A recent phase 2 clinical trial has evaluated the efficacy and safety of cusatuzumab, an anti-CD70 antibody, in combination with azacitidine for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients ineligible for intensive chemotherapy. The randomized, open-label, dose-optimization study, known as CULMINATE, was conducted across 40 hospitals and centers in seven countries. Funded by Janssen Research & Development and argenx, the study results were published in The Lancet Haematology in November 2023.
The primary aim of the CULMINATE trial was to determine the optimal dose of cusatuzumab for future studies when used in combination with azacitidine in this patient population. The study enrolled 103 adult patients aged 18 years or older with newly diagnosed AML who were not eligible for intensive chemotherapy. To be included, patients needed to have Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-2. Key exclusion criteria included acute promyelocytic leukemia, active leukemic involvement of the central nervous system, other active malignancies or systemic infections, previous treatment with hypomethylating agents for AML or myelodysplastic syndromes, and use of immunosuppressive agents within the past 4 weeks.
In part one of the trial, participants were randomly assigned 1:1 to receive either 10 mg/kg or 20 mg/kg intravenous cusatuzumab on days 3 and 17 of each 28-day cycle. This was combined with subcutaneous or intravenous azacitidine 75 mg/m² on days 1-7 of each cycle. The primary efficacy outcome was the rate of complete remission in the intention-to-treat population. Safety analyses were conducted on all patients who received at least one dose of study drug.
Of the 103 enrolled patients, 51 were assigned to the 10 mg/kg group and 52 to the 20 mg/kg group. The median age of participants was 74 years in the 10 mg/kg group and 75 years in the 20 mg/kg group. The majority of patients were male (55% overall) and white (76% overall). Notably, 62% of patients had an ECOG performance status of 2, indicating a population with poor functional status. Nearly half of the patients (47% overall) had adverse-risk cytogenetics according to European LeukemiaNet 2017 criteria.
The results showed that the complete remission rate was 12% (6 of 51 patients; 95% CI 6-23) in the 10 mg/kg group and 27% (14 of 52 patients; 95% CI 17-40) in the 20 mg/kg group. When including complete remission with partial hematological recovery (CRh) and complete remission with incomplete hematological recovery (CRi), the overall response rates were 29% (95% CI 19-43) and 40% (95% CI 28-54) for the 10 mg/kg and 20 mg/kg groups, respectively.
Median overall survival was 5.1 months (95% CI 3.3-11.3) in the 10 mg/kg group and 9.9 months (95% CI 5.5-16.2) in the 20 mg/kg group. The 20 mg/kg dose was also associated with longer duration of response and higher rates of transfusion independence compared to the 10 mg/kg dose.
Regarding safety, the incidence and nature of treatment-emergent adverse events (TEAEs) were similar between the two dose cohorts. The most common grade 3 or higher TEAEs included thrombocytopenia (52% overall), anemia (40% overall), neutropenia (39% overall), leukopenia (28% overall), and pneumonia (25% overall). Serious TEAEs occurred in 82% of patients overall. Infusion-related reactions were observed in 18% of patients but were mostly grade 1-2 in severity.
The study had several limitations that should be considered when interpreting the results. First, it was not designed to formally compare the two dose cohorts for efficacy. The open-label design and local assessment of disease responses may have introduced bias. Additionally, the study was conducted during the early stages of the COVID-19 pandemic, which could have affected patient management and evaluations. The small sample size limited the ability to assess responses by cytogenetic risk features and to interpret the relationship between immunogenicity and drug exposure.
Based on the totality of the data, the study authors concluded that cusatuzumab 20 mg/kg plus azacitidine represents the optimal dose for further investigation. They noted that while the efficacy results were modest, the combination demonstrated clinical activity and had a manageable safety profile. The authors suggest that the novel mechanism of action of cusatuzumab could potentially enhance outcomes when combined with current standard therapies.
The potential clinical impact of this study is multifaceted. While the results do not suggest that cusatuzumab plus azacitidine should replace current standards of care, they provide a rationale for further exploration of cusatuzumab in combination with other agents. Notably, a phase 1b study investigating the triple combination of cusatuzumab with venetoclax and azacitidine is already underway (NCT04150887). This approach aims to leverage the synergistic effects observed in preclinical studies between cusatuzumab and venetoclax in eliminating leukemic stem cells.
The CULMINATE trial also provides valuable insights into the challenges of treating older, unfit AML patients. The high proportion of patients with adverse cytogenetic features and poor performance status in this study population highlights the unmet need for effective and well-tolerated therapies in this difficult-to-treat group. The observation that some patients achieved transfusion independence with cusatuzumab plus azacitidine is noteworthy, as this can significantly impact quality of life for AML patients.
Furthermore, the study's biomarker analyses, although preliminary, suggest the potential of CD70 expression as a marker of response to cusatuzumab-based therapy. If confirmed in larger studies, this could pave the way for more personalized treatment approaches in AML, allowing for better patient selection and potentially improving outcomes.
It is important to note that the landscape of AML treatment has evolved rapidly in recent years, particularly with the approval of venetoclax plus azacitidine as a new standard of care for older, unfit patients. The CULMINATE study was initiated before these developments, which ultimately led to the decision not to proceed with part two of the trial. This underscores the challenges of conducting clinical trials in a rapidly changing therapeutic landscape and highlights the need for adaptive trial designs in oncology.
In conclusion, while the CULMINATE trial did not demonstrate superiority of cusatuzumab plus azacitidine over current standards, it provides valuable data on the safety and potential efficacy of this novel combination in a difficult-to-treat AML population. The results support further investigation of cusatuzumab, particularly in combination with venetoclax and azacitidine, as a potential strategy to improve outcomes for patients with AML who are ineligible for intensive chemotherapy. As research in this area continues, medical professionals should stay informed about ongoing trials and emerging data that may shape future treatment paradigms for AML.
References
Pabst T, Papayannidis C, Demirkan F, et al. Cusatuzumab plus azacitidine in newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy (CULMINATE): part one of a randomised, phase 2, dose optimisation study. Lancet Haematol. 2023;10(11):e902-e912. doi:10.1016/S2352-3026(23)00207-7
