Editorial theme | Novel combination therapies using targeted agents 

During the American Society of Clinical Oncology (ASCO) meeting in 2018, the AGP spoke to Uma Borate about how targeted therapies will impact the treatment of AML. Uma Borate discussed targeted agents, such as venetoclax, azacitidine, ivosidenib, and enasidenib.

Precision medicine may have a particular role in the treatment of older patients, since this population are often unable to receive allo-HSCT or intensive chemotherapy regimens. During the 61^st American Society of Hematology (ASH) meeting, the AGP spoke to John Byrd about how precision medicine may be used to improve the outcomes of older patients with AML.

The AGP interviewed Courtney DiNardo about the treatment of elderly or frail patients with AML at the 1^st National Cancer Research Institute (NCRI) AML Academy Meeting. Watch Courtney DiNardo discuss how the treatment approach for this patient group has changed in recent years with the advent of combination therapies below.

Isocitrate dehydrogenase (IDH) inhibitor combinations

Studies have shown that epigenetic dysregulation can promote a preleukemic state that precedes leukemic transformation. Drugs targeting epigenetic dysregulation have been developed and include: azacitidine and decitabine, which are hypothesized to reverse DNA hypermethylation and reactivate repressed tumor suppressor genes; ivosidenib and enasidenib, which target IDH1 and IDH2 mutations thought to be involved in aberrant DNA hypermethylation.² Combining these agents may improve patient outcome compared to azacitidine monotherapy.

Ivosidenib/enasidenib plus azacitidine: phase I/II study: AG221-AML-005 (NCT02677922)^5,6,7

Patients with newly diagnosed AML, with either IDH1 mutations (mIDH1) or IDH2 mutations (mIDH2), were treated with azacitidine plus ivosidenib (for mIDH1) or enasidenib (for mIDH2).

• The phase Ib results were presented at the European Hematology Association (EHA) meeting in 2018.^5,6
• The ivosidenib cohort has progressed to a multicenter, double-blind placebo controlled, randomized, phase III trial, AGILE (NCT03173248). This trial will compare ivosidenib versus placebo in combination with azacitidine in previously untreated patients with AML with IDH1^5,6
• Updated results from the phase II randomized study of enasidenib versus azacitidine monotherapy were recently presented at the 61st ASH meeting.⁷ The results showed enasidenib plus azacitidine significantly improved overall response rate (71% vs 42%,respectively) and complete response rate (53% vs 12% respectively) compared to azacitidine alone and was well tolerated.⁷

Ivosidenib/enasidenib plus standard chemotherapy⁸

• Phase I study (NCT02632708) of patients with AML who are unfit for intensive chemotherapy at diagnosis
• Ivosidenib (n= 49) or enasidenib (n= 89) with cytarabine and either daunorubicin or idarubicin
  • Induction (1–2 cycles): ivosidenib or enasidenib with cytarabine and daunorubicin or idarubicin
  • Consolidation (≤4 cycles): ivosidenib or enasidenib plus cytarabine
  • Maintenance (up to two years from Day 1 of induction): ivosidenib or enasidenib
• CR (ivosidenib vs enasidenib): 71% vs 56%
• Estimated 12-month overall survival (OS) after induction Day 1 (ivosidenib vs enasidenib): 79% vs 75%

A phase III study, HOVON 150/AMLSG 29-18, is comparing enasidenib or ivosidenib (by mIDH status) plus chemotherapy (7+3) versus placebo.⁹ An overview of IDH inhibitors, including further information on the data from trials involving these combination therapies, is available here.

FLT3 inhibitor combinations

Other new targets for AML therapies are the FLT3 pathways. FLT3 is a transmembrane tyrosine kinase with two mutational subtypes: an internal tandem duplication (ITD) or point mutations in the tyrosine kinase domain (TKD).⁴ A third of patients with de novo AML have mutations in the FLT3 gene and patients with FLT3-ITD AML have a poor prognosis. FLT3 is therefore an attractive target for therapeutic agents, with several FLT3 inhibitors in clinical development, such as sorafenib, midostaurin, quizartinib, crenolanib, and gilteritinib.^2,4

Examples of combination therapies involving FLT3 inhibitors are shown in Table 1 below. One example of a trial involving a FLT3 inhibitor is the RATIFY (NCT00651261) trial. The RATIFY trial assessed whether the addition of midostaurin to standard chemotherapy could prolong survival in newly diagnosed adult patients with FLT3-ITD AML compared to placebo + chemotherapy. The results showed midostaurin prolonged median OS and event-free survival (EFS) compared to placebo¹⁰:

• Median OS (midostaurin vs placebo): 74.7 (95% CI, 31.5–not reached) vs 25.6 (95% CI, 18.6–42.9) months
  • Hazard ratio (HR) for death: 0.78; 95% CI, 0.63–0.96; p= 0.009
• Median EFS (midostaurin vs placebo): 8.2 (95% CI, 5.4–10.7) vs 3.0 (95% CI, 1.9–5.9) months
  • HR for an event: 0.78; 95% CI, 0.66–0.93; p= 0.002

However, the authors questioned if more specific FLT3 inhibitors could further improve outcomes.¹⁰

Venetoclax combinations

Another example of a targeted agent for the treatment of AML is venetoclax, which is a Bcl-2 inhibitor. Venetoclax is approved by the U.S. Food & Drug Administration (FDA) for the treatment of newly diagnosed patients with AML who are not eligible for intensive induction chemotherapy, in combination with azacitidine, decitabine, or low dose cytarabine.¹³

Results from a phase Ib study (NCT02203773) investigating venetoclax with decitabine or azacitidine showed that these combination therapies led to a 61% complete remission or complete remission with incomplete marrow recovery rate in newly diagnosed patients with AML aged 65 and over.¹⁴ A phase III study (NCT02993523) comparing venetoclax plus azacitidine to azacitidine alone in patients with treatment-naïve AML is ongoing.¹⁵

During the Acute Leukemias XVII Biology and Treatment Strategies biennial symposium, Andrew Wei gave a presentation on novel therapeutic combinations containing venetoclax for the treatment of AML.

There are a number of ongoing studies of venetoclax in combination therapies and examples of these include⁴:

• Venetoclax + gilteritinib — R/R AML — NCT03625505
• Venetoclax + ivosidenib — IDH1 mutated AML — NCT03471260
• Venetoclax + azacitidine vs azacitidine alone — treatment-naïve patients with AML who are ineligible for standard induction — NCT02993523

During the 2018 ASCO meeting, the AGP spoke to Courtney DiNardo about the combination of venetoclax with hypomethylating agents (HMAs).

Subsequently, during the Society of Hematologic Oncology (SOHO) meeting in 2019, the AGP spoke to Jeffrey Lancet about the potential of venetoclax + HMAs to replace induction chemotherapy.

The AGP spoke to Marina Konopleva at the 2019 EHA meeting about Bcl-2 as a universal target in AML.

Conclusion

The development of targeted therapies and novel combinations holds promise for the treatment of AML, especially when compared to currently approved options. In some cases, these combinations may be more efficacious than intensive induction chemotherapy. In addition, some patients have been able to undergo allo-HSCT following treatment with a novel combination, which may indicate that the future of AML treatment will be in novel combinations and involve less chemotherapy. Additionally, these combinations appear tolerable to date.

Despite the promising results seen so far, not all patients respond equally. In order to maximize response to these therapies, it will be important to identify the right patient subgroups, with specific mutations, and may require particular combinations of agents to be used.²