Targeted Therapies End the Dry Spell in AML Drug Development

Mark J. Levis, MD, PHD

Courtney Dinardo, MD, MSCE

Targeted agents are routinely used to treat many cancers and have improved outcomes for patients with solid tumors and hematological malignancies alike. Recently, targeted therapies made their way into the armamentarium for acute myeloid leukemia (AML), representing the first therapeutic advances for AML in decades.¹Since 2017, the FDA has approved at least 6 molecularly targeted drugs for AML, including inhibitors of FMS-like tyrosine kinase 3 (FLT3), isocitrate dehydrogenase (IDH) 1, IDH2, B-cell lymphoma 2 (BCL2), and the Hedgehog pathway. The advances are especially pertinent for elderly patients, who account for most new diagnoses, are more likely to have cytogenetic aberrations, and have worse outcomes than their younger counterparts.²Elderly patients are often unfit for standard intensive chemotherapy or hematopoietic stem cell transplant.^3,4

Ongoing clinical trials are evaluating other investigational agents and combination regimens, making it likely the armamentarium for AML will continue to expand. In addition to agents that target IDH or FLT3, investigators are assessing drugs with novel targets, such as BET, LSD1, NPM1, DOT1L, BRDR4, or MDM2.¹Antibody—drug conjugates that target CD33 and other isotopes are in development.

FLT3 Inhibitors

FLT3 inhibitors are classified as first- or second-generation based on their selectivity for FLT3, a receptor tyrosine kinase that promotes proliferation and survival of hematopoietic cells.⁵

“FLT3 is the gene most commonly mutated in AML;FLT3mutations occur in more than one-quarter of all patients,” said Mark J. Levis, MD, PhD, director of the Adult Leukemia Service and professor of oncology, medicine, and pharmacology at Johns Hopkins University School of Medicine in Baltimore, Maryland. AnFLT3mutation predicts more aggressive disease.^1,6Approximately 75% ofFLT3mutations are internal tandem duplication (ITD) mutations,⁷and the rest are point mutations in the tyrosine kinase domain (TKD).⁸FLT3 inhibitors are further categorized as type I (pan-FLT3 inhibitors) when active againstFLT3-ITD andFLT3-TKD mutations or as type II when active primarily againstFLT3-ITD mutations.⁵Treatment with type II FLT3 inhibitors can lead to the emergence of FLT3-TKD—resistant clones and faster relapse.¹

Midostaurin (Rydapt) was the first FLT3 inhibitor approved by the FDA and is indicated in combination with standard induction and consolidation chemotherapy for FLT3-positive adults with newly diagnosed AML.⁹Approval was based on findings from the phase III randomized placebo-controlled RATIFY trial, which included 717 patients aged 18 to 61 years with an activatingFLT3mutation.⁷Compared with placebo, midostaurin significantly prolonged overall survival (OS; HR, 0.78; 1-sidedP= .009) and event-free survival (EFS; HR, 0.78; 1-sidedP= .002) with similar efficacy in patients withFLT3-ITD orFLT3-TKD mutations.⁷

Gilteritinib (Xospata) is a highly selective FLT3 inhibitor approved as monotherapy for relapsed or refractory AML in FLT3-positive adults.⁶Gilteritinib also inhibits AXL, a receptor tyrosine kinase frequently upregulated in AML that drives resistance to FLT3 inhibition.⁶Levis is an investigator for the phase III ADMIRAL trial that led to FDA approval in November 2018, which he described as “the culmination of years of effort to develop an FLT3 inhibitor.” The FDA also approved a companion assay to screen patients forFLT3mutations. “Patients should be tested at diagnosis and at every major clinical change, such as relapse or disease progression,” said Levis.

The ADMIRAL trial compared gilteritinib 120 mg daily with salvage chemotherapy in adults with relapsed or refractory AML and an FLT3 mutation.¹⁰An unpublished interim analysis showed 21% (29/138) of patients in the gilteritinib arm had achieved complete remission (CR) or CR with partial hematologic recovery at median follow-up of 4.6 months.¹⁰Detailed safety data were not reported, but in the phase I/II CHRYSALIS trial, a dose-escalation study of gilteritinib salvage therapy, the most common treatment-related adverse events (TRAEs) were diarrhea, fatigue, and elevated liver enzymes.⁶

Levis said gilteritinib is more potent and better tolerated than midostaurin or sorafenib (Nexavar), a multikinase inhibitor studied in AML.⁶“Gilteritinib can induce responses as a single agent, which is never the case for midostaurin and is much less likely with sorafenib,” Levis said. Several clinical trials “incorporating this drug into all phases of therapy—from frontline to posttransplant maintenance” are underway and that a head-to-head comparison of gilteritinib versus midostaurin in newly diagnosed AML will soon begin recruiting, he said.

In the phase III QuANTUM-R trial, 367 adults with relapsed/ refractoryFLT3-ITD—positive AML were randomized 2:1 to quizartinib monotherapy or chemotherapy.¹¹Quizartinib prolonged OS significantly more than chemotherapy (6.2 vs 4.7 months, respectively; HR, 0.76; 95% CI, 0.58-0.98; 1-sidedP= .0177) but did not significantly improve EFS.¹¹The CR composite rate was 48% in the quizartinib arm versus 27% in the chemotherapy arm (P= .0001). The most common grade ≥3 TRAEs in both arms were infections and cytopenia. An approval decision from the FDA regarding quizartinib is anticipated in May 2019.¹²

Crenolanib was evaluated with intensive chemotherapy in a phase II trial that included 44 adults with newly diagnosed AML and activatingFLT3mutations.¹³Analyses of data for 27 participants aged ≤60 years found that 81% were alive at median follow-up of 24 months. Investigators are now recruitingFLT3-positive patients aged 18 to 60 with newly diagnosed AML for a phase III randomized trial comparing crenolanib with midostaurin after induction and consolidation therapy.¹³

IDH Inhibitors

IDH1andIDH2are primarily somatic mutations that occur in about 20% of patients with AML.¹⁴The FDA recently approved ivosidenib (Tibsovo) and enasidenib (Idhifa). Ivosidenib is indicated for patients with relapsed or refractory AML with anIDH1mutation and enasidenib is indicated for patients with relapsed or refractoryIDH2-mutated AML.

