ASH 2018 Meeting Highlights - Dec. 1

Highlights from Dec. 1, 2018

Retrospective analyses shed light on the long-term effects of CAR T therapy for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia

Ana Cordeiro (Fred Hutchinson Cancer Research Center, Seattle, Wash., USA and Centero Paulista de Oncologia, Sau Paulo, Brazil), discussed a retrospective study investigating the long-term effects anti-CD19 CAR T therapy for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In all, researchers analyzed the medical records of 60 patients (NHL = 43, CLL = 17, age = 34 – 73, median four prior lines of therapy) enrolled in a clinical trial (NCT01965617) and survived for at least one year after treatment with anti-CD19 CAR T therapy. At median follow-up of 25 months (12.6 – 62.6), 78 percent of patients remained alive (n=47, NHL = 32, CLL = 15). Ten patients died due to progressive disease, and three patients died due to complications with allogeneic hematopoetic stem cell transplant (allo-HCT) post-CAR T therapy. Concerning long-term complications, late hypogammaglobulinemia (IgG less than 400 mg/dL and/or intravenous immunoglobiulin replacement beyond 90 days post-infusion) observed in 29 percent of patients (n = 29, NHL = 18, CLL = 11). Additionally, 138 infection events were observed, most commonly of the respiratory tract. New malignancies developed in 17 percent of patients (n = ten, therapy-related myelodysplastic syndrome = four, non-melanoma skin cancer = five, non-invasive bladder cancer = one). Late neurological events were observed in three patients who did not have immediate neurotoxicities after CAR T administration, including one fatal cerebrovascular event in the setting of allo-HCT post-CAR T and thrombotic microangiopathy. Graft vs host disease (GVHD) was observed in only one of nine patients who hade received allo-HCT prior to CAR T cell therapy. In summary, these data suggest limited long-term adverse events due to CAR T treatment, and continue to support long-term therapeutic efficacy of this modality.

Co-expression of 4-1BBL in “armored” anti-CD19 CAR T cells may help increase treatment efficacy in patients with hematologic malignancies

Jae Park, MD (Memorial Sloan Kettering Cancer Center, New York, N.Y., USA), presented preliminary results from a Phase I clinical trial (NCT03085173) assessing safety and efficacy of anti-CD19 “armored” CAR T cells that co-express 4-1BBL for the treatment of adult patients with hematologic malignancies. Pre-clinical data indicate that expression of 4-1BBL in anti-CD19 CAR T cells that contain a CD28 costimulatory domain helps potentiate anti-tumor activity through increased CD8/CD4 T cell ratios, increased IL-2 secretion, and prevention of T cell exhaustion. As such, 30 patients (CLL = 18 [Richter’s transformation = four], diffuse large B cell lymphoma [DLBCL] = 11, indolent NHL =  five, acute lymphoblastic leukemia [ALL] = one) enrolled in this first-in-human clinical trial, 29 of which received conditioning chemotherapy (fludarabine/cyclophosphamide) prior to escalating doses of anti-CD19 CAR T cells expressing 4-1BBL (1x105 – 3x106 CAR T cells/kg). In all, 15 complete responses (CR) and eight partial responses (PR) were observed in 28 evaluable patients at median follow-up of 4.8 months (1-12.3). Peak CAR T cell expansion was observed between 7-14 days post-infusion (median = nine days [2-82]) and CAR T cells are detectable in patient blood six months post-infusion. Cytokine release syndrome affected 62 percent of patients overall (n = 18), with no cases above grade two. No neurotoxicities above grade three (n = six) were noted. Together, these early clinical data suggest acceptable safety and promising efficacy of anti-CD19 CAR T cells expressing 4-1BBL in patients with hematologic malignancies.

Preliminary clinical trial data suggest promising safety and efficacy of a novel “2:1” CD20-CD3 bispecific T cell engager for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma

Martin Hutchings, MD, PhD (Copenhagen University Hospital, Copenhagen, Denmark), presented clinical data from patients with relapsed/refractory NHL treated with the novel bispecific T cell engager CD20-TCB (RG6026) that possesses two CD20 binding sites in addition to a CD3 binder. Pre-clinical data suggest that CD20-TCB can increase T cell activation and cytokine release to facilitate increased anti-tumor activity. Additionally, the “2:1” structure of CD20-TCB allows for combinations with other anti-CD20 agents to be used. As such, 98 patients with NHL (median age = 62 [range 28-82] with a median of 4 prior lines of therapy [range one - ten]) received a single dose of anti-CD20 obinutuzumab seven days prior to CD20-TCB treatment to help debulk circulating B cells and mitigate potential CRS, this was followed with escalating doses of CD20-TCB (5ug – 10mg Q2W for 12 cycles or Q3W for eight cycles [>10mg]) after. Thus far, the maximum-tolerated dose of CD20-TCB has not yet been reached. While grade 3/4 treatment-related adverse events have been observed in 53 patients (54 percent), no grade 3/4 CRS has been documented. Three grade 3/4 neurotoxicities have been observed. Overall response rate (ORR) improves in patients in a dose-dependent fashion. For example, in patients with DLBCL, ORR was 21 percent in patients receiving 600-1000ug (3/14, two CR, one PR), 29 percent in patients receiving 1800-4000ug (2/7, one CR, one PR), and 55 percent in patients receiving 10000-16000ug, respectively (6/11, three CR, three PR). Additionally, all patients who achieved CR remain in remission at median follow-up of 94 days. In all, these early data suggest that CD20-TCB may help provide durable response to patients with relapsed/refractory NHL, and that it provides an acceptable safety profile in combination with obinutuzumab.

