Sakk 35/14 Randomized Trial of Rituximab With or Without Ibrutinib for Untreated Patients With Advanced Follicular Lymphoma in Need of Therapy

The Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) conducted the SAKK 35/14 randomized phase-2 trial (NCT02451111) to evaluate the safety and efficacy of frontline treatment with ibrutinib plus rituximab compared to rituximab plus placebo in adult patients (pts) with advanced follicular lymphoma in need of therapy. Ibrutinib was administered orally (560 mg once a day) for 24 months (104 weeks), while rituximab was given intravenously (375 mg/m2) on day 1 of weeks 1, 2, 3, and 4, and subsequently every 2 months for 12 maintenance administrations, given either intravenous (375 mg/m2) or subcutaneous (1400 mg flat dose) based on local policy. The primary endpoint was the complete remission (CR) rate at 24 months after randomization determined on PET/CT scans by an independent review panel. In total, 192 pts were randomized (98 in arm A rituximab + placebo; 94 in arm B rituximab + ibrutinib) with stratification by rituximab maintenance route, lymphoma grade, follicular lymphoma international prognostic index, and bulky (≥6 cm) disease. The CR rate at 24 months was 36% (95% CI, 26%–46%) in arm A and 40% (95% CI, 30%–51%) in arm B with an odds ratio (OR) of 0.80 (95% CI, 0.44–1.46; p = 0.233). At a median follow-up of 42 months, the 3-year progression-free survival (PFS) rate was 36% in arm A (95% CI, 19%–54%) and 45% (95% CI, 25%–64%) in arm B, with a hazard ratio (HR) of 1.63 (95% CI, 0.99–2.7; p = 0.056). At 3 years after randomization, 45% (95% CI, 36%–56%) of pts in arm A and 39% (95% CI, 30%–50%) in arm B had already required a new treatment, with a HR of 1.47 (95% CI, 0.93–2.32; p = 0.099). The 3-year overall survival rate (OS) approximated 96% in both arms (95% CI, ∼89%–99%) with a HR of 1.02 (95% CI, 0.29–3.55; p = 0.979). The percentage of pts experiencing at least one adverse event (AE) was similar in the two arms (100% and 99%). However, 29% of pts experienced at least one AE of grade ≥3 in arm A while this was the case for 49% of pts in arm B. The percentage of pts experiencing AEs related to trial treatment was also lower in arm A (67%) than in arm B (84%). A total of 93 SAEs were reported, 42 in arm A, affecting 26% of pts, and 51 in arm B, involving 39% of pts. A total of 7 SUSARS occurred, 1 in arm A and 6 in arm B. The most frequent AEs of grade ≥3 during treatment were neutropenia (8% in arm A and 14% in arm B), lymphocytosis (5% in arm A and 10% in arm B), hypertension (5% in each arm), and maculo-papular skin rash (not observed in arm A, 11% in arm B). The SAKK35/14 study was partly funded by Janssen Cilag AG, Roche Pharma (Schweiz) AG, and the Hubacher Fonds. Keywords: immunotherapy, indolent non-Hodgkin lymphoma, molecular Targeted Therapies Conflicts of interests pertinent to the abstract A. Stathis Consultant or advisory role: Janssen, Roche Research funding: Abbvie, ADC Therapeutics, Amgen, AstraZeneca, Bayer, Cellestia, Incyte, LoxoOncology, Merck, Novartis, Pfizer, Philogen, Roche Educational grants: AstraZeneca Other remuneration: Expert testimonies: Bayer, Eli/Lilly F. Hitz Consultant or advisory role: Takeda, Abbvie, Roche E. Zucca Consultant or advisory role: BeiGene, BMS/Celgene, Celltion Healthcare, Curis, Eli/Lilly, Incyte, Ipsen, Janssen, Kyte (a Gilead Company), Merck, Roche Research funding: AstraZeneca, BMS/Celgene, Incyte, Janssen, Merck, Roche Educational grants: Abbvie, BeiGene, Janssen, Roche.