resistance, “There are mutations called FLT3 F691L, and there are mutations in NRAS and KRAS…F691L is what’s called a gatekeeper mutation. So, an amino acid gets mutated in the FLT3 protein that prevents the binding of gilteritinib.”

Moving on to IDH1 and IDH2 mutations, which are found in nearly a quarter of patients with AML, Stein covered OS of the single agents, ivosidenib (Tibsovo), an IDH1 inhibitor, and enasidenib (Idhifa), an IDH2 inhibitor. “At 12 to 16 months is where patients are start to show signs of relapse. You see a similar thing with the IDH2 inhibitor and enasidenib, where there is a drop off and patients become resistant to this therapy, even if they initially responded.”

Stein pointed out that common causes for resistance in cancer and especially AML are second site mutations and clonal evolution, including RAS pathway mutations.

Stein noted a colleague of his at Memorial Sloan Kettering Cancer Center, Brian Ball, MD, who found effective results using intense induction chemotherapy to get rid of RAS mutations in patients with AML.⁴ “These patients with RAS mutations received intensive induction chemotherapy. The RAS mutations went away. And at the time of clinical relapse…those RAS mutations did not reappear. So, [an argument could be made] that maybe we should be combining some of these targeted agents, like FLT3 and IDH inhibitors, with intensive chemotherapy to eliminate…the most common source of clonal evolution, which is RAS-mutant disease,” he posed.

Stein presented the findings from the RATIFY study (NCT00651261), which looked at treatment-naïve patients with AML with activating FLT3 mutations.5 Patients were randomized to receive cytarabine (Cytosar-U), daunorubicin (Cerubidine), and midostaurin or cytarabine, daunorubicin, and placebo. Results showed that the median OS favored the midostaurin group at 74.7 months (95% CI, 31.5-not reached) vs the placebo group with a median OS of 25.6 months (95% CI, 18.6-42.9; P = .009). These results support midostaurin and intense induction chemotherapy as a standard of care for patients with FLT3-mutant AML.

A recent phase 3 trial, QuANTUM-First (NCT02668653) met its primary end point of OS.6 Quizartinib added to standard induction chemotherapy demonstrated significantly better OS compared to chemotherapy alone in patients with FLT3-ITD positive AML. Safety of quizartinib was also manageable. These results further support the combination of FLT3 inhibitors used in combination with chemotherapy.

IDH inhibitors added to induction chemotherapy had a similar effect. In a phase 1 study (NCT02632708), researchers at Memorial Sloan Kettering Cancer Center administered either ivosidenib, IDH1 inhibitor, or enasidenib, an IDH2 inhibitor, along with intensive chemotherapy to patients with newly diagnosed AML.7“And when you combine ivosidenib with induction chemotherapy, you get a 70% overall survival at about 2.5 years. It’s similar when you combine enasidenib with intensive induction chemotherapy.”

In conclusion, Stein covered that single agents find resistance when it comes to second site mutations and clonal evolution, and RAS pathway are a common form of clonal evolution and resistance to FLT3 and IDH inhibitors. He suggested that combining targeted therapies with broadly active treatments, like chemotherapy, should be investigated further. 

_References

_{1. Stein, E. Clinical benefits and challenges with targeted therapies in AML. 26th Annual International Congress on Hematologic Malignancies. February 24-27, 2022. General Session. https://event.arraylive.com/arraylearn/virtual-client-app/home?view=d1938cfd-e330-4969-9fe8-31c2d4cb7252}

_{2. Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial [published correction appears in Lancet Oncol. 2019 Jul;20(7):e346]. Lancet Oncol. 2019;20(7):984-997. doi:10.1016/S1470-2045(19)30150-0}

_{3. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688}

_{4. Ball BJ, Hsu M, Devlin SM, et al. The prognosis and durable clearance of RAS mutations in patients with acute myeloid leukemia receiving induction chemotherapy. Am J Hematol. 2021;96(5):E171-E175. doi:10.1002/ajh.26146}