Courtney DiNardo, MD, MSCE, assistant professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, helped develop ivosidenib. “About 8% of patients with AML have anIDH1mutation. They are enriched in the older patient population, so the older you are, the more likely anIDH1mutation is present,” said DiNardo. Approval was based on data for 174 adult patients with relapsed/refractoryIDH1-positive AML who received ivosidenib 500 mg daily in a single-arm during a phase I dose-escalation trial.¹⁵The rate of CR plus CR with partial hematologic recovery was 32.8% (95% CI, 25.8%-40.3%). “About 20% of patients who respond to ivosidenib actually clear theIDH1mutation,” DiNardo said, adding that this may predict more durable responses, although more data are needed.

The most frequent serious TRAEs in the study were leukocytosis, QT prolongation, and differentiation syndrome, a potentially fatal event.¹⁶Labels for both ivosidenib and enasidenib include a black box warning concerning differentiation syndrome,^{16, 17}which according to a FDA study occurs in approximately 20% of patients.¹⁸Symptoms include dyspnea, unexplained fever, weight gain, hypotension, acute kidney injury, and pulmonary infiltrates/ pleuropericardial effusion. Differentiation syndrome can arise days or months after starting treatment and requires prompt corticosteroid treatment.^16,17

Enasidenib was evaluated in a phase I/II trial featuring 109 adults with relapsed/refractory AML and anIDH2mutation.¹⁹The overall response rate was 40%, median response duration was 5.8 months, and median OS was 9.3 months. Approximately 19% of patients attained CR.¹⁹

Ivosidenib and enasidenib are each being evaluated in combination with standard induction and consolidation therapy for newly diagnosed AML.¹⁴Both are also being investigated in combination with azacitidine in patients with newly diagnosed AML who are ineligible for intensive chemotherapy. Several other IDH inhibitors are being studied in clinical trials, including AG-881, which is active against IDH1 and IDH2.¹⁴

Treatment of AML in Patients Unsuited for Intensive Chemotherapy

Individuals 65 years and older account for almost 60% of new cases²and generally have a poor prognosis.²⁰Comorbidities often prevent elderly patients from receiving intensive chemotherapy. Other biological factors may preclude patients of any age from receiving intensive chemotherapy, including unfavorable cytogenetic profile, prior systemic therapy, or a history of myelodysplastic syndrome or myeloproliferative neoplasm.²⁰

In 2018, the FDA approved 2 targeted agents for patients with newly diagnosed AML who are 75 years or older or otherwise ineligible for intensive chemotherapy: venetoclax (Venclexta), a BCL2 inhibitor; and glasdegib (Daurismo), a Hedgehog pathway inhibitor.^{21, 22}Although both are molecularly targeted agents, their use is not restricted to individuals with cytogenetic abnormalities. Venetoclax is administered with a hypomethylating agent (HMA) such as azacitidine, decitabine, or low-dose cytarabine (LDAC); and glasdegib is given with LDAC.^21,22

Accelerated approval of venetoclax was based on findings from 2 open-label clinical trials involving patients with newly diagnosed AML. Study M14-358 included 145 patients 65 years and older who were ineligible for intensive chemotherapy. Overall, 67% of patients achieved CR or CR with incomplete count recovery, maintained for a median of 11.3 months.²³Median OS was 17.5 months overall and not reached in the cohort treated with 400-mg venetoclax plus an HMA. Study M14-387 included 61 patients 60 years and older who received venetoclax plus LDAC.²⁴DiNardo said the combination of venetoclax with an HMA was “well tolerated and effective” and she expects it will become standard care for patients who cannot tolerate intensive chemotherapy. She said a phase III study of venetoclax plus azacitidine is underway, as are other combination studies.

Glasdegib received FDA approval based on results from the phase II BRIGHT 1003 trial, which randomly assigned adults with newly diagnosed AML 2:1 to glasdegib plus LDAC (n = 77) or LDAC only (n = 38).²⁵The CR rate in the combination arm was 18.2% compared with 2.6% in the LDAC-only arm. The addition of glasdegib to LDAC was associated with a 54% reduction in the risk of death.²⁵

Conclusions

Drug discovery for AML is encouraging, with several new drugs approved and others under investigation in clinical trial results. “These therapies are already improving the outcomes of patients in the clinic,” DiNardo said. “Future rational combinations with these novel agents will serve to even further improve upon AML therapy,” she said.

“The addition of targeted therapies—in combination with the ability to do a bone marrow transplant more safely—is increasing the overall cure rate for most patients,” Levis said. The next focus “is to use targeted agents only, phasing out intensive chemotherapy,” he added.

The National Comprehensive Cancer Network has updated its guidelines for AML²⁶to help physicians determine when it is appropriate to incorporate the newly approved therapies. Physicians should also consult the prescribing information for additional information about the risks, benefits, and precautions required when treating patients with one of the new AML drugs.

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