POLARIX: Upgrading R-CHOP With Polatuzumab Vedotin for Vincristine Improves Progression-Free Survival

The classic chemotherapy regimen known as R-CHOP may get an upgrade for patients who are newly diagnosed with diffuse large B-cell lymphoma (DLBCL), after results presented Tuesday showed that replacing an old therapy, vincristine, with polatuzumab vedotin (Polivy), improved progression-free survival (PFS) by 27%.

The findings, from the phase 3 POLARIX trial, were presented in the late-breaking session on the final day of the 63rd Annual American Society of Hematology (ASH) Annual Meeting in Atlanta, which also offered sessions online. Results were simultaneously published in the New England Journal of Medicine.

In POLARIX, an international team of investigators set out to find a better treatment for the combination of rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin hydrochloride), vincristine (Oncovin), and prednisone (R-CHOP) that has long been the first-line treatment in DLBCL. Although this combination cures 60% of patients, 40% see their cancer progress and may require salvage therapy and autologous stem cell transplant (ASCT).

Polatuzumab vedotin is an antibody drug conjugate that targets CD79b, which is expressed on the surface of malignant B cells; it received accelerated approval in 2019 in combination with bendamustine and rituximab to treat relapsed or refractory DLBCL. It is made by Genentech, which previously announced the topline results.

Vincristine is a widely used chemotherapy that blocks cell division. But one challenge with this drug: it’s also been in short supply, as some longtime manufacturers have stopped producing it.

In a press briefing before the Tuesday’s session, study co-author Gilles Salles, said there have been many attempts over the 20 years that R-CHOP has been used to modify the combination to boost its success rate, but none have panned out until now.

Although POLARIX found no significant difference in complete response rates or overall survival at the 2-year mark, patients who took the new combination were less likely to need additional treatment compared with those taking the usual regimen.

“This is the first randomized phase 3 study that has shown a benefit in patients with first-line DLBCL. It shows that it is possible to significantly reduce disease progression, including in patients with difficult-to-treat subtypes,” Salles said. “I think this could be a practice-changing result.”

Study Design and Results

Investigators randomized 879 patients aged 18 to 80 years; 440 were assigned to the polatuzumab regimen (called pola-R-CHP) and 439 were assigned to R-CHOP; both groups received 6 cycles of their respective regimen plus 2 cycles of rituximab alone.

The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety.

After a median follow-up of 28.2 months, the share of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group:

• PFS for pola-R-CHP was 76.7% (95% CI: 72.7- 80.8) vs 70.2% for R-CHOP (95% CI: 65.8-74.6] at 2 years; stratified hazard ratio (HR) for progression, relapse, or death was 0.73 by Cox regression (95% CI: 0.57-0.95; P = 0.02).
• The complete response rate was similar with pola-R-CHP vs R-CHOP (78.0% vs 74.0%; P = 0.16); however, disease-free survival responses point to a more durable response with pola-R-CHP than with R-CHOP (HR 0.70; 95% CI: 0.50-0.98), according to the ASH abstract.
• Overall survival at 2 years did not differ significantly between the groups: 88.7% (95% CI: 85.7-91.6) in the pola-R-CHP group vs 88.6% (95% CI: 85.6-91.6) in the R-CHOP group; HR for death, 0.94 (95% CI: 0.65-1.37; P = 0.75).
• The 2 groups had similar safety profiles.

Salles said the POLARIX investigators will keep following participants to learn more about long-term responses and outcomes. They also want to learn more about patient subgroups, to understand whether tumor biology contributes to the different responses to initial treatment. Better first-line treatment for DBCL may give patients hope and time, as much ASH has focused on moving chimeric antigen receptor (CAR) T-cell therapy into earlier lines of treatment in LBCL.

“It is quite satisfying that we were able to improve outcomes without significantly impairing patients’ quality of life,” said Salles.

Reference

Tilly H, Morschhauser F, Sehn LH, et al. The POLARIX Study: polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy in patients with previously untreated diffuse large B-cell lymphoma. Presented at: 63rd Annual American Society of Hematology Meeting and Exposition. LBA-1. December 14, 2021.