Phase 2 Results of the iR2 Regimen (Ibrutinib, Lenalidomide, and Rituximab) in Patients with Relapsed/Refractory (R/R) Non-Germinal Center B Cell-like (Non-GCB) Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Ramchandren Radhakrishnan , Johnson Peter , Ghosh Nilanjan , Ruan Jia , Ardeshna Kirit M. , Johnson Roderick , Verhoef Gregor , Cunningham David , de Vos Sven , Kassam Shireen , Fayad Luis , Radford John , Bailly Sarah , Offner Fritz , Morgan David , Munoz Javier , Ping Jerry , Kwei Kevin , Eckert Karl , Neuenburg Jutta K. , Goy Andre 
Published: February 2020

Background : DLBCL is an aggressive non-Hodgkin lymphoma (NHL) with poor outcomes in the R/R setting; overall survival (OS) is 28% at 1 year and 20% at 2 years in refractory patients (Crump, Blood 2017). Outcomes are particularly poor for patients ineligible for stem cell transplant (SCT). Ibrutinib is the only once-daily inhibitor of Bruton's tyrosine kinase and is approved for the treatment of various B-cell malignancies. Based on preclinical models, ibrutinib and lenalidomide, an immunomodulator that downregulates the MYD88 pathway, may synergize when combined (Yang, Cancer Cell 2012). Rituximab, an anti-CD20 antibody, has shown activity combined with ibrutinib in NHL (Wang, Lancet Onc 2016). PCYC-1123 is a multicenter, open-label phase 1b/2 study (NCT02077166) evaluating the combination of ibrutinib, lenalidomide, and rituximab (iR2) in R/R DLBCL.
Methods : Patients ≥18 years of age with R/R non-GCB DLBCL ineligible for SCT received lenalidomide 20 or 25 mg orally on Days 1-21 of each 28-day cycle plus ibrutinib 560 mg orally once daily and rituximab 375 mg/m2 IV on Day 1 of Cycle 1-6. Treatment was continued until progressive disease (PD) or unacceptable toxicity. Immunohistochemistry (IHC) was performed by central laboratory per the Hans algorithm. The primary endpoint was overall response rate (ORR); secondary endpoints were complete response (CR), duration of response (DOR), progression-free survival (PFS), OS, and safety. Response was determined by investigator assessment per Cheson (J Clin Oncol 2014) every 3 treatment cycles for the first 24 months (mos) and then every 6 cycles thereafter.
Results: In total, 89 patients were enrolled and treated in phase 2 (n=55 and n=34 in the lenalidomide 20 mg and 25 mg cohorts, respectively). The median patient age was 64 years; 58% were male. At study entry, 53% of patients were refractory to their last therapy and 16% were primary refractory, 47% had relapsed, and 63% had stage IV disease. Median number of prior DLBCL therapies was 2 (range 1-5), with the most common being R-CHOP (73%), RICE (26%), and R-DHAP (13%). Twenty patients had prior SCT. All patients were non-GCB by IHC; for the 47 patients with tumor tissue available for nanostring testing by GEP, there was 84% concordance in non-GCB status (activated B-cell [ABC] or unclassified). The median time on study was 16 mos (range &lt;1-28 mos); 20 patients (22%) and 4 patients (4%) received iR2 treatment for ≥1 and ≥2 years, respectively, with 25 patients (28%) receiving iR2 treatment at the time of the analysis. The median time to response was 2.7 mos. Of the 85 response-evaluable patients with follow-up response assessment, the ORR was 47% (95% CI 36-58), including 28% with CR and 19% with partial response; 16% had stable disease. The median DOR (n=40) was 18 mos (range &lt;1-22 mos) overall and in the 20 mg cohort and was not reached (NR) in the 25 mg cohort. For patients with CR, the median DOR was NR. Estimated PFS was 31% (95% CI 21-41) at 18 mos, and median PFS was 5 mos (95% CI 3-6). Estimated OS was 44% (95% CI 32-56) at 18 mos, and median OS was 14 mos (95% CI 10 mos-not estimable [NE]) (Figure 1A). For the 40 responders, median PFS was 21 mos (95% CI 11-NE), and median OS was NR (95% CI 18 mos-NE). 14 patients (16%) were in CR for &gt;1 year (Figure 1B). The most common adverse events (occurring in &gt;30% of patients) were diarrhea (53%), fatigue (42%), neutropenia (40%), cough (34%), anemia (33%), peripheral edema (33%), and maculopapular rash (31%). The most common Grade 3/4 AEs were neutropenia (36%) and maculopapular rash (18%); Grade 3/4 atrial fibrillation occurred in 2% of patients. Grade 5 TEAEs occurred in 12 patients; of these, 7 were due to worsening of DLBCL, and 5 were not related to PD (pneumonia [n=3], sepsis [n=1], and cardiac arrest [n=1]). AEs led to discontinuation in 17% of patients (n=15) overall (those occurring in ≥2 patients were worsening of DLBCL [n=4], pneumonia [n=2], and thrombocytopenia [n=2]).
Conclusions : The iR2 combination of ibrutinib, lenalidomide, and rituximab showed an ORR of 47% in patients with follow-up response assessment, with 28% CRs, including durable CRs of up to 22 mos. The safety profile was manageable in this phase 2 study of patients with R/R non-GCB DLBCL ineligible for SCT. Further evaluation of the iR2 regimen is ongoing.

Disclosures
Ramchandren: Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz-Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pharmacyclics LLC, an Abbvie company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding. Johnson:Boehringer Ingelheim: Honoraria; Incyte: Honoraria; Epizyme: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Genmab: Honoraria; Celgene: Honoraria; Kite: Honoraria. Ghosh:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; Forty Seven Inc: Research Funding; Bristol-Myers Squibb: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding. Ruan:Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Kite: Consultancy; Pharmacyclics LLC, an AbbVie company: Research Funding; Juno: Consultancy. Ardeshna:Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Johnson:Takeda: Other: Travel, accomodations, expenses; Roche: Consultancy, Honoraria, Speakers Bureau. Cunningham:Clovis: Research Funding; Eli Lilly: Research Funding; 4SC: Research Funding; Bayer: Research Funding; MedImmune: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Merck: Research Funding; Merrimack: Research Funding. de Vos:Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy; Bayer: Consultancy. Radford:Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Research Funding; GSK: Equity Ownership; Novartis: Consultancy, Honoraria; AstraZeneca: Equity Ownership, Research Funding; BMS: Consultancy, Honoraria. Morgan:Biogen: Equity Ownership; Eli Lilly: Equity Ownership; Gilead: Equity Ownership; Johnson and Johnson: Equity Ownership; Merck: Equity Ownership; Novo Nordisk: Equity Ownership; Pfizer: Equity Ownership; Vertex: Equity Ownership; Zoetis: Equity Ownership. Munoz:Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Ping:Pharmacyclics LLC, an AbbVie company: Employment; AbbVie: Equity Ownership. Kwei:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie company: Employment; AbbVie: Equity Ownership. Eckert:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. Neuenburg:Pharmacyclics LLC, an AbbVie company: Employment, Other: Travel, accomodations, expenses. Goy:University of Nebraska: Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Other: Grants outside of the submitted work, Research Funding; Hackensack University Medical Center, RCCA: Employment; Hakensackumc: Research Funding; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Takeda: Other: Grants outside of the submitted work; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

OffLabel Disclosure:
Ibrutinib in combination with lenalidomide and rituximab is not approved by the FDA for treatment of diffuse large B-cell lymphoma (DLBCL)