Update on the role of brentuximab vedotin in classical Hodgkin lymphoma

Abstract

Brentuximab vedotin (BV) is an effective and well-tolerated treatment for patients with classical Hodgkin lymphoma (HL). It was initially approved by the US FDA for the treatment of HL after failure of autologous hematopoietic stem cell transplant (autoHSCT) or after failure of at least two prior lines of multiagent chemotherapy in patients who are not transplant candidates, and