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Earlier this year, the FDA approved a new frontline option for patients with diffuse large B-cell lymphoma (DLBCL): the antibody-drug conjugate polatuzumab vedotin (Polivy) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP).

Combination chemotherapy involving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) -- and before that, CHOP alone -- has been the established option for frontline therapy in DLBCL for decades, but the now lists both R-CHOP and pola-R-CHP as preferred regimens for patients with stage II (with extensive mesenteric disease) or stage III-IV DLBCL.

Polatuzumab is a CD79b-directed antibody and microtubule inhibitor conjugate. Jakub Svoboda, MD, of Penn Medicine in Philadelphia, explained that since vincristine and polatuzumab can both cause neuropathy, the pola-R-CHP regimen omitted vincristine, but is otherwise the same in terms of the schedule and doses of R-CHOP.

The phase III POLARIX trial compared six cycles of pola-R-CHP or R-CHOP plus two cycles of rituximab alone in 879 patients with previously untreated intermediate-risk or high-risk DLBCL, and demonstrated 2-year progression-free survival (PFS) rates of 76.7% versus 70.2% (HR 0.73, 95% CI 0.57-0.95).

"While the study met its endpoint and showed that the polatuzumab-containing arm showed benefit in 2-year progression-free survival over the standard arm, the total benefit was relatively modest -- about 6% -- and there was no improvement in overall survival [OS]," Svoboda said, adding that it was also reassuring that the new regimen had a toxicity profile similar to the R-CHOP arm.

"R-CHOP is a great therapy that can cure anywhere from 60% to 90% of DLBCL [patients] with six cycles of treatment," said Michael Jain, MD, PhD, of Moffitt Cancer Center in Tampa, Florida. "Running a clinical trial head-to-head against R-CHOP is hard because patients likely to not succeed with R-CHOP are often the ones not able to enter a clinical trial."

Put another way, newly diagnosed DLBCL patients who are extremely sick and in the hospital will often be started on R-CHOP almost immediately, while the better-risk patients who may not need to start on treatment right away are typically the ones able to make it onto clinical trials. So studies trying to improve on R-CHOP are often enriched with these better-risk patients, making it more difficult to beat the established regimen.

Without a dramatic benefit, therefore, whether clinicians choose to use pola-R-CHP may depend on a few factors.

For example, Svoboda pointed out that of the POLARIX data revealed that patients with the activated B-cell subtype of DLBCL may benefit much more compared with those with germinal center B-cell (GCB) DLBCL. "These are the patients for whom I would strongly consider this regimen," Svoboda said.

In addition to patients with GCB subtype, DLBCL patients with underlying neuropathy may not be good candidates for any vinca alkaloid-based agent, including polatuzumab or vincristine, he said.

Cost may also be a consideration. "The improvement is incremental regardless of how you look at it because R-CHOP is so effective," Jain said. "There needs to be more discussion around whether or not a system should fund [pola-R-CHP] or in what context."

comparing pola-R-CHP and R-CHOP projected that pola-R-CHP could be more cost-effective "from both a societal and a payer perspective"; higher total costs with pola-R-CHP were largely offset by lower costs for subsequent therapy and routine care, for example, and could increase a patient's work productivity. that assuming a 5-year PFS rate of 69.6% with pola-R-CHP and 62.7% with R-CHOP, the former was cost-effective at a willingness-to-pay threshold of $150,000.

Svoboda said that from his own experience, "any second-line treatment of DLBCL is extremely expensive, including CAR [chimeric antigen receptor] T-cell therapies or transplants. Therefore, if we can prevent 5-10% of relapses in the frontline, we could be saving a large number of resources and costs in the second line."

Finally, it will likely be years before any trial could possibly show an OS benefit for either regimen in a disease like DLBCL because of the variety of available options for relapsed disease.

"Patients may live for years following their initial progression, but it is possible that with longer follow-up we will ultimately see OS benefit as we saw in other settings," Svoboda said, adding that it is also important to keep in mind that any changes in frontline therapy often affect a patient's options in later settings.

"For example, we were often using polatuzumab with rituximab as an effective bridge during CAR-T manufacturing in second line, and that is not going to be a good option in patients progressing shortly after pola-R-CHP," he explained. "Some of our strategies for relapsed/refractory disease may need to be modified when using pola-R-CHP upfront."

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