ICML 2017 | Ongoing trials in B-cell NHL including ROBUST, MCL-R2 Elderly, and SYMPATICO – Focus On Session 

On the afternoon of Thursday 15^th June, the Lymphoma Hub attended the “Focus On” Ongoing Trials Session at the 14^th International Conference on Malignant Lymphoma (ICML), which was chaired by Professor Martin Dreyling from the Hospital of the University of Munich, Munich, Germany.

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The first abstract was presented by Annalisa Chiappella, MD, from Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy, and contained results of subtype analysis of patients enrolled in the phase III, randomized, double-blind, multicenter ROBUST study (NCT02285062).

Patients with Activated B-Cell-like (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) have been reported to have very poor outcomes after receiving chemo-immunotherapy. The immunomodulatory agent lenalidomide has previously demonstrated significant single-agent activity in Relapsed/Refractory (R/R) DLBCL, mainly ABC type, and upfront in newly diagnosed DLBCL when combined with R-CHOP (i.e., R²-CHOP). Before now, real-time identification of COO subtype as a biomarker to inform therapy choice and strategy was not a realistic approach due to limitations with the technology.

The ROBUST study aimed to compare the efficacy and safety of R²-CHOP to placebo plus R-CHOP chemotherapy in patients with newly diagnosed ABC-DLBCL.

Eligibility criteria included:

• Previously untreated, histologically confirmed ABC-type, CD20+ DLBCL
• Measurable disease ≥5cm in longest diameter and in 2 perpendicular directions by CT/MRI
• Age >18 years
• IPI ≥2
• ANC ≥5 x 10⁹/L
• Platelet count ≥75 x 10⁹/L
• Creatinine clearance ≥30ml/min
• Contraception as appropriate

Patients were randomly assigned 1:1 to oral lenalidomide (15mg, d1–14/21) + standard R-CHOP or placebo-R-CHOP for 6 cycles with two optional, additional rituximab doses. Central pathology labs based in Beijing (China), Edinburgh and Heston (UK), and Valencia (USA) determined COO type on Formalin Fixed Paraffin Embedded (FFPE) biopsy samples within approximately 3 days (plus 2 days shipping) using real-time Gene Expression Profiling (GEP) with the NanoString nCounter Dx analysis system. Overall, 257 active sites from across 21 countries took part in the ROBUST study.

As of 1^st June 2017, 530 of the planned 560 patients have been enrolled onto the trial. As of 24^th February 2017, of patients whose samples underwent subtyping, 1,402/1,530 patients had samples successfully tested. ABC subtype made up 43% of patients and the remaining 57% were non-ABC (GCB plus unclassified). Unsuccessful tests took place for 128 patients (8% of those screened for COO); this was due to a range of technical reasons such as incorrect or insufficient material, low tissue RNA concentration or purity, and low RNA signal hybridization. The mean turnaround time for identification of DLBCL subtype was 2.56 days.

It was concluded that real-time COO identification by GEP was feasible in the phase III ROBUT study. The rapid mean turnaround time for COO screening for most patients did not negatively affect the length of the screening period. The turnaround time in ROBUST (2.56 days) is much improved compared to 10 working days reported in the REMoDL-B trial (Davies et al. ASH. 2015. Abstract #812). The proportion of ABC versus non-ABC samples was consistent with what has previously been found. These results have crucial implications for the design and size estimation of future trials looking at DLBCL using COO as a biomarker.

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Professor Ulrich Jäger from the Medical University of Vienna, Austria, gave the second talk in this session, which gave an update on a phase II study (NCT03003520) of durvalumab plus R-CHOP or lenalidomide plus R-CHOP to treat newly diagnosed, high-risk DLBCL patients. While at ICML, we interviewed Prof. Jäger on this; watch it here.

