Low-dose nivolumab combined with AVD chemotherapy (Nivo40-AVD) for advanced stage classic Hodgkin lymphoma

Abstract

Abstract Recently published SWOG S1826 trial demonstrated high efficacy and low toxicity of first-line nivolumab combined with adriamycin, vinblastine, dacarbazine (N-AVD) in newly-diagnosed advanced stage classic Hodgkin lymphoma (cHL) with the two-year progression-free survival (PFS) of 92%. This regimen may change the frontline treatment of advanced-stage HL in developed countries. However, due to the unique mechanism of action nivolumab doses as low as 0.1–0.33 mg/kg were demonstrated to achieve clinically meaningful responses. Finally, a very recent systematic review and meta-analysis revealed the high efficacy and acceptable toxicity of low-dose PD-1 inhibition in relapsed or refractory cHL with objective response rate (ORR) with low-dose nivolumab of 83.8% and a complete response (CR) rate of 43.3%. This approach was also associated with lower toxicity as compared to registrational trials on full-dose PD-1 inhibitors. With the aim of improving treatment short and long-term outcomes and reducing toxicity associated with the current standard of care (ABVD or BEACOPP-based regimens) in this population we conducted this investigator-initiated clinical trial on low-dose nivolumab (40 mg) in combination with doxorubicin, vinblastine and dacarbazine (Nivo40-AVD) in the frontline treatment setting of advanced cHL (NCT06984146). The trial was approved by Institutional Ethical and Scientific Review Boards. The anticipated number of enrolled participants in this single-center study is 54 (statistical power > 80%, significance level 5%). Eligible patients must be older than 18 years, have advanced cHL defined as per GHSG criteria (stage IIB with a large mediastinal mass and/or extranodal disease or stage III-IV), adequate left ventricle ejection fraction, no past history of autoimmune disease, and ECOG performance status of 0-4. Exclusion criteria include decompensated organ failure not associated with underlying lymphoma, pregnancy, uncontrolled infection, and inability to sign informed consent. Eligible patients will receive 6 cycles of Nivo40-AVD (nivolumab 40 mg fixed dose day 1 and 15; doxorubicin 25 mg/m2day 1 and 15; vinblastine 6 mg/m2day 1 and 15; dacarbazine 375 mg/m2day 1 and 15) with interim (after 2 cycles) and end of treatment PET/CT scan. Interim PET/CT will not affect clinical decisions and is done as part of the study on the impact of response biomarkers. In patients achieving only partial metabolic response after 6 cycles (Deauville score ≥ 4) radiation therapy is allowed. The primary endpoint is 2-year PFS. Secondary endpoints include ORR and CR rates, 2-year overall survival, and adverse events rate.