FL,   DLBCL,  MCL,  MZL,  CLL/SLL,  HL,  WM

Novel combinations and treatments for relapsed NHL: three clinical studies from ASH2017

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.

ASH 2017 Oral Abstract #414 – Pembrolizumab with rituximab shows high CR in relapsed FL: Phase II study results

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. 

Study Highlights
  • 32 eligible patients were enrolled in the study
  • Patients received treatment with rituximab (375 mg/m2 IV on days 1, 8, 15 and 22 of cycle 1) and pembrolizumab (200 mg IV every 3 weeks for up to 16 cycles starting on day 2 of cycle 1)
  • Median follow-up: 13.8 months
  • Median age: 64 years (range 43–84); 73% of patients had an ECOG PS of 0; median prior therapy: 1 (range 1–4); median PFS of last therapy: 28 months (3–162)
  • ORR: 67%
    • CR: 50%
  • Median duration of response: 14.1 months (11–not reached[NR])
  • Median PFS: 11.4 months (8.25–NR)
  • Median PFS was 13.8 months (8.5–NR) vs1 months (3.6–NR) in patients with PFS > 1 year vs ≤ 1 year following most recent therapy (P=0.01)
  • PD-L1 status was not a significant predictor of response (I=0.71)
    • PD-L1 expression was tested in 19 tumour samples using PD-L1 22C3 IHC pharmDx and was detected in histiocytes in all 19 samples. PD-L1 was undetectable on tumour cells in 8 samples, was present in only 1–8% of tumour cells in 10 samples and in 20% of tumour cells in 1 sample
  • Immune cell gene signature analysis in baseline tumours by Nansotring in 18 patients showed an association between presence of high levels of CD8+ T-effector score and achieving a CR
  • Peripheral blood IFN-γ gene signature score was a significant independent predictor of response in the 26 samples analysed
Safety
  • Adverse events (AEs) regardless of causality were mild, most were grade 1–2
  • One patient experienced grade 4 transaminitis. Grade 3 AEs included nausea (N=2) and diarrhoea (N=1)
  • Immune-related (IR) AEs included diarrhoea (grade 1, N=8; grade 2, N=3; grade 3, N=1), rash (grade 1, N=3; grade 2, N=4), transaminitis (grade 1, N=7), pneumonitis (grade 2, N=2), esophagitis (grade 2, N=1), aseptic meningitis (grade 3, N=1), and hypothyroidism (grade 1, N=2).
  • Six patients discontinued therapy due to recurrent IR-AEs:
    • 3 patients discontinued due to (grade 2, N=2; grade 3, N=1)
    • 2 patients due to pneumonitis (grade 2)
    • 1 patient due to rash (grade 2)

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.

ASH 2017 Oral Abstract #410: Preliminary results of the CITADEL-101 Phase 1/2 study of INCB050465, a PI3Kδ Inhibitor, in relapsed or refractory B-cell malignancies

 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.

