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Azacitidine-nivolumab combination safe, effective in certain patients with acute myeloid leukemia
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The combination of azacitidine and nivolumab appeared associated with encouraging response rates and survival outcomes among patients with relapsed or refractory acute myeloid leukemia, according to results of a nonrandomized phase 2 study.
The regimen was particularly effective for patients who had not previously received hypomethylating agents, as well as those who had a higher frequency of CD3 cells in bone marrow samples before treatment.
“Identification and selection of patients using molecular and immune biomarkers is critical to enhancing therapy in AML,” Naval Daver, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “We are routinely using biomarkers such as FLT3, IDH1 and IDH2, CD33 [and] CD123 to select patients for specific therapies. ...
“We believe that ... patients should be selected for immune checkpoint-based therapy based on pretherapy bone marrow [CD3-positive] or CD8 infiltration,” Daver added. “Patients who have more CD3-positive cells in their pretherapy bone marrow should be identified and considered for azacitidine plus PD-1 therapies, whereas those who have less CD-positive cells in the pretherapy bone marrow may be better served on other AML therapies.”
The single-center, open-label study included 70 patients with AML (median age, 70 years; range, 22-90) who had undergone a median two (range, 1-7) prior treatments. More than half of the patients (64.2%) previously had been treated with hypomethylating agents.
Treatment was administered in 28-day cycles.
All participants received IV or subcutaneous azacitidine, a standard chemotherapy drug (75 mg/m2 on days 1-7). They also received IV nivolumab (Opdivo, Bristol-Myers Squibb), an anti-PD-1 antibody (3 mg/kg on days 1 and 14).
Cycles were repeated every 4 to 6 weeks. Study participants received a median three cycles (range, 1-25).
The study’s primary endpoints were safety and overall response rate, which included complete remission, complete remission with incomplete recovery of peripheral counts, partial response, morphologic leukemia-free state or sustained hematologic improvement.
Secondary endpoints included OS, EFS and duration of response.
Daver and colleagues reported an ORR of 33%. Fifteen patients (22%) achieved complete remission or complete remission with incomplete recovery of counts. One participant achieved partial response, and seven (10%) demonstrated hematologic improvement for at least 6 months.
Six patients (9%) achieved stable disease for at least 6 months.
Results showed a higher ORR among patients with no prior exposure to hypomethylating agents (58% vs. 22%).
Median OS in the entire cohort was 6.3 months. Median EFS among responders and patients who achieved stable disease was 4.5 months. Median duration of response was 5.2 months.
Factors associated with improved OS included salvage 1 status, presence of ASXL1 mutation, and the achievement of any response or stable disease after treatment.
Fifteen patients (21%) experienced grade 3 or grade 4 adverse events. These included five cases (7%) of lung infection and four cases (6%) of febrile neutropenia.
Eight patients (11%) experienced grade 3 to grade 4 immune-related adverse events. These included two cases (3%) of elevated alanine transaminase or aspartate transaminase levels, two cases (3%) of pruritus, and one case each of colitis, cytokine release syndrome, erythema multiforme and pneumonitis.
Researchers have initiated a randomized phase 3 study of this combination.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Daver said in a press release. – by Jennifer Byrne
For more information:
Naval Daver , MD, can be reached The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 428, Houston, TX 77030; ndaver@mdanderson.org.
Disclosure : Daver reports research funding and honoraria from and a consultant role with Bristol-Myers Squibb. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Relapsed/refractory AML remains a significant challenge, especially after prior treatment with hypomethylating agents (HMAs) and/or allogeneic hematopoietic stem cell transplant. Options are particularly limited for elderly patients with relapsed/refractory AML. Given the activity of allogeneic HSCT in AML, there has been optimism that other immune-based therapies — notably checkpoint inhibition — would prove effective against this disease. However, despite the dramatic responses seen in many tumor types — and recognized by the recently awarded Nobel Prize in Medicine — results thus far with single-agent checkpoint inhibition in relapsed/refractory AML have been disappointing.
Daver and colleagues report more promising results with a single-arm, early-phase combination of nivolumab plus azacitidine. This regimen yielded an ORR of 33% — with a composite complete remission rate of 22% — among all patients, and an ORR of 52% in HMA-naive patients. These figures compare favorably with historical controls of other HMA-based regimens, particularly given that the trial population was skewed toward older patients and more who had received prior HMA therapy and/or allogeneic HSCT. However, it should be noted that much of the improved response rate was due to hematologic improvement rather than complete remission. Further, although durability of response was superior to that of historical controls — including venetoclax (Venclexta; AbbVie, Genentech) plus HMA — the statistics were still humbling, with a median duration of response of just 5.2 months and OS for those who achieved remission of only 17.1 months.
Immune features — in particular pretreatment bone marrow CD3-positive counts — appeared to correlate with responses, consistent with findings in other tumor types. However, these were imperfect predictors of response (sensitivity of 74% and specificity of 65%), reflecting the need for further refinement of predictive biomarkers. The authors also identified upregulation of CTLA4 as a potential means of resistance to nivolumab plus azacitidine. That said, caution must be taken in too aggressively blocking the checkpoint pathway, as the addition of nivolumab to azacitidine already introduced notable side effects, with 23% of patients experiencing grade 2 to grade 4 immune toxicities, leading to discontinuation of nivolumab among 13% of the trial cohort. Moreover, there were two deaths (3%) attributable to immune-related adverse events.
As the authors note, there may be better success moving checkpoint inhibition earlier in the course of therapy, before critical immune cellular populations are depleted by other therapies and more resistance mechanisms evolve. As they also point out, immune-based approaches may prove more effective in the minimal residual disease state, in which the leukemic burden is more manageable and the immune system is at fuller strength. Lastly, the addition of other novel agents — such as venetoclax and/or targeted therapies — to the backbone combination of an immune checkpoint inhibitor and an HMA may further improve outcomes in AML. After decades of challenges in the treatment of AML, these new strategies offer genuine hope.
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Daver N. et al. Cancer Discov. 2018;doi:10.1158/2159-8290.CD-18-0774.
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