Improved clinical outcome in a randomized phase II study of anti-PD-1 camrelizumab plus decitabine in relapsed/refractory Hodgkin lymphoma

Abstract

Background: Programmed death-1 (PD-1) blockade monotherapy induced durable remission in a subset of patients with relapsed/refractory classical Hodgkin lymphoma (cHL). We asked whether the anti-PD-1 agent, camrelizumab, combined with the DNA demethylating agent, decitabine, improves progression-free survival (PFS) in patients with relapsed/refractory cHL over camrelizumab alone.

Methods: This extended follow-up of an ongoing randomized phase II trial analyzed PFS among patients enrolled from January 2017 through July 2018. Sixty-one patients with relapsed/refractory cHL who were clinically naïve to PD-1 blockade and had received ≥2 previous therapies were randomized 1:2 to receive either camrelizumab (200 mg) monotherapy or camrelizumab (200 mg, day 8) combined with decitabine (10 mg/day, days 1-5) every 3 weeks.

Results: With a median follow-up of 34.5 months, complete remission was 79% (95% CI 63% to 90%) in the decitabine-plus-camrelizumab group versus 32% (95% CI 13% to 57%) in the camrelizumab group (p=0.001). Median duration of response was not reached in the decitabine-plus-camrelizumab group, with an estimated 63% (95% CI 46% to 75%) of patients maintaining a response at 24 months. Median PFS with decitabine-plus-camrelizumab therapy was 35.0 months (95% CI not reached) and 15.5 months (95% CI 8.4 to 22.7 months) with camrelizumab monotherapy (HR, 0.46; 95% CI 0.21 to 1.01; p=0.02). Female gender, lower tumor burden, and fewer previous therapies were favorable prognostic factors for durable remission with camrelizumab monotherapy. The PFS benefits of decitabine-plus-camrelizumab versus camrelizumab were observed in most subgroups, especially in patients with relative larger tumor burdens and those treated with ≥3 prior therapies. After decitabine-plus-camrelizumab treatment, the percentage increase of circulating peripheral central memory T-cells correlated with both improved clinical response and PFS, suggesting a putative biomarker of decitabine-plus-camrelizumab therapy for cHL.

Conclusions: Decitabine-plus-camrelizumab results in longer PFS compared with camrelizumab alone in patients with relapsed/refractory cHL.

Trial registration numbers: NCT02961101 and NCT03250962.

Keywords: clinical trials; combination; drug therapy; immunotherapy; phase II as topic; t-lymphocytes.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Consolidated Standards of Reporting Trials diagram. CR, complete remission.

Figure 2

DOR in patients with CR and PR. (A) Response onset and duration for all responders. Blue bars indicate patients in the camrelizumab group and green bars indicate patients in the decitabine-plus-camrelizumab group. The length of the bar shows the time from first dosing until the patient had a CR or PR, along with the duration of the response. The onset of first response (CR or PR) was indicated as a red square (CR) or blue dot (PR), respectively. (B) Kaplan-Meier estimates of DOR in patients with CR and PR. The red curves represent patients treated with decitabine-plus-camrelizumab and the blue those treated with camrelizumab monotherapy. The median DOR and DOR rates at 12 months and 24 months are shown. Plus signs indicate censored data. (C–F) Kaplan-Meier estimates of response duration in responders who were men (C), had tumor burden SPD ≥20 cm2 (D), SPD ≥50 cm2 (E), or with ≥3 lines of previous therapy (F). The red curves represent patients treated with decitabine-plus-camrelizumab and the blue those treated with camrelizumab monotherapy. The median DOR and DOR rates at 12 months and 24 months are shown. Plus signs indicate censored data. (G) Kaplan-Meier estimates of CR duration in patients who acquired a CR after decitabine-plus-camrelizumab or camrelizumab monotherapy. The red curves represent patients treated with decitabine-plus-camrelizumab and the blue those treated with camrelizumab monotherapy. The median duration of CR was not reached and duration of CR rate at 24 months is shown. Plus signs indicate censored data. CR, complete remission; DOCR, duration of complete remission; ORR, objective response rate; PR, partial response; SPD, sum of the products of diameters.

Figure 3

PFS analysis. (A) Kaplan-Meier estimates of PFS in all evaluable 61 patients. The red curves represent patients treated with decitabine-plus-camrelizumab and the blue those treated with camrelizumab monotherapy. The median PFS and PFS rates at 12 months and 24 months are shown. Plus signs indicate censored data. (B) Two-year PFS rates in patient subgroups according to baseline characteristics. (C) Forest plot of median PFS for patient subgroups according to baseline demographics and disease characteristics indicating favored treatment of each subgroup. ASCT, autologous stem cell transplantation; PFS, progression-free survival; SPD, sum of the products of diameters.

Figure 4

Fold change of percentages in peripheral T-cell subsets during decitabine-plus-camrelizumab or camrelizumab treatment. Peripheral blood was collected from patients at the indicated times (Cnd0 indicates before the treatment cycle, n refers to treatment cycle; C1d6 indicates the day following 5-day decitabine administration in cycle 1). (A, B) Percentages of peripheral CCR7+CD45RA+ Tnaïve, CCR7+CD45RA− Tcm, CCR7−CD45RA− Tem, and CCR7−CD45RA+ Ttemra cells in CD8+ (or CD4+) T-cells at the indicated times in the camrelizumab group or decitabine-plus-camrelizumab group, analyzed by FACS. (C, D) Fold change of percentages of peripheral CCR7+CD45RA− Tcm cells in CD8+ (or CD4+) T-cells at the indicated times compared with baseline (C1d0) in the camrelizumab group or decitabine-plus-camrelizumab group, analyzed by FACS. The two-way repeated-measures analysis of variance was conducted to evaluate the effect of time–group interaction, and p value was shown. (E, F) Fold change of percentages of peripheral CCR7+CD45RA− Tcm cells in CD8+ (or CD4+) T-cells at the indicated times compared with baseline (C1d0) among patients who had different clinical responses after decitabine-plus-camrelizumab treatment. (G, H) Fold change in percentages of CCR7+CD45RA− Tcm cells in CD8+ (or CD4+) T-cells at the indicated times compared with baseline (C1d0) among patients who had different clinical responses after camrelizumab treatment. Data represent the mean±SEM. *p<0.05; **p<0.01. CR, complete response; NSHL, Nodular Sclerosis Hodgkin Lymphoma; PR, partial response; SD, stable disease.

Figure 5

Association of percentage alteration in peripheral T-cell subsets with CR rate and PFS. (A) The percentage of peripheral CCR7+CD45RA− Tcm, CCR7−CD45RA− Tem, CCR7+CD45RA+ Tnaïve, and CCR7−CD45RA+ Ttemra cells in CD8+ (or CD4+) T-cells detected at C5d0 or C1d6 as compared with baseline (C1d0) with CR rate in patients after camrelizumab monotherapy or decitabine-plus-camrelizumab combination. C1d6 indicates day 6 (after 5-day decitabine treatment) in the first cycle, C5d0 indicates the day before the fifth cycle. (B–E) PFS among subgroups according to CCR7+CD45RA−CD8+, CCR7+CD45RA−CD4+ ratios detected on C5d0 or C1d6 compared with baseline with decitabine-plus-camrelizumab therapy. A p value <0.05 was considered to indicate statistical significance. CR, complete response; PFS, progression-free survival.