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Response to Immune Checkpoint Tx Low in Relapsed/Refractory DLBCL

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) had a disappointing low response to the programmed death-1 (PD-1) inhibitor nivolumab (Opdivo) used as a single agent, a phase II, open-label study indicated.

At a median follow-up of 9 months (range, 0.1 to 25 months) in patients for whom autologous hematopoietic cell transplantation (auto-HCT; n=87) had failed and 6 months (range, 0.2 to 24 months) in patients who were ineligible for auto-HCT (n=34), the overall response rates to nivolumab were 10% and 3%, respectively.

The study by Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and colleagues found that median progression-free survival (PFS) was 1.9 months in the cohort for whom auto-HCT had failed and 1.4 months for those not eligible for transplantation.

Overall survival (OS) rates for both groups were also low, at 12.2 months and 5.8 months, respectively. “Patients with refractory DLBCL or those who are unsuitable for or who have experienced relapse after auto-HCT have limited treatment options, with a median survival of only 6 to 10 months from progression,” Ansell and colleagues wrote online in the Journal of Clinical Oncology.

“In this phase II study, nivolumab monotherapy was associated with a low incidence of objective response in patients with relapsed/refractory DLBCL, and the study thus did not meet the primary end point,” the researchers concluded.

A total of 121 patients received treatment with nivolumab at a dose of 3 mg/kg, given intravenously over 60 minutes, every 2 weeks, until disease progression, unacceptable toxicity, or withdrawal from the study. The median number of doses received in the auto-HCT-failed group was four, and in the auto-HCT-ineligible group, three.

“In patients with archival tumor biopsies, 9p24.1 genetic alterations were evaluated using a fluorescence in situ hybridization (FISH) assay,” Ansell and co-authors noted, explaining that PD-1 and its ligands PD-L1/PD-L2 are immune checkpoints that downregulate immune responses. “Nivolumab … blocks tumor cell signaling via the PD-1 pathway, which releases T cells from the inhibitory effects of tumor cells and restores T-cell–mediated antitumor immune responses,” the team continued. Genes that encode PD-L1/PD-L2 are located on chromosome 9p24.1.

The primary end point for the study was objective response rate (ORR), defined as either partial remission (PR) or complete remission (CR), as assessed by an independent radiology review committee (IRC). And although ORRs were low in both groups, almost one-third of patients in the failed transplantation group achieved stable disease or better in response to nivolumab, including a CR in three of the nine patients with a duration of response of 11 months or more.

At 6 months, the IRC-assessed PFS rate was 19.1% in the auto-HCT failed cohort versus 5.2 months for the auto-HCT-ineligible cohort, the researchers added. Approximately 24% of adverse events (AEs) were judged to be treatment-related, the most common of which were nausea, fatigue, and diarrhea, all mostly low grade. There were also low rates of immune-mediated adverse events. Most patients died from disease progression and no deaths were felt to be related to toxicity from nivolumab, the researchers stated.

“In total, 74 of 112 patients had evaluable tumor biopsy specimens for 9p24.1,” Ansell and co-authors noted, adding that results from the analysis showed that genetic alterations in 9p24.1 were infrequent.

Ansell told MedPage Today that initial trials done several years ago showed promising initial results with nivolumab, particularly in Hodgkins lymphoma. “However, the cohort of patients with large cell lymphoma or aggressive B cell lymphomas in these initial trials was very small — only around 15 patients. So the feeling was that we needed to validate responses in a larger study.”

Unfortunately, results from the current study demonstrated that the response rate to single-agent nivolumab was “disappointingly low,” he said, explaining that in an unselected population of patients like the ones included in the study, “the response rate to immune checkpoint therapy is very low.”

And while immune checkpoint therapy may still benefit a small subset of patients such as those with 9p24.1 genetic alteration, since this group made up only a very small proportion of the study population, no correlations could be made.

In contrast to the results with immune checkpoint therapy, treatment with chimeric antigen receptor or CAR T-cell immunotherapy is meeting with much greater success in a similar population of failed or ineligible DLBCL patients, he continued. “Results so far with CAR T-cell therapy are looking extremely promising — substantially more promising than immune checkpoint therapy alone. The downside of CAR T-cell therapy is that more than half of patients receiving treatment still progress and the cost of immunotherapy is often prohibitive so that not everyone is either eligible or has access to it.”

The study was supported by Bristol-Myers Squibb (BMS), which markets nivolumab.

Ansell reported receiving honoraria from WebMD and Research to Practice, as well as research funding donated to his institution from BMS, Seattle Genetics, Affimed Therapeutics, Regeneron, Pfizer, LAM Therapeutics, and Trillium Therapeutics; most of the study co-authors also reported financial ties to BMS.