Novel Therapies in Hodgkin Lymphoma Coming to Clinics

Anas Younes, MD

Recent Treatments

Although treatments and cure rates have increased significantly over the past 60 years for patients with Hodgkin lymphoma (HL), it is crucial that practitioners stay up-to-date on research that can affect outcomes for their patients with this uncommon form of cancer. Anas Younes, MD, professor of medicine, chief, lymphoma service, Memorial Sloan Kettering Cancer Center, presented recent data at the 19th Annual International Congress on Hematologic Malignancies (February 20-21, 2015) regarding therapies in clinical trials and others that are now available for use.According to Younes, recent treatment for favorable early-stage HL has involved 2 cycles of ABVD plus 20 Gy of radiation therapy (XRT) and for unfavorable early-stage HL, 4 cycles of ABVD plus 30 Gy of XRT has been the standard. Bulky mediastinal disease has traditionally been treated with 6 cycles of ABVD plus 30 Gy of XRT. Another option included 2 cycles of BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin, procarbazine, and prednisone) and 2 cycles of ABVD plus 30 Gy of XRT.

In the past, a radiation-free approach has included 6 cycles of ABVD with no XRT. Younes maintained that an increasingly PET-guided approach is being used in treatment decisions and that overall survival (OS) and progression-free survival (PFS) have shown some similarities with XRT compared with non-XRT approaches.

The RAPID trial,¹ which looked at patients with stage IA or IIA prognosis, included 3 cycles of ABVD followed by PET. Patients who were PET negative were randomized to no treatment and observation or given involved field radiation therapy (IFRT). Patients who were PET positive were given 1 cycle of ABVD plus IFRT. Overall survival and PFS were similar between the XRT and non-XRT groups (PFS: 94.5% vs 90.8% respectively; hazard ratio [HR] 1.51; P = .23. OS: 97.1% vs 99.5% respectively; HR 0.15; P = .07).

For patients with advanced-stage disease, 6 cycles of ABVD has been the standard of care. If the patient experiences a complete remission or a PET-negative partial response, observation is recommended, according to Younes, but if the patient is PET positive with a residual mass, a biopsy may be performed, and if the biopsy is positive then therapy may be changed to an ifosfamide, carboplatin, vinblastine (ICE) along with ASCT or an equivalent salvage regimen. Some studies have shown positive results when treating patients who are PET positive, who have smaller lesions, without the use of radiation, Younes said; however, traditionally this approach is not used with patients with advanced-stage disease.

Brentuximab vedotin

Patients who relapse after ABVD, may be given a platinum-based regimen. If no response occurs, a gemcitabine-based regimen could then be administered, and if response does not follow this regimen (transplant ineligible), then a third-line treatment could include brentuximab vedotin or an investigational agent, according to Younes.Brentuximab is an antibody drug conjugate (ADC) that combines the anti-CD30 antibody with a cytotoxic tubulin-disrupting agent. The drug is approved by the FDA for the treatment of patients with HL after failure of ASCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not candidates for ASCT. Brentuximab has demonstrated substantial activity and low toxicity in patients with refractory or chemoinsensitive HL.^2,3 “The goal is to achieve a response regardless of the regimen,” Younes said. “And if you achieve a good response, the standard of care is still to take the patient to autologous transplant, and if you do that, you can cure approximately 50% to 60% of patients, regardless of the salvage regimen.”

When a patient fails after autologous transplant, the expected OS is usually about 2.4 months. “That is why these patients represent an urgent unmet medical need. “That is why all of us are involved in trying to develop novel agents to try to prolong the survival of these patients,” Younes said.

In the phase II pivotal trial of brentuximab, 102 patients with relapsed/refractory HL post ASCT benefited and had disease reductions. Seventy-five percent of patients achieved objective response (95% confidence interval [CI], 64.9%, 82.6%), with 34 patients experiencing a complete response (CR) (95% CI, 25.2%, 44.4%).3

Complete responses were also prolonged. At the March 2014 data cutoff, the median duration of response for the 34 patients who achieved a CR had not been reached (95% CI: 20.5 mos, —).4 Therefore the question, according to Younes, is, ‘Should these patients be given immediate transplant, or is there room for observation?’

