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Abstract
Background Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor. Due to this molecular design, nemvaleukin treatment leads to preferential expansion of antitumor CD8+ T and NK cells, with minimal expansion of immunosuppressive regulatory T cells (Tregs).1 We present results from an exploratory biomarker analysis of immunophenotyping data from the ARTISTRY-1 clinical trial.
Methods Group 1, melanoma & renal cell carcinoma treated with nemvaleukin (6 μg/kg); Group 2, patients from Group 1 who did not respond or progressed and rolled over to combination (nemvaleukin 3 μg/kg and pembrolizumab); Group 3, combination of nemvaleukin (3 or 6 μg/kg) and pembrolizumab in various solid tumors. Immunophenotyping of whole blood by flow cytometry was conducted (Tregs, T cells and subtypes, CD19, NK cells and subtypes); results were reported as absolute counts (cells/µL). Timepoints: day (D) 1 of each cycle (C); C1D8, first timepoint that shows immune expansion; C2D8, next timepoint when immune expansion reaches maximum/plateaus/decreases. Best overall response (BOR) assessment is as of March 27, 2023. Scans occurred every 6 (±1) weeks. Treatment cycles were 21 days except C1 Group 1 (14 days).
Results The ratio of absolute count for NK cells (defined by CD16+CD56+) at C2D8/C1D8 was identified as a potential predictive marker of response in all groups.
Analytical validation of the biomarker in Group 1-monotherapy cohort can be seen using BOR (table 1), percent change in target lesion (figure 1A), and progression-free survival (PFS) (figure 1B). A cutoff >1.14 for the NK cell ratio demonstrated a strong negative predictive value, correlated with a greater decrease in target lesion, and showed a significant difference in PFS, thus offering early insight into treatment effect. Logistic regression analysis adjusting for baseline NK cell numbers, age, sex, and prior treatment lines for Group 1 melanoma patients showed NK cell ratio as the only predictor associated with response (defined as complete/partial response [CR/PR] and stable disease [SD] >12 weeks). The largest proportion of NK cells at C1D8 and C2D8 were CD56dimCD16bright cytotoxic phenotype.
Importantly, a cutoff of >1.14 also demonstrated a significant difference in PFS for the combination cohorts as shown in figures 2 (Group 2) and figures 3 (Group 3).
Conclusions This exploratory analysis establishes the foundation for NK cell expansion as a novel predictive biomarker of response to nemvaleukin in melanoma and other solid tumors and warrants further prospective validation in larger ongoing studies.
Acknowledgements The authors would like to thank all patients who are participating in this study and their families. This study is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Parexel, and funded by Alkermes, Inc.
Trial Registration www.clinicaltrials.gov NCT02799095
Reference
Vaishampayan UN, Tomczak P, Muzaffar J, et al. Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors: ARTISTRY-1. J Clin Oncol. 2022;40:16.
Ethics Approval The study protocol and its amendments, patient informed consent form, and all relevant documents were approved by an institutional review board or local ethics committee. This study is being conducted according to Declaration of Helsinki and all applicable guidelines from the International Council on Harmonisation (ICH) E6 Good Clinical Practice, US Code of Federal Conduct, and state, local and federal laws. All patients are required to provide written informed consent to participate.
Analytical validation of the C2D8/C1D8 NK cell ratio (biomarker) in Group 1-monotherapy cohort (nemvaleukin 6 μg/kg RP2D; median number of cycles, 6 [min-max, 2-52]; median duration of treatment, 19.6 weeks [min-max, 5-178]) using best overall response
Analytical validation of the C2D8/C1D8 NK cell ratio (biomarker) in Group 1 monotherapy cohort (nemvaleukin 6 µg/kg RP2D; median number of cycles, 6 [min-max, 2–52]; median duration of treatment, 19.6 weeks [min-max, 5–178]) using percent change in target lesion (A)a and progression-free survival (B)b.
Progression-free survival by the C2D8/C1D8 NK cell ratio (biomarker) predictive of response in combination cohort (Group 2: nemvaleukin 3 µg/kg and pembrolizumab; median number of cycles received, 8 [min-max, 2–32]; median duration of treatment, 26.1 weeks [min-max, 6.3–111.1]).
Progression-free survival by the C2D8/C1D8 NK cell ratio (biomarker) predictive of response in combination cohort (Group 3: nemvaleukin 3 µg/kg or 6 µg/kg and pembrolizumab; median number of cycles received, 5 [min-max, 2–43]; median duration of treatment, 17.1 weeks [min-max, 4–137.1]).
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