Kamakshi V Rao, PharmD, BCOP, FASHP University of North Carolina Medical Center UPDATE IN REFRACTORY HODGKIN LYMPHOMA

Kamakshi V Rao, PharmD, BCOP, FASHP University of North Carolina Medical Center UPDATE IN REFRACTORY HODGKIN LYMPHOMA

Objectives Describe the current standard approach for patients with relapsed/refractory Hodgkin lymphoma (rel/ref HL) and associated outcomes Summarize currently available data for novel agents in the management of rel/ref HL Determine the proper place in therapy and selection of therapy for a patient with rel/ref HL based on patient and disease specific factors

Hodgkin Lymphoma Clonal lymphoid malignancy that occurs at a rate of 2-3 per 100,000 persons 8500 new cases in the US in 2016 Treatment is generally successful Nearly 80% of patients are cured with standard frontline therapy, which may include chemotherapy, radiotherapy, or a combination of both

Relapsed/refractory HL 20% of patients have either primary refractory disease or relapse after attainment of an initial remission Standard of care for these patients is salvage chemotherapy followed by autologous HCT Cure rate of up to 50% Patients relapsing after HCT have a much poorer prognosis Median overall survival of 25 months from HCT

Options for Rel/Ref HL For patients relapsing after autologous HCT, options are limited Allogeneic HCT offers potential for long term disease control, but relapse is still frequent Issues with tolerability of allogeneic transplant (ablative vs. reduced intensity), availability of donors, etc. Salvage therapy has not been standardized Novel therapies now show promise

Brentixumab vedotin (BV) BV is an antibody-drug conjugate that combines an anti-cd30 monoclonal antibody to monomethyl auristatin E (MMAE) Upon binding to CD30 on cell surface, the complex is internalized and cleaved, where MMAE can then act as a potent antimicrotubule agent

Brentuximab Landmark Trial in 2011 established the role and activity of brentuximab after failure of auto HCT for patients with HL ORR of 75%, CR rate of 34% 5 year follow up demonstrated durability of response Based on initial activity, subsequent trials have evaluated the role of brentuximab consolidation after autohct, the use of brentuximab pre-transplant to improve disease control, and combining brentuximab with other agents (bendamustine) to augment response and potentially bridge to allogeneic transplant Younes A, Gopal AK, Smith SE et al. J Clin Oncol 2012;30(10)2183-9

Brentuximab Phase I Trial Dose escalation trial in 45 patients (42 with HL) Doses escalated from 0.1 to 3.6 mg/kg Q3weeks 51% with stage 3 or 4 disease Median of 3 prior therapies (range 1-7) 73% received prior autologous transplant Primary outcomes were safety and tolerability/ae Response assessed every 6 weeks Younes A, Gopal AK, Smith SE et al. J Clin Oncol 2012;30(10)2183-9

Safety/MTD Brentuximab Phase I Trial - results 1.8 mg/kg defined as highest dose that did not cause unacceptable toxicity Most common AE included fatigue, pyrexia, diarrhea, nausea, and peripheral neuropathy Dose delays due to AE s occurred in 16 patients Younes A, Gopal AK, Smith SE et al. J Clin Oncol 2012;30(10)2183-9

Brentuximab Phase I Trial Response Results Younes A, Gopal AK, Smith SE et al. J Clin Oncol 2012;30(10)2183-9

Checkpoint Inhibitors in HL Programmed death (PD-1) is an immune checkpoint receptor Reed Sternberg cells frequently overexpress programmed death-ligand 1 (PD-L1) Led to investigation of PD-1 inhibitors for use in HL 2 currently investigated PD-1 inhibitors Nivolumab (NIV) Pembrolizumab (PEM)

Nivolumab in HL 2 landmark trials led to the FDA s approval of nivolumab in the treatment of HL Phase I dose escalation and expansion study evaluating NIV after at least one therapy Phase II evaluating NIV in patients with HL who failed auto HCT with/without BV failure Ansell SM, Lesokhin M, Borrello I et al. N Engl J Med 2015;372(4):311-19 Younes A, Santoro A, Shipp M et al. Lancet Oncol 2016;17:1283-94

N=23 Nivolumab in HL Phase I trial Dose escalation cohort determined 3mg/kg dose for expansion cohort In expansion cohort, patients with rel/ref HL received 3mg/kg at week 1, week 4, then every 2 weeks until progression, CR, or for a max of 2 years Primary objective safety/ae profile Ansell SM, Lesokhin M, Borrello I et al. N Engl J Med 2015;372(4):311-19

