Press "Enter" to skip to content

Add-On PI3K Inhibitor Wins in Relapsed, Indolent NHL

Adding the PI3K inhibitor copanlisib (Aliqopa) to rituximab reduced the risk of disease progression or death for patients with relapsed indolent non-Hodgkin’s lymphoma (NHL), including those unfit for chemotherapy, a phase III trial called CHRONOS-3 showed.

Among more than 450 patients receiving rituximab, the median progression-free survival (PFS) reached 21.5 months with copanlisib, as compared to 13.8 months for those assigned placebo (HR 0.52, 95% CI 0.39-0.69, P<0.0001), reported Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York City.

“Copanlisib here represents the first PI3K inhibitor to be safely combined with rituximab, and the first to demonstrate broad and superior efficacy in combination with rituximab across the indolent histologic subtypes,” he said during a press briefing ahead of the American Association for Cancer Research (AACR) annual meeting.

With 19.2 months follow-up, a significant PFS benefit with copanlisib versus placebo, respectively, was seen across most NHL subtypes:

  • Follicular lymphoma: 22.2 vs 18.7 months (HR 0.58, 95% CI 0.40-0.83)
  • Marginal zone lymphoma: 22.1 vs 11.5 months (HR 0.48, 95% CI 0.25-0.92)
  • Small lymphocytic lymphoma: 14.2 vs 5.7 months (HR 0.24, 95% CI 0.11-0.53)

No significant difference was seen among the subgroup with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, but median PFS numerically favored the combination, at 33.4 months versus 16.6 months with rituximab plus placebo (HR 0.44, 95% CI 0.16-1.23). Overall survival data were immature at the time of analysis.

The overall response rate was 81% with the combination of copanlisib plus rituximab, including complete responses (CRs) in 33.9%, as compared to 47.7% with rituximab plus placebo, including CRs in 14.6%.

Findings from the study were published simultaneously in The Lancet Oncology.

Prior attempts at combining rituximab with the PI3K inhibitors idelalisib (Zydelig) or duvelisib (Copiktra) were unsuccessful due to toxicity, particularly enteritis, hepatitis, pneumonitis, and infections, explained Matasar.

“We did not experience the same rates of adverse events in the CHRONOS-3 trial, highlighting differences between copanlisib and these other agents. They are very different,” he said, noting that as idelalisib and duvelisib are both oral drugs administered daily, they have greater gastrointestinal exposure and generate regulatory T-cell suppression.

Copanlisib is a selective inhibitor of PI3K-alpha and PI3K-delta isoforms administered weekly intravenously, and lacks the chronic regulatory T-cell suppression. The drug is currently approved for follicular lymphoma in patients that have received at least two lines of systemic therapy.

“The combination of copanlisib and rituximab appears to be safe and effective,” Jonah Shulman, MD, of the Tisch Cancer Institute at Mount Sinai in New York City, told MedPage Today.

“Copanlisib has been used as a single agent for follicular lymphoma and has significant but generally manageable toxicities,” added Shulman, who was not involved with the research. “Rituximab is very well-tolerated and doesn’t add much toxicity. This combination could be an option for many patients with relapsed indolent NHL.”

In CHRONOS-3, the safety profile with the combination was consistent with the toxicities of the individual agents, said Matasar, who told MedPage Today that discontinuation rates were quite low with the combination.

“Most of those relatively few patients who discontinued due to severe toxicity came off early in the course of therapy,” he said. “I think the combination is an appropriate choice for patients who fit the study criteria, most notably without severe baseline diabetes or uncontrolled hypertension as well, as hyperglycemia and hypertension are directly caused by the alpha inhibitor of copanlisib.”

Common treatment-emerged adverse events (AEs) of any grade for the copanlisib and placebo arms, respectively, included hyperglycemia (69.4% vs 23.3%), hypertension (49.2% vs 19.2%), diarrhea (33.6% vs 9.6%), neutropenia (20.8% vs 16.4%), pyrexia (20.5% vs 7.5%), and upper respiratory tract infection (18.2% vs 16.4%).

Common grade ≥3 AEs included hyperglycemia (56.4% vs 8.2%), hypertension (39.7% vs 8.9%), neutropenia (15.6% vs 12.3%), and diarrhea (4.9% vs none).

Serious AEs were twice as frequent with copanlisib-rituximab (47.2% vs 18.5%), and there were six deaths in the combination arm (one deemed treatment-related) versus one in the rituximab-placebo arm. Pneumonitis, an AE of special interest, occurred in 6.8% of patients on the combination versus 1.4% with rituximab-placebo.

“This is a potential new treatment option for relapsed disease across all subtypes of indolent non-Hodgkin’s lymphoma for patients with a long remission after first-line therapy or who are unfit for chemotherapy,” said AACR Annual Meeting Program Chair Charles Swanton, MBPhD, of the Francis Crick Institute in London. “But one should also bear in mind the toxicities associated with the addition of the class I PI3 kinase inhibitor.”

CHRONOS-3 was a phase III trial that randomized 458 patients with relapsed indolent NHL 2:1 to rituximab (375 mg/m2 via IV) plus either copanlisib (60 mg via IV for 3 weeks on, 1 week off) or matching placebo until disease progression or unacceptable toxicity.

All patients were required to have CD20-positive indolent B-cell lymphoma; to have relapsed following treatment containing an anti-CD20 agent such as rituximab or obinutuzumab (Gazyva); and to have had a progression- and treatment-free interval of at least a year (80%) or be unfit for chemotherapy (20%).

Median patient age was 63 years, 15% had diabetes, and 36.5% had a history of hypertension. Most had follicular lymphoma (60%), followed by marginal zone lymphoma (20.7%), small lymphocytic lymphoma (10.9%), and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (8.3%).

Median time from initial diagnosis was 63.2 months and time since prior anti-CD20 treatment was 25.2 months. About half of the patients had received one prior regimen, 25% had received two, and 27% had three or more.

  • Ian Ingram joined MedPage Today in 2018 as Deputy Managing Editor, and covers oncology for the site.

Disclosures

CHRONOS-3 was sponsored by Bayer AG.

Matasar reported relationships with Bayer AG, Roche/Genentech, GlaxoSmithKline, ImmunoVaccine Technologies, Janssen, Pharmacyclics, Juno, Merck, Rocket Medical, Seattle Genetics, Takeda, and Teva.

Source: MedicalNewsToday.com