“Some of these patients are expected to have long-term remission,” Younes said. He prefers the observation approach for these patients who achieve CR. If they progress, he said, “you can retreat again with brentuximab vedotin.”

The current landscape of brentuximab-based therapy may include ABVD/AVD in the frontline, followed by pretransplant brentuximab plus ICE, and brentuximab plus either temsirolimus or mocetinostat in the post-transplant setting. A phase I trial for ABVD/AVD plus brentuximab in the frontline setting included three cohorts in the brentuximab group, studying 0.6, 0.9, or 1.2 mg/kg respectively, and the brentuximab plus an AVD group included a cohort administered 1.2 mg/kg and an expansion cohort (1.2 mg/kg). All patients in the AVD expansion cohort are currently receiving treatment, according to Younes.

Ninety-five percent of patients in the ABVD-plus-brentuximab arm (n=25) and 96% of patients in the AVD-plus-brentuximab group (n=26) achieved CR at the end of therapy. However, 11 patients in the ABVD-plus-brentuximab arm experienced pulmonary toxicities; whereas none of those toxicities were experienced in the AVD-plus-brentuximab group. “This led to a black box warning which indicated that you should not combine bleomycin with brentuximab,” Younes said.

A clinical trial in newly diagnosed patients with advanced-stage non-Hodgkin lymphoma is currently accruing, and will randomize patients to 6 cycles of ABVD or AVD plus brentuximab. According to Younes, results from this study can be expected in two years, and if the results are positive, it could change the standard of care.

Table. Brentuximab Vedotin in Pre-ASCT Therapy

N

%CR

%CR With BV

Reference

ICE

97

60

N/A

Mockowitz C, Blood 2012

BV->ICE

46

80

30%

Moskowitz A, ASH 2013

BV

36

33

33%

Chen R, ASH 2014

BV plus benda

34

82

N/A

LaCasce A, ASH 2014

Benda indicates bendamustine, BV, brentuximab vedotin, CR, complete response, ICE, ifosfamide-carboplatin-vinblastine.

Both concurrent and sequential administrations of brentuximab and ICE are being studied in the pretransplant setting (Table). Moskowitz et al⁵ studied 45 patients who were administered 1.2 mg/kg of BV every week for 3 weeks for two cycles followed by a week of rest. Then patients were restaged. If the patient achieved PET-negative status, stem-cell collection and ASCT followed. If the patients were PET positive (73%), they were administered ICE — 69% of these patients achieved PET-negative status and proceeded to stem-cell collection and ASCT.

“Another approach is to keep the same salvage regimen and give brentuximab in the adjuvant or management setting after ASCT in those patients who you think are at high risk of relapse,” Younes said.

Anti-PD-1 Inhibitors

Nivolumab

The ATHERA double-blind, placebo-controlled clinical trial⁶ involved salvage therapy in patients who were refractory to frontline treatment, had relapsed <12 months on frontline therapy, or who relapsed ≥12 months with extranodal involvement. If stable PR or CR was achieved, patients then had ASCT. After ASCT, patients were randomly assigned to receive either brentuximab (16 doses) or placebo. Median PFS was 43% in the patients who received brentuximab compared with 24% in patients who received placebo.Nivolumab is a fully-human IgG4 monoclonal PD-1—blocking antibody that increases the effect of anti-tumor T-cell activity, and has demonstrated clinical efficacy in several solid tumors.⁷ First-analysis results of a phase I study⁷ of nivolumab in patients with relapsed or refractory HL were presented at the 2014 ASH Meeting and Exposition.

Twenty-three patients with HL received nivolumab 3 mg/kg every 2 weeks until confirmed tumor progression or excessive toxicity. Safety was the primary endpoint of the study. Patients were heavily pretreated; 78% had prior brentuximab treatment.

