While 2017 was a watershed moment for the treatment of AML with the approval of the FLT3 inhibitor Rydapt® (midostaurin, Novartis), IDH2 inhibitor Idhifa® (enasidenib, Agios / Celgene), liposomal chemotherapy Vyxeos™ (CPX-351, Jazz) and re-introduction of the CD33 antibody-drug conjugate Mylotarg® (gemtuzumab ozogamicin, Pfizer), 2018 is shaping up to be even more impactful. This year there have been FDA approvals for the IDH1 inhibitor Tibsovo® (ivosidenib, Agios) and the FLT3 inhibitor Xospata® (gilteritinib, Astellas) in the relapsed setting, and approvals of the SMO inhibitor Daurismo™ (glasdegib, Pfizer) and the BCL2 inhibitor Venclexta® (venetoclax, Roche / AbbVie) for newly-diagnosed patients. This influx of new therapies with novel mechanisms of action for molecularly and clinically defined patient types is absolutely stunning given that up until 2017 there were no targeted agents approved for treating AML.
Addressing unmet need in unfit/elderly patients
Treatment for frontline AML remains heavily dictated by a patient’s ability to receive intensive chemotherapy. “Fit” patients who can tolerate an aggressive induction regimen are most often treated with a combination of cytarabine and an anthracycline (7 + 3 or 5 + 2 dosing schedule). While highly toxic, these regimens can induce high rates of remission, upwards of 60-70%. For elderly patients or those “unfit” for intensive chemotherapy (estimated at 30% to 40% of patients1), treatment options are limited and more tolerable single agent hypomethylating agents (HMA) such as azacitdine or decitabine, or low-dose cytarabine (LDAC) are standards of care. The unmet need in these patients is high, and the lack of therapeutic options that induce high remission rates has manifest in higher rates of no treatment in elderly versus young patients1 and dismal survival rates (2.6% for age >75 years of age) that have not improved over the last 40 years2.
New options for unfit/elderly include agents that effectively target leukemic stem cells.
In patients who are aged 75 years and older or are ineligible for intensive chemotherapy due to coexisting medical conditions, Venclexta in combination with either azacitidine, decitabine or lose-dose cytarabine (LDAC), and Daurismo in combination with LDAC, were approved by the FDA in November 2018.
Daurismo garnered approval based on the randomized Phase II BRIGHT 1003 study (NCT01546038) in which 115 patients with newly-diagnosed AML who were unfit for intensive induction therapy were randomized 2:1 to receive Daurismo plus LDAC or LDAC alone. The median overall survival (mOS) was 8.3 months for the combination compared with 4.3 months with LDAC alone (HR 0.46, p=0.0035)3. The complete response (CR) rate was 18.2% with the combination compared with 2.6% with LDAC alone. The combination was well tolerated, and toxicities were consistent with LDAC alone with associated Hedgehog inhibitor class side effects such as fatigue, myalgia, dysgeusia, and alopecia.
Venclexta also gained accelerated approval, however across a broader range of combinations based on two single arm Phase Ib/II studies. Data originally presented at ASCO 2018 from the Phase 1b M14-358 study (NCT02203773) showed Venclexta in combination with azacitidine or decitabine resulted in an impressively high CR plus complete remission with incomplete heme recovery (CRi) rate totaling 73%4. The median overall survival (OS) in all Venclexta dose groups was 17.5 months and considered ground-breaking when put in historical context of single agent HMA CR/CRi rates of 18-28% and mOS of 7.7-10.4 months5,6. Common side effects include nausea, diarrhea, constipation, cytopenias, although notably there were no instances of clinical tumor lysis syndrome (TLS).
The approval for Venclexta combined with LDAC is based on the Phase I/II M14-387 study (NCT02287233), presented at EHA 2018, which showed a similarly impressive CR/CRi rate of 62% and a median OS of 11.4 months7. This activity is impressive compared to historical data that shows LDAC produces CR/CRi rates of 25% and mOS of ~4 months8.
Updated data at ASH 2018 on Venclexta suggests rapid, deep and durable responses.