Study Highlights
  • 72 patients were enrolled
  • Median age: 66 years [range 30–89]
  • Baseline tumour subtypes treated included NHL (diffuse large B-cell lymphoma, FL, mantle cell lymphoma, marginal zone lymphoma), Hodgkin lymphoma, CLL, and WM
  • 43 patients (60%) had received ≥3 prior systemic regimens
  • Six doses of INCB050465 were investigated during dose escalation (5, 10, 15, 20, 30, 45 mg). No dose-limiting toxicities were observed and the maximum tolerated dose (MTD) was not reached. Based on PK/PD, the 20 and 30 mg once daily (QD) cohorts were expanded. The final dose that was selected was 20 mg
  • An intermittent dosing schedule was introduced in November 2016
    • New patients received 20 mg QD for 9 weeks, followed by 20 mg QW
    • Existing patients on treatment for ≥ 9 weeks were switched to QW
  • QD dosing at steady state: approximately linear PK was observed with all doses of INCB050465. All doses tested remained above the IC90 for target inhibition throughout the dosing interval
  • Based on PK simulation, serum INCB050465 levels resulting from the 20 mg QW dosing were predicted to exceed the IC90 for target inhibition for approximately 36 hours
  • All patients with FL, MZL and MCL had a reduction from baseline in target lesion size. Approximately 45% of patients with DLBLCL also had a reduction in target lesion size
  • 93% of the objective responses were observed at the first assessment (around 9 weeks; median 2.07 months)
    • This supports the switch to QW dosing after the first assessment to manage long-term tolerability
Safety
  • The most frequent non-hematologic TEAEs were diarrhoea/colitis (n=26), nausea (n = 26), fatigue (n = 22), rash (n = 22), cough (n = 17) and vomiting (n = 17)
  • New or worsening haematological TEAEs included neutropenia (n = 32), thrombocytopenia (n = 33) and anaemia (n = 20)
  • Serious TEAEs were reported in 40% of patients, most frequently diarrhoea/colitis (n = 8), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3)
  • TEAEs of special interest:
    • AST and ALT elevations: 26% and 25% of patients, respectively
    • Hypertension: 7% patients (all grade 1/2)
    • Hyperglycaemia: 10% patients (including one patient with grade 3 hyperglycaemia)
  • Dose interruption occurred in 42% of patients, dose reduction in 6% of patients and discontinuation in 19% patients due to TEAEs
  • AEs during QW dosing:
    • No discontinuations due to TEAEs (105 patient months)
    • No grade 4 non-haematologic TEAEs
    • No grade 4 neutropenia

 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.

ASH 2017 Oral Abstract #411: the first study to investigate the combination of CC–122, a novel cereblon modulating agent, and obinutuzumab in relapsed and refractory B-cell NHL

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.

Study Highlights
  • 44 patients were enrolled: 19 patients with DLBCL, 24 with FL, and 1 with MZL
  • Median age: 60 years (range, 26–81)
  • Median number of prior systemic cancer therapies: 3 (1–11)
  • 50% of patients were rituximab refractory
  • ORR in the overall population: 68%, with 12 patients (27%) achieving a CR
  • ORR/CR rate in DLBCL and FL/MZL patients were 47%/11%; and 84%/40% respectively
  • Median DoR: 11.3 months (3.7–21.2)
  • 6-month PFS rate: 55 months (37–70)
  • Median DOR: 19.4 months (7.9–NR)
  • Subgroup analysis was performed to further examine the high-risk early relapse (ER) and double refractory (DR) patients with FL. PFS was comparable between the high-risk (ER + DR) and non-high-risk FL patients
  • A CC-122 dose of 3 mg with obinutuzumab is the recommended dose for further development
 Safety
  • Two patients experienced a DLT:
    • One patient had grade 4 neutropenia (3.0 mg CC–122 + obinutuzumab)
    • One patient had grade 5 tumour flare reaction/TLS (4.0 mg CC–122 + obinutuzumab)
  • The most frequent (≥ 15%) grade 3/4 AEs included neutropenia (52%) and thrombocytopenia (25%)

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.

References
  1. Forero-Torres A. et al. 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). Oral Abstract #410: ASH 59th Annual Meeting and Exposition, December 2017, Atlanta, GA
  2. Michot JM. et al. CC-122, a Novel Cereblon Modulating Agent, in Combination with Obinutuzumab (GA101) in Patients with Relapsed and Refractory (R/R) B–Cell Non–Hodgkin Lymphoma (NHL). Oral Abstract #411: ASH 59th Annual Meeting and Exposition, December 2017, Atlanta, GA.
  3. Nastoupil Loretta. et al. High Complete Response Rates with Pembrolizumab in Combination with Rituximab in Patients with Relapsed Follicular Lymphoma: Results of an Open-Label, Phase II Study. Oral Abstract #414: 59th ASH  Annual Meeting and Exposition, December 2017, Atlanta, GA.