Sebastian Kaulitzki - Fotolia.com
On October 29, Roche reported that MabThera (rituximab), known as Rituxan outside Europe, had been approved for first-line maintenance treatment of follicular lymphoma (FL) by the European Commission. The go-ahead was based on data from the PRIMA Phase III study showing rituximab maintenance therapy halved the risk of relapse in patients with FL who had responded to induction therapy with a combination of rituximab and chemotherapy.
The trial outcome and results of several other trials over the past few years, though, still leave physicians and patients with some challenging decisions about whether and how to use rituximab in this clinical setting.
In 1997, Rituxan became the first approved mAb for cancer in the U.S. when it was sanctioned for the treatment of relapsed or refractory low-grade or follicular CD20+ non-Hodgkin lymphoma. Although rituximab is already indicated as a first- and second-line treatment in the U.S., maintenance clearance provides further upside and completes the mAb’s dominance of the FL arena, according to analysts.
Rituximab, in addition to non-Hodgkin lymphoma, is also approved for chronic lymphocytic leukemia and rheumatoid arthritis. The product had more than $5 billion in global sales in 2009, with about half coming from the U.S., where it is co-marketed by Biogen Idec and Genentech, a Roche subsidiary.
Roche markets the drug as MabThera in the rest of the world except Japan, where the drug is co-marketed by Chugai and Zenyaku Kogyo.
PFS a Clear Advantage
In the U.S., labeling for maintenance therapy in FL specifies that approval applies only to its use in patients who received induction therapy with cyclophosphamide, vincristine, and prednisone (CVP). Sanction was based on the E1496 study, which began in 1997 when induction was carried out with chemotherapy alone. Since then, clinical practice has evolved, and induction is now commonly carried out with rituximab in combination with cyclophosphamide, adriamycin, vincristine, and prednisone, also known as CHOP.
In March Genentech submitted an sBLA to the FDA based on the PRIMA study, which ran between December 2004 and April 2007. It enrolled 1,217 patients, 75% of whom had received induction therapy with rituximab plus CHOP (R-CHOP); the remainder received rituximab with other chemotherapy combinations. Patients were then randomized to receive rituximab maintenance (one dose every eight weeks for two years) or to be followed for observation alone.
At follow-up at 25 months, which was the median time point, 82% of patients who received rituximab maintenance were in remission compared to 66% of patients who did not receive maintenance therapy. The benefits were observed regardless of the patients' stage of remission, age, or previous treatment regimen.
Rituximab maintenance therapy was well tolerated, and there was no impact on quality of life, Roche stated. The most commonly observed adverse effects reported were infections (37% in the rituximab group and 22% in the observation group).
The PRIMA trial did not establish an improvement in overall survival (OS) for patients on rituximab maintenance therapy, however. “Lymphoma is a chronic disease that is likely to need chronic therapy,” commented George W. Sledge Jr., M.D., ASCO’s current president. “It is not clear yet whether improved progression-free survival (PFS) will translate to improved OS, but this study is an important step in this direction.”
Overall Survival and Side Effects
The European Organization for Research and Treatment of Cancer also conducted an assessment of rituximab first-line maintenance therapy. The EORTC 20981 trial enrolled 334 patients who had experienced complete or partial remission in response to induction therapy with either six cycles of CHOP or rituximab plus CHOP. They were randomly assigned to receive either rituximab maintenance treatment every three months or to be observed only. The study had a median follow-up of six years. Rituximab maintenance was seen to significantly improve PFS, with a median of 3.7 years compared to 1.3 years for the observation group.
OS at five years was 74% among patients receiving rituximab maintenance and 64% in the observation arm, which was not a statistically significant improvement. Patients who relapsed prior to the five-year endpoint were treated with rituximab as “salvage therapy.” Fifty-nine percent of the original CHOP followed by observation patients and 26% of R-CHOP followed by rituximab maintenance patients had a 9.7% and 2.4% increase in grades 3 and 4 infections, respectively.
Another study, published in the Journal of the National Cancer Institute, and headed by Liat Vidal, M.D., of the Rabin Medical Center in Israel, pooled data from five randomized trials involving 1,143 adult patients that compared maintenance therapy with no maintenance therapy. Most patients had FL that had relapsed or become refractory. The trials were conducted between 1998 and 2004.
OS data was available for 985 patients. Rituximab maintenance therapy was associated with a 40% improvement in OS relative to observation or retreatment with rituximab at relapse. The improvement in OS was statistically significant for patients with relapsed or refractory lymphoma but not for previously untreated patients.
Study investigators concluded, “Our results suggest that rituximab maintenance therapy for up to two years, either as four weekly infusions every six months or as a single infusion every two to three months, should be added to standard therapy of patients with relapsed or refractory follicular lymphoma after successful induction treatment.”
They added, however, that “the higher rate of infections with rituximab therapy should be taken into consideration when making treatment decisions.” Patients treated with rituximab maintenance therapy had nearly twice the rate of infection-related adverse events as patients who did not have prolonged rituximab therapy.
Wyndham Wilson, M.D., Ph.D., chief, lymphoid therapeutics section, Center for Cancer Research at the NCI, noted, “We know that patients with follicular lymphoma benefit from treatment with rituximab, but we cannot conclude from this analysis that maintenance therapy is the optimal approach to administering rituximab.”
Rituximab’s cost when used as a maintenance treatment compared to the cost of treating relapses could impact the decision to use the antibody for chronic FL treatment. In light of the expense associated with treating side-effects associated with multiple rounds of chemotherapy, treatment with the antibody could prove more cost-effective.
PharmacoEconomics reported the results of an assessment of the long-term costs of rituximab maintenance therapy after induction therapy for the French national health services. A model was developed comparing rituximab maintenance with patients who received nothing and were under observation. PFS and OS were obtained from the EORTC 20981 trial, which had a median follow-up of 28 months and extrapolated. PFS and OS benefits of rituximab were conservatively assumed to last five years.
The report concluded that rituximab maintenance therapy “may be a cost-effective strategy in the management of relapsed/refractory FL in France, with incremental cost-effectiveness ratios below those observed for other therapies in the oncology field. The cost of rituximab was partly offset by the lower cost of relapse due to a longer time in the disease-free health state for patients in the rituximab arm.”
Cancer is increasingly considered a chronic disease requiring chronic treatment. The decision to use rituximab as a maintenance therapy rests ultimately with individual physicians and their patients. While patients do seem to show disease progression-free benefits, there has been no clear demonstration of OS improvement reported in any maintenance therapy clinical study to date.
And there are signs of an increased risk of serious toxicities including leukoencephalopathies. A study published in the May 2009 issue of Blood reported 57 cases of progressive multifocal leukoencephalopathy (PML) following the administration of rituximab, usually with additional therapy, in HIV-negative patients. PML, a viral infection that affects the white matter of the brain, is usually fatal. The finding prompted the FDA to issue a Black Box warning for the antibody.
In comments to GEN, Dr. Vidal reiterated, “Rituximab maintenance after first induction has improved PFS but not OS. I think that the survival benefit of maintenance rituximab for patients with follicular lymphoma in the relapse setting has placed it as the standard of care for these patients.
“Rituximab maintenance does increase the risk of infections, and I believe that the longer a patient is treated the risk might further increase,” he added. “The effect of rituximab maintenance on quality of life and the risk of infection should be considered. For that reason I think that in this setting the decision to treat or not should be taken after discussion with the patient.”