Increased PD-1/PD-L1 expression and soluble PD-L1 levels have been found to be indicators of poor prognosis in terms of Overall Survival (OS) in DLBCL patients. Durvalumab (MEDI4736) is a selective, human IgG1κ monoclonal antibody that binds PD-L1 and has been shown to have anti-tumor activity in xenograft models. It overcomes PD-L1 mediated inhibition of T-cell activation, thereby allowing T-cells to identify and kill tumor cells. Clinically meaningful activity and favorable safety profiles have been shown in early studies of various PD-1 and PD-L1 inhibitors in R/R Lymphoma.  

The phase II study has a primary outcome measure of PFS at 2 years; secondary endpoints included safety and clinical response to study treatment in biomarker-defined subpopulations.

Inclusion criteria included:

• Age ≥18 years
• Histologically confirmed CD20+ DLBCL
• Ann Arbor stage 3–4 or stage 2 with bulky disease (≥7.0cm) and intermediate-high disease risk (IPI ≥3 or NCCN-IPI ≥4)
• ECOG PS 0–2
• Bi-dimensionally measurable disease ≥2.0cm
• No prior anti-lymphoma treatment
• Able and willing to undergo tumor/lymph node biopsy during screening, on treatment and at progression

The induction and consolidation treatment regimens were summarized by Prof. Jäger in a table:

The MEDI4736-DLBCL trial began enrollment in December 2016 and is currently actively recruiting patients. Target recruitment is a total of 120 patients mostly from centers based in the US and Europe. Screening is ongoing and current enrollment is 5 as of May 18^th 2017.

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The third talk was given by Lakshmi Nayak from the Dana-Farber Cancer Institute, Boston, MA, USA, and gave an update on the CheckMate 647 trial.

Primary Central Nervous System Lymphoma (PCNSL) and Primary Testicular Lymphoma (PTL) are rare, clinically aggressive forms of Large B-Cell Lymphoma with similar genetic signatures. There is high unmet need in PCNSL and PTL due to high relapse rates, limited treatment options, limited prospective clinical data to inform treatment, poor long-term outcomes, and the toxicity of current treatment options for PCNSL.

Both tumors exhibit frequent 9p24.1 Copy Number Alterations (CNAs) and associated with the expression of PD-L1 and PD-L2. Both pre-clinical and clinical studies have demonstrated that lymphoid malignancies with 9p24.1/PD-L1/PD-L2 aberrations are genetically predisposed to rely on PD-1-mediated immune evasion. Activation of PD-1 signaling by PD-L1/PD-L2 limits T-cell responses and reducing anti-tumor immune surveillance.

Targeting the PD-1 receptor pathway may be a promising therapeutic strategy for PCNSL and PTL. This strategy has been shown to be effective for classical Hodgkin Lymphoma. Nivolumab is a fully humanized IgG4 monoclonal antibody specific for the PD-1 receptor immune checkpoint pathway, and restores T-cell activation and anti-tumor responses.

In a retrospective study of nivolumab in 5 R/R PCNSL (n=4) or PTL (n=1) patients (median age of 64 years; range, 54–85 years), all achieved clinical and radiographic responses (4 complete radiographic responses and 1 partial radiographic response in a patient with PCNSL). All patients had been previously treated with standard regimens including HD-MTX based chemotherapy, ASCT, and whole-brain radiotherapy. Of the 5 patients, 3 remain progression free at 13+ to 17+ months. The median number of treatments to objective response was 3 (range, 2–4) and persistent ocular disease was observed in one patient (Nayak et al. Blood. 2017).

The CheckMate 647 trial (NCT02857426) is a phase II, open-label, single-arm, two-cohort study assessing nivolumab in patients with R/R PCNSL or PTL. The primary endpoint is ORR and secondary endpoints include PFS, OS, and DoR. The trial had a planned enrollment of 65 patients (45 PCNSL, 20 PTL) and is estimated to complete in December 2019.

