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The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion in favor of the approval of polatuzumab vedotin for use in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone in patients with previously untreated diffuse large B-cell lymphoma.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion in favor of the approval of polatuzumab vedotin (Polivy) for use in combination with rituximab (Mabthera) plus cyclophosphamide, doxorubicin, and prednisone (R-CHP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL).1
The recommendation is based on findings from the phase 3 POLARIX trial (GO39942; NCT03274492), which found that at a median follow-up of 28.2 months (range, 0.1-43.4), the polatuzumab vedotin combination significantly prolonged progression-free survival (PFS) vs rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; HR, 0.73; 95% CI, 0.57-0.95; P < .02).2
“A significant proportion of people newly diagnosed with DLBCL, an aggressive form of blood cancer, do not respond adequately to existing therapies,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, stated in a press release. “Therefore, more treatment options are needed that could increase a person’s chance of cure, and we look forward to bringing this new [polatuzumab vedotin] combination to people with DLBCL as soon as possible.”
The double-blind, placebo-controlled, international, phase 3 trial enrolled patients with CD20-positive DLBCL who had not previously received treatment for lymphoma, were between the ages of 18 years and 80 years and had an ECOG performance status ranging from 0 to 2.
To be eligible for enrollment, patients needed to have a baseline International Prognostic Index score between 2 and 5, and also have acceptable hematologic, renal, hepatic, and cardiac function irrespective of the cell of origin or the presence of MYC, BCL2, or BCL6 rearrangements.
If patients had a history of indolent lymphoma, a contraindication to any component of R-CHOP, previously received anthracycline agents, or had known central nervous system involvement, they were excluded.
A total of 879 participants were randomized 1:1 to receive polatuzumab vedotin plus R-CHP (n = 440) vs R-CHOP (n = 439). Eight cycles comprised of 21 days each were planned. In the first 6 cycles, patients received either polatuzumab vedotin plus R-CHP or R-CHOP. On day 1 of each cycle, they received either polatuzumab vedotin at 1.7 mg/kg and a placebo matching intravenous vincristine, or a placebo matching polatuzumab vedotin and vincristine at a dose of 1.4 mg/m2, plus rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2, and doxorubicin at 50 mg/m2.
All patients were given oral prednisone at a once-daily dose of 100 mg on days 1 through 5 of each of the first 6 cycles of treatment. In cycles 7 and 8, patients in both arms were given single-agent rituximab at a dose of 375 mg/m2.
Patients were stratified based on IPI score (2 vs 3 to 5), bulky disease (present vs absent), and geographic region (Western Europe, the United States, Canada, and Australia vs rest of world).
The primary end point of the trial was PFS per investigator assessment, and secondary end points included investigator-assessed event-free survival (EFS), positron emission tomography and computed tomography (PET-CT)–based complete response (CR) at the end of treatment per blinded independent central review, and overall survival (OS). Safety was also analyzed.
The median age among the overall population was 65 years (range, 19-80), and stratification factors and centrally evaluated disease subtypes were noted to be balanced between the 2 arms. The median time to diagnosis, as well as the initiation of treatment, in these patients also proved to be similar, at 26 days and 27 days, respectively.
The majority of patients received all 6 planned doses of polatuzumab vedotin or vincristine in the investigative and control arms, at 91.7% and 88.5%, respectively. Moreover, 88.0% of those in the polatuzumab vedotin arm and 85.9% of those on the R-CHOP arm received all 8 cycles of treatment.
Additional data published in The New England Journal of Medicine showed that the percentage of patients who survived without disease progression at 2 years was 6.5 percentage points higher in the investigative arm vs the control arm, at 76.7% (95% CI, 72.7%-80.8%) and 70.2% (95% CI, 65.8%-74.6%), respectively.
Data from the subgroup analysis revealed that those who were aged 60 years or younger, those with germinal-center B-cell–like subtype, those with bulky disease, and those who had lower IPI scores, did not experience a clear benefit with the polatuzumab vedotin combination over R-CHOP.
Investigator-assessed EFS proved to be lower in the polatuzumab vedotin arm vs the R-CHOP arm, with 2-year EFS rates of 75.6% (95% CI, 71.5%-79.7%) and 69.4% (95% CI, 65.0%-73.8%), respectively (HR, 0.75; 95% CI, 0.58-0.96; P = .02). The percentage of participants who achieved a CR at the end of treatment was not found to significantly differ between the investigative and control arms, at 78.0% and 74.0%, respectively (P = .16).
Notably, however, those who received the polatuzumab vedotin combination and achieved a CR as their best response were noted to have a higher likelihood of persistent remission than those who received R-CHOP and experienced a CR (HR, 0.70; 95% CI, 0.50-0.98).
OS was not found to significantly differ between the 2 treatment arms. Disease progression or relapse with central nervous system involvement was experienced by 3.0% of those in the investigative arm and 2.7% of those in the control arm.
At the time of data cutoff, which was June 28, 2021, 22.5% of patients in the polatuzumab vedotin arm vs 30.3% of those in the R-CHOP arm went on to receive at least 1 subsequent course of therapy for lymphoma that had not been specified in the trial protocol. A lower percentage of patients on the investigative arm received radiotherapy than those in the control arm, at 9.3% and 13.0%, respectively.
This was also true with regard to systemic therapy, at 17.0% and 23.5%, respectively, which included stem cell transplantation (3.9% vs 7.1%, respectively) and CAR T-cell therapy (2.0% vs 3.6%).
Regarding safety, the profile of the polatuzumab vedotin combination was comparable to that of R-CHOP. Grade 3 or 4 adverse effects (AEs) were experienced by 57.7% of those on the investigative arm vs 57.5% of those on the control arm; serious AEs occurred in 34.0% and 30.6% of patients, respectively, and grade 5 toxicities were observed in 3.0% and 2.3% of patients, respectively. Toxicities led to dose reductions in 9.2% of those who received polatuzumab vedotin vs 13.0% of those who were given R-CHOP.