Activity of Brentuximab Vedotin Plus Nivolumab Clinically Meaningful for Subset of Patients with HL

The combination of brentuximab vedotin (Adcetris) and nivolumab (Opdivo) demonstrated activity in patients with previously untreated Hodgkin lymphoma who had comorbidities in a phase 2 clinical trial, despite the trial not meeting its prespecified criteria for activity.

A report of the multicenter, single-arm, phase 2 trial, which was published in the Lancet Hematology, also showed the combination of brentuximab vedotin/nivolumab to be well-tolerated in patients.

The current standard-of-care therapy for previously untreated Hodgkin lymphoma is doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but patients over the age of 60 are typically ineligible to receive ABVD. The toxicity associated with the regimen is intolerable for the older population. With the emergence of novel nonchemotherapeutic agents for the treatment of Hodgkin lymphoma, which includes the CD30-directed antibody-drug conjugate, brentuximab vedotin, and 2 immune checkpoint inhibitors, nivolumab and pembrolizumab (Keytruda), older patients now have safer options. In prior studies, brentuximab vedotin demonstrated an overall response rate of 75%, making it of particular interest to be evaluated as treatment of older patients with Hodgkin lymphoma.

In the study of brentuximab vedotin plus nivolumab, 46 patients were enrolled who had a median age of 71.5 years (interquartile range [IQR], 64-77). The population was 46% female and 54% male. The majority of patients had an ECOG performance status of 1 (54%), followed by a performance status of 0 (30%), and 2 (13%). The population was also 85% White, 4% Black, 4% Asian, and race was not reported for the remaining 7% of patients. Most of the patients had stage IV disease at baseline (46%), but 33% had stage II, 20% had stage III, and 2% had stage I. A large percentage of the population (96%) did not have a mediastinal mass with a diameter > 10 cm. In terms of symptom presentation at baseline, 54% of patients were asymptomatic, 39% were symptomatic, and 7% had an unknown symptom burden.

Patients were categorized into groups based on age group and comorbidities. Ninety-six percent of patients were aged ≥ 60 years and 4% were < 60 and ineligible to receive ABVD chemotherapy. In terms of comorbidities, 100% of patients in the < 60 years old group had cardiac disease, and 50% had pulmonary disease.

Patients were followed for a median of 21.5 months (IQR, 15.6-29.9), and 76% of them completed all 8 cycles of therapy. Efficacy data were reported for 25 evaluable patients who were included in the interim analysis of the study.

Following 8 cycles of treatment with brentuximab vedotin in combination with nivolumab, complete metabolic responses were seen in 52% of the evaluable patients and partial metabolic responses were observed in 12%. The overall response rate (ORR) was 64% (95% CI 43-82). The median duration of response was not reached (NR) in the study (95% CI, 11.1 months to NR). However, 75% of patients did maintain their response with 17 achieving a response for more than 6 months and 14 continuing a response through 12 months. The prespecified criteria indicated that an ORR below 65% deemed the regimen ineffective, and the study, therefore, stopped accrual after the 64% ORR result.

An assessment of response across the subgroup populations explored in the study showed that patients with stage I/II disease and stage II/IV disease had similar complete metabolic response rates of 63% and 60%, respectively.

Four of the 25 patients developed progressive metabolic disease, and 5 patients did not complete all 8 cycles of therapy. Patients continued to be enrolled in the study while the first 25 patients received treatment for the interim analysis. A total of 21 additional patients were accrued and no patients were still receiving treatment at the time of data cutoff.

Survival was assessed in all 46 patients. Median follow-up for the population was 21.2 months (IQR 15∙6-29∙9). At the time of data cutoff, 70% of patients were free of disease progression, and 94% were still living.

The median overall survival was also not reached in the study, but the median progression-free survival (PFS) was 18.3 (95% CI, 12.7 to NR). Baseline factors such as age, sex, and clinical stage did not correlate with PFS.

A proportion of the patients who progressed during treatment with brentuximab vedotin plus nivolumab were given subsequent therapy with either doxorubicin, vinblastine, and dacarbazine, the ABVD regimen, cyclophosphamide, doxorubicin, vincristine, and prednisone or, the combination of gemcitabine, vinorelbine, and doxil. All subsequent regimens were followed by treatment with single-agent brentuximab vedotin, bendamustine, and brentuximab vedotin or chemotherapy.

The study design did not prespecify evaluation of response to subsequent therapies, but the investigators led by Bruce D. Cheson, MD, noted that some patients had a durable response to their subsequent treatment.

Brentuximab vedotin plus nivolumab led to grade 1/2 adverse events (AEs) in at least 10% of patients. Grade 3 AEs that were possibly attributed to the study combination occurred in 65% of patients. Two percent of patients discontinued nivolumab due to events of hepatotoxicity, rash, nephritis, and diarrhea. Brentuximab vedotin was discontinued in 11% of patients as a result of neuropathy. Additionally, a dose reduction of brentuximab vedotin was required in 30% of patients.

Cheson et al concluded that although the regimen did not meet expectations in patients with previously untreated Hodgkin lymphoma who had comorbidities, the fact that patients who achieved a complete metabolic response have not yet experienced relapsed signals a clinically meaningful benefit for that group of patients.

_Reference:

_{Cheson BD, Barlett NL, LaPlant B, et al. Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. Lancet Haematol. Published Online October 1, 2020. doi: 10.1016/ S2352-3026(20)30275-1}