A Phase 2 Study of Nivolumab Using a Fixed Dose of 40 mg (Nivo40) in Patients With Relapsed/Refractory Hodgkin Lymphoma

Lepik, K.; Fedorova, L.; Kondakova, Elena; Zalyalov, Y.; Babenko, Elena V.; Lepik, Elena E.; Kotselyabina, P.V.; Beinarovich, A.V.; Popova, M.; Volkov, Nikita; Stelmakh, L.; Baykov, Vadim; Moiseev, Ivan S.; Mikhailova, N.B.

doi:10.1097/hs9.0000000000000480

Cited by 18 publications

(17 citation statements)

References 27 publications

(90 reference statements)

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“…The use of low but possibly effective dosing of available anti-PD-1 ICI in the adjuvant setting could potentially result in a lower financial burden, at the same time allowing more patients to potentially benefit from ICI therapy in countries where access is limited [43]. Recently published data from a phase II trial that investigated a fixed dose of nivolumab (40 mg every 2 weeks) in 30 patients with relapsed or refractory Hodgkin lymphoma resulted in a promising objective response rate, indicative that the utility of low-dose regimens may expand beyond the indication of adjuvant melanoma therapy [44]. Hence, our investigated regimens could be economically advantageous alternatives for patients in countries that do not have access to standard regimens.…”

Section: Discussionmentioning

confidence: 99%

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial

Schwarze

Garaud

Jansen

et al. 2022

Cancers

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Background: Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. Methods: Following the complete resection of melanoma metastases, patients were treated with a single fixed dose of ipilimumab (50 mg) plus 4 bi-weekly fixed doses of nivolumab (10 mg) (cohort-1), or nivolumab for 1 year (10 mg fixed dose, Q2w x9, followed by Q8w x4) (cohort-2). Twelve-months relapse-free survival (RFS) served as the primary endpoint. Results: After a median follow-up of 235 weeks for cohort-1 (34 patients), and 190 weeks for cohort-2 (21 patients), the 12-months RFS-rate was, respectively, 55.9% (95% CI, 39–72), and 85.7% (95% CI, 70–100). Treatment-related adverse events occurred in 27 (79%), and 18 (86%) patients, with 3 (9%), and 1 (5%) grade 3 adverse events in cohort-1 and -2, respectively. Immunohistochemical quantification of intra- and peritumoral CD3+ T cells and CD20+ B cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. Conclusions: One year of adjuvant low-dose nivolumab could be an effective and economically advantageous alternative for standard dosing, at the condition of further confirmation in a larger patient cohort. A shorter low-dose nivolumab plus ipilimumab regimen seems inferior and less tolerable.

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Section: Discussionmentioning

confidence: 99%

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial

Schwarze

Garaud

Jansen

et al. 2022

Cancers

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“…This study included retrospective data of patients with r/r cHL treated with nivolumab 3 mg/kg or 40 mg flat dose from February 2016 to March 2021 at RM Gorbacheva Research Institute, Pavlov University. The dose of nivolumab varied due to the ongoing clinical study of the nivolumab 40 mg efficacy [ 36 ]. At the time of analysis, the median follow-up was 55 (13–63) months.…”

Section: Methodsmentioning

confidence: 99%

Immunosuppressive Microenvironment and Efficacy of PD-1 Inhibitors in Relapsed/Refractory Classic Hodgkin Lymphoma: Checkpoint Molecules Landscape and Macrophage Populations