Inclusion criteria for the CheckMate 647 trial are listed below:

• Adults aged ≥18 years
• Progressed after, or did not respond to, ≥1 line of standard of care therapy
• PCNSL patients: measurable disease on MRI
• PTL patients: ≥1 extranodal or nodal lesion
• KPS of ≥70
• Tumor tissue for PD-L1/PD-L2 expression and alterations

Exclusion criteria include:

• Prior treatment with checkpoint inhibitors or T-cell co-stimulatory drugs
• Prior treatment with BTK inhibitors (patients with PCNSL)
• Intraocular PCNSL with no evidence of measurable brain disease
• Patients with brain stem lesions
• Patients with prior history of allogeneic CT <6 months before screening
• Dexamethasone requirement of >2mg/day within the 14 days prior to first dose of nivolumab
• Intra-ocular disease, patients with PCNSL who cannot undergo MRI, and PCNSL patients with systemic disease

Lakshmi Nayak concluded the update by emphasizing that the CheckMate 647 study is currently enrolling patients with R/R PCNSL or PTL.

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Ribrag from the Institut Gustave Roussy, Villejuif, France, presented the next abstract in this session on the MCL-R2 Elderly phase III study (NCT01865110).

The talk began with some historical background of treatment for older patients with Mantle Cell Lymphoma (MCL). For example, R-CHOP followed by rituximab maintenance has been reported to achieved over 80% OS. Moreover, it has been suggested that the combination of rituximab and lenalidomide (R²) demonstrates high efficacy (Ruan et al. N Engl J Med. 2015).

The MCL-R2 Elderly trial aims to assess the efficacy of alternating immunichemotherapy consisting of R-CHOP plus R-HAD compared to R-CHOP alone, followed by maintenance of R² versus rituximab alone for older MCL patients.

The primary outcome measure of the trial is PFS. The key inclusion criteria consist of:

• Biopsy-proven MCL according to WHO classification, including evidence of cyclin D1 overexpression of the t(11;14)(q13;q32) translocation
• ≥60 years of age and ineligible for ASCT
• Ann Arbor stage II–IV
• Previously untreated
• ECOG PS ≤2

Enrolment began in November 2013 and as of June 12^th 2017, 314 patients have been randomized for induction out of the target of 633, and 196 patients out of a target of 443 have been randomized for maintenance treatment. Nearly three-quarters (74%) of patients randomized for induction are randomized for maintenance. Further details on the current status of enrollment were presented by Ribrag in a table, the protocol submission for Poland is in preparation:

Between November 4^th 2013 and 30^th May 2017, 145 Serious Adverse Events (SAEs) were reported (2 before treatment, 89 during induction, and 54 during maintenance). Specifically, during induction, 89 SAEs in 54 patients were observed, 2 were fatal in the R-CHOP arm (GI hemorrhage and general physical health deterioration). During maintenance, 54 SAEs were observed in 33 patients. One death from two SAEs pulmonary embolism and infarction) was reported in the R-CHOP arm.

Ribrag concluded this abstract presentation by stating that a similar number of SAEs were found in both induction and maintenance arms. Moreover, there was no significant differences regarding SAEs in both induction and maintenance arms except for general disorders and administration site conditions which were more common in the R-CHOP arm (10 vs. 1). Furthermore, secondary primary malignancies were more common in the R² arm (10 vs. 2), mainly Basal Cell or Squamous Cell Carcinoma (7 in 2 patients vs. 1).

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The penultimate talk in this session was focused on the phase III PCYC-1143 (SYMPATICO) study of ibrutinib plus venetoclax for R/R MCL, and was presented by C.S. Tam from the Peter McCallum Cancer Center and St. Vincent’s Hospital, Melbourne, Australia.

Ibrutinib is the first-in-class, once-daily inhibitor of BTK. It is approved in the EU for R/R MCL and WM after one or more previous therapies or as first-line treatment of patients unsuitable for chemoimmunotherapy. Ibrutinib inhibits BTK, which decreases downstream signaling and resulting in NF-κB mediated apoptosis. Venetoclax is an oral BCL-2 inhibitor and is approved in the EU for R/R CLL with or without del(17p)/TP53 mutation. When venetoclax binds to BCL-2 it displaced BIM, meaning it can interact with BAX or BAK. The BIM-BAX complex results in exit of cytochrome C from mitochondria, triggering apoptosis.

