Rationalization of Anti-PD-1 Therapy Using Receptor Occupancy Data to Guide Drug Dosing – a Single Arm Phase II Trial Using Immunomodulation in Relapsed/Refractory Hodgkin Lymphoma

Checkpoint inhibitors (CPIs) are highly effective in the treatment of Classical Hodgkin lymphoma (cHL), however at approved doses, high costs limit their use in lower- and middle-income countries. Phase I data established safety and efficacy but not the ideal dose or schedule of CPIs. Based on our own preliminary data on PD-1 receptor occupancy with low-dose nivolumab, we initiated a Phase II trial for patients >15 yrs with cHL in first relapse/progression. All patients received nivolumab (IV) at a flat dose of 40mg every 2 weeks, along with lenalidomide 10mg (21/28).

To assess dose adequacy and drug persistence, PD-1 receptor occupancy on T cells were analyzed by flow cytometry with antibodies against PD-1, at baseline, 1-hr post-1^st infusion and just prior to the 2^nd infusion. As part of an exploratory study, plasma drug levels were measured using ELISA: 1hr post-2^nd dose, 5 days post-2^nd dose, 10 days post-2^nd dose and a trough level prior to the 3^rd dose. Treatment response was assessed with F-18 FDG-PET-CT after 4 doses of nivolumab using the Deauville score and LYRIC criteria (where applicable). Monitoring for immune-related adverse events (iRAEs) was based on patient symptoms only.

Between September 2022 and May 2024, 35 patients were screened, of whom 20 consented and were enrolled.1 patient had relapsed after autologous transplant (protocol violation) and was excluded from further analysis. Seven (36.8%) patients were in 1^st relapse and 12 (63.2%) had primary progression. Fifteen (79%) were stage III/IV, and none had bulky disease. Sixteen (84.2%) were male, and the median age was 31yrs (range 16-66). Mean delivered dose of nivolumab was 0.6mg/kg (SD 0.11).

PD-1 Receptor occupancy: At baseline, CD4⁺PD1⁺ comprised 17.7% (median) of all CD4⁺ cells (range 1.9-89.4), median MFI of 241 (range 66-1187). One-hour post-1^st infusion, the CD4⁺PD1⁺ subset reduced to 0.05% (range 0-1.3), indicating near-total PD-1 receptor occupancy. Pre-2^nd infusion, median CD4⁺PD1⁺ T cells subset was 0% (range 0-16.8), indicating persistence of PD-1 receptor saturation at trough (in all but one patient).

Pharmacokinetics: The mean (SD) AUC_tau and t^1/2 were 1955.90mg.h/L (569.71) and 205.3hrs (65.4). Simple linear regression did not identify sex, age, creatinine clearance or body weight as significant factors influencing the AUC_tau, The AUC_tau and elimination rate constant did not influence clinical outcome.

Clinical response: All infusions were out-patient based, and no patient developed grade 3 cytopenia or febrile neutropenia. One patient developed an iRAE after 2 doses and was taken off trial. The remaining 18 patients completed 4 doses of nivolumab, with responses as follows: CR 11 (61.1%), PR 4 (22.2%), PD 2 (11.1%), SD 1 (5.5%). ORR was 83.3%. Four patients with PR were given 2 more doses of nivolumab, with no further improvement in response. 10 patients (9 CR, 1PR) proceeded directly to autologous transplant (ASCT), 4 underwent further salvage and 4 did not undergo ASCT (financial constraints). There were no statistically significant predictors of response (primary progressive/relapse, stage, gender, PD-1 occupancy, plasma drug levels).

Stem cell transplant: In the 10 who underwent ASCT the mean CD34+ cell dose was 11.7 x 10^6/kg (SD 6.1). White cell and platelet recovery occurred at median 11days and 13.5days respectively (range 9-17 and 7-20). OS of the entire cohort was 100% at 18mths. The one-year PFS was 90% for the 10 patients in CR/PR who underwent SCT (median follow-up 18.9mths).

Conclusion: This proof-of-concept Phase II trial demonstrates firstly that a chemo-free regimen in relapsed/refractory Hodgkin lymphoma is feasible, effective and well tolerated when compared to conventional salvage chemotherapy. Secondly, a low dose of nivolumab is sufficient to completely saturate PD-1 receptors even at “trough” levels, challenging the current 3mg/kg dose and 2-weekly dosing schedule. Thirdly, with a fixed, low dose of nivolumab, there is no significant inter-patient variation in plasma drug levels. Larger prospective trials are required for a head-to-head comparison of low dose nivolumab and standard chemotherapy, and T-cell receptor occupancy by flow cytometry may help to guide dose and frequency, which will rationalize the use of PD-1 inhibitors.

CTRI/2022/04/042179 [Registered on: 26/04/2022]