Mitul Gandhi, MD

The combination of brentuximab vedotin (Adcetris), nivolumab (Opdivo), dacarbazine, and doxorubicin elicited strong response in patients with early-stage I and II classic Hodgkin lymphoma, according to interim efficacy and safety data from part C of the phase 2 SGN35-027 trial (NCT03646123; EudraCT 2020-004027-17) presented at the 2022 ASH Annual Meeting.

Findings showed that patients evaluable at the end of treatment (n = 76) achieved an overall response rate of 95% (95% CI, 87.1%-98.5%), including a complete response (CR) rate of 92% (95% CI, 83.6%-97.0%). Additionally, among all patients to receive at least 1 study dose (n = 125), 98% experienced at least 1 treatment-related adverse effect (TRAE), and grade 3 or higher TRAEs were reported in 26% of patients; however, the low rate of peripheral neuropathy and the absence of febrile neutropenia compared favorably with other current frontline treatments for this patient population.

“This [combination] represents what all of us have been looking for when utilizing 2 of the more active agents early in curative-intent therapy with a tapered down cytotoxic backbone,” Mitul Gandhi, MD, explained. “Look for future studies that will compare [this combination] to the existing standard of care such that this may supplant and, ultimately, hopefully, become the new standard of care.”

In an interview with OncLive^®, Gandhi discussed the rationale of combining brentuximab vedotin, nivolumab, dacarbazine, and doxorubicin for patients with early-stage classic Hodgkin lymphoma, the key findings from part C of the SGN35-027 trial, and the next steps for investigating this combination. He is a medical oncologist at Virginia Cancer Specialists in Gainesville, Virginia.

OncLive^®: What was the rationale for investigating this brentuximab vedotin combination in patients with early-stage classic Hodgkin lymphoma?

Gandhi: This was a multicenter, multipart study evaluating patients across several different stages in Hodgkin lymphoma. Part C looked at patients with early-stage disease, stage I and II Hodgkin lymphoma, evaluating a novel combination with brentuximab vedotin, nivolumab, dacarbazine, and doxorubicin to assess efficacy and safety.

This [combination] leveraged 2 of the most active drugs in Hodgkin lymphoma, both of which have regulatory approval in the relapsed setting. [These were] nivolumab, which is a checkpoint inhibitor, and brentuximab vedotin, which is an antibody-drug conjugate targeting CD30.

Both [nivolumab and brentuximab vedotin] represent active single agents, and the rationale was to combine them in a tapered-down, cytotoxic backbone in early-stage disease for an abbreviated course of chemoimmunotherapy in an effort to elicit durable long-term responses and minimize toxicity.

What is the current standard-of-care treatment for these patients?

Typically, in stage I and II Hodgkin lymphoma, approaches vary from a combination modality of chemotherapy followed by consolidative radiation therapy, or chemotherapy alone. The regimen that is most widely used in this setting is doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD].

This novel regimen represents a slight departure by tapering out and omitting bleomycin and vinblastine, replacing them with biologically active agents.

What key efficacy and safety findings from part C of the SGN35-027 trial were presented at the 2022 ASH Annual Meeting?

Based on the available data, the combination appears to be quite active, achieving a 92% CR rate with a manageable toxicity profile. [Twenty-six percent] of patients experienced grade 3 [or higher] toxicities ranging from nausea to fatigue to peripheral sensory neuropathy. However, the majority of patients were able to successfully complete therapy and seemed to be enjoying a durable remission with abbreviated follow-up.

There are known safety elements with brentuximab vedotin, which exacerbates underlying peripheral neuropathy, which was 1 of the grade 3 treatment-emergent [adverse effects] that was identified. Immune-mediated phenomenon associated with nivolumab was seen here, ranging from endocrinopathies, specifically hypothyroidism and hyperthyroidism, along with cutaneous manifestations with rash.

What are the next steps for investigating this regimen in Hodgkin lymphoma?

The combination appears to be quite active, and it appears to be well tolerated. The rational next step is comparing the combination with the existing standard of care of ABVD with or without radiation. [We can also evaluate] how much cytotoxic therapy is needed [to determine] what can be pared back [and still allow patients] to achieve an equivalent long-term outcome.

Reference

Lee HJ, Abramson JS, Bartlett NL, et al. Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (AN+AD) for early stage classic Hodgkin lymphoma: interim efficacy and safety results from the single-arm phase 2 study (SGN35-027 part C). Blood. 2022;140(suppl 1):9399-9401. doi:10.1182/blood-2022-156576