Nivolumab/Brentuximab Vedotin Combo Is Highly Active in Relapsed/Refractory PMBCL

Pier Luigi Zinzani, MD, PhD

Nearly three-fourths of patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) responded to a combination of nivolumab (Opdivo) plus brentuximab vedotin (Adcetris), according to results from the phase I/II CheckMate-436 trial that were presented at the 15^th International Conference on Malignant Lymphoma.

At a median follow-up of 11.1 months (IQR, 9-16), 25 of 30 treated patients were eligible for response evaluation. Results showed that the overall response rate (ORR) was 73%, including 11 patients with a complete response (CR), and 10 who achieved a partial response (PR).

Reduction of target lesion was observed in 23 (92%) patients and 13 (52%) patients had a reduction >50%. Two (8%) patients had no reduction in target lesion tumor burden.

“These results suggest that brentuximab vedotin and nivolumab work synergistically to target CD30 expression and PD-L1 to provide a greater response,” said lead study author Pier Luigi Zinzani MD, PhD.

In a presentation during the meeting, Zinzani, professor of hematology, head of Lymphoma Group, Institute of Hematology, University of Bologna in Bologna, Italy underscored the need for new treatments for relapsed/refractory PMBL.

“These patients have poor outcomes; the response to salvage chemotherapy is approximately 25% and the rate of 2-year survival after diagnosis is 15%,” he said, adding that there are no standard therapies available.

The efficacy and safety of nivolumab in combination with brentuximab vedotin have been established in phase I/II studies in relapsed/refractory classical Hodgkin lymphoma, which shares genetic features with PMBL, Zinzani explained.

“In relapsed/refractory PMBL, brentuximab vedotin and PD-1 blockade alone are associated with an ORR of 13% and 41%, respectively,” he said, noting that a combination of the 2 agents would be tolerated in patients with PMBL, and could even work synergistically to provide a greater response than seen with either drug separately.

In the open-label, phase I/II CheckMate-436 trial (NCT02581631), investigators evaluated nivolumab plus brentuximab vedotin in 30 patients with relapsed/refractory PMBL and measurable disease who had received either high-dose conditioning chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT) or ≥2 multi-agent chemotherapy regimens. Since brentuximab vedotin targets CD30, patients were also required to have CD30 expression ≥1% on the tumor or on tumor-infiltrating lymphocytes.

The median age was 36 years (range, 19-83) and 57% were female. The median lines of prior therapies was 2 (range, 2 to 5), including rituximab (Rituximab; 100%), radiotherapy (27%), and AHSCT (13%). At enrollment, the majority (67%) of patients had refractory disease, 20% were relapsed, and 13% were both.

Twenty-nine patients were treated with oral nivolumab at 240 mg IV plus brentuximab vedotin at 1.8 mg/kg IV every 3 weeks; 1 patient received only brentuximab vedotin until disease progression or unacceptable toxicity.

The primary endpoints were investigator‐assessed ORR according to Lugano 2014 criteria, and safety; secondary endpoints included duration of response (DOR), CR rate, duration of CR, progression-free survival (PFS), and overall survival (OS). Assessments were made by the investigator and by blinded independent central review (BICR) as a post-hoc analysis.

At a median follow-up of 11 months, results showed that the investigator-assessed PFS was not reached (NR) and the 6-month PFS rates via investigator and BICR were 63.5% (95% CI, 42.5%-78.6%) and 73.3% (95% CI, 52.0%-86.3%), respectively.

The median DOR and duration of CR were NR. The median time to first objective response was 1.3 months (IQR, 1.3-1.6) and the median time to CR was 3.2 months (IQR, 2.5-5.6).

Of the 5 patients who were not evaluable for response, 2 had died, 1 had inconsistent tumor codes, and 2 had measurements after progression.

Subsequent to this study, 11 (50%) of the responders proceeded to undergo stem cell transplant. At the time of transplant, 6 patients remained in CR and 5 were in PR; at 100 days post-transplant, 10 (100%) patients experienced a CR and there were no PRs. One patient underwent transplant <100 days prior to the assessment and could not be included.

At the time of data cut-off, a median 5 doses of nivolumab (range, 1-22) and 5 doses of brentuximab vedotin (range, 1-20) were given. Four (13%) patients remain on treatment and 26 (87%) patients discontinued. Ten (33%) patients discontinued due to their maximum benefit being reached; other cases were due to disease progression in (27%) and toxicity (7%). One patient requested discontinuation and 3 patients stopped treatment for other reasons.

Regarding safety, the majority (83%) of patients had ≥1 treatment-related adverse event (TRAE). The most frequently reported all-grade TRAEs were neutropenia (30%), peripheral neuropathy (27%), and peripheral sensory neuropathy (13%), thrombocytopenia (13%), rash (13%), hyperthyroidism (13%), and pyrexia (10%).

Grade 3/4 TRAEs leading to discontinuation occurred in 5 patients and were due to peripheral neuropathy in 3 (10%) patients, and 1 (3%) patient each had rash or immune mediated hepatitis. One patient (3%) each experienced serious TRAEs consisting of colitis, maculopapular rash, immune-mediated hepatitis, fall, acute kidney injury, or pyrexia.

“The AEs reported in this trial were consistent with the safety profiles of nivolumab and brentuximab vedotin treatment alone,” he noted.

Also at the time of data cutoff, 3 of the responders had progressed or died before starting subsequent therapy.

“Nivolumab combined with brentuximab vedotin demonstrated a high investigator&#8208;assessed ORR in relapsed/refractory PMBL where generally a poor outcome may be expected,” Zinzani concluded.

Zinzani PL. Nivolumab combined with brentuximab vedotin for relapsed/refractory primary mediastinal large b-cell lymphoma: efficacy and safety from the phase 2 CheckMate 436 study. Presented at: 15th International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 108.

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