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Third-Line BTK Inhibitor Combo Doubles PFS in Follicular Lymphoma

— Significantly more responses, CRs with zanubrutinib-obinutuzumab versus anti-CD20 drug alone

Ƶ MedicalToday

CHICAGO -- A third-line combination involving a newer-generation Bruton's tyrosine kinase (BTK) inhibitor plus obinutuzumab (Gazyva) led to superior oncologic outcomes in follicular lymphoma compared to obinutuzumab alone, a randomized phase II trial found.

The ROSEWOOD study of more than 200 patients with relapsed or refractory disease met its primary endpoint, with a significantly greater overall response rate in patients receiving zanubrutinib (Brukinsa) plus obinutuzumab compared to those receiving the anti-CD20 drug alone (68.3% vs 45.8%, P=0.0017), and the benefit was consistent across subgroups, reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Responses lasting 18 months or longer were seen in 70.9% and 54.6%, respectively (median duration not reached in either arm), and complete responses (CRs) were observed in 37.2% with the combination and 19.4% with single-agent obinutuzumab (P=0.0083), according to findings presented at the American Society of Clinical Oncology (ASCO) annual meeting.

Risk of disease progression or death was reduced by 49% with zanubrutinib-obinutuzumab (HR 0.51, 95% CI 0.32-0.81, P=0.004), with a median progression-free survival (PFS) of 27.4 months versus 11.2 months with obinutuzumab alone. And time to next anti-lymphoma treatment was also significantly prolonged with the combination (HR 0.37, 95% CI 0.23-0.60, P<0.0001).

"In order to understand where this combination fits in the follicular lymphoma landscape, we should test it against established second-line regimens, such as lenalidomide [Revlimid]-based regimens," said ASCO discussant Juan Pablo Alderuccio, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami, during a poster discussion session.

"With former generations of BTK inhibitors, we saw relatively low response rates in follicular lymphoma," said study co-investigator Christopher Flowers, MD, of MD Anderson Cancer Center in Houston. "I think we're starting to understand some of the mechanisms of action and sensitivities in follicular lymphoma to BTK inhibition, and there now are emerging biological data to be able to support that."

Alderuccio highlighted how single-agent ibrutinib (Imbruvica) as third- or later-line treatment for relapsed or refractory follicular lymphoma only showed a 21% response rate and 11% CR rate in the .

While the current study was not powered to detect an overall survival (OS) improvement, OS results fell in favor of zanubrutinib-obinutuzumab as well (HR 0.44, 95% CI 0.22-0.88, P=0.017), with 18-month rates of 85.4% as compared to 72.6% with obinutuzumab alone.

"We need more granular data to try to understand why there is this [OS] difference, especially in the patients where crossover was allowed," said Alderuccio.

Rates of response (24.1%) and CR (7%) were lower in the 29 patients from the obinutuzumab-alone arm who crossed over to the combination upon disease progression.

"I think part of it is we really need to better understand mechanisms of resistance in follicular lymphoma and to understand when there is progression on therapy, particularly on single-agent therapy with anti-CD20 antibodies, what those full mechanisms of resistance are," said Flowers. "Those may be particular mechanisms that BTK inhibition is not able to overcome."

Common treatment-emergent adverse events (TEAEs) for the combination versus obinutuzumab alone included infections (47.6% vs 36.6%, respectively), thrombocytopenia (34.3% vs 23.9%), neutropenia (27.3% vs 25.4%), and hemorrhage (26.6% vs 8.5%). In the combination group, atrial fibrillation occurred in 2.1%, hypertension in 3.5%, and major bleeding in 1.4%; rates were similar with obinutuzumab alone.

Grade ≥3 TEAEs occurred in 54% of patients on the combination and 48% of those on obinutuzumab alone, with the most common being decreased neutrophil counts or neutropenia (22% vs 20%, respectively), infections (19% vs 13%), thrombocytopenia or decreased platelet counts (14% vs 7%), anemia (4% vs 6%), and secondary cancers (4% vs 0%).

Flowers said that patient-reported outcomes from the trial will be reported in the near future.

ROSEWOOD was an international phase II trial that, from 2017 to 2021, enrolled 217 patients with relapsed or refractory follicular lymphoma and randomized them 2:1 to either oral zanubrutinib (160 mg twice daily) plus obinutuzumab (at standard doses) or obinutuzumab alone.

Eligibility requirements included that patients had grade 1-3a disease, had received at least two or more prior lines of therapy, and had not received prior BTK inhibition. Patients were stratified by number of prior regimens (median three), rituximab refractory status, and geographic region. The primary endpoint was overall response rate by Lugano classification on independent central review.

At data cutoff (Oct. 8, 2021), 50% of patients in the combination arm remained on treatment versus 26% of those assigned to obinutuzumab alone.

Baseline characteristics were well balanced. Patients had a median age of 63-66, about half had a high Follicular Lymphoma International Prognostic Index score, and 39%-43% had bulky disease.

About half of the patients in both arms were refractory to rituximab, and slightly more patients in the obinutuzumab-alone arm were refractory to their last line of therapy (40% vs 32%) and had progressive disease within 2 years of completing first-line therapy (42% vs 35%).

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    Ian Ingram is Managing Editor at Ƶ and helps cover oncology for the site.

Disclosures

The study was funded by BeiGene.

Zinzani disclosed relationships with BeiGene, ADC Therapeutics, Bristol-Myers Squibb, Celltrion, EUSA Pharma, Gilead, Incyte, Janssen-Cilag, Kyowa Hakko Kirin, Merck, Novartis, Roche, Sandoz, Secura BIO, Servier, Takeda, and TG Therapeutics.

Flowers disclosed a consulting or advisory role with BeiGene, Abbvie, Bayer, Celgene, Denovo Biopharma, Epizyme, Genentech/Roche, Gilead Sciences, Karyopharm Therapeutics, Pharmacyclics/Janssen, and Spectrum Pharmaceuticals.

Alderuccio disclosed relationships ADC Therapeutics, Agios, Foundation Medicine, Inovio Pharmaceuticals, and Puma Biotechnology.

Primary Source

American Society of Clinical Oncology

Zinzani PG, et al "Zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) monotherapy in patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL): Primary analysis of the phase 2 randomized ROSEWOOD trial" ASCO 2022; Abstract 7510.