Lenalidomide maintenance ups PFS in elderly with DLBCL
Lenalidomide maintenance significantly prolonged progression-free survival (PFS) compared with placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) who responded to first-line rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), according to the REMARC* study.
Rates of PFS and overall survival (OS) at 3 years remain at 60 and 70 percent, respectively, after first-line induction with R-CHOP; and increasing R-CHOP dose or adding cytotoxic drugs to the regimen have failed to improve patient outcomes in previous studies. [Lancet Oncol 2013;14:525-533; Lancet Oncol 2008;9:435-444]
The oral immunomodulator lenalidomide, having shown significant activity when used alone or with rituximab in relapsed DLBCL, was therefore tested as a maintenance therapy in the multinational, double-blind phase III REMARC study. A total of 650 elderly patients (aged 60–80 years) with DLBCL or other aggressive B-cell lymphoma, who achieved a complete or partial response (CR or PR) to R-CHOP, were randomized to lenalidomide maintenance 25 mg daily or placebo for 21 days every 4 weeks, with the cycle repeated for 2 years. [J Clin Oncol 2017;35:2473-2481]
After a median 39-month follow-up, the primary endpoint of PFS was significantly extended in the lenalidomide vs the placebo arms (median, not reached vs 58.9 months, hazard ratio [HR], 0.708; p=0.01). The results remained regardless of gender, age, International Prognostic Index adjusted for age, response after R-CHOP, or positron emission tomography (PET) status at randomization.
While median OS was not reached in both arms after a median 52-month follow-up, it was not significantly different between the two arms (HR, 1.218; p=0.26), with lymphoma being the main cause of death (59 percent vs 62 percent).
“At the time of this analysis, we do not yet fully understand the basis for lack of OS benefit despite the positive PFS data,” said the researchers.
“The PFS benefit has not yet translated into an OS benefit. Salvage at disease progression was successful in patients randomly assigned to placebo, such that their OS was the same as that of patients receiving lenalidomide maintenance,” according to Dr Thomas Witzig from the Mayo Clinic, Rochester, Minnesota, US, in an editorial. [J Clin Oncol 2017;35:2459-2460]
Analysis based on cell of origin revealed that the PFS benefit of lenalidomide was only significant in DLBCL with a germinal centre B-cell–like (GCB) subtype (60.9 vs 52.7 months, HR, 0.491; p=0.04), but not in those with a non-GCB profile. OS was similar in in both treatment arms regardless of GCB profile.
In addition, more patients in the lenalidomide arm converted from PR to CR than the placebo group (33 percent vs 29 percent; p=0.56), with a higher conversion rate from a positive to a negative status on PET scan with lenalidomide (21 percent vs 14 percent; p=0.20), although the difference was not significant.
“[T]he clinical benefit observed in the lenalidomide [maintenance] arm could be due to ... an immunomodulatory mechanism ... [rather than] a direct tumouricidal effect,” said the researchers. “[This] is supported by the observation that PR-to-CR conversion is similar between the lenalidomide maintenance and placebo in this trial.”
“Interestingly, patients with PR, particularly those with a positive PET scan, converted to CR within 6 months in both arms, which suggested that induction treatment may be more responsible for this conversion than the maintenance treatment,” they added.
Treatment-emergent adverse events were reported at least once in 92 percent of lenalidomide-treated patients and 83 percent of those on placebo, leading to dose reductions in 66 percent and 32 percent of patients, respectively. The most common grade 3/4 adverse events observed in the lenalidomide vs the placebo arms were neutropenia (56 percent vs 22 percent) and cutaneous reactions (5 percent vs 1 percent).
“It will be important in REMARC to identify any reliably predictive biomarkers to understand the effect of lenalidomide and [to] better use this drug in routine treatment of aggressive B-cell lymphoma,” the authors said.
“[T]he benefit with lenalidomide maintenance is likely for those truly elderly or infirm, non–transplantation-eligible patients who remain PET positive at the end of R-CHOP and agree to take a tolerable dose of lenalidomide to reduce the risk of relapse,” wrote Witzig, noting that other options are available for younger patients besides maintenance therapy.