Frontline Brentuximab Vedotin As Monotherapy or in Combination for Older Hodgkin Lymphoma Patients

Abstract

Introduction: Older patients with classical Hodgkin lymphoma (cHL) have poor outcomes relative to younger patients, often due to comorbidities and toxicities related to standard first-line (1L) chemotherapy (5-yr PFS: 30%-45% vs 75%-80%) (Evens 2008; Proctor 2009). Brentuximab vedotin (BV), a CD30-directed antibody-drug conjugate, has robust activity in patients refractory to several lines of chemotherapy. Methods: This phase 2, open-label study, SGN35-015 (NCT01716806), evaluated efficacy and tolerability of BV alone or combined with single-agents in treatment-naive cHL patients ≥60 yr. The full-analysis set (FAS) includes all patients who received BV (1.8 mg/kg IV). Patients in Part A received BV monotherapy on Day 1 of every 3-week cycle (n=26); Part B: BV+dacarbazine (DTIC; 375 mg/m2; n=19); Part C: BV+bendamustine (benda; 70 mg/m2; n=20); and Part D: BV+nivolumab (nivo; 3 mg/kg; n=20). The efficacy evaluable (EE) set includes FAS who had at least 1 post-baseline response assessment (n=25, 19, 17, 19). Results: Demographic characteristics were generally similar: median age 78, 69, 75, and 72 yr in Parts A, B, C, and D, respectively, and 62% of patients (range 45%-70%) reported impaired physical functioning at baseline. Most patients had disease stage III/IV (62%, 68%, 75%, 80%), were ECOG 0/1 (77%, 74%, 80%, 95%), and male (54%, 68%, 50%, 75%). Median time from diagnosis was 1.2 to 1.5 mo (FAS; 10 Jan 2020 data cutoff). ORR were high (92% [95% CI: 74%, 99%], 100% [95% CI: 82.4%, 100%], 100% [95% CI: 80.5%, 100%], 95% [95% CI: 74%, 99.9%]) at a median follow-up of 59.4, 58.6, 51.3, and 19.4 mo in the EE data set. Median PFS in the EE set was 10.5 mo (95% CI: 5.6, 77.5) with monotherapy and 46.8 mo (95% CI: 11.0, 68.7), 40.3 mo (95% CI: 4.8, NR), and not reached (95% CI: 9.4, NR) in the combination parts. Median OS in the FAS set was 77.5 mo (95% CI: 40.1, NR) with monotherapy; 64.0 (95% CI: 53.4, NR), 46.9 (95% CI: 6.8, NR), and not reached (95% CI: NR, NR) in the combination parts. Treatment-related adverse event (AE) ≥ Grade 3 occurred in 50%, 37%, 70%, and 60% of patients; peripheral neuropathy (PN) was most common (35%, 26%, 20%, 35%). Treatment-related serious AEs occurred in 12%, 11%, 40%, and 5% of patients. Part C enrollment (BV+benda) closed early due to multiple acute toxicities. There were no treatment-related deaths in any part of the study. The median treatment cycles per patient were 8.0, 12.0, 5.0, and 14.5. Treatment discontinuation due to related AEs occurred in 42%, 42%, 40%, and 30% of patients, most commonly due to PN (38%, 37%, 30%, 20%). Conclusions: Older patients with cHL and multiple comorbidities have very high response rates and a clinically meaningful improvement in PFS with BV as monotherapy or combined with other single agents and improved tolerability versus combination chemotherapy. Median overall survival exceeded 6 yrs with BV monotherapy. BV+nivo or BV+DTIC appeared to be the most reasonable combination treatment options in this study. Disclosures Yasenchak: BeiGene: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria. Bordoni:Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Guardant Health: Honoraria, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Patents & Royalties; Northside Hospital Cancer Institute: Other: Uncompensated relationship; Practice Point Communications: Other: Uncompensated relationship; Foundation Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Speakers Bureau; G1 Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Patel-Donnelly:Gilead: Research Funding; Boston Biomedical: Research Funding; Roche: Research Funding; LAM Therapeutics: Research Funding. Goldschmidt:Amgen: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Blue Ridge Cancer Care: Current Employment. Boccia:Rigel: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cline:Pfizer: Honoraria; Reflexion Medical: Consultancy, Other: Travel expenses; Texas Oncology: Current Employment. Sacchi:Bristol-Myers Squibb Company: Current Employment. Forero-Torres:Seattle Genetics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sims:Seattle Genetics, Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Travel expenses. Liu:Seattle Genetics, Inc.: Current Employment, Current equity holder in publicly-traded company. Friedberg:Roche: Other: Travel expenses; Portola Pharmaceuticals: Consultancy; Bayer: Consultancy; Astellas: Consultancy; Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Kite Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding.

Older patients (aged ≥60 years) with previously untreated advanced-stage classical Hodgkin lymphoma: a detailed analysis from the phase III ECHELON-1 study

“…Median PFS and OS had not been reached in the nivolumab arm, with median follow up 19.4 months. 26 The authors concluded that brentuximab vedotin plus dacarbazine or nivolumab were reasonable combinations in this more unfit/frail patient population. The nivolumab combination was associated with a higher rate of Grade ≥ 3 treatment-related adverse events compared with the dacarbazine combination (60% vs 37%), including peripheral neuropathy (35% vs 26%), but a lower rate of serious treatment-related adverse events (5% vs 11%) and treatment discontinuations due to adverse events (30% vs 42%).…”

“…Brentuximab vedotin has also been assessed as monotherapy and in combination with bendamustine, dacarbazine or nivolumab. 15,17,25,26 Importantly, patients enrolled in this study were ineligible for frontline conventional chemotherapy combinations (via investigator's judgement). Initial assessment of brentuximab vedotin monotherapy demonstrated promising efficacy with 92% of patients (median age 78 years) achieving an ORR (CR: 73%).…”

“…The nivolumab combination was associated with a higher rate of Grade ≥ 3 treatment-related adverse events compared with the dacarbazine combination (60% vs 37%), including peripheral neuropathy (35% vs 26%), but a lower rate of serious treatment-related adverse events (5% vs 11%) and treatment discontinuations due to adverse events (30% vs 42%). 26 Another phase 2 study of brentuximab vedotin plus nivolumab in previously untreated older patients (≥60 years) suggested a lower ORR of 64%, including 52% with CR, at an interim analysis, which indicated that the combination was active in this population but did not meet predefined criteria that required a higher level of activity for further enrolment in the trial to proceed. 28 The overall incidence of treatment-emergent AE in ECHELON-1 was comparable between the A+AVD and ABVD arms.…”

Clinical Dilemmas in the Treatment of Elderly Patients Suffering from Hodgkin Lymphoma: A Review

“…BV monotherapy has been addressed in three different trials [ 65 , 66 , 67 ]. The data obtained show limited activity of BV monotherapy, warranting its use in combination regimens.…”

“…A high discontinuation rate was observed due to AEs, mainly peripheral neuropathy (PN). The same study examined the role of adding bendamustine; however, due to unacceptable toxicity and high TRM, this arm was terminated early [ 67 , 68 ]. The HALO trial also examined the use of the latter regimen in 49 frail patients [ 69 ].…”