Combining the checkpoint inhibitor durvalumab with standard of care azacitidine did not improve the response rate among treatment-naïve patients with higher-risk myelodysplastic syndromes (MDS), according to the results of a phase II study published in Blood Advances. The addition of frontline daratumumab to azacitidine also did not improve outcomes among patients with acute myeloid leukemia (AML) who were enrolled in a separate cohort within same study. The AML cohort results were published separately in Blood Advances.
“In my view, this well-conducted study has effectively ruled out durvalumab, an anti-PD-L1 antibody, as a potential useful treatment for MDS or AML,” said Amer Zeidan, MBBS, of Yale School of Medicine in New Haven, Connecticut.
Azacitidine is frequently used as a frontline therapy for those patients diagnosed with higher-risk MDS. Prior studies have suggested that the hypomethylation induced by azacitidine therapy promotes the immune system to recognize tumor cells, but that the treatment may also increase expression of inhibitory immune checkpoint (ICP) molecules, which likely prevent the activation and action of immune cells to kill tumor cells. Dr. Zeidan and co-authors hypothesized that adding an anti-PD-L1 checkpoint antibody to azacitidine therapy may facilitate immune activation and tumor cell death.
A total of 84 patients were randomized to receive either subcutaneous azacitidine for seven consecutive days or azacitidine plus intravenous durvalumab every four weeks. The median patient age was 73.5 years, and 58% of patients were male.
Patients in the monotherapy and combination therapy arms received a median of 7.9 and 7.0 monthly treatment cycles, respectively. Most patients received at least four cycles in both treatment arms (73.7% and 65.9% in the monotherapy and combination therapy arms, respectively).
The overall response rate – a composite of complete response (CR), marrow (m)CR, partial response, or hematologic improvement based on modified International Working Group (2006) response criteria –was 61.9% (26 of 42 patients) in the azacitidine arm and 47.6% (20 of 42 patients) in the azacitidine plus durvalumab arm (p=0.18). There was no difference in the median time to a response between the two study arms. The median overall survival was 11.6 months (95% CI 9.5, non-evaluable) and 16.7 months (95% CI 9.8-23.5; p=0.74) in the monotherapy and combination therapy arms, respectively.
Azacitidine-related adverse events (AEs) were similar in the monotherapy and durvalumab arms, 82% and 81%, respectively. More patients reported grade 3 or 4 hematologic AEs in the azacitidine monotherapy arm (89.5%) compared to the combination therapy arm (68.3%). The most frequent treatment-related AEs were neutropenia (68.4% in the monotherapy arm vs. 53.7% in the combination therapy arm), constipation (57.9% vs. 48.8%), and thrombocytopenia (52.6% vs. 43.9%). Seven durvalumab-related immune-mediated AEs were reported.
“In biomarker analyses, we found minimal immune activation in patients treated with durvalumab, which likely resulted in the lack of clinical activity over azacitidine alone,” Dr. Zeidan said.
One-third of patients in the study harbored a TP53 mutation and about half of patients in each treatment arm were classified as very high-risk, yet the authors did not find a subset of patients who appeared to benefit from the combination therapy.
According to Dr. Zeidan, whether other classes of ICP inhibitors – including anti-PD-1, anti-CTLA4, anti-TIM3, or anti-CD47 antibodies – may be efficacious among patients with MDS remains a question that should be tested in randomized clinical trials.
The authors did not specifically describe study limitations. However, they noted that because of the study’s small sample size, it is possible that patients with some MDS subtypes may benefit from ICP blockade. They suggested that extensive correlative and immunologic analyses should be incorporated in future trials to help detect biomarkers for clinical benefits, which might facilitate biomarker-driven patient selection in larger trials. Further, given proven clinical activity of durvalumab against other tumors, the authors noted that results from this trial suggest anti-PD-L1 therapy as a class is likely not helpful in all patients with high-risk MDS, but these results cannot be extrapolated to other classes of ICP blockade.
For Dr. Zeidan, approaches that combine chemotherapy, hypomethylating agents, and targeted agents with ICP-targeted therapies are likely to eventually work, but many more research and clinical trials are needed to understand the best combinations and settings for various subgroups of patients with MDS and other hematologic malignancies.
Any conflicts of interest declared by the authors can be found in the original article.
Zeidan AM, Boss I, Beach CL, et al. A randomized phase 2 trial of azacitidine ± durvalumab as first-line therapy for higher-risk myelodysplastic syndromes [published online ahead of print, 2021 Dec 31]. Blood Adv. doi: 10.1182/bloodadvances.2021005487.