ALBERT

Description: 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 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)

Description: Background : Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have poor treatment outcomes, especially patients who are ineligible for stem cell transplantation (SCT). Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the US for various B-cell malignancies. Preclinical data suggest potential synergy when combining ibrutinib with lenalidomide, a thalidomide analogue that disrupts signaling downstream of B-cell receptor and MYD88. An open-label, multicenter, phase 1b/2 study (NCT02077166) was initiated to evaluate the iR2 regimen of ibrutinib, lenalidomide, and rituximab in R/R DLBCL. Results from the ongoing phase 2 portion of the study evaluating the safety and activity of the iR2 regimen in SCT-ineligible adults aged ≥18 y with R/R non-germinal center B-cell-like (non-GCB) DLBCL per Hans method are presented here. Methods : The iR2 regimen was administered at the recommended phase 2 dose (RP2D) of once-daily 560 mg PO ibrutinib with 20 mg PO lenalidomide on Days 1-21 and 375 mg/m2 IV rituximab on Day 1 of Cycles 1-6 in 28-day cycles (additional 25-mg cohort ongoing). The primary phase 2 efficacy endpoint was ORR; the null hypothesis of an ORR of 40% will be tested against the alternative hypothesis of an ORR 〉60%. Secondary endpoints included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Response was based on investigator assessments and performed using CT or MRI scans after every 3 treatment cycles for the first 24 mo and every 6 mo thereafter. For rash and neutropenia, if clinically indicated, study medication was withheld until resolution or improvement to grade 1, and treatment with oral corticosteroids and antihistamines (for rash) or hematopoietic growth factors (for neutropenia) was initiated. Results : A total of 55 patients were enrolled and treated at the RP2D with 20 mg PO lenalidomide in phase 2. The median age was 63 y; 58% were male; 64% had stage IV disease; 24% had primary refractory disease; 53% were refractory to the last therapy. Patients had received a median of 2 (range: 1-5) prior systemic therapies for DLBCL; the most common regimens were R-CHOP (71%), RICE (29%), and R-DHAP (16%). Among the 44 response-evaluable patients with follow-up imaging, the ORR was 55% (95% CI: 39%-70%; n=24) and included CR in 30% (n=13) and PR in 25% (n=11); 5 patients (11%) had stable disease. The median DOR was 9 mo for all responders and 10 mo for those who achieved a CR. The median maximum percent change from baseline in the size of the target lesion(s) was −61%. Among all 55 treated patients, the median duration of iR2 treatment was 4 mo (range: 0-13), and almost half (45%) of patients were still receiving iR2 treatment at the time of analysis (Figure 1A). Progressive disease was the most common reason for treatment discontinuation (45%). Median PFS was 5 mo (95% CI: 3-12; Figure 1B), with 6-mo and 12-mo PFS rates of 44% and 28%, respectively. Median OS was 17 mo (95% CI: 8-17), with 6-mo and 12-mo OS rates of 85% and 58%, respectively. For the 24 responders, median PFS was 12 mo (95% CI: 6-12), and median OS was 17 mo (95% CI: not evaluable). The majority (85%) of patients experienced a grade 3-4 TEAE; events reported in ≥5% of patients included neutropenia (33%), maculopapular rash (15%), anemia (11%), diarrhea, dyspnea, fatigue, and hypokalemia (5% each). Neutropenia, maculopapular rash, and anemia were the only grade 3-4 TEAEs in 〉2 patients considered related to either ibrutinib or lenalidomide. Of the 8 patients with grade 3/4 maculopapular rash, 7 received concomitant corticosteroids. Grade 5 TEAEs were experienced by 6 patients and included worsening of DLBCL (n=3), pneumonia (n=2), and sepsis (n=1). Doses of study treatment were temporarily interrupted or reduced due to TEAEs in 62% and 29% of patients, respectively. Discontinuation due to TEAEs occurred in 11% of patients (worsening of DLBCL [5%], pneumonia [4%], and sepsis [2%]). No cases of febrile neutropenia were reported. Conclusions : The iR2 combination regimen of 560 mg ibrutinib, 20 mg lenalidomide, and 375 mg/m2 rituximab demonstrated promising activity with a manageable safety profile in these difficult-to-treat R/R non-GCB DLBCL patients ineligible for SCT. Evaluation of the iR2 regimen using a dose of 25 mg lenalidomide and biomarker analyses, including GEP, are ongoing. Disclosures Ramchandren: Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Johnson:Genmab: Consultancy; Novartis: Honoraria; Takeda: Honoraria, Travel, accommodations, expenses; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Janssen: Consultancy, Research Funding; Kite: Consultancy; Incyte: Consultancy; Boeringher Ingelheim: Consultancy; Bristol-Myers Squibb: Honoraria; Epizyme: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Eisai: Research Funding. Ghosh:Forty seven Inc: Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; Juno: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; Spectrum: Consultancy; F. Hoffman-La Roche Ltd: Research Funding. Ardeshna:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Johnson:Takeda Pharma: Other: Funded an educational place for me to attend the Lugano Lymphoma conference in June 2017. Cunningham:Roche pharmaceuticals: Research Funding. Kassam:AbbVie: Equity Ownership. Radford:Pfizer: Research Funding; BMS: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership; Celgene: Research Funding; Novartis: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau. Bailly:Abbvie: Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses; Takeda: Other: Travel, Accommodations, Expenses. Munoz:Bayer: Consultancy, Speakers Bureau; Janssen: Consultancy; Kite Pharmaceuticals: Consultancy, Speakers Bureau; Juno: Consultancy; Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Alexion: Consultancy; Pharmacyclics LLC, an ABBVIE Company: Consultancy. Ping:Pharmacyclics, an Abbvie company: Employment; Abbvie: Equity Ownership. Co:Abbvie: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Neuenburg:Pharmacyclics, an Abbvie company: Employment.