ONCAlert | 2017 San Antonio Breast Cancer Symposium

Immunotherapy Makes a Difference in Relapsed Hodgkin Lymphoma

Lisa Astor
Published Online: Oct 25,2017
Immunotherapy agents have shown significant activity in patients with Hodgkin lymphoma and made a marked difference in treating patients with relapsed or refractory disease, according to Javier Briones, MD, PhD. 

Briones, chief of the Hematology Service, Hospital de la Santa Creu i Sant Pau in Barcelona, Spain, discussed the rationale for treating patients with Hodgkin lymphoma with 3 immunotherapy approaches during the 2nd Annual European Congress on Immunotherapies in Cancer™, hosted by Physicians’ Education Resource®, LLC. 

CD30 is an ideal target for immunotherapy, he said, as it is expressed in all malignant cells in patients with Hodgkin lymphoma but there’s little to no expression in normal cells. “In fact, it’s such a typical biomarker, you cannot diagnose Hodgkin lymphoma if there’s no expression of CD30 on the tumor cell.” 

Brentuximab vedotin (Adcetris) is an antibody−drug conjugate that targets CD30. It is approved for use in Hodgkin lymphoma and recently received a breakthrough therapy designation for frontline use in combination with chemotherapy in classical Hodgkin lymphoma (cHL). 

In a pivotal phase II trial of 102 patients with relapsed/refractory CD30-positive Hodgkin lymphoma, brentuximab vedotin demonstrated a high rate of objective responses in patients following autologous stem cell transplantation (ASCT).

A majority (71%) of the patients were refractory to their frontline therapy; patients had received a median of 3.5 prior chemotherapy regimens and all had undergone ASCT. 

The overall response rate (ORR) was 75% (95% CI, 65%-83%) by independent review; 34% achieved a complete response (CR) and 40% achieved a partial response. The median overall survival (OS) was not reached. The estimated 1-year OS rate was 88%. 
Frequent treatment-emergent adverse events included peripheral sensory neuropathy (47%), fatigue (46%), nausea (42%), upper respiratory tract infection (37%), diarrhea (36%), pyrexia (29%), and neutropenia (22%). 

Among patients who had a CR, 9% did not receive any further treatment, Briones said, “so we can say that at least 9% of those patients were probably cured with just brentuximab monotherapy.” 

The AETHERA trial led to the expansion of brentuximab vedotin’s label for use as a consolidation therapy following ASCT in patients at risk of relapse or progression. 

In the phase III trial, patients at an increased risk of relapse were randomized to brentuximab vedotin or placebo 30 to 45 days after ASCT. The median progression-free survival (PFS) by independent review was 43 months compared with 24 months in the placebo group (hazard ratio [HR], 0.57; 0.40-0.81; P = .001).

Briones noted that the benefit was greater in patients who had the highest risk of relapse. “This is an approach that can allow us to significantly reduce relapse in those patients who receive an ASCT and have a very high risk of relapse after this procedure.” 
Combination regimens have been initiated, such as the Echelon-1 trial of brentuximab vedotin plus doxorubicin (Adriamycin), vinblastine, and dacarbazine in comparison with standard ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy as frontline therapy for patients with advanced cHL (NCT01712490). Data from this now completed trial will be presented by the end of the year, Briones noted, but preliminary findings show that PFS was improved with brentuximab. 

Also of great interest to Briones were combination studies with immune checkpoint inhibitors, as checkpoint inhibitors have shown promising efficacy in Hodgkin lymphoma as single agents. 

Briones explained that approximately 90% of patient with Hodgkin lymphoma express PD-L1 on their tumors for many reasons, including due to chromosome 9 gains and amplifications, JAK2 activation, and Epstein-Barr virus infection. This high rate of expression makes PD-L1 a good target using anti–PD-1 therapy; 2 of these agents, nivolumab (Opdivo) and pembrolizumab (Keytruda) have already been approved for use in Hodgkin lymphoma. 

In a phase II study of nivolumab in patients with relapsed/ refractory Hodgkin lymphoma after ASCT and brentuximab vedotin, the ORR was 66% (95% CI, 54.8%-76.4%), including 9% who had CRs.3 The median PFS was 10 months, with a 6-month PFS rate of 76.9%. The toxicity profile was similar to that of other immune checkpoint inhibitors, Briones noted. 

An ongoing phase I/II study of nivolumab in combination with brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma showed promising interim findings.4 All the patients had failed frontline chemotherapy, which was ABVD in 90% of patients. To date, the ORR is 85% and the CR rate is 64%, “which is much higher than any other standard chemotherapy that we can use for those patients who relapse after first-line therapy,” Briones said. 

Additionally, he noted that the toxicity profile was not significantly worse than when either of these antibodies are given alone. 
Chimeric antigen receptor (CAR) T-cell therapy is also an area of great interest in Hodgkin lymphoma as CAR T-cell therapies have already shown impressive responses in hematologic malignancies. 

Results of a phase I study of CART-30, CD30-targeting CAR T cells, in patients with progressive relapsed/refractory Hodgkin lymphoma show early efficacy for this modality.5 Eighteen patients received conditioning chemotherapy followed by a median dose of 1.5 x 107/kg of the infusion. Seven patients experienced a partial remission and 6 had stable disease. The median PFS was 6 months. 

Although cytopenias and fever were observed in all patients, no severe cytokine release syndrome was reported, which has been a concern in other CAR T-cell therapies. This approach, however, requires further investigation in patients with Hodgkin lymphoma. 
 
 
References:
  1. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189. doi: 10.1200/JCO.2011.38.0410.
  2. Moskowitz CH, Nademanee A, Masszi T, et al; AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862. doi: 10.1016/S0140-6736(15)60165-9.
  3. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283-1294. doi: 10.1016/S1470- 2045(16)30167-X.
  4. Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Hematol Oncol. 2017;35(suppl S2):85-86. doi: 10.1002/hon.2437_73.
  5. Wang CM, Wu ZQ, Wang Y, et al. Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkin lymphoma: an open-label phase I trial. Clin Cancer Res. 2017;23(5):1156-1166. doi: 10.1158/1078-0432.CCR-16-1365.



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Immunotherapy Makes a Difference in Relapsed Hodgkin Lymphoma
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