Brentuximab Vedotin Plus Nivolumab Impresses in Older Patients With Hodgkin Lymphoma

Christopher A. Yasenchak, MD

Patients over the age of 60 years with classical Hodgkin lymphoma (cHL) often experience treatment-related toxicities with standard frontline chemotherapy or multiagent regimens, said Christopher A. Yasenchak, MD, who added that a novel combination with brentuximab vedotin (Adcetris) and nivolumab (Opdivo) could provide a more tolerable option for this population.

"Roughly 20% of patients with cHL are older than age 60," said Yasenchak. "Historically, those patients do not tolerate multiagent chemotherapy well and often develop fairly significant toxicities. Treatment-related deaths may also occur in this patient population. As a result of this, a novel treatment strategy is necessary."

A phase 2 study (NCT01716806) presented at the 2019 ASH Annual Meeting evaluated the safety of brentuximab vedotin in combination with nivolumab in 21 patients aged ≥60 years with newly diagnosed cHL.¹ Patients had a median age of 72 years and were either ineligible for or refused conventional treatment.

In the trial, patients received 1.8 mg/kg of brentuximab vedotin intravenously (IV) plus 3 mg/kg of nivolumab IV every 3 weeks for up to 16 cycles. Prophylactic premedication was also administered on the first day of each cycle to mitigate infusion-related reactions (IRRs).

The combination led to a 100% overall response rate (ORR) among 18 evaluable patients. Moreover, 72% and 28% of patients achieved a complete response (CR) and a partial response, respectively.

At the time of data cutoff, 7 patients remained on treatment and 6 completed treatment. In addition, 4 patients withdrew consent, 1 withdrew due to pneumocystis jiroveci pneumonia, and 1 experienced unrelated grade 3 acute renal failure and sepsis, which resulted in death.

According to the study results, the regimen was well tolerated. The most common all-grade treatment-related adverse events (TRAEs) included fatigue, peripheral sensory neuropathy, diarrhea, infusion-related reactions, and pyrexia. Importantly, no IRRs required intervention with steroids.

Grade ≥3 elevated lipase and peripheral motor neuropathy occurred in 19% and 14% of patients, respectively. Additionally, grade ≤3 immune-related toxicities occurred in 3 patients.

The combination was originally evaluated in a phase 1/2 study (NCT02572167) in patients with relapsed/refractory Hodgkin lymphoma. In this trial, the ORR was 85% and the CR rate was 62%.²

In an interview with OncLive, Yasenchak, an associate chair of Hematology Research, The US Oncology Network, and hematologist at Willamette Valley Cancer Institute and Research Center, discussed findings from the phase 2 trial with brentuximab vedotin and nivolumab in patients with newly diagnosed cHL.

OncLive: Could you discuss this trial design?

Yasenchak: The trial was designed for patients 60 years of age and older who were ineligible for or declined conventional therapy. It was a frontline study; only patients who had not received prior therapy were eligible for enrollment.

Patients received the combination of brentuximab vedotin and nivolumab every 3 weeks for up to 16 cycles.

The data showed a very high ORR of 95%, and almost 70% of patients achieved a CR.

What was the safety profile of the combination?

The safety profile was quite acceptable. We were a little concerned that patients could have immune-mediated inflammatory toxicities with nivolumab. In fact, grade 3 TRAEs were rare, and all of the immune-mediated inflammatory toxicities resolved with the use of steroids.

With brentuximab vedotin, neuropathy can be an issue. Neuropathy was not significant in this study, resolving in the majority of patients when it presented. The average time until resolution was 22 weeks.

The last issue that arose with this regimen in earlier studies was IRRs. In this study, IRRs were grade 1/2 and did not limit the ability to treat patients.

What are the next steps for this research?

Right now, we have limited follow-up. The median follow-up is only 7 months, so we are going to have to see. We saw a nice response rate, and the combination was well tolerated, but we have to see what the durability looks like.

Depending on what the long-term data show, we will figure out what the next steps should be.

There are parts E and F of this study, which are currently accruing patients. Part E is utilizing single-agent brentuximab vedotin to better understand the agent as monotherapy. This was a request by the FDA.

[The data] we have so far are quite significant for this patient population. [The combination] allows us to provide patients with an effective therapy with reduced toxicity; hopefully, these responses will be durable.

References

1. Yasenchak CA, Bordoni R, Yazbeck V, et al. Phase 2 study of frontline brentuximab vedotin plus nivolumab in patients with Hodgkin lymphoma aged ≥60 years. Blood. 2019;134(suppl_1; abstr 237). doi: 10.1182/blood-2019-124866
2. Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018;131(suppl_11):1183-1194. doi: 10.1182/blood-2017-10-811224