Polatuzumab vedotin regimen extends PFS in diffuse large B-cell lymphoma
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The addition of polatuzumab vedotin to chemotherapy significantly extended PFS compared with standard first-line treatment for patients with diffuse large B-cell lymphoma, according to results presented at ASH Annual Meeting and Exposition.
The experimental regimen reduced risk for progression, relapse or death by 27%, results of the randomized phase 3 POLARIX study showed.
The findings — presented during ASH’s late-breaking abstract session and published simultaneously in The New England Journal of Medicine — also showed the experimental and control regimens exhibited comparable safety profiles.
“We believe these results support the use of [the polatuzumab vedotin regimen] in the initial management of patients with DLBCL,” Gilles Salles, MD, PhD, chief of the lymphoma service at Memorial Sloan Kettering Cancer Center, said during a press conference.
R-CHOP chemotherapy — which consists of rituximab (Rituxan; Genentech, Biogen) plus cyclophosphamide, doxorubicin, vincristine and prednisone — has been standard first-line therapy for newly diagnosed DLBCL for more than 20 years. However, an estimated 40% of patients are not cured by this regimen.
“In the last 2 decades, there have been numerous trials trying to improve upon R-CHOP, either by modifying the dose or schedule of the drugs delivered within R-CHOP or by introducing new agents,” Salles said. “Overall, these attempts have been unsuccessful. Therefore, there remains an unmet need for patients with previously untreated DLBCL.”
Polatuzumab vedotin (Polivy, Genentech), an anti-CD79b antibody-drug conjugate, is approved in the United States for use in combination with rituximab and bendamustine for treatment of relapsed or refractory DLBCL.
A prior phase 1B/phase 2 trial showed polatuzumab vedotin demonstrated promising activity in the first-line setting when combined with R-CHP chemotherapy, which consists of rituximab, cyclophosphamide, doxorubicin and prednisone.
The international, double-blind POLARIX study included 879 patients (median age, 65 years; range, 19-80) with previously untreated DLBCL. All patients had an International Prognostic Index of 2 to 5 and ECOG performance status of 0 to 2.
Researchers randomly assigned 440 patients to six cycles of polatuzumab vedotin plus R-CHP, with placebo instead of vincristine. The other 439 patients received R-CHOP, with placebo instead of polatuzumab vedotin.
Study protocol specified a 1.8 mg/kg dose of polatuzumab vedotin or a 1.4 mg/m2 dose of vincristine on day 1 of each 21-day treatment cycle. Treatment continued for six cycles, and all patients received two additional cycles of rituximab dosed at 375 mg/m2.
Investigator-assessed PFS served as the primary endpoint.
Secondary endpoints included investigator-assessed EFS, independent review committee-assessed complete response rate at the end of treatment by PET/CT, DFS, OS and safety.
The experimental and standard treatment groups appeared balanced with regard to age (median, 65 years vs. 66 years), sex (male, 54% vs. 53%), presence of bulky disease (44% each), high-intermediate or high-risk International Prognostic Index categories (62% each), MYC/BCL2 expression (38% vs. 41%) and MYC/BCL2/BCL6 rearrangement (8% vs. 6%).
Median follow-up was 28.2 months.
Results favored the polatuzumab plus R-CHP regimen with regard to PFS (HR = 0.73; 95% CI, 0.57-0.95) and 2-year PFS (76.7% vs. 70.2%).
Researchers observed no significant difference in end-of-treatment complete response rate between patients assigned polatuzumab vedotin plus R-CHP vs. those assigned R-CHOP (78% vs. 74%); however, DFS results suggested patients assigned the polatuzumab vedotin regimen achieved more durable responses (HR = 0.7; 95% CI, 0.5-0.98).
Results showed no difference in OS between the experimental and standard therapy groups (HR = 0.95; 9% CI, 0.65-1.37).
“[Although] OS was not different at the time of analysis, we observed the burden of additional treatment was higher for patients receiving R-CHOP,” Salles said.
At data cutoff, 99 patients (23%) assigned polatuzumab vedotin plus R-CHP and 133 patients (30%) assigned R-CHOP had received at least one subsequent anti-lymphoma therapy. Fewer patients assigned the polatuzumab vedotin regimen received subsequent radiotherapy (9.3% vs. 13%), stem cell transplantation (3.9% vs. 7.1%) or chimeric antigen receptor T-cell therapy (2% vs. 3.6%).
Researchers reported comparable safety profiles between the experimental and standard regimens, including for rates of any-grade adverse events (97.9% vs. 98.4%), grade 3/grade 4 adverse events (60.7% vs. 59.8%), serious adverse events (34% vs. 30.6%), grade 5 adverse events (3% vs. 2.3%), adverse events that led to dose reductions (9.2% vs. 13%) and adverse events that led to discontinuation of any study drug (6.2% vs. 6.6%).
Researchers also reported similar rates of peripheral neuropathy between the experimental and standard therapy groups (any grade, 52.9% vs. 53.9%; grade 3/grade 4, 1.6% vs. 1.1%).
References:
Tilly H, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2115304.
Tilly H, et al. LBA-1. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
Perspective
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Shazia K. Nakhoda, MD
R-CHOP has been the standard of care for front-line management of diffuse large B-cell lymphoma, and previous efforts to improve this regimen with the addition of targeted therapies have been unsuccessful. The phase 3 ROBUST study and the PHOENIX study — evaluating the addition of lenalidomide (Revlimid, Bristol Myers Squibb) and ibrutinib (Imbruvica; Pharmacyclics, Janssen), respectively, to R-CHOP for patients with non-GCB subtype DLBCL — both failed to meet their primary endpoints.
In the phase 3 POLARIX study, researchers randomly assigned patients with CD20-positive DLBCL to either R-CHOP with a polatuzumab vedotin placebo or polatuzumab vedotin and R-CHP with a vincristine placebo. The study met its primary endpoint of PFS with otherwise similar safety profiles, including rates of peripheral neuropathy. Results did not show an OS benefit. This study did not exclude patients based on cell of origin and included patients with an International Prognostic Index of 2 to 5.
Although these results appear to be practice-changing, further data presented at ASH may guide which subgroups derive the greatest benefit to justify the increased cost associated with this regimen. Additionally, longer follow-up will allow for further assessment of OS benefit.
Active investigation of other combination therapies in the front-line DLBCL setting is ongoing and may yield competing front-line regimens for specific patient subgroups. Although the PHOENIX study failed to meet its primary endpoint, planned subgroup analysis showed an EFS, PFS and OS benefit of adding ibrutinib to R-CHOP for patients aged younger than 60 years with non-GCB subtype, identifying a population that may benefit from front-line incorporation of Bruton tyrosine kinase inhibitor therapy. The front-line ESCALADE study, which is investigating the better-tolerated second-generation Bruton tyrosine kinase inhibitor acalabrutinib (Calquence, AstraZeneca) in combination with R-CHOP, is ongoing.
Reference:
Wilson WH, et al. Cancer Cell. 2021;doi:10.1016/j.ccell.2021.10.006.
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Jane N. Winter, MD
Patients with relapsed disease have limited options, so providing durable — and hopefully curative — options upfront is very important. The complete response rates between treatment groups in this study were not different. However, we think we are seeing deeper and more profound complete remissions [with the experimental regimen] that hopefully will translate to improved OS. It may be a while until that can be demonstrated because of crossover and the alternatives available to patients, so further follow-up will be very important.
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Tilly H, et al. LBA-1. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
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