Nivolumab Phase I Ansell SM, Lesokhin M, Borrello I et al. N Engl J Med 2015;372(4):311-19

Nivolumab Phase I Results Significant response rates in overall population and in subgroups Ansell SM, Lesokhin M, Borrello I et al. N Engl J Med 2015;372(4):311-19

Nivolumab Phase II Phase II single arm evaluation in 80 patients with HL after failure of AutoHCT and BV Patients were treated with nivolumab 3mg/kg IV Q2 weeks until progression, toxicity, withdrawal of consent, or end of study Primary outcome: % response rate (CR+PR) Younes A, Santoro A, Shipp M et al. Lancet Oncol 2016;17:1283-94

Demographic data Median age 37 years ECOG PS 0-1 Nivolumab Phase II 68% with Stage IV disease Median of 4 prior therapies (49% received >5 lines of prior therapy) 93% received 1 prior auto HCT, 8% with 2+ auto HCT 55% were within 3 months of most recent regimen Younes A, Santoro A, Shipp M et al. Lancet Oncol 2016;17:1283-94

Nivolumab Phase II Results Overall response seen in 53 patients (66.3%) 52/53 had a >50% reduction in target lesion size 9% CR, 58% PR Median time to response was 2.1 months PFS at 6 months was 76.9% Younes A, Santoro A, Shipp M et al. Lancet Oncol 2016;17:1283-94

Nivolumab Phase II Results Safety 79/80 patients reported any AE Drug related grade 3 or 4 AE s included Grade 3 Grade 4 Fatigue Infusion reaction Rash Arthralgia Pyrexia Nausea Elevated lipase neutropenia All available tumor samples tested positive for PD-L1 expression Younes A, Santoro A, Shipp M et al. Lancet Oncol 2016;17:1283-94

Pembrolizumab Humanized monoclonal antibody that blocks interaction between PD-1 and its ligand Dose range in other studies defined at 2-10 mg/kg, leading to determination of a fixed dose of 200mg once every 3 weeks. Image at www.keytruda.com

KEYNOTE-87 Multicenter, single arm phase II study 3 cohorts of patients with rel/ref HL Auto HCT followed by BV Chemoresistant disease (salvage chemo and BV, ineligible for HCT) Auto HCT without subsequent BV Excluded patients with prior allo HCT, those with CNS involvement, and other standard inclusion/exclusion criteria Chen R, Zinzani PL, Fanale MA. J Clin Oncol 2017;35(19)2125-2132

KEYNOTE-87 Study Design and Endpoints Patients received PEM 200mg IV Q3weeks for up to 24 months or until disease progression, toxicity, or investigator decision Patients who attained a CR could stop PEM after minimum of 6 months treatment, as long as at least 2 doses received after documentation of CR Primary endpoint: ORR by blinded independent review Secondary endpoints: ORR by investigator review, CR rate, progression free survival, duration of response, and overall survival Chen R, Zinzani PL, Fanale MA. J Clin Oncol 2017;35(19)2125-2132

Patient Demographics Chen R, Zinzani PL, Fanale MA. J Clin Oncol 2017;35(19)2125-2132

Results Chen R, Zinzani PL, Fanale MA. J Clin Oncol 2017;35(19)2125-2132

Results Median duration of response was not reached in all cohorts At 6 months, overall survival rate=99.5%, progression free survival rate = 72.4% Median OS not reached Chen R, Zinzani PL, Fanale MA. J Clin Oncol 2017;35(19)2125-2132

Results 176 or 177 samples of tumor tissue stained positive for PD-L1 Adverse events Hypothyroidism Pyrexia Neutropenia Dyspnea Diarrhea Grade 3/4 Chen R, Zinzani PL, Fanale MA. J Clin Oncol 2017;35(19)2125-2132

Conclusions The past 5-7 years has seen the first significant improvements to response rates and outcomes for patients with rel/ref HL The role of BV in the post-auto HCT setting is clear, but emerging data will determine if moving therapy pre-transplant or combining with other agents can improve outcomes further The inclusion of checkpoint inhibitors represents the next step in improving the durability of response to therapy for patients with rel/ref HL

Audience Response Question CP is a 27 year old male with a diagnosis of relapsed HL. He initially received induction with ABVD, but relapsed after 9 months. Following re-induction with ICE, CP underwent an autologous HCT, and attained a second CR. At his 6 month follow up, his HL was found to have recurred again. What is the appropriate next treatment option for CP at this time? Single agent therapy with nivolumab Single agent therapy with brentuximab vedotin Single agent therapy with pembrolizumab Salvage therapy with chemotherapy followed by allogeneic transplant