Combined targeted modality in cHL: a risky bet?

In this issue of Blood, Lee et al¹ conclude that the brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (BV-N-AD) regimen shows a tolerable safety profile and high and durable response rates in the first-line treatment of early-stage bulky and advanced-stage classical Hodgkin lymphoma (cHL).

Combined modality treatment has made cHL one of the cancers with the best prognosis. However, this comes at the price of significant acute toxicities including hematologic toxicity, febrile neutropenia (FN), infections, pulmonary complications, and peripheral neuropathy (PNP). In addition, chemotherapy and radiotherapy lead to long-term organ complications and second cancers.² 

In the last decade, 2 targeted therapeutics were introduced into the treatment of cHL: the anti-CD30 antibody–drug conjugate BV and the anti–programmed cell death protein 1 (PD1) antibodies nivolumab and pembrolizumab were first approved for relapsed disease. Shortly thereafter, both modalities were introduced into first-line treatment. The BV, doxorubicin, vinblastine, and dacarbazine (BV-AVD) regimen became one of the standard regimens for advanced-stage cHL.³ BV-AVD reduced the rate of pulmonary toxicity and increased efficacy as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); however, rates of grade 3 PNP and FN of 11% and 19%, respectively, and a 6-year progression-free survival (PFS) of 82.3 % clearly leave room for improvement. The recently reported GHSG HD21 phase 3 trial compared the BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) regimen with conventional bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP).⁴ BrECADD was better tolerated than eBEACOPP and, with the caveat of a FN rate of 28%, BrECADD showed an unprecedented 4-year PFS of 94.3 %. Notably, owing to positron emission tomography (PET)-guided treatment, 64% of patients received shorter treatment with 4 cycles of once every 3 weeks, and the grade 3 sensory PNP rate was 1%. Also reported in 2024, the SWOG S1826 phase 3 trial compared 6 cycles of BV-AVD with nivolumab-AVD (N-AVD).⁵ With a median follow-up of 2.1 years, S1826 demonstrated greater efficacy in the N-AVD arm (2-year PFS, 92% vs 83%) and better tolerability with nearly all adverse events (AEs) occurring more frequently with BV-AVD. With N-AVD, the rates of FN and grade 3 sensory PNP were 6% and 1%, respectively. Thus, BrECADD and N-AVD currently represent the regimens with the most favorable efficacy to toxicity ratios in advanced-stage cHL.

The phase 2 trial reported by Lee et al is, to our knowledge, the first to combine an anti-PD1 antibody with BV and chemotherapy in first-line treatment of fit patients with cHL. BV-N-AD was hypothesized to increase efficacy while reducing toxicity by omitting vinblastine and thereby avoiding the overlapping toxicity of the 2 microtubule disruptors BV and vinblastine that cause PNP and hematotoxicity. Fifty-seven adult patients with stage I/II bulky (32%) and stage III/IV (68%) disease received ≤6 cycles of BV-N-AD without subsequent radiotherapy. The complete response (CR) rate (primary end point) was 88%, and after a median follow-up of 24.2 months, the 2-year PFS rate was 88%. PFS was higher in patients with bulky stage I/II than in patients with stage III/IV, with 2-year rates of 94% and 85%, respectively (see figure). Most frequent grade ≥3 treatment-related AEs were alanine aminotransferase increase (11%) and neutropenia (9%); 44% of patients had sensory PNP (grade 1-2, 40%; grade 3, 4%). Notably, with 49% of patients having received granulocyte colony-stimulating factor prophylaxis, no FN occurred. Treatment-emergent AEs led to discontinuation of BV and nivolumab in 12% and 16% of patients, respectively. With corticosteroid-based prophylaxis to mitigate infusion-related reactions and nausea in all patients, the treatment-emergent immune-mediated AEs grade ≥3 rate was 14%. Altogether, the efficacy and safety data with BV-N-AD seem promising in comparison with conventional treatment; however, the tolerability of BV-N-AD as compared with N-AVD in the SWOG S1826⁵ is not clearly superior. In fact, the rate of FN (0% vs 5%) is in the same low range and the frequency of sensory PNP trends to be higher with BV-N-AD as compared with N-AVD (grade 1-2, 40% and grade 3, 4% vs grade 1-2, 28% and grade 3, 1%). Additionally, the 2-year PFS rate of 85% with BV-N-AD in patients with stage III/IV does not compare favorably with 92% with N-AVD. Although the FN rate is lower, the efficacy of BV-N-AD with a 2-year PFS of 88% does not favorably compare with the 4-year PFS of 94.3% with BrECADD in the HD21 trial,⁴ which has a low rate of grade 3 PNP (1%). With the limitations of indirect cross-trial comparisons and small patient numbers, the combination of 2 targeted modalities with chemotherapy in the BV-N-AVD regimen does not outperform N-AVD or BrECADD and it comes at an increased cost. As another potential caveat, treatment with BV-N-AVD might reduce the therapeutic options at relapse.

The main question arising from the phase 2 trial performed by Lee et al is if and how targeted drugs and their combinations should best be included in the first-line treatment of cHL to maintain or improve the high cure rates while reducing dose and duration of classical combined modality treatment. PET-guided treatment is currently being evaluated in several ongoing trials combining ABVD variants with BV (ClinicalTrials.gov identifiers: NCT04685616 and NCT03517137), anti-PD(ligand)1 antibodies (NCT03617666 and NCT05008224), or both (NCT03712202 and NCT03233347) to try to further reduce toxicity and maximize efficacy. Moreover, the upcoming Pembro-FLASH trial (NCT06045195) will combine PET-guided BrECADD with pembrolizumab to increase the percentage of patients receiving only 4 cycles. Finally, the ongoing INDIE trial (NCT04837859) for early-stage unfavorable cHL evaluates a chemotherapy- and radiotherapy-free treatment for patients achieving early CR after single-agent therapy with the anti-PD1 antibody tislelizumab.

Besides PET guidance, biologic classification and minimal residual disease (MRD) monitoring by circulating tumor DNA^6,7 as well as other biomarkers^8,9 might allow for subtype-specific and MRD-guided treatment approaches in the future. Similar to many solid cancers, cHL has finally entered the era of targeted and biologically directed treatments. It is now the time to establish comprehensive correlative studies to dissect mechanisms of sensitivity and resistance aiming at further individualization of therapy. The results reported by Lee et al will help us to optimally combine and sequence the armamentarium of targeted and conventional therapies toward an ideal toxicity to efficacy ratio in cHL treatment.

Conflict-of-interest disclosure: P.J.B. is an advisor or consultant for Hexal, Merck Sharp & Dohme, Need Inc, Stemline, and Takeda; holds stock options in Need Inc; has received honoraria from AstraZeneca, BeiGene, Bristol Myers Squibb (BMS)/Celgene, Lilly, Merck Sharp & Dohme, Need Inc, Stemline, and Takeda; has received research funding from BeiGene (institutional), BMS (institutional), Merck Sharp & Dohme (institutional), and Takeda (institutional); and reports an excellence stipend of the Else-Kröner-Fresenius Foundation. B.v.T. is an advisor or consultant for Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, IQVIA, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, QualWorld, Regeneron, Roche, Sobi, and Takeda; has received honoraria from AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Novartis, Roche, and Takeda; reports research funding from Esteve (institutional), Merck Sharp & Dohme (institutional), Novartis (institutional), and Takeda (institutional); reports travel support from AbbVie, AstraZeneca, Gilead Kite, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis; and is a member of steering committees for Regeneron and Takeda.