DLBCL

Relapsed/refractory aggressive NHL treatment – Session at the 22nd Congress of the EHA

On Saturday 24th June, during the 22nd Congress of the European Hematology Association (EHA), a session took place discussing therapy for aggressive relapsed/refractory Non-Hodgkin Lymphoma (NHL). The session was co-chaired by Dolores Caballero from the University Hospital of Salamanca, Salamanca, Spain, and Martin Hutchings from Copenhagen University Hospital, Copenhagen, Denmark. Below are the key highlights from the final two presentations that made up this session, the first three presentations were discussed here.

Abstract S469: Selinexor - Phase IIb SADAL study

The fourth abstract in this session was presented by Marie Maerevoet from the Institute Jules Bordet, Brussels, Belgium, on the the results of the interim analysis of the phase IIb SADAL study of single agent selinexor in R/R DLBCL patients (NCT02227251).

Selinexor is a first-in-class inhibitor of exportin 1 (XPO1), a nuclear export protein which is upregulated in certain malignancies including DLBCL. XPO1 transports key proteins out from the nucleus into the cytoplasm including tumour suppressor proteins, in addition to mRNA encoding proteins known to be important in cancer, such as c-Myc and BCL-XL. Selinexor, through inhibiting XPO1, results in the inhibition of cell growth, reduces oncoprotein expression, and blocks NF-kB signalling.

The randomized phase IIb SADAL study compared 60mg vs. 100mg selinexor doses, on a twice per week schedule of a 28-day cycle. The primary endpoint was ORR, and the secondary endpoints were DoR, OS, and safety.

Summary:
  • Total number of patients recruited (May 2017) = 90
  • Number of patients in the interim analysis = 63
    • Selinexor 60 mg = 32 pts
    • Selinexor 100 mg = 31pts
  • Combined: ORR = 33.3%, CR = 14.3%, PR = 19%
  • Selinexor 60 mg: ORR = 34.3%, CR = 12.5%, PR = 21.9%
  • Selinexor 100 mg: ORR = 32.2%, CR = 16.1%, PR = 16.1%
  • GCB vs. Non-GCB subtype: ORR = 28.1% vs. 38.7%, CR = 12.5% vs. 16.1%

  • Most common grade 3 or higher adverse events (AEs) in the 60 mg vs. 100 mg group were: thrombocytopenia (28.2% vs. 41%), fatigue (10.9% vs. 25%) and neutropenia (17.4% vs. 18.2%)
  • Safety data showed that 60 mg was better tolerated than 100 mg with lower incidence of grade 3 or higher AEs (shown below)
  • It was suggested that AEs can be managed successfully with dose reductions or interruptions in addition to supportive care

In summary, Dr. Maerevoet stated that selinexor demonstrated activity in R/R DLBCL with an ORR of 33.3%, a median DoR of more than 7 months, and a median OS of 8 months (NR in responding patients). However, due to toxicity the 100 mg arm was stopped, but recruitment is ongoing for an additional 90 patients to receive the 60 mg dose. Dr. Maerevoet discussed this data with the Lymphoma Hub in a video after this presentation from EHA 2017.

Abstract S470: L-MIND phase II study of MOR208 combined with lenalidomide

The final abstract from this session was presented by Kami Maddocks on the preliminary results of the L-MIND phase II study of the combination of MOR208 and lenalidomide (Len) in R/R DLBCL (NCT02399085). In total 34 patients with a median ages of 73 years qualified for inclusion in the efficacy analysis as of March 2017. MOR208 is an humanized CD19 monoclonal antibody which has previously been shown to have a synergistic antitumor effect when used in combination with lenalidomide in in vivo and in vitro studies.

The primary endpoint was ORR of MO208 + Len, with secondary endpoints including OS, PFS, DoR, and safety of the combination. Inclusion criteria of note included patients must have received at least one prior therapy, but no more than three prior therapies, with at least one being an anti-CD20. Additionally, patients must not have been eligible for stem cell transplant or high-dose chemotherapy, and double/triple-hit DLBCL patients were excluded.

Summary:
  • ORR =56%
    • CR = 32% (11 pts)
    • PR = 24% (8 pts)
    • SD = 12% (4 pts)
    • PD/Not evaluable = 32% (11 pts)
  • Ongoing responses seen in 84% pts (16/19)
  • Most common grade 3/4 TEAEs:
    • Neutropenia = 43%, pneumonia = 11% thrombocytopenia = 9%
  • No reported infusion-related reactions for MOR208
  • Lenalidomide dose adjustment was not required in 55% of patients (27% did have dose reductions)

In conclusion, it was stated that the combination of MOR208 with lenalidomide was well tolerated in this preliminary analysis, with 27% of patients requiring a dose reduction in lenalidomide. Furthermore, it was stated that this combination showed ‘encouraging preliminary activity’ in R/R DLBCL patients with a poor prognosis and ineligible for stem cell transplant. During ICML 2017 in Lugano, Professor Gilles Salles spoke about this trial, and Dr. Maddocks also spoke about this trial after her presentation in Madrid.

References:

  1. Cabellero D.Hutchings M. Aggressive Non-Hodgkin Lymphoma – Relapsed/refractory. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain.
  2. Maerevoet M. et al.Single agent oral selinexor exhibits durable responses in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) of both GCB and non-GCB subtypes: The phase 2b SADAL study. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain. [Abstract S469].
  3. Maddocks K.et al. L-MIND: MOR208 combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large B-cell lymphoma (R-R DLBCL) – a single-arm phase II study. 22nd Congress of the European Hematology Association; 2017 June 22–25; Madrid, Spain. [Abstract S470].