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The 59th Annual Meeting & Exposition of the American Society of Hematology (ASH) took place in Atlanta, GA, on December 9–12, 2017. On Sunday December 10th, an oral abstract session was held between 12.00-1.30pm in “Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Indolent Lymphomas, Novel Therapies, and Diagnostics”. This session was moderated by Emanuele Zucca, IOSI-Oncology Inst. of Southern Switzerland and Harry C. Schouten, University Hospital Maastricht. Three talks from the session are summarized in the article below. Data from the live session at ASH are used and therefore may supersede information in the pre-published Abstracts.
Abstract #414 was presented during this session, titled “High Complete Response Rates with Pembrolizumab in Combination with Rituximab in Patients with Relapsed Follicular Lymphoma: Results of an Open-Label, Phase II Study” by Loretta Nastoupil, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, and colleagues.
The combination of pembrolizumab and rituximab (R) in the treatment of follicular lymphoma (FL) was evaluated in an open-label, non-randomized, single institution, phase II trial. It was hypothesized that the combination of pembrolizumab, an anti-PD-1 antibody, and rituximab (R), an anti-CD20 antibody that induces tumour cell killing by ADCC, would likely be synergistic through activation of both the innate and adaptive immune systems and result in enhanced clinical activity in FL.
The primary endpoint was overall response rate (ORR). Secondary objectives included safety and tolerability, complete response (CR) rate, progression free survival (PFS), overall survival (OS), and to compare the PFS between patients relapsing ≤ 1-year vs > 1 year after last prior therapy. Key inclusion criteria included adult patients (age ≥ 18 years), with FL grade 1–3a, ECOG performance status (PS) 0-1, in relapse after ≥1 prior therapy and R sensitive disease.
Dr Nastoupil concluded that promising efficacy was observed with pembrolizumab and R in relapsed FL with meaningful overall and CR rates. The combination also appears to be associated with a favourable toxicity profile. Peripheral blood IFN-γ gene signature but not PD-L1 expression status in the tumor may help to identify patients who are most likely to respond to this combination, but this needs to be validated in larger studies.
Abstract #410 was presented during this session, titled “Results from a Phase 1/2 Study of INCB050465, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies (CITADEL-101)” by Andres Forero-Torres, University of Alabama Birmingham, Birmingham, AL, and colleagues.
Constitutive activation of the PI3Kδ pathway is associated with increased malignant B-cell proliferation and survival. INCB050465 is a highly selective and highly potent next-generation PI3Kδ inhibitor (≥19,000-fold more selective for PI3Kδ vs other isoforms), designed to eliminate hepatotoxicity associated with first-generation PI3Kδ inhibitors.
The primary objective of the study was to assess the safety, tolerability, preliminary efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of INCB050465 in patients with relapsed or refractory B-cell malignancies
Adult patients were eligible for study participation if they had relapsed or refractory lymphoid B-cell malignancies, ≥1 prior treatment regimen, and had not responded or were not a candidate for SCT or other potentially curative therapy.
Dr Forero-Torres concluded that INCB050465 is a potent, highly selective, next-generation PI3Kδ Inhibitor, which demonstrated dose-proportional PK. INCB050465 monotherapy effected a high rate of rapid, deep and durable objective responses. The rapid response rate supports the short-term QD dosing, followed by switch to QW dosing to manage long-term tolerability. INCB050465 was not associated with significant transaminase elevations or with any new or unexpected SAEs. Phase 2 clinical studies are ongoing.
Abstract #411 was presented during this session titled “a Novel Cereblon Modulating Agent, in Combination with Obinutuzumab (GA101) in Patients with Relapsed and Refractory (R/R) B–Cell Non–Hodgkin Lymphoma (NHL)” by Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France, and colleagues.
CC–122 is a novel oral agent that targets cereblon and induces degradation of the hematopoietic transcription factors Aiolos and Ikaros, resulting in potent anti-lymphoma and immune modulation activities. Obinutuzumab is a second generation anti-CD20 monoclonal antibody. Preliminary results from CC–122–NHL–001, a phase 1b study of CC–122 in combination with obinutuzumab, have shown promising response rates in patients with R/R B–cell NHL. Dr Michot presented the updated safety and efficacy results from the CC–122–NHL–001 study with a further 12 months of follow up.
The primary study objectives were to examine the safety and tolerability of CC-122 when co-administered with obinutuzumab and to identify the non-tolerated dose, MTD and the recommended phase 2 dose of CC-122 when co-administered with obinutuzumab. Secondary objectives included ORR, DoR, PFS and PK at the MTD.
Patients were eligible for study participation if they were aged ≥ 18 years, ECOG PS 0–1, histologically or cytologically confirmed DLBCL, FL or MZL, CD20+. CC–122 was given orally (days 1–5 of every 7 days) for 28–day cycles in escalating doses plus a fixed dose of intravenous obinutuzumab 1000 mg on day 2, 8, 15 of cycle 1 (c1), and d1 of c2–8.
Dr Michot concluded that this was the first study to investigate the combination of CC–122 and obinutuzumab in relapsed and refractory B-cell lymphomas. The tolerability profile was consistent with either therapy alone, with no unexpected toxicities. The combination demonstrates similar activity in high-risk and standard-risk FL patients. The dose expansion CC–122–NHL–001 study at 3mg, focussed on relapsed and refractory FL is ongoing.
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