“Pembrolizumab ... will be an important component of future treatment for patients with Hodgkin lymphoma.”

— Stephen M. Ansell, MD, PhD

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AN EFFECTIVE antitumor immune response relies on cytotoxic T cells that are activated and able to target the malignant clone. As T cells become activated, they upregulate suppressive receptors including programmed cell death protein 1 (PD-1). Upregulation of inhibitory signals is important to prevent overactivity of the immune system and subsequent autoimmunity. In cancer, this process is used by malignant cells as a mechanism to evade the immune system. In Hodgkin lymphoma particularly, there is substantial upregulation of the ligands for PD-1, including programmed cell death ligand 1 (PD-L1) and PD-L2.^1-3 

In recent work, genetic alterations at chromosome 9p24.1 have shown that copy number gain or genetic alterations account for high expression of PD-L1 and PD-L2 on Reed-Sternberg cells. It has also been found that high expression of PD-L1 and PD-L2 is seen across the board in all classical Hodgkin lymphoma patients, is present at diagnosis, and is associated with patient outcome. Clearly, the interactions between PD-L1 and PD-L2 and the receptor PD-1 are critically important in Hodgkin lymphoma, and targeting this signaling pathway has been shown to be an effective therapeutic approach. 

Clinical Trials 

IN INITIAL PHASE I clinical trials in Hodgkin lymphoma, PD-1 blockade showed very high response rates with both pembrolizumab (Keytruda) and nivolumab (Opdivo).4,5 Overall response rates of 65% to 87% were seen, suggesting that this is a highly effective therapeutic strategy. 

As reviewed in this issue of The ASCO Post, recent data presented in the Journal of Clinical Oncology by Chen and colleagues now detail the phase II experience with pembrolizumab in patients with relapsed or refractory classical Hodgkin lymphoma.⁶ The results from this trial are very encouraging in that they confirm the high response rates seen in initial studies and also confirm that the responses are durable and that patients can continue to receive this therapy over an extended period. The findings in the study supported the recent U.S. Food and Drug Administration approval of pembrolizumab in the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma or those who have relapsed after at least three prior lines of therapy. 

In this trial, three cohorts of patients were evaluated and included those who had received both an autologous stem cell transplant and previous brentuximab vedotin (Adcetris), those who had received salvage chemotherapy and brentuximab vedotin but were ineligible for an autologous transplant, and those who had undergone a transplant but had not received brentuximab vedotin. The outcome in each of these cohorts was similar, and the 69% overall response rate for all patients was similar to that seen in the phase I experience. 

Particularly encouraging was the fact that prior therapy and resistance to previous treatment did not seem to play a significant role in the efficacy of pembrolizumab therapy. Response rates remained high in patients whose disease had been refractory to multiple prior lines of therapy and were similar to patients who had responded and subsequently experienced progression with previous treatment. Response rates also remained high regardless of whether patients had received previous brentuximab vedotin. 

A median duration of response was not reached in all patients or in any of the three cohorts, suggesting not only that response rates were high, but responses are very durable. Also of considerable importance, patients could receive treatment for an extended period; although some toxicities were seen, the median number of cycles was 13. The side effects reported were those commonly seen with immune checkpoint therapy and often the result of immune system activation. 

Conclusions 

OVERALL, THE RESULTS seen in this phase II trial confirm the initial promise of PD-1 blockade. Excellent results are seen in patients with relapsed or refractory disease regardless of prior treatment, and the safety profile appears manageable. Pembrolizumab, therefore, will be an important component of future treatment for patients with Hodgkin lymphoma, and randomized trials are currently underway to test the drug against standard therapy as well as to incorporate PD-1 blockade into earlier lines of treatment. ■

DISCLOSURE: Dr. Ansell has received institutional research funding from Bristol-Myers Squibb, Merck, and Seattle Genetics.

REFERENCES 

1. Green MR, Monti S, Rodig SJ, et al: Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116:3268-3277, 2010. 

2. Roemer MG, Advani RH, Ligon AH, et al: PDL1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol 34:2690-2697, 2016. 

3. Green MR, Rodig S, Juszczynski P, et al: Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and post-transplant lymphoproliferative disorders: Implications for targeted therapy. Clin Cancer Res 18:1611-1618, 2012. 

4. Armand P, Shipp MA, Ribrag V, et al: Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 34:3733-3739, 2016. 

5. Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311-319, 2015. 

6. Chen R, Zinzani PL, Fanale MA, et al: Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. April 25, 2017 (early release online).