Tam summarized previous findings of ibrutinib and venetoclax in the treatment of R/R MCL:

The AIM study evaluating ibrutinib plus venetoclax in R/R MCL was recently completed and presented as a poster at the 2017 ASCO Annual Meeting (Tam et al. ASCO. 2017. Abstract #7520). This trial found, at 16 weeks, an ORR of 71% (63% CR [PET]) with MRD-negativity achieved in 77%. 

SYMPATICO (NCT03112174) is a multi-national, randomized, double-blind trial aiming to compare the efficacy and safety of ibrutinib plus venetoclax to ibrutinib plus placebo in patients with MCL. The primary outcome measures are occurrence of Tumor Lysis Syndrome (TLS), occurrence of Dose Limiting Toxicities (DLTs), and PFS.

Key inclusion criteria consisted of:

• Age ≥18 years of age
• Pathologically confirmed MCL (in tumor tissue) with
  • Documentation of cyclin D1 overexpression with other relevant markers (e.g. CD19, CD20, PAX5, CD5) or
  • Evidence of t(11;14) as assessed by cytogenetics, FISH or PCR
• At least one measurable disease site on cross-sectional imaging (CT/PET)
• 1–5 prior treatment for MCL
• Failure to achieve at least PR with, or documented PD after, the most recent treatment

Enrolment for the SYMPATICO trial opened in April of this year, aiming to recruit 287 patients worldwide.

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The last abstract presentation in this session was given by Christian Buske from Ulm University Hospital, Ulm, Germany, and discussed a phase III head-to-head trial (NCT03053440) comparing BGB-3111 and ibrutinib in patients with Waldenström Macroglobulinemia (WM).

The talk began with an overview of WM, a rare B-cell malignancy that is characterized by bone marrow infiltration of IgM-secreting lymphoplasmacytic cells. Incidence is approximately 3 cases per million, equating to around 1,000–1,500 new diagnoses each year in the US. Over 90% of patients harbor a recurrent somatic activating mutation of the MYD88 gene (MYD88^L265P) that triggers downstream IRAK-mediated NF-κB signaling, contributing to WM cell survival.

BTK, a key component of the BCR pathway, is constitutively activated in WM and have been demonstrated to be a key mediator of tumor cell survival. Inhibiting BTK is becoming a promising therapeutic strategy for B-cell malignancies, including WM and especially those with the MYD88^L265P mutation. Previous investigation has found that ibrutinib has activity in WM, achieving a major response rate of 73% (including 16% VGPR [Very Good Partial Response]) and 68% 3-year EFS. BGB-3111 is a potent inhibitor of BTK, designed to have minimal off-target inhibition of TEC- and EGFR-family kinases.

Results from an ongoing phase I trial, with 44 patients on study, have been encouraging in terms of activity of BGB-3111 in patients with WM:

• ORR = 90%
• Major response rate = 76% (including 43% VGPR)
• Response depth improved over time

This early data also suggested that BGB-3111 carries an acceptable safety profile; no unanticipated safety signals based on the known profile of BTK inhibition in WM were observed. Three patients discontinued because of AEs (prostate cancer, bronchiectasis, adenocarcinoma of the pylori).

The current phase III study aimed to compare the efficacy of BGB-3111 versus ibrutinib in patients with MYD88^L265P WM as measured by rate of CR or VGPR.

Key inclusion criteria consisted of:

• Measurable WM (IgM >0.5g/dL)
• Newly diagnosed WM must be considered unsuitable for standard chemoimmunotherapy
• Age ≥18 years
• ECOG PS 0–2
• Neutrophils ≥0.75 x 10⁹/L
• Platelets ≥50 x 10⁹/L
• AST and ALT ≤3 x ULN
• CrCl ≥30ml/min by Cockcroft-Gault or eGFR
• Post-SCT relapse must be ≥3 months after ASCT or ≥6 months after allo-SCT

The study opened enrolment on January 25^th 2017 and is currently accruing patients from around 70 participating sites based in Europe, Asia-Pacific, and North America.