Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy &gt;180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy &gt;180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy &gt;180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy &gt;180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT &gt;180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. </jats:sec

Long-Term Follow-up of Idelalisib Monotherapy in Patients with Double-Refractory Marginal Zone Lymphoma or Lymphoplasmacytic Lymphoma/ Waldenstrom's Macroglobulinemia

Introduction: Marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) comprise approximately 7% and 2%, respectively, of non-Hodgkin's lymphomas (NHL) (Teras 2016). MZL is further subclassified as splenic MZL (sMZL), nodal MZL (nMZL), or extranodal MZL (eMZL). Standard first-line therapies for LPL/WM include rituximab plus an alkylating agent and/or proteasome inhibitor or ibrutinib (Castillo 2017), while standard first-line treatment for MZL varies by subtype (Rosand 2017). There are limited treatment options for patients who have relapsed after first-line therapy. Idelalisib, a selective oral inhibitor of PI3Kδ, demonstrated efficacy in indolent NHL (iNHL), including MZL and LPL/WM, at a median follow-up of 9.7 months (mos) in a phase 2 study (NCT01282424; 101-09; Gopal 2014). Here, we present the final, long-term results for patients with double-refractory MZL and LPL/WM from the 101-09 study. Methods: Eligible iNHL patients had measurable disease and were refractory to both rituximab and an alkylating agent. Refractory status was defined as lack of response to or progression of lymphoma within 6 mos of completion of preceding therapy, documented by imaging. Oral idelalisib 150 mg twice daily was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee using standard criteria (Cheson 2007; Owen 2013). Endpoints included overall response rate (ORR), time to response, duration of response (DOR), lymph node response, progression-free survival (PFS), overall survival, and safety. The final data cutoff date was 22 Oct 2018. Results: Of 125 patients enrolled, 15 (12%) had MZL (sMZL, n = 1; nMZL, n = 5; eMZL, n = 9) and 10 (8.0%) had LPL/WM. Median age was 65 years and most were non-Hispanic (n = 24; 96%) and White (n = 23; 92%). At diagnosis, 80% of MZL and 100% of LPL/WM patients had stage IV disease. The largest lesion at baseline was ≥5 cm for 5 (33%) MZL and 3 (30%) LPL/WM patients. Baseline median IgM level was elevated for 80% of LPL/WM patients (median 1.9, IQR 1.0-2.7 g/dL). Baseline beta2-microglobulin level was &gt;3 µg/mL for 1 of 9 LPL/WM patients with values recorded (median 2.5 [range 1.7-3.1] µg/mL). For MZL and LPL/WM patients, 7 (47%) and 7 (70%) had ≥3 prior therapies, respectively. Common regimens for all 25 patients included rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (44%), rituximab-cyclophosphamide-vincristine-prednisone (40%), rituximab only (28%), bendamustine only (24%), and bendamustine-rituximab (20%). For MZL, the ORR (95% confidence interval [CI]) was 47% (21%, 73%), with median duration of therapy of 6.4 (range 1.8-37) mos. Of 7 responders, 1 had a complete response and 6 had partial responses (PR). Seven had stable disease (SD) and 1 had progressive disease (PD). Fourteen (93%) patients had reduction in lymph nodes, with 8 (53%) having ≥50% reduction in the sum of the products of the greatest perpendicular diameters (SPD). Median PFS was 6.6 (95% CI 3.5, 22) mos and median DOR was 18 (range 0-18) mos (Table). For LPL/WM, the ORR (95% CI) was 80% (44%, 98%), with a median duration of therapy of 29 (range 6.4-51) mos. Of 8 responders, 7 had PR and 1 had a minor response. There was 1 SD and 1 PD. Nine (90%) patients had lymph node reduction, with 5 (50%) having ≥50% reduction in SPD. Median PFS was 22 (95% CI 1.4, 56) mos and median DOR was 20 (range 1.7-50) mos (Table). All 25 patients had ≥1 treatment-emergent adverse event (TEAE), 16 (64%) had a serious AE, and 11 (44%) had dose reduced due to a TEAE. Grade ≥3 TEAEs occurred for 22 (88%) patients; neutropenia (n = 7, 28%), diarrhea (7, 28%), alanine aminotransferase increased (4, 16%), asthenia (3, 12%), and pneumonia (3, 12%) were the most frequent. All patients eventually discontinued treatment due to disease progression (14, 56%), AE (6, 24%), death (3, 12%), investigator request (1, 4%), or other (1, 4%). Ten patients have died, 3 during the study and 7 during the long-term follow-up. Conclusions: Monotherapy with idelalisib showed high rates of antitumor activity in this small subset of patients with MZL and LPL/WM refractory to prior therapy with rituximab and an alkylating agent; prolonged disease control was achieved for LPL/WM patients. No new safety signals were identified despite longer follow-up. Disclosures Wagner-Johnston: Bayer: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Schuster:Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Patents &amp; Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; AstraZeneca: Honoraria; Pharmacyclics: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Loxo Oncology: Honoraria; Nordic Nanovector: Honoraria; Pfizer: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. de Vos:Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Salles:Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jurczak:Bayer: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Celtrion: Research Funding; MorphoSys: Research Funding; Gilead: Research Funding; Roche: Research Funding; Servier: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria. OffLabel Disclosure: Idelalisib is a selective oral inhibitor of PI3K-delta that has shown antitumor activity in previously treated indolent non-Hodgkins lymphomas in phase 1 and 2 studies. It is approved for treatment of relapsed follicular lymphoma that has progressed on 2 prior systemic therapies, relapsed chronic lymphocytic leukemia in combination with rituximab when rituximab alone would be considered appropriate due to other comorbidities, and relapsed small lymphocytic lymphoma that has progressed on 2 prior systemic therapies. In this presentation, we provide results of 2 less common subgroups of indolent non-Hodgkins lymphoma, Âmarginal zone lymphoma and lymphoplasmacytic lymphoma/Waldenstrom's Macroglobulinemia, Âfrom the completed phase 2 trial with long-term follow-up. </jats:sec

