Relapsed/Refractory PMBCL Shows High Response Rate to Nivolumab and Brentuximab Vedotin

Pier Luigi Zinzani, MD, PhD

Pier Luigi Zinzani, MD, PhD

A combination of nivolumab (Opdivo) plus brentuximab vedotin (Adcetris) was highly active in 73% of patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), based on results from the phase I/II CheckMate 436 trial, recently announced during the 15th 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) consisted of 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 &ge;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.

&ldquo;The AEs reported in this trial were consistent with the safety profiles of nivolumab and brentuximab vedotin treatment alone,&rdquo; he noted.

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

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

Reference

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.