Lonah Trial: A Phase III Randomized Study of Low Dose Nivolumab Plus AVD or ABVD in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

The current standard of care for newly diagnosed advanced-stage Hodgkin lymphoma (HL) in lower- and middle-income countries continues to be doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which has proven to be an affordable and easily administrable regimen, the risk of pulmonary toxicity not-withstanding. Following data from the RATHL trial, a negative interim PET scan has allowed for the omission of bleomycin from further cycles, with non-inferior results. However, about 15% of patients will have a positive interim PET scan, and though escalated therapy with BEACOPP is considered standard, immediate and delayed toxicities are well known.

Recently, excellent results were shown from the interim analysis of the SWOG 1826 trial comparing brentuximab vedotin AVD (BV-AVD) to nivolumab AVD (N-AVD), with preliminary data suggesting superiority of N-AVD. While this regimen may change the frontline treatment of advanced-stage HL in developed countries, the prohibitive costs of checkpoint inhibitors (CPIs) at approved doses/schedules make this approach out of reach for most of the world’s population. An alternative strategy would be the use of CPIs at low doses, supported both by the lack of a dose-response relationship in Phase I studies, as well as real-world data showing the efficacy of low dose nivolumab in the setting of relapsed/refractory HL.

With the aim of incorporating CPIs into the frontline therapy of HL in a cost-effective manner, investigators from the Haematology Cancer Consortium, India initiated discussions on conducting a clinical trial in our setting, where for practical and cost issues, ABVD alone is the default standard of care.

The LoNAH trial (Low dose Nivolumab in Advanced Hodgkin Lymphoma) (CTRI/2024/03/063942 [Registered: 11/03/2024]) is a randomized, phase III study in patients with newly diagnosed advanced-stage HL, comparing ABVD to a new regimen n-AVD (comprising of low dose nivolumab (flat dose of 40mg) + AVD) using a risk-adapted strategy. Eligible patients must be 12 years or older and have stage IIBX, III or IV HL. After stratification for bulk disease and IPS score, patients will be centrally randomized in a 1:1 ratio to receive the initial phase of therapy with 2 cycles of either n-AVD or ABVD. An interim PET scan will be done after the first 2 cycles (iPET2). If the iPET2 is negative (Deauville score 1-3), treatment will be de-escalated on both arms to a further 4 cycles of AVD alone. iPET2-positivity (Deauville score 4-5) will be marked as an event for the primary outcome and patients will then receive center-specific protocols, either with BEACOPP or continuation/addition of low dose nivolumab to AVD (n-AVD).

‘Failure of therapy’ will be defined as any one of the following events for the purpose of this trial (1) iPET2 positivity (2) relapse/progression at any time-point (3) death due to any cause. The decision to include an iPET2 score of 4 or 5 as an event for primary outcome represents an attempt to use a real-world standard, which marks iPET2 positivity as an “early failure of ABVD”, with resultant escalation of therapy in ideal clinical practice.

Patients with initial bulk disease will not receive RT if the iPET2 is negative. Patients will be eligible to receive RT to residual metabolically active foci at the end of treatment (EOT) PET scan, at the discretion of the treating investigator. The primary endpoint is the two-year event-free survival. Secondary endpoints include overall survival, progression-free survival, EOT response rates in iPET2 positive patients treated further with BEACOPP or continuation of n-AVD, safety/tolerability of n-AVD compared to ABVD, and a cost-benefit analysis of this approach.

280 eligible patients are expected to be accrued over 3 years, assuming a screening failure rate of 30% (a high screening failure rate is anticipated, because despite the high diagnostic load at a referral center, patients often opt to go back to smaller oncology facilities closer to home, for chemotherapy).

The LoNAH trial represents a collaborative effort enabled by the Haematology Cancer Consortium (https://www.hemecancer.org/), a platform for haematology centers in India to test hypotheses that will answer region-specific questions, in this case the use of CPIs in a cost-effective manner for advanced stage HL.

Funding: Indian Council for Medical Research NHRP-2023-0001796