Interim PET-adapted de-escalation chemotherapy regimen for advanced stage classical Hodgkin lymphoma using brentuximab vedotin, pembrolizumab, doxorubicin, and dacarbazine: Phase 2 study Free

Background: Brentuximab vedotin (Bv), Nivolumab (N) and Pembrolizumab (P) have revolutionized the management of advanced stage classical Hodgkin Lymphoma (AS cHL). Significant improvements in both safety and efficacy have been observed with the Echelon-1 (E1) and SWOG S1826 studies. In GHSG HD18 & HD21, PET adapted strategy showed that the numbers of cycles could be reduced without affecting impact on the efficacy. Pembrolizumab followed by AVD in frontline AS cHL with minimal immune mediated adverse events (IMAE) (Allen et al Blood Advances 2023). This study incorporates pembrolizumab into the Bv+AD regimen based on the lower incidence of IMAE observed with pembrolizumab and utilizes a PET-adapted strategy to reduce chemotherapy exposure for participants (pts) with a negative interim PET scan. NCT05922904

Methods: Study enrolled pts with newly diagnosed stage I/II bulky mediastinal disease (≥10 cm), stage III, or stage IV cHL. Pts received 3 cycles of BvP+AD (Bv 1.2 mg/kg capped at 100kg), pembrolizumab 400 mg [P], doxorubicin 25 mg/m2 [A], and dacarbazine 375 mg/m2 [D]). Pembrolizumab was administered in Q6 week dosing intervals (C1D1, C2D15, C4D1 and C5D15). Interim PET scan was performed after cycle 3. Subjects achieving PET negativity defined as Deauville scores (DS) of 1 or 2 or 3 with > 90% reduction in total metabolic tumor volume (TMTV) continued in the de-escalation arm. Lesion cut off SUV of 4.0, using MIM software Version 7.4. Subjects on the de-escalation arm completed 3 additional cycles of only BvP. Those pts who received DS of 4, 5 or 3 with less than 90% reduction of TMTV would go on to complete 3 additional cycles of BvP+AD, for a total of 6 BvP+AD. The primary efficacy endpoint is CR rate at the end of therapy (EOT). Key secondary endpoints include safety and tolerability, ORR, duration of response (DOR), duration of complete response (DOCR), and progression-free survival (PFS). Disease response and progression are assessed using Lugano Classification Revised Staging System for malignant lymphoma, incorporating Lymphoma Response to Immunomodulatory Therapy Criteria for nodal non-Hodgkin and Hodgkin lymphomas.

Results: Study opened on Jan 2024, planned for 25 pts and the total of 25 were enrolled: median age 31 (19-65), male 52% (13/25), female 48% (12/25), Stage III 20% (5/25) stage IV 44% (11/25) and Stage I/II Bulky 36% (9/25). Caucasian 72% (18/25) Latino 12% (3/25) Asian 12% (3/25).

25 pts completed all six cycles and were evaluable for AE. The most common treatment-related adverse events (AE) of any grade were nausea (20/25, 80%), ALT increase (15/25, 60%), fatigue (15/25, 60%), alopecia (14/25, 56%). 5 SAEs were observed, 3 pts reported fever, 1 pt reported NHL; 1 pt reported diarrhea, however, colonoscopy ruled out colitis; AE of special interest, any grade peripheral sensory neuropathy (20/25, 80%) G1 (16/25, 64%) G2 (4/25, 16%) and no G3. No neutropenic fever was observed. G-CSF was used in 11/25 (44%) pts for primary prophylaxis. No treatment emergent IMAEs were observed, 2 pts developed hypothyroidism. 2 pts discontinued Pembrolizumab, one discontinued due to fever, second due to G3 LFT. 4 pts had dose reduction on Bv due to G2 neuropathy.

Twenty five pts completed interim PET scan, 2 pts achieved DS1, 16 pts DS2, and all 7 pts with DS3 achieved >90% TMTV reduction. All 25 pts proceeded to the de-escalation arm to complete 3 additional cycles of BvP only; EOT PET scan reported 5 pts achieved DS1, 15 pts DS2, 2 pts DS3 and 3 pts DS4.

At a median follow-up of 11.2 months (6.14 - 19.0 months). The primary endpoint of complete remission at EOT was 88% (22/25), there were no progressions reported. No consolidative radiation therapy was used.

Three pts had DS4 at the EOT, one pt had repeat PET follow up demonstrating DS2. Second pt with DS4, at repeat PET continued to have DS4 without increase in size of residual treated mass, which was biopsied demonstrating no evidence of lymphoma. Third pt with DS4 is awaiting biopsy evaluation.

Conclusions: PET adapted de-escalation therapy of BvP+AD in AS cHL demonstrated reasonable safety profile and promising efficacy in frontline setting. All pts achieved de-escalation arm, which represented a 50% reduction in anthracycline and alkylating agent exposure, minimizing chemotherapy in young Hodgkin lymphoma population without compromising efficacy. Longer follow up and larger cohort will be needed to provide more robust evidence.