Ibrutinib Plus Chemoimmunotherapy Fails to Improve PFS in Pretreated Follicular Lymphoma, MZL

The addition of ibrutinib (Imbruvica) to bendamustine plus rituximab (Rituxan; BR) or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) did not lead to a statistically significant improvement in progression-free survival (PFS) vs either chemoimmunotherapy regimen alone in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma (MZL), according to findings from the phase 3 SELENE trial (NCT01974440) presented at the 17th Annual International Conference on Malignant Lymphoma.¹

In the intention-to-treat (ITT) population, median PFS was 40.5 months with the addition of ibrutinib vs 23.8 months with chemoimmunotherapy alone, with median follow-up of 84 months (HR, 0.81; 95% CI, 0.63-1.04; P=.0922). Similar results were seen in patients with MZL in the ibrutinib (median, not reached; 95% CI, 49.25–not evaluable [NE]) and chemoimmunotherapy alone (median, 91.6 months; 95% CI, 9.23-NE) arms by investigator (HR, 0.73; 95% CI, 0.31-1.68; P = .4505) and independent review committee assessment (HR, 0.52; 95% CI, 0.23-1.18; P = .1118).

“Further analyses are needed to define specific follicular lymphoma/MZL subgroups that could potentially benefit from extended treatment with ibrutinib following chemoimmunotherapy,”

lead study author Loretta J. Nastoupil, MD, associate professor, deputy chair, director of the Lymphoma Outcomes Database, and section chief of New Drug Development in the Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in a presentation of the data.

Follicular lymphoma and MZL comprise approximately 20% and 12% of non-Hodgkin lymphoma subtypes, respectively. R-CHOP and BR represent the most used chemoimmunotherapy regimens for patients with relapsed/refractory disease. However, survival outcomes remain poor, rates of which decrease with each added line of therapy.

In prior phase 2 study, ibrutinib demonstrated activity in patients with relapsed/refractory follicular lymphoma and MZL, with objective response and duration of response (DOR) rates of 21% and 19.4 months, and 58% and 27.6 months, respectively.^2,3

As such, the agent was tested in the phase 3 SELENE trial to see whether its addition to standard therapy could improve outcomes in this population. Eligible patients included those with relapsed/refractory follicular lymphoma or MZL with at least 1 measurable disease site; receipt of at least 1 prior treatment with an anti-CD20 chemoimmunotherapy regimen; and an ECOG performance status of 0 or 1.

From March 2014 to November 2015, 403 patients were randomly assigned 1:1 to receive BR or R-CHOP plus ibrutinib (n = 202) or BR or R-CHOP plus placebo (n = 201). Ibrutinib, which was administered at 560 mg daily, and placebo were given until progressive disease or unacceptable toxicity.

Investigator-assessed PFS served as the primary end point of the trial. Secondary end points included overall survival, complete response (CR) rate, overall response rate (ORR), DOR, patient-reported outcomes, and safety.

The study was designed with 80% power to detect a 2-sided significance level of 5%. Assumption of a 0.7 hazard ratio was made, equating to an 8.6-month median increase from 20.0 months with chemoimmunotherapy alone to 28.6 months with the addition of ibrutinib.

Of the 201 and 199 patients who were started on ibrutinib and placebo, respectively, 36 remained on treatment with ibrutinib and 35 remained on therapy with placebo as of data cutoff.

Demographics and baseline characteristics were “well balanced across treatment groups,” Nastoupil said. Most patients in both arms were under the age of 65 years, had an ECOG performance status of 0, and had received 1 prior line of therapy, most commonly anthracycline based (65.0%). Additionally, most patients had relapsed disease, disease progression within 24 months of prior therapy, were receiving BR, and were low risk according to the PRIMA prognostic index.

Additionally, most patients had follicular lymphoma (86.1%); 13.9% of patients had MZL.

