Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study

Abstract

Talacotuzumab, a humanized anti-CD123 monoclonal antibody, was evaluated in combination with decitabine in elderly patients with acute myeloid leukemia (AML) not eligible for intensive chemotherapy. A multicenter, phase 2/3 study was initiated to determine the recommended phase 2 dose (RP2D) of talacotuzumab (Part A) followed by an open-label, randomized comparison of talacotuzumab in combination with decitabine versus decitabine alone to assess achievement of complete response (CR) and overall survival (OS) in Part B. Ten patients were enrolled in Part A and 316 in Part B; the results presented here are based on a database lock on January 25, 2018. Part A confirmed the RP2D of talacotuzumab to be 9 mg/kg. In Part B, CR was achieved in 12/80 (15%) patients receiving combination therapy and in 9/82 (11%) patients receiving decitabine alone (odds ratio: 1.4; 95% confidence interval [CI]: 0.6-3.6; p = 0.44). Median (95% CI) OS was 5.36 (4.27-7.95) months for combination therapy versus 7.26 (6.47-8.64) months for decitabine alone (hazard ratio: 1.04; 95% CI: 0.79-1.37; p = 0.78). Combination therapy showed no improvement in efficacy versus decitabine alone, resulting in the Independent Data Monitoring Committee's recommendation of early termination of enrollment and discontinuation of talacotuzumab treatment.

Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents

“…The study was initially powered to include a total of 43 patients, but the SAMBA trial was prematurely terminated because the manufacturer decided to stop the entire TAL study program due to lack of efficacy and high toxicity rates in a pivotal study involving TAL in combination with DAC as first line treatment in AML (NCT02472145) [13]. Consequently, only 24 patients (19 AML and 5 HR-MDS) with a median age of 77 years (range 71-90) who either failed to achieve CR, PR, HI, or relapsed after at least six AZA or four DAC treatment cycles were included in the study from November 2016 until June 2017.…”

Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

“…66 In a recent trial, talacotuzumab, a humanized anti-CD123 antibody, was administered in combination with decitabine in older AML patients not eligible for poly-chemotherapy. 67 However, the drug combination did not result in a better outcome compared to decitabine alone. 67 Other surface targets that have been considered in the context of AML and antibody-mediated elimination of LSC include CD44, CD45, CD47, CD93, CD96, CD157, CD330f, and CLL-1.…”

“…67 However, the drug combination did not result in a better outcome compared to decitabine alone. 67 Other surface targets that have been considered in the context of AML and antibody-mediated elimination of LSC include CD44, CD45, CD47, CD93, CD96, CD157, CD330f, and CLL-1. 8,[30][31][32][33][34]38,43,[68][69][70] However, so far, no major AML-eradicating activity was obtained in clinical trials.…”

“…However, when evaluating efficacy of CSL360 in a clinical phase I trial in chemotherapy‐refractory AML, no major antileukemic activity was observed in most patients enrolled 66 . In a recent trial, talacotuzumab, a humanized anti‐CD123 antibody, was administered in combination with decitabine in older AML patients not eligible for poly‐chemotherapy 67 . However, the drug combination did not result in a better outcome compared to decitabine alone 67 …”

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

“…Only 10% of patients achieved CR on combination therapy compared to 11% of patients receiving decitabine alone, resulting in early termination of enrollment and discontinuation of treatment. 375 Noted in these studies was the limitation of patients' natural killer (NK) lymphocytes present and preclinical studies have suggested the use of human allogeneic NK cells in combination with talacotuzumab to promote NK cell antibodydependent cell-mediated cytotoxicity. 376 Another way to improve cytotoxicity of mAb therapies is using a CD123-targeting ADC.…”