According to results from the phase III CHRONOS-3 trial, patients with relapsed indolent non–Hodgkin lymphoma may benefit significantly from the addition of copanlisib, a pan-PI3K inhibitor, to standard rituximab. The combination was safe and nearly halved the risk of disease progression or death, compared with placebo and rituximab.

Patients with relapsed indolent non–Hodgkin lymphoma (NHL) may benefit significantly from the addition of copanlisib (Aliqopa; Bayer), a pan-PI3K inhibitor, to standard rituximab (Rituxan; Genentech). These findings, from the phase III CHRONOS-3 study, were presented during the first virtual American Association for Cancer Research Annual Meeting 2021, being held April 10–15, and concurrently published (Lancet Oncol 2021 Apr 10 [Epub ahead of print]).

“We now have a PI3K inhibitor plus rituximab combination that appears both effective and safe,” said lead investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. Previous trials pairing rituximab with idelalisib (Zydelig; Gilead) or duvelisib (Copiktra; Secura Bio) were halted due to severe toxicity—enteritis, pneumonitis, and infectious complications. Both are oral PI3K inhibitors given daily, Matasar explained, “so there was GI tract exposure and likely chronic effects against regulatory T cells, which may have mediated the adverse events seen.” Copanlisib is administered intravenously and intermittently, “so we were able to improve disease control, with a manageable safety profile.”

CHRONOS-3′s 458 patients were randomized 2:1 to receive combination therapy or rituximab with placebo. Most had follicular lymphoma, indolent NHL's most common form; marginal zone lymphoma, small lymphocytic lymphoma, and Waldenström macroglobulinemia were also represented. Copanlisib–rituximab reduced the risk of disease progression or death by 48%. Median progression-free survival was 21.5 months, compared with 13.8 months in the control group. Overall response rates were 80% and 47.7%, respectively, including complete response rates of 33.9% versus 14.6%. Copanlisib's main side effects were hypertension and hyperglycemia, both largely transient, Matasar said.

“This is the first randomized combination trial to show clinical benefit across a broad swath of indolent NHL subtypes,” he added. “I think copanlisib–rituximab is a very reasonable option to discuss with patients. While there is modest additional toxicity involved, the disease control improvement is remarkable.” Copanlisib is an approved monotherapy for relapsed follicular lymphoma, and to Matasar, “these data support a label expansion.”

“There's no approved PI3K inhibitor for Waldenström's, so although this study's sample size was small, if the FDA grants a label, it would open a new door for these patients,” observed Ajay Gopal, MD, of Fred Hutchinson Cancer Research Center in Seattle, WA.

Finding consensus on patient management is key, Gopal added. New studies should take into account “the big picture with indolent NHL—it's chronic, but most patients will have a normal life span. In terms of benefit over their lifetime, it's still unclear whether available drugs should be given concurrently or sequentially.”

Loretta Nastoupil, MD, of The University of Texas MD Anderson Cancer Center in Houston, agreed. Calling CHRONOS-3 “well-conducted and confirmatory,” she added that “the question now is how to sequence therapies, given an ever-expanding treatment landscape and the paucity of biomarkers to inform decisions.”

Gopal noted that a different rituximab-based combination, featuring lenalidomide (Revlimid; Bristol Myers Squibb), is already approved for relapsed indolent NHL, based on the AUGMENT study (J Clin Oncol 2019;37:1188-99). “The efficacy does seem to favor lenalidomide–rituximab, albeit keeping in mind major caveats of cross-trial comparisons,” he said. “What's needed is assessing lenalidomide and copanlisib head-to-head alongside rituximab, which could provide more clear-cut data.” Such a trial is unlikely, however, so “we'll have to use our best judgment.”

Meanwhile, new PI3K inhibitors are emerging for indolent NHL, including umbralisib (Ukoniq; TG Therapeutics) and zandelisib (MEI Pharma), Matasar said. “This being a chronically relapsing disease, we always need more options.” –Alissa Poh