The objective response rate (ORR) was 87% (20/23), with 4 patients (17%) achieving CR, and 16 (70%) obtaining PR. The remaining 3 patients (13%) had stable disease (SD). All 23 patients experienced a reduction in tumor burden.

Drug-related adverse events (AEs) of any grade occurred in 78% of patients, the most common of which were rash (22%), decreased platelet count (17%), diarrhea, nausea, pruritus, fatigue, and pyrexia (each at 13%). Drug-related grade 3/4 AEs occurred in 22% of patients. Three patients experienced 1 serious AE each (grade 3 myelodysplastic syndrome, grade 3 pancreatitis, and grade 2 lymph node pain).

Pembrolizumab

Based on these results, the FDA granted nivolumab breakthrough status in relapsed, classical HL and a large, multinational, phase II trial of this therapy is currently under way.Pembrolizumab, another PD-1—blocking agent, has shown comparable results in a cohort of an ongoing, multicenter, open-label phase 1b clinical trial⁸ in hematologic malignancies.

Patients are being treated with pembrolizumab 10 mg/kg, intravenous, every 2 weeks until confirmed tumor progression, excessive toxicity, or completion of 2 years of therapy. The main endpoints of this study are safety, tolerability, and complete remission rate.

Thus far, there have been no serious AEs, and only 1 patient experienced grade 3-5 AEs (grade 3 pain and grade 3 joint swelling). Overall, 10 patients experienced ≥1 AE. The most common drug-related AEs were grade 1-2 respiratory events (20%) and thyroid disorders (20%). One patient discontinued treatment because of grade 2 pneumonitis, and 3 patients ended therapy after progressive disease.

Conclusion

Based on investigator assessment, 3 patients (20%) had a CR at 12 weeks. Five additional patients (33%) had partial remission as best overall response, for an overall response rate of 53%. Four patients (27%) experienced PD, and all 4 experienced a decrease in their overall tumor burden.Younes said it can be expected that these anti-PD-1 agents will be combined with brentuximab and other combination strategies will be used in clinics in the near future. Although brentuximab changed the standard of care only a couple of years ago, Younes maintained, “as the field is rapidly changing with the introduction of PD-1 targeted agents and the incorporation of brentuximab vedotin with multiple treatment spaces in the frontline; in pretransplant and post-transplant setting, in the future, I am confident that the standard of care will change again in the next few years.”

References

1. Radford J, Barrington S, Counsell N, et al: Involved field radiotherapy versus no further treatment in patients with clinical stages IA and IIA Hodgkin lymphoma and a ‘negative’ PET scan after 3 cycles ABVD: Results of the UK NCRI RAPID trial. 2012 Annual Meeting of ASH. Abstract 547. Presented December 10, 2012.
2. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; November 2014.
3. 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—9
4. Gopal AK, Chen R, Smith SE. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood: 125 (8). http://www.bloodjournal.org/content/125/8/1236?sso-checked=true. Accessed February 21, 2014.
5. Moskowitz AJ, Schöder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosfamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncology. Published online first. DOI: http://dx.doi.org/10.1016/S1470-2045(15)70013-6. Accessed February 21, 2015.
6. Moskowitz C, Nadamanee A, Masszi T, et al. The Aethera Trial: Results of a randomized, double-blind, placebo-controlled phase 3 Study of brentuximab vedotin in the treatment of patients at risk of progression following autologous stem cell transplant for Hodgkin lymphoma. Presented at the 56th ASH Annual Meeting and Exposition, San Francisco, CA; December 8, 2014. Abstract 673.
7. Armand P, Ansell SM, Lesokhin AM, et al. Nivolumab in patients with relapsed or refractory Hodgkin lymphoma - preliminary safety, efficacy and biomarker results of a phase I study. Presented at the 56th ASH Annual Meeting and Exposition, San Francisco, CA; December 8, 2014. Abstract 289.
8. Moskowitz CG, Ribrag V, Michot JM, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). Presented at the 56th ASH Annual Meeting and Exposition, San Francisco, CA; December 8, 2014. Abstract 290.

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