Opdivo-Adcetris Combo Shows Promise in Advanced PMBL Patients in Trial

Opdivo-Adcetris Combo Shows Promise in Advanced PMBL Patients in Trial

Combining Opdivo (nivolumab) with Adcetris (brentuximab vedotin) could be a promising option for people with advanced primary mediastinal B-cell lymphoma (PMBL), an aggressive and hard-to-treat disease, results from the CheckMate-436 trial show.

About 70% of the patients responded to this combination, and the lymphoma completely disappeared in 37% of them after a median of follow-up of 11 months, while treatment safety was manageable, its researchers said.

Given this combo’s high antitumor activity, it may also serve as a bridge to consolidation treatments intended to reach a cure, including blood stem cell transplant.

The data was reported in the study “Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study,” published in the Journal of Clinical Oncology.

Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive type of non-Hodgkin’s lymphoma, accounting for up to 10% of diffuse large B-cell lymphomas (DLBCLs).

It has particularly poor outcomes in people that have not responded to treatment (refractory) or whose disease has come back (relapsed). No standard of care has been defined for these patients.

Despite being a type of DLBCL, PMBL has a distinct genetic signature and shares many similarities with classic Hodgkin’s lymphoma (cHL). Specifically, it contains abnormal chromosome expansions that can confer sensitivity to cancer therapies known as checkpoint inhibitors. One such therapy is Opdivo, an anti-PD-1 antibody marketed by Bristol-Myers Squibb, and approved to treat certain advanced skin and lung cancers.

Similar to classical Hodgkin’s lymphoma, PMBL tumors may also display a surface marker called CD30, making them targetable by anti-CD30 therapies such as Seattle Genetics‘ antibody-drug conjugate Adcetris.

Adcetris is approved for use in systemic anaplastic large cell lymphoma (ALCL), a type of non-Hodgkin’s lymphoma, when chemotherapy has failed, as well as for Hodgkin’s lymphomas.

Some trials support use of an Opdivo–Acetris combination in patients with relapsed or refractory classical Hodgkin’s lymphoma. Those studies also suggest that the two agents act synergistically to halt cancer progression.

Given the common features between PMBL and cHL, Bristol-Myers and Seattle Genetics sponsored the CheckMate-436 Phase 1/2 trial (NCT02581631). This two-part  and open-label study aims to determine if a combination of Opdivo and Adcetris is safe and effective in people with relapsed or refractory non-Hodgkin’s lymphomas, including PMBL.

After a dose-escalation first part, the open-label trial expanded to include PMBL patients and those with other forms of non-Hodgkin’s lymphomas. All were grouped by their disease: DLBCL, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), and mediastinal gray zone lymphoma (MGZL).

Here, researchers report only primary results in the study’s 30 people with relapsed or refractory PMBL. These patients had failed to respond to either autologous hematopoietic (blood) stem cell transplant (auto-HCT) or at least two prior lines of chemotherapy.

Trial participants received Opdivo and Adcetris, given by infusions into the vein (intravenously), every three weeks until disease progression or unacceptable toxicity.

Tumor response was assessed by F-18 fluorodeoxyglucose, or FDG, PET-CT scans through the course of the study.

At a median follow-up of 11.1 months, 73% of the treated PMBL patients were responding to treatment, with 11 patients (37%) achieving a complete remission (disappearance of detectable signs of cancer), and another 11 (37%) reaching a partial remission, as assessed by trial researchers. Three other patients (10%) had stable disease.

An additional assessment, blinded and independent, determined that 70% of the patients responded to treatment, and complete remission was achieved in 43% of them.

Median duration of response, time to disease progression or death, and overall survival had not been reached at the time of the study publication, meaning that more than 50% of  patients are still responding to treatment, alive, and progression free.

Eleven patients responding favorably to the combo were given consolidation treatment with autologous (using patient’s own cells) or allogeneic (cells from a donor) stem cell transplant.

Treatment-related side effects were reported in 25 patients (83%), 16 of which were serious to life-threatening events after a median five cycles of treatment. The most common were low counts of neutrophils (a type of white blood cell), low platelet counts, and peripheral neuropathy (damage to nerves outside the brain and spinal cord). No deaths related to treatment were registered.

For patients with relapsed or refractory PMBL, an Opdivo–Adcetris combination “represents a promising option, with high antitumor activity and a manageable safety profile,” the researchers concluded.

This dual treatment “may be synergistic and is highly active … serving as a potential bridge to other consolidative therapies of curative intent,” they added.

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