A novel antibody-drug conjugate targeting CD79b, polatuzumab vedotin (Genentech/Roche) has shown activity in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) who are ineligible for autologous stem cell transplant. The antibody was used with the combination of bendamustine and rituximab and significantly improved outcomes compared with bendamustine/rituximab alone.
"We found that adding polatuzumab vedotin to bendamustine and rituximab significantly improved response rates, progression-free survival, and overall survival in DLBCL regardless of prior lines of treatment or refractoriness," said lead author Laurie H. Sehn, MD, from the BC Cancer for Lymphoid Cancer, Vancouver, British Columbia, Canada.
Based on these findings, polatuzumab vedotin has been granted Breakthrough Therapy Designation by the US Food and Drug Administration (FDA) and PRIME (PRIority MEdicines) designation by the European Medicines Agency for the treatment of r/r DLBCL.
The study was presented here at the European Hematology Association (EHA) 2018 Congress.
Novel Target, First-in-Class Drug
CD79b is a protein expressed in follicular lymphoma as well as DLBCL, and earlier phase 1 studies showed safety and an encouraging objective response rate with polatuzumab in treatment of both of these types of lymphoma.
With bendamustine an active regimen commonly used in both follicular lymphoma and DLBCL, the researchers explored the effects of adding this novel drugs to the standard combination and designed a trial that included patients with both types of lymphoma.
The study included 80 patients with follicular lymphoma and 80 with r/r DLBCL who were not eligible for stem cell transplants and therefore had poor prognoses.
The patients were randomly assigned 1:1 to treatment with polatuzumab 1.8 mg/kg combined with bendamustine/rituximab or bendamustine/rituximab alone for six cycles.
Patients in the DLBCL group were slightly older, with a median age of 67 to 71 years, compared with 63 to 65 years in the follicular lymphoma group. The median dose intensity was similar between groups.
The patients were stratified according to whether response to their previous treatment was 12 months or less, or more than 12 months, and patients with follicular lymphoma were also stratified according to low vs high disease burden.
The primary endpoint was complete response as determined by independent review of positron emission tomography scans 6 to 8 weeks after the end of treatment.
In the patients with follicular lymphoma, complete response did not significantly differ between the two treatment groups (27% for the combination vs 26% for bendamustine/rituximab). The objective response rate (ORR) was 30% in both treatment groups.
However, it was a different story for the patients with DLBCL; here the differences were significant. The complete response rate was 40% in the polatuzumab/bendamustine/rituximab group compared with 15% in the bendamustine/rituximab group (P = .01); the ORRs were 45% and 18%, respectively (P = .008).
At a median follow-up of 15 months, the median progression-free survival in the patients with DLBCL was 6.7 months in the polatuzumab/bendamustine/rituximab group compared with 2.0 months in the bendamustine/rituximab group (hazard ratio [HR], 0.31; P < .0001) and the overall survival was 11.8 months compared with 4.7 months (HR, 0.35; P = .0008).
Importantly, the improvements with triple therapy were significantly higher regardless of whether patients had two, three, or more prior lines of therapy and regardless of whether they were relapsed or refractory.
Adverse events grade 3 to 5 that were higher in the polatuzumab/bendamustine/rituximab group compared with bendamustine/rituximab, in both the follicular lymphoma and DLBCL patients, were highly related to cytopenias, febrile neutropenia, and infections.
Serious adverse events occurred more frequently in the polatuzumab/bendamustine/rituximab group, at 55%, than in the bendamustine/rituximab group, at 33%; these included febrile neutropenia in follicular lymphoma as well as DLBCL, while infection occurred in patients with follicular lymphoma only.
Rates of grade 5 adverse events were similar between the treatment groups according to histology, occurring in 5% of patients with follicular lymphoma and 18% of those with DLBCL.
"The majority of toxicities were generally low grade, including peripheral neuropathy," Sehn said when discussing the findings at a press conference.
"Only one patient had grade 3 or higher peripheral neuropathy, most were grade 1 or 2, and the majority were reversible."
Patients With Poor Prognosis
Driving the interest in the drug is the significant need for better treatment options for people with r/r DLBCL, who generally have poor prognoses, Sehn explained.
While DLBCL, the most common form of non-Hodgkin's lymphoma, is aggressive but very curable, up to 40% of patients do not respond or relapse after initial treatment.
Because many patients are older or have significant comorbidities, subsequent treatment approaches, such as high-dose chemotherapy followed by stem cell transplant, are often not options, Sehn said.
"Survival (in older relapsed or refractory patients ineligible for stem cell transplant) is generally quite short and the responses to successive therapy worsen with multiple relapses, so we do need better treatment options for these patients," she said.
In response to a question regarding bendamustine/rituximab as the control regimen in the study, Sehn acknowledged that its efficacy is lackluster at best — but few, if any, other options are available.
"The control arm (bendamustine/rituximab) does not do very well, but I think it's fair to say there is no standard of care in this population and no known drug combination that does do very well," Sehn said.
"Moving forward, whether this drug will be combined with bendamustine/rituximab or other novel therapies is an important question and hopefully other combinations will show benefit," she added.
Approached for comment, Anton Hagenbeek, MD, PhD, a professor of hematology at the University of Amsterdam, the Netherlands, commented that he is looking forward to seeing what additional benefits polatuzumab may offer in r/r DLBCL.
"In this population, I think these patients will likely not be cured by this second-line regimen, but they may have a better progression-free survival and maybe overall survival," he told Medscape Medical News.
"But I think the major implication is to bring this drug combination — or another combination with polatuzumab — to relapsing or refractory patients who may indeed be eligible for autologous stem cell transplant, and if the patients respond well to the therapy, then they can go on to stem cell transplant and we could expect better outcomes in that scenario."
"Meanwhile, the toxicity is tolerable, so I think this is a good next step in the treatment of DLBCL," he concluded.
Sehn's disclosures include honoraria, consulting, or research funding from Roche/Genentech, TG Therapeutics, AbbVie, Seattle Genetics, Celgene, Gilead, Janssen, Amgen, and Lundbeck. Hagenbeek is an advisor for Takeda Oncology.
European Hematology Association (EHA) 2018 Congress. Abstract S802. Presented June 16, 2018.
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