A Multicentre, Retrospective Observational Study to Evaluate the Clinical Outcomes of Patients with Chronic Lymphocytic Leukaemia (CLL) Treated with Idelalisib and Rituximab in the UK (RETRO-idel) - a Cohort of 110 Patients

Background: B-cell receptor signalling pathway plays a key role in CLL pathogenesis. Overexpression of phosphatidylinositol 3-kinase delta isoform (PI3Kδ) is a characteristic of malignant lymphoid cells {Zhang 2014}. Idelalisib is an oral, selective PI3Kδ inhibitor approved for the treatment of CLL {Brown 2014}. Since its approval there has been a paucity of real world clinical effectiveness and safety data on idelalisib-rituximab (IDELA-R). A large U.S.-based national, retrospective series of 682 CLL patients (pts) explored the optimal sequence of targeted agents in this setting, but included only 62 (9%) pts treated with IDELA-R {Mato 2017}. Aims: To evaluate the effectiveness of IDELA-R in pts with CLL in routine clinical practice in the UK through a protocol-led, retrospective cohort study; RETRO-idel (NCT03582098). Methods: Secondary or tertiary care centres (sites) across the UK were invited to participate. Data were collected retrospectively from sites by study personnel from source data-verified medical records using electronic case report forms (eCRFs). Eligible pts included those who initiated IDELA-R as part of routine clinical management of CLL from Sep 2014 (following European approval), up to and including 31 Dec 2017. Primary endpoint was overall response rate (ORR) defined as the proportion of pts who achieved an objective clinical response after the initiation of IDELA-R treatment. Secondary endpoints included overall survival (OS), progression free survival (PFS), time to next treatment (TTNT), duration of response (DOR), and safety (including serious adverse events [SAE] and AEs of special interest [AESI]). Results: A total of 110 pts were included in the study from 16 UK sites, of whom 74 (67.3%) were males and the median age at IDELA-R initiation was 72 years (range 48 - 90) (Fig 1a). Median number of prior therapies was 1 (range 0 - 8; 23.6% 1st line). Seven (6.4%) pts had received prior ibrutinib. Median time since diagnosis was 7 years (range: 0 - 23), and 54 (49.1%) pts tested had TP53 mutated / del (17p) CLL. Median duration of follow-up was 39.1 months (range 0.1 - 51.9), with 65 (59.1%) pts followed &gt;2 years. Ninety-two (83.6%) pts received pneumocystis jirovecii pneumonia (PJP) prophylaxis and 8 (7.3%) pts had received a stem-cell transplant (SCT) [(before IDELA-R; 2 (1.8%) alloSCT; 2 (1.8%) autoSCT); after IDELA-R; 4 (3.6%) alloSCT)]. The median duration of therapy with IDELA was 12 months (range 0 - 41). The ORR was 88.2% (95% CI: 82.2 - 94.2) and median DOR 32.7 months (95% CI 19.7 - NR). Seven (6.4%) pts had no documented response and response data were missing for 6 (5.4%) pts. Median OS was not reached (95% CI: 31.5 - NR) and median PFS was 29.5 months (95% CI: 22.1, NR) (Fig 1b, c). Median TTNT was 29.2 months 95% CI; 25.3 - 42.8). Overall, 108 (98.2%) pts experienced an SAE or AESI. Diarrhoea was reported in 34 (30.9%) pts, followed by lower respiratory tract infection [LRTI] in 24 (21.8%), neutropenia in 23 (20.9%), rash in 18 (16.4%) and pneumonia in 18 (16.4%). Ten (9.1%) pts had colitis, of which Gr 3/4 colitis occurred in 6 (5.5%). A total of 71 (64.5%) pts experienced a Gr 3/4 AEs including pneumonia in 14 (12.7%), LRTI in 10 (9.1%), neutropenia