Phase 2 clinical trial data suggest that combination anti-CD19 monoclonal antibody MOR208 + lenalidomide may be a safe and effective treatment option for patients relapsed/refractory diffuse large B cell lymphoma

Gilles Salles, MD, PhD (Centre Hospitalier Lyon Sud, Pierre Benite, France), presented results from the phase II L-MIND clinical trial (NCT02399085) assessing safety and efficacy of lenalidomide in combination with the anti-CD19 antibody MOR208 for the treatment of patients with relapsed/refractory DLBCL. In all, 81 adult patients (refractory to at least one prior therapy including one CD20 targeted therapy, not candidates for high-dose chemotherapy of autologous stem cell transplant) received MOR208 (cycles 1-3: 12mg/kg Q4W d1, 8, 15, 22; cycles 4-12: 12mg/kg Q4W d1, 15) in combination with lenalidomide (25mg/d p.o d1-21 for up to 12 cycles). ORR as determined by investigator assessment was 58 percent (27 CR [33 percent], 20 PR [25 percent]). At 12-month median follow-up, median progression-free survival was 16.2 months (95 percent CI: 6.3 – not yet reached), and median duration of response (DOR) not yet reached (95 percent CI: NR – NR). Median overall survival (OS) has not yet been reached (95 percent CI: 18.6 mos – NR), and 12-month OS rate is 73.3 percent (95 percent CI: 63.2 – 85.1). Observed treatment related adverse events greater than or equal to grade three include neutropenia (43 percent), thrombocytopenia (17 percent), and anemia (9 percent). 41 patients (50.6 percent) required a dose reduction of lenalidomide, of which 72 percent of patients were able to remain on daily doses of 20mg or greater. Together, these data suggest that combination lenalidomide + anti-CD19 MOR208 is well tolerated and has promising efficacy in patients with relapsed/refractory DLBCL.

KEYNOTE-013 and KEYNOTE-170 data reaffirm efficacy of pembrolizumab for the treatment of patients with relapsed/refractory primary mediastinal B cell lymphoma

Philippe Armand, MD, PhD (Dana Farber Cancer Institute, Boston, Mass., USA), presented data from two clinical trials – phase 1b KEYNOTE-013 (NCT01953692) and phase 2 KEYNOTE-170 (NCT02576990) – evaluating safety and efficacy of anti-PD-1 pembrolizumab for the treatment of patients with relapsed/refractory primary mediastinal B cell lymphoma (PMBCL). Concerning KEYNOTE-013, 21 total patients with relapsed/refractory PMBCL (median three prior lines of therapy, 13 = ineligible for allo-HCT) received pembrolizumab for up to two years, with the initial 10 enrollees receiving 10mg/kg Q3W, while the remaining 11 patients received 200mg Q3W. In KEYNOTE-170, 53 patients with relapsed/refractory PMBCL (median three prior lines of therapy, 39 = ineligible for allo-HCT) received pembrolizumab (200mg Q3W) for up to two years. ORR was 48 percent (seven CR, three PR) and 45 percent (seven CR, 11 PR) in KEYNOTE-013 and KEYNOTE-170, respectively. 12-month DOR is 78 percent and 76 percent for KEYNOTE-013 and KEYNOTE-170, respectively. Median PFS in KEYNOTE-013 was 10.4 mos (95 percent CI: 3.4 – NR) and median OS was 31.4 mos (95 percent CI: 4.9 – NR). Median PFS in KEYNOTE-170 was 5.5 mos (95 percent CI: 2.8 – 12.1) and median OS has not yet been reached (95 percent CI: 7.3 – NR). In all, grade 3/4 adverse events were observed in 24 percent and 23 percent of KEYNOTE-013 and KEYNOTE-170 patients, respectively. Interestingly, biomarker analyses of PD-L1 and PD-L2 membrane expression by IHC (available for 42 and 41 patient samples, respectively) indicate that progression free survival was associated with PD-L1+ disease and lack of expression of both surface markers correlated with a lack of overall response. In all, these combined results suggest that pembrolizumab is safe and effective as treatment for patients with relapsed/refractory PMBCL, and that PD-L1 may serve as a biomarker to indicate therapeutic success.