R-CHOP Toppled in First-Line DLBCL Trial

ATLANTA — After 15 years as standard of care for previously untreated diffuse large B-cell lymphoma (DLBCL), R-CHOP has fallen to a new, though similar, regimen in a randomized trial.

At a median 28.2 months follow-up, investigator-assessed progression-free survival (PFS) was significantly improved when the vincristine in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) was dropped for polatuzumab vedotin (Polivy), a recently approved antibody-drug conjugate (stratified HR 0.73, 95% CI 0.57-0.95, P=0.02), reported Gilles Salles, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City.

At 2 years, PFS rates in the POLARIX trial were 76.7% with the so-called pola-R-CHP regimen versus 70.2% with R-CHOP, according to findings presented at the American Society of Hematology annual meeting and published simultaneously in the New England Journal of Medicine.

“We believe that these results support the use of pola-R-CHP in the initial management of DLBCL,” said Salles during a press briefing.

While overall survival (OS) was nearly identical at this 2-year timepoint (88.7% vs 88.6%, respectively; HR 0.94, 95% CI 0.65-1.37, P=0.75), he said the “burden of additional treatment” was higher in the R-CHOP arm.

Patients that failed R-CHOP more frequently received systemic therapy (23.5% vs 17% in the pola-R-CHP arm), more frequently received autologous transplant (7.1% vs 3.9%), and more frequently received CAR T-cell therapy (3.6% vs 2.0%).

“Another line of treatment — and to undergo procedures such as transplant or CAR T-cell therapy, despite the very good results presented during this meeting — is clearly a burden,” said Salles. “And if we can avoid that and cure them with first-line therapy, it’s a very significant benefit.”

While R-CHOP has been the standard of care for previously untreated DLBCL since the mid-2000s, only 60% of patients are cured with the regimen. Multiple trials have attempted to improve upon this standard — either by introducing new agents or by modifying the dose, schedule, or drugs delivered within R-CHOP — but “were unsuccessful,” said Salles.

Polatuzumab vedotin is an antibody-drug conjugate that targets CD79b, which is “ubiquitously” expressed on the surface of mature B-cell lymphomas, noted Salles, and the drug has a similar toxicity profile to vincristine. Polatuzumab vedotin is currently only approved in the relapsed setting.

Will the POLARIX data usher in a new standard for the first-line treatment of DLBCL?

Reached for comment, co-investigator Jonathan Friedberg, MD, of the University of Rochester Medical Center in New York, told MedPage Today that “many will wait for FDA approval, which I anticipate will occur over the next several months.”

“The study is compelling to me, since it was a double-blind randomized trial, and toxicity data suggest very similar tolerability,” he said.

At the press briefing, moderator Jane Winter, MD, of Northwestern University in Chicago, said confirmation of the results will be important.

She pointed out that while complete remission rates were not significantly different between arms on central review (78.0% with pola-R-CHP vs 74.0% with R-CHOP; P=0.16), it’s possible remissions with the novel regimen may be “more profound.”

“The durability seems to be different, perhaps a deeper remission biologically, and that hopefully will translate in time to substantial differences in [OS],” said Winter. “Providing durable and hopefully curative options upfront is important, so I think further follow-up is going to be very important.”

While the trial was not sufficiently powered for subgroup analyses, the researchers noted that point estimates favored pola-R-CHP among patients older than 60, those with an International Prognostic Index (IPI) score of 3 to 5, and in those with activated B-cell-like DLBCL.

The “most difficult-to-treat” patients in the trial — including double expressors (MYC, BCL2) — “significantly benefited on this therapy,” said Salles.

However, no clear benefit was seen for younger patients, those with lower IPI scores or bulky disease, and those with the germinal-center B-cell-like subtype.

The new regimen appeared similarly tolerable, with 6.2% of those on pola-R-CHP and 6.6% on R-CHOP discontinuing one of the study drugs (4.4% stopped polatuzumab vedotin and 5% stopped vincristine). Overall, dose reductions occurred in 9.2% and 13.0%, respectively.

Safety was also comparable, with grade 3/4 adverse events (AEs) occurring in 58% of both the pola-R-CHP and R-CHOP arms. Rates of grade 2 neuropathy (13.8% and 16.7%, respectively) and grade 3/4 neutropenia (28.3% vs 30.8%) were also similar. Deaths due to AEs occurred in 13 patients on pola-R-CHP and in 10 patients on R-CHOP, primarily due to infections.

Study Details

POLARIX randomized 879 adults with previously untreated DLBCL in the U.S., Canada, Europe, Australia, and Asia to six cycles of pola-R-CHP (with polatuzumab vedotin given at 1.8 mg/kg) or R-CHOP, plus two cycles of rituximab alone. Patients were required to have an IPI score of 2-5 and an Eastern Cooperative Oncology Group performance status of 0-2. Stratification factors included IPI score, bulky disease, and region.

Secondary analyses in the overall study population for investigator-assessed event-free survival (HR 0.75, 95% CI 0.58-0.96) and disease-free survival (HR 0.70, 95% CI 0.50-0.98) both favored pola-R-CHP, supporting the primary analysis.

Baseline characteristics were well balanced between arms, and represented the typical DLBCL population, said Salles, with a median age of around 65 years and 62% having an IPI score of 3-5. For cell of origin, 50-56% had germinal-center B-cell-like subtype and 31-35% had activated B-cell-like subtype. Around 40% had double-expressor (MYC, BCL2) lymphoma, and 6-8% had double- or triple-hit lymphoma.

After disease progression, unblinding was permitted and some patients in the R-CHOP group received polatuzumab vedotin as a subsequent treatment.