Updated data with longer follow-up in the 400 mg Venclexta expansion cohort of M14-358 (84 patients treated with Venclexta plus azacitidine, 31 treated with Venclexta plus decitabine) was presented by Daniel Pollyea at the 2018 annual meeting of the American Society of Hematology (ASH)9. Here, CR/CRi rates of 71% and 74% and mOS of 16.9 months and 16.2 months were reported for the Venclexta plus azacitidine and Venclexta plus decitabine combinations, confirming prior observations. Importantly the efficacy measures were independent of cytogenetic risk category, mutation type, or AML type (de novo or secondary). Furthermore, the time to response was rapid - 1.2 months (with azacitidine) and 1.9 months (with decitabine).
Even more impressive was the OS attained in patients achieving CR/CRi – 40.3 months for Venclexta plus azacitidine (versus 4.5 months for those who did not attain CR/CRi) and 18.2 months for Venclexta plus decitabine (versus 4.8 months for those who did not attain CR/CRi). The 12-month no-event rates were 72% and 74%. Furthermore, across both treatment groups and in those with CR/CRi, 45% of patients achieved minimal residual disease (MRD), below 10-3 cutoff. The ability to induce MRD is a key contribution of Venclexta to this regimen.
Similarly, updated data with more patients for trial M14-387 was provided by Stephen Strickland10 and support the prior findings for the Venclexta plus LDAC combination. Here a 54% CR/CRi (vs. 11% historical control), and a mOS of 10 months (vs. 5 months historical control) was reported. Again, the contribution of Venclexta resulted in 32% of patients with CR/CRi achieving MRD.
With new options for newly diagnosed elderly/unfit patients, what will physicians choose?
At present, the current label for Venclexta allows for combination with azacitidine, decitabine or LDAC, while Daurismo can only be combined with LDAC. Seeing that, LDAC is a much less commonly used agent in elderly/unfit patients, this gives Venclexta a broader potential use. Over one-third of patients in the US and EU5 utilize single agent HMAs for induction in elderly/unfit patients, compared to low single digit utilization of LDAC1. While ongoing studies (Phase 3 BRIGHT AML 1019, and Phase1b BRIGHT 1012) are already exploring the combination of Daurismo with azacitidine11, in the short term the combination with LDAC may play more prominent roles in patients who have experienced previous HMAs (such as those progressing from MDS) and where a different backbone might be preferred.
In addition, the higher rates of response and survival observed in these multiple studies favors the Venclexta plus HMA combinations over Daurismo plus LDAC. That said, these are cross-trial comparisons and head to head trials (or at a minimum larger Phase 3 trials with comparable patient demographics) would best delineate these differences. Azacitidine may be the optimal HMA to combine with Venetoclax based on the efficacy data in the M14-358 study; the preferential use of azacitidine instead of decitabine in both the US and Western Europe markets will further impact choice of that regimen. It is also possible that physician comfort with Venclexta as an already marketed product in CLL may promote its use.
Therapeutic options for AML patients have rapidly evolved across all treatment settings in the last two years. With the recent introduction of Venclexta and Daurismo as the newest options for elderly/unfit patients and anticipated future combinations and emerging MOAs, the last two years will stand tall as a turning point in the history of this disease.
- Kantar Health, CancerMPact®, Treatment Architecture US and EU5, Acute Myeloid Leukemia, accessed from www.cancermpact.com, December 3, 2018.
- Kantarjian H, et al. Cancer. 2010. 116: 4896-4901.
- Cortes JE, et al. ASH Annual Meeting; 2016 Dec 1 – 4, San Diego, CA, USA. Abstract #99.
- Dinardo CD, et al. ASCO Annual Meeting; 2018 Jun 1 – 5, Chicago, IL, USA. Abstract #7010.
- Dinardo CD, et al., Blood. 2018 Oct 25. pii: blood-2018-08-868752.
- Kantarjian HM et al.J Clin Oncol. 2012 Jul 20;30(21):2670-7.
- Wei AH, et al. EHA Annual Meeting; 2017 Jun 22 – 25, Madrid, Spain. Abstract #S473.
- Burnett AK, et al, Cancer. 2007 Mar 15;109(6):1114-24.
- Pollyea DA, et al. ASH Annual Meeting; 2018 Dec 1 – 4, San Diego, CA, USA. Abstract #285.
- Strickland SA, et al. ASH Annual Meeting; 2018 Dec 1 – 4, San Diego, CA, USA. Abstract #284.
- Kantar Health, CancerLandscape®, accessed from cancerlandscape.khapps.com, December 3, 2018