Gusak

Fedorova

Lepik

et al. 2021

Cancers

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To date, the impact of the tumor microenvironment on the prognosis of patients with classic Hodgkin lymphoma (cHL) during anti-PD-1 therapy has been studied insufficiently. This retrospective study included 61 primary samples of lymph nodes from patients who had relapsed/refractory (r/r) cHL and were treated with nivolumab. Repeated samples were obtained in 15 patients at relapse or disease progression after immunotherapy. Median follow-up was 55 (13–63) months. The best overall response rate and progression-free survival (PFS) were analyzed depending on the expression of CD68, CD163, PD-1, LAG-3, TIM-3, CTLA-4, TIGIT, CD163/c-maf in the tumor microenvironment in primary and sequential biopsies. The combination of CD163/c-maf antibodies was used for the identification of M2 macrophages (M2). A low number of macrophages in primary samples was associated with inferior PFS during nivolumab treatment (for CD163-positive cells p = 0.0086; for CD68-positive cells p = 0.037), while a low number of M2 with higher PFS (p = 0.014). Complete response was associated with a lower level of M2 (p = 0.011). In sequential samples (before and after nivolumab therapy) an increase in PD-1 (p = 0.011) and LAG-3 (p = 0.0045) and a depletion of CD68 (p = 0.057) and CD163 (p = 0.0049)-positive cells were observed. The study expands understanding of the cHL microenvironment structure and dynamics during nivolumab therapy in patients with r/r cHL.

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“…We retrospectively evaluated 21 patients with r/r cHL treated with combination of anti-PD1 antibody nivolumab (3.0 mg/kg or 40 mg; IV, 60 min infusion) and brentuximab vedotin (1.8 mg/kg; IV, 30 min infusion) in 3 week cycles until disease progression, unacceptable toxicity, or planned allo-HSCT. Doses of nivolumab varied due to the ongoing clinical study of the nivolumab 40 mg efficacy [38]. The initiation of this study is related to previous nivolumab pharmacokinetics studies demonstrated that median PD-1 receptor occupancy on peripheral blood CD3 + T cells from patients with melanoma treated at a dose of 0.1-10.0 mg/kg was similar for every dose level over 0.3 mg/kg, independent of nivolumab concentrations [40].…”

Section: Methodsmentioning

confidence: 99%

“…Considering this data, the possibility of combining PD-1 inhibitors with BV is undoubtedly interesting. Available studies investigated the role of this combination before ASCT as the first salvage therapy [32,33] and after ASCT failure [34][35][36][37][38]. This combination also was studied in patients who had previously received BV monotherapy [34][35][36][37]39].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of nivolumab combined with brentuximab vedotin after nivolumab monotherapy failure in patients with relapsed and refractory classic Hodgkin lymphoma

et al. 2021

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Objectives Therapy of patients with relapsed and refractory classic Hodgkin lymphoma (r/r cHL) after PD-1 inhibitors failure remains an unresolved issue. The aim of this study was to evaluate the efficacy and safety of the combination of nivolumab with brentuximab vedotin (Nivo + BV) after nivolumab monotherapy failure. Methods This study retrospectively analyzed 21 patients with r/r cHL who were treated with the combination of Nivo + BV after Nivo failure. The response was evaluated by PET-CT scan according to the LYRIC criteria. Adverse events (AEs) were assessed according to NCI CTCAE v.4.03. Results Median follow-up was 19 (9-47) months. The ORR was 57%. The median OS was not reached, 24 month OS was 80% (95% CI 50-93%). Median PFS was 12 months with 24 month PFS of 31% (95% CI 12-53%). Any grade AEs were observed in 12 patients (63%), 3-4 grade AEs in 2 patients (10%). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after Nivo + BV was performed in 8 (38%) patients. The median time between Nivo + BV and allo-HSCT was 8 (5-21) months. Conclusions Combination of Nivo + BV in r/r cHL after nivolumab monotherapy failure is potentially an effective and safe approach.

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A Phase 2 Study of Nivolumab Using a Fixed Dose of 40 mg (Nivo40) in Patients With Relapsed/Refractory Hodgkin Lymphoma

Abstract: Supplemental Digital Content is available in the text

Cited by 18 publications

References 27 publications

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial

Immunosuppressive Microenvironment and Efficacy of PD-1 Inhibitors in Relapsed/Refractory Classic Hodgkin Lymphoma: Checkpoint Molecules Landscape and Macrophage Populations

Efficacy and safety of nivolumab combined with brentuximab vedotin after nivolumab monotherapy failure in patients with relapsed and refractory classic Hodgkin lymphoma

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