Avelumab Active in Hodgkin Lymphoma

Robert W. Chen, MD

Avelumab (Bavencio) demonstrated clinical activity and an acceptable safety and tolerability profile in heavily pretreated patients with classical Hodgkin lymphoma (cHL), investigators reported at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland.¹

Patients treated with avelumab demonstrated an objective response rate (ORR) that was similar to the response observed with other PD-1 inhibitors.

At a median follow-up of 43.3 weeks (range, 20.6-57.6) the median duration of avelumab treatment in 31 patients was 16.9 weeks. The best ORR was 41.9%, which comprised 5 patients (16.1%) with a complete response (CR), and 8 (25.8%) with a partial response (PR). The disease control rate was 71.0%, which included 9 additional patients (29%) who demonstrated stable disease (SD). Progressive disease was observed in 5 (16.1%) and 4 patients (12.9%) were not evaluated.

“PD-L1 blockade is sufficient to produce clinical responses in classical Hodgkin lymphoma and PD-L2 blockade may not be necessary to achieve the therapeutic effect observed with PD-1 inhibitors in some patients,” commented Robert W. Chen, MD, assistant professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California.

Amplification of the 9p24.1 amplicon is frequently observed in cHL, which results in overexpression of PD-L1 and PD-L2 immune checkpoint genes, making blockade of the PD-1 pathway especially relevant, according to Chen. Additionally, anti—PD-1 checkpoint inhibitors are an approved treatment for patients with relapsed/refractory cHL.

His team investigated the contribution of PD-L2 to the clinical response of PD-1 checkpoint blockade by using avelumab, a fully human IgG1 monoclonal antibody that selectively binds to PD-L1 but leaves the PD-1/PD-L2 interaction intact in patients with relapsed/refractory cHL. Avelumab also differs from other immunotherapies by directly targeting tumor cells rather than T cells and has demonstrated antitumor activity in lung, bladder, and renal cancer, according to results of the JAVELIN Solid Tumor trial.²

The phase Ib open-label, multicenter JAVELIN Hodgkin study enrolled 31 patients with histologically confirmed cHL who experienced disease progression following either autologous or allogeneic stem cell transplant (SCT), or were SCT-ineligible. Patients were randomized to receive 1 of 5 dosing regimens of avelumab: 70 mg, 350 mg, 500 mg administered every 2 weeks, 500 mg every 3 weeks, or 10 mg/kg every 2 weeks for the lead-in phase.

Thereafter, patients demonstrating >90% mean target occupancy with 1 treatment cycle or 3 or more objective responses entered the dose-expansion phase, which included safety and ORR by Response Criteria for Malignant Lymphoma as its selective endpoints.

The patients in the lead-in phase had a median age of 38 years (range, 22-81), 80.6% were male and 64.5% had received ≥4 prior therapies. All patients had received prior brentuximab vedotin; 5 and 8 patients progressed following autologous SCT and allogeneic SCT, respectively, and the remaining 25 patients were ineligible for SCT.

To date, patients have received a median of 6 cycles (range, 1-23) of avelumab. Responses were observed across all dosing groups, except in the 350-mg cohort with ORRs of 50%, 0%, 83.3%, 33.3%, and 50%, respectively. At follow-up, 9 patients (29.9) remained on avelumab.

Tumor shrinkage ≥50% was achieved by 23 patients and 3 patients had tumor growth of ≥50%.

The best ORR in the 5 patients who had an autologous SCT was 20.0% due to 1 PR. However, avelumab had a greater benefit in the 8 post-allogeneic SCT patients who demonstrated an ORR of 62.5% with 2 patients (25%) achieving a CR and 3 PRs (37.5%).

“The response observed in the postallogeneic SCT setting suggests that PD-L1 blockade may potentiate the graft versus lymphoma response,” said Chen.

Grade 3 liver graft versus host disease occurred in 2 patients who had received prior allogeneic SCT that completely resolved after immunosuppressive therapy and discontinuation of avelumab.

The incidence of treatment-related adverse events (TRAEs) was similar across all dosing cohorts; commonly reported TRAEs of any grade were infusion-related reactions (30%), nausea (20.0%), rash (16.7%), and fatigue (13.3%). Grade 3/4 TRAEs occurred in 36.7% of patients including infusion-related reactions (6.7%), nausea (3.3%), increased alanine aminotransaminase (6.7%), increase lipase (6.7%) and 3.3% of patients each reported increased gamma-glutamyl transferase, immune thrombocytopenic purpura, and thrombocytopenia.

No treatment-related deaths were reported. Two patients (6.7%) discontinued treatment due to immune-related events.

Chen commented: “Based on the observed efficacy and safety profiles and the unmet need, this study has recently been amended to focus the expansion on patients who progress post-all SCT.”

References

1. Chen R, Gibb AL, Collins GP, et al. Blockade of the PD-1 checkpoint with anti-PD-L1 antibody avelumab is sufficient for clinical activity in relapsed/refractory classical Hodgkin lymphoma (cHL). Hematol Oncol. 2017;35(suppl S2):67. doi: 10.1002/hon.2437_54.
2. Heery CR, O’Sullivan-Coyne G, Madan RA, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017; 18(5)587-598. doi: 10.1016/S1470-2045(17)30239-5.

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“Anti—PD-1 antibodies block interaction between PD-1 and both of its ligands, PD-L1 and PD-L2, but it has not yet been established whether blockade of just the PD-1/PD-L1 is sufficient for the therapeutic effect observed in CHL,” Chen explained.