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The ‘Hematologic Malignancies-Lymphoma and Chronic Lymphocytic Leukemia’ poster discussion session took place on Monday June 6, 2016, between 13:15–14:45. The session was jointly chaired by Susan Mary O’Brien, MD, Associate Director for Clinical Science, at Chao Comprehensive Cancer Center in the University of Irvine, California, and John Leonard, MD, of Weill Cornell Medicine, New-York.
Nancy L Bartlett, MD, Professor of Medicine at the Siteman Cancer Center, Washington University in Saint-Louis, MO, presented ‘Discussion – PD-1 Inhibitors in Hodgkin Lymphoma, Abstracts 7535, 7555’.
Abstract 7535: Checkmate 205: Nivolumab (nivo) in classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV)—A phase 2 study
Amplification of 9p24.1 resulting in overexpression of PD-1 ligands is a characteristic of Classical Hodgkin Lymphoma (cHL); therefore, PD-1 blockade presents as a potential therapeutic strategy. Nivolumab is an anti-PD-1 IgG4 monoclonal antibody which has achieved promising results in R/R cHL patients in a phase Ib study (NCT02181738; Ansell et al 2015).
The data presented in this abstract is from the phase II Checkmate 205 study (NCT02181738), which in its second cohort (B) aimed to assess the efficacy and safety of nivolumab in cHL patients who had been administered brentuximab vedotin after failed Autologous Stem-Cell Transplant (ASCT). Patients with cHL who relapse after ASCT or progress after brentuximab vedotin have a very poor outcomes.
The conclusion of this abstract is that nivolumab achieved a high responses and was well tolerated in patients with cHL post-ASCT and brentuximab vedotin, including patients with no prior responses to brentuximab vedotin. The PFS and OS are encouraging in this heavily pretreated population.
Abstract 7555: Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087 study
Pembrolizumab is another humanized monoclonal IgG4 antibody which targets PD-1 abrogating its binding to PD-L1 and PD-L2. Pembrolizumab has been shown to have efficient antitumor activity (ORR = 65%) in the phase Ib KEYNOTE-013 study of heavily pretreated cHL patients (NCT01953692). To confirm the clinical activity of pembrolizumab, the phase II KEYNOTE-087 (NCT02453594) multicohort study was initiated. The study contained 3 cohorts:
Pembrolizumab was administered at a 200mg IV Q 3w fixed dose. As of 1st February 2016 (data cut-off), 60 patients from cohorts 1 and 2 were evaluable:
The conclusion of this abstract was that pembrolizumab demonstrated early responses in heavily pretreated cHL patients; in particular an unprecedented high ORR (80%) in patients who were not eligible for ASCT and who failed brentuximab vedotin.
Nancy Bartlett began by outlining the different phase II treatment regimens:
Time to response and durability with nivolumab was then discussed.
The presentation then focused on whether standard PET criteria are adequate for response assessment. Possible false positive PETs occur due to PD-1 blockade activating T-cells at tumor site, this may explain lower CR rates and differences in investigator determined CR vs IRRC (28% vs. 9%).
It was then discussed if nivolumab could act as a bridge to allo-SCT. However, a “warning and precaution” has been issued by the FDA for complications of allo-SCT post-nivolumab. In a phase I/dose expansion study using nivolumab as a bridge to allo-SCT, 4/5 patients died of transplant complications (Ansell ASH, 2015, Blood, 126:583). It is of utmost important to follow patients closely for hyperacute and severe acute GVHD, VOD, and other immune-mediated reactions. In a phase II Nivolumab study, 6 patients went on to allo-SCT (all alive at data cut-off).
A possible treatment option in the post-transplant relapsed setting is immunotherapy combinations; for example:
Nancy Bartlett concluded the talk by highlighting that pembrolizumab and nivolumab as single-agents achieve high response rates in patients with cHL who are multiply R/R; with ORRs between 66–83% and CR rates between 9–28%. However, longer follow-up is required in order to determine the durability of responses. These agents are well tolerated, but Bartlett cautioned that close attention is needed to detect any immune-mediated adverse reactions early. Lastly, these agents could be used in exciting potential combinations to treat post-transplant failures and as well for earlier lines of therapy.
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