in 7 (6.4%), diarrhoea in 7 (6.4%) and neutropenic sepsis in 7 (6.4%). There were 85 (77.2%) discontinuations; 54 (56.3%) due to toxicity, 18 (18.8%) due to PD, 11 (11.5%) by investigator discretion, and 2 (2.1%) by subject decision. There were 11 (11.5%) deaths reported whilst pts were receiving IDELA-R. Richter's transformation was documented in 1 (0.9%) pt. At the time of analysis, 46 (41.8 %) pts had died. Conclusions: We report to our knowledge the largest cohort of CLL pts treated with IDELA-R outside of the clinical trial setting. Our findings corroborate those from interventional studies of IDELA {Furman 2014, Sharman 2019}. Longer PFS observed in our study versus prospective trials probably reflects the relatively fewer median number of prior therapies. Median TTNT was slightly shorter than median PFS possibly due to certain pts discontinuing IDELA-R without PD and continuing to a subsequent therapy. Safety profile of IDELA-R was consistent with trial experience, and no new safety signals were identified. IDELA-R remains an effective treatment option for CLL pts. Analyses assessing a) response duration and TTNT in pts stopping therapy due toxicity and b) predictors of PFS (univariable and multivariable analysis) are ongoing and will be presented. Disclosures Eyre: Janssen: Honoraria; Roche: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Abbvie: Honoraria. Islam:Gilead: Honoraria, Other: Conference attendance sponosrship. Nicholson:Pfizer: Other: Conference attendance sponosrship; Takeda: Other: Conference attendance sponsorship. Fegan:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Consultancy, Other: Conference attendance sponsorship. Smith:Gilead: Employment, Equity Ownership. Cursley:Gilead: Employment. Ramroth:Gilead Sciences: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. </jats:sec

Phase 1b study to investigate the safety and tolerability of idelalisib in Japanese patients with relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia

Abstract Objective Idelalisib is an orally administered, highly selective inhibitor of phosphatidylinositol 3-kinase-δ. In this phase 1b study, the safety, tolerability and pharmacokinetics of idelalisib, an oral inhibitor of phosphatidylinositol 3-kinase-δ, were evaluated in Japanese patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma. Methods In total, six patients (follicular lymphoma: n = 3, chronic lymphocytic leukemia: n = 3) were enrolled to receive idelalisib 150 mg twice daily. Results No dose-limiting toxicities were reported. The most common adverse events were diarrhea (n = 5), gastritis (n = 3), insomnia (n = 3) and pyrexia (n = 3). The most common ≥grade 3 adverse events were diarrhea (n = 2), increased transaminase levels (n = 2) and decreased appetite (n = 2). The maximum idelalisib plasma concentrations (Cmax) were achieved at 2.50 h (range: 1.50–4.00 h). The mean idelalisib plasma concentrations decreased over time but remained detectable in most patients at 12 h. All enrolled patients underwent efficacy evaluation by investigators, and five patients (follicular lymphoma: n = 2, chronic lymphocytic leukemia: n = 3) achieved partial response. The median duration of partial response was 14.5 months (range: 3.7–31.3 months). Conclusion Idelalisib 150 mg twice daily was considered tolerable in Japanese patients with follicular lymphoma or chronic lymphocytic leukemia. (Clinical trial registration: NCT02242045) </jats:sec