In the ITT population, responses were similar between the 2 arms. In the ibrutinib arm, the ORR was 91.6%, consisting of CRs (55.0%) and partial responses (PRs; 36.6%); 2.5%, 2.0%, and 4.0% of patients had stable disease, progressive disease, and unknown response, respectively. In the placebo arm, the ORR was 90.5% and included CRs (50.2%) and PRs (40.3%); 5.5%, 1.0%, and 3.0% of patients had stable disease, progressive disease, and unknown response, respectively.

Similar patterns of response were noted in the MZL subgroup. In this population, the ORR and CR rates were 89.3% and 64.3% with ibrutinib vs 82.1% and 60.7% with placebo, respectively.

Median DOR was 44.3 months (95% CI, 32.89-60.02) with ibrutinib vs 21.7 months (95% CI, 17.61-32.36) with placebo. In the MZL subgroup, median DOR was not reached with ibrutinib vs 89.2 months with placebo.

PFS with ibrutinib was consistent across subgroups, with the greatest magnitudes of benefit reported in men (HR, 0.66; 95% CI, 0.47-0.91) and patients with baseline ECOG performance status of 1 or 2 (HR, 0.63; 95% CI, 0.42-0.95).

Median OS was not reached in either treatment arm, with estimated 7-year rates of 67.4% with ibrutinib and 68.3% with chemoimmunotherapy alone (HR, 0.98; 95% CI, 0.69-1.40; P = .9115). In the MZL population, estimated 7-year OS rates with ibrutinib and placebo were 76.6% and 68.5%, respectively (HR, 0.69; 95% CI, 0.24-2.00; P = .4964).

Regarding safety, the ibrutinib-based regimen was “broadly well tolerated with no new safety signals,” Nastoupil said.

Grade 3 or greater treatment-emergent adverse effects (TEAEs) occurred in 85.6% of patients in the ibrutinib arm vs 75.4% of those in the placebo arm. The most frequent grade 3 or greater AEs were thrombocytopenia, neutropenia, anemia, and diarrhea. Grade 3 or greater thrombocytopenia and anemia were more common with ibrutinib vs placebo, at 10.0% vs 5.0% and 11.4% vs 4.0%, respectively. Rates of grade 3 or greater neutropenia were comparable in both arms at 30.8% vs 31.2%.

Other common any-grade AEs occurring in at least 20% of patients included nausea, fatigue, rash, pyrexia, vomiting, cough, upper respiratory tract infection, and decreased appetite.

Notably, TEAEs leading to dose reduction or discontinuation with ibrutinib were double that seen in the placebo arm, at 20.4% and 30.8% vs 10.6% and 18.6%, respectively.

Treatment-emergent AEs of special interest in the ibrutinib and placebo arms, respectively, included infections and infestation (78.6% vs 70.9%), major hemorrhage (3.0% vs 1.0%), arthralgia (13.9% vs 18.1%), hypertension (9.5% vs 9.5%), and atrial fibrillation (6.5% vs 2.0%).

Disclosures: Dr Nastoupil reported honoraria for AbbVie, ADC Therapeutics, BMS/Celgene, Caribou Biosciences, Daiichi Sankyo, DeNovo, Epizyme, Genentech, Gilead/Kite, Incyte, Janssen, Merck, Novartis, Pfizer, and Takeda; and research funding from BMS/Celgene, Caribou Biosciences, Daiichi Sankyo, Epizyme, Genentech, Gilead/Kite, IGM Biosciences, Janssen, Merck, Novartis, and Takeda.

References

1. Nastoupil LJ, Hess G, Arturo Pavlovsky M, et al. Ibrutinib plus BR or R-CHOP in previously treated patients with follicular or marginal zone lymphoma: the phase 3 SELENE study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract LBA2.
2. Gopal AK, Schuster SJ, Fowler NH, et al. Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: results from the open-label, multicenter, phase II DAWN study. J Clin Oncol. 2018;36(23):2405-2412. doi:10.1200/JCO.2017.76.8853
3. Noy A, de Vos S, Coleman M, et al. Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis. Blood Adv. 2020;4(22):5773-5784. doi:10.1182/bloodadvances.2020003121