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Nivolumab associated with Brentuximab vedotin for relapsed / refractory mediastinal gray zone lymphoma: primary efficacy and safety analysis of phase 2 CheckMate 436 study


Mediastinal gray zone lymphoma ( MGZL ) is a rare form of non-Hodgkin lymphoma ( NHL ) with intermediate features between classical Hodgkin lymphoma ( cHL ) and primary mediastinal B-cell lymphoma ( PMBL ); shared features include tumor CD30 expression, 9p24.1 chromosomal alterations, and programmed death 1 ( PD-1 ) ligand expression.
Compared with primary mediastinal B-cell lymphoma, patients with mediastinal gray zone lymphoma have inferior survival outcomes.

Nivolumab ( Opdivo ) is a fully human IgG4 PD-1 immune checkpoint inhibitor antibody commonly used in combination with Brentuximab vedotin ( Adcetris ), an anti-CD30 antibody–drug conjugate.

The ongoing CheckMate 436 study includes patients with relapsed / refractory ( R/R ) NHL subtypes with CD30 expression ( DLBCL, PTCL, CTCL, PMBL, MGZL ); Nivolumab + Brentuximab vedotin treatment has demonstrated a high objective response rate ( ORR; 73% ) and complete response ( CR ) rate ( 37% ) in patients with primary mediastinal B-cell lymphoma.

An analysis has evaluated the efficacy and safety of Nivolumab + Brentuximab vedotin in the MGZL cohort of the open-label, phase 1/2 CheckMate 436 study.

The expansion cohort of the study enrolled adult ( 18 years or more ) patients with ECOG performance status of 0 or 1, who had confirmed R/R mediastinal gray zone lymphoma after autologous hematopoietic cell transplantation ( auto-HCT ) or, if ineligible for auto-HCT, after 2 or more multi-agent chemotherapy regimens.
Patients received 240 mg Nivolumab ( day 8 of cycle 1, then day 1 of later cycles ) and 1.8 mg/kg Brentuximab vedotin ( cycle day 1 ) every 3 weeks until disease progression or unacceptable toxicity.
Primary endpoints were investigator-assessed ORR ( Lugano 2014 criteria ) and safety.

Among 10 treated, evaluable patients, median age ( range ) was 35 ( 25–72 ) years; 6 patients ( 60% ) were male.
Patients had a median of 2 prior lines of systemic therapy and none had received prior auto-HCT.

At 8 months after the last patient received the first treatment ( database lock ), all patients had discontinued treatment: 5 due to disease progression, 3 due to maximum clinical benefit, 1 due to allogeneic (allo)-HCT, and 1 due to auto-HCT.
Patients received a median of 7 doses each of Nivolumab and Brentuximab vedotin.

ORR was 70% ( 80% CI, 45–88 ), with 5 patients ( 50% ) achieving CR. Time to CR was 1.2–4.8 months; duration of CR was 1.5–3.2 months before patients were censored for subsequent therapy.

Patients who achieved complete response were bridged to HCT ( 4 allo-, 1 auto- ) and censored ( all were alive at database lock ).
Eight of 9 ( 89% ) patients who were evaluable for response had more than 25% tumor reduction.

At a median follow-up of 12.4 ( range, 0.1–25.5 ) months, the 6-month overall survival rate was 80.0% ( 95% CI, 40.9–94.6 ).

Duration of response and progression-free survival could not be estimated due to censoring of patients who received subsequent therapies.

Nine patients ( 90% ) experienced treatment-related adverse events ( TRAEs ); the most common were neutropenia ( n = 3; 1 grade 1, 1 grade 2, and 1 patient experienced 4 grade 1/2 events and 1 grade 3 event ) and paresthesia ( n = 3; all grade 1 ).
Three patients had grade 3–4 TRAEs.
Infusion-related reaction occurred in 1 patient ( grade 1 ). One patient had an immune-mediated adverse effect ( grade 2 maculopapular rash; resolved without systemic steroids ).
One patient had a serious drug-related adverse effect ( grade 3 febrile neutropenia ). All 3 deaths were caused by disease progression.

In patients with R/R MGZL, Nivolumab plus Brentuximab vedotin has demonstrated a high investigator-assessed ORR of 70%, with a 50% CR rate and a tolerable safety profile, similar to findings in primary mediastinal B-cell lymphoma.
The regimen represents a potential option for bridging to HCT based on the rapid and frequent responses and favorable safety profile compared with standard chemotherapy. ( Xagena )

Source: British Society for Haematology ( BSH ) Annual Scientific Meeting, 2021

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