Adjunctive Volasertib in Patients With Acute Myeloid Leukemia not Eligible for Standard Induction Therapy: A Randomized, Phase 3 Trial

Abstract

In this phase 3 trial, older patients with acute myeloid leukemia ineligible for intensive chemotherapy were randomized 2:1 to receive the polo-like kinase inhibitor, volasertib (V; 350 mg intravenous on days 1 and 15 in 4-wk cycles), combined with low-dose cytarabine (LDAC; 20 mg subcutaneous, twice daily, days 1–10; n = 444), or LDAC plus placebo (P; n = 222). Primary endpoint was objective response rate (ORR); key secondary endpoint was overall survival (OS). Primary ORR analysis at recruitment completion included patients randomized ≥5 months beforehand; ORR was 25.2% for V+LDAC and 16.8% for P+LDAC (n = 371; odds ratio 1.66 [95% confidence interval (CI), 0.95–2.89]; P = 0.071). At final analysis (≥574 OS events), median OS was 5.6 months for V+LDAC and 6.5 months for P+LDAC (n = 666; hazard ratio 0.97 [95% CI, 0.8–1.2]; P = 0.757). The most common adverse events (AEs) were infections/infestations (grouped term; V+LDAC, 81.3%; P+LDAC, 63.5%) and febrile neutropenia (V+LDAC, 60.4%; P+LDAC, 29.3%). Fatal AEs occurred in 31.2% with V+LDAC versus 18.0% with P+LDAC, most commonly infections/infestations (V+LDAC, 17.1%; P+LDAC, 6.3%). Lack of OS benefit with V+LDAC versus P+LDAC may reflect increased early mortality with V+LDAC from myelosuppression and infections.

MYC and therapy resistance in cancer: risks and opportunities

“…Furthermore, inhibition of PLK1 with BI6727 (volasertib) synergized with the BCL2 inhibitor ABT199 (venetoclax) to kill MYC/BCL2 double‐hit lymphoma cell lines [ 164 ]. The clinical development of volasertib was discontinued in 2018 due to failure of reaching the primary endpoint in a phase III study in AML patients [ 165 ], but should resume following a licensing agreement with a new developer ( https://www.nfcr.org/blog/ricardo‐garcia‐the‐power‐of‐repurposing/ ).…”

Novel Investigational Agents and Pathways That May Influence the Future Management of Acute Myeloid Leukemia

“…Renner et al demonstrated that AML cell lines overexpress PLK1 compared to CD34+ stem cells and inhibition with PLK1 led to decreased proliferation of blasts without affecting HSCs [27]. PLK contains two C-terminal polo-box domains and an N-terminal ATP binding site targeted by PLK1 inhibitors like volasertib, which competitively bind to the ATP binding site and inhibit mitosis [28]. However, the large phase 3, double-blind, placebo-controlled trial that used a combination of volasertib IV 350 mg on days 1 and 15 along with low dose cytarabine 20 mg IV on days 1 to 10 of a 28-day cycle in 666 patients over 65 years old with newly diagnosed AML who were not eligible for intensive induction did not meet its primary endpoint ORR [28].…”

“…PLK contains two C-terminal polo-box domains and an N-terminal ATP binding site targeted by PLK1 inhibitors like volasertib, which competitively bind to the ATP binding site and inhibit mitosis [28]. However, the large phase 3, double-blind, placebo-controlled trial that used a combination of volasertib IV 350 mg on days 1 and 15 along with low dose cytarabine 20 mg IV on days 1 to 10 of a 28-day cycle in 666 patients over 65 years old with newly diagnosed AML who were not eligible for intensive induction did not meet its primary endpoint ORR [28]. The study arm had an ORR of 25.2% compared to the placebo and low-dose cytarabine arm 16.8% (p = 0.071).…”

Therapeutic Targeting of DNA Damage Response in Cancer

“…The primary endpoint was met as the rate of complete remission was superior with the volasertib combination (31% vs. 13%), but this was at the expense of hematologic toxicities [120]. However, in a phase 3 trial, this combination turned out to be unsuccessful, as volasertib in combination with low-dose cytarabine did not bring significant prolongation of overall survival despite the higher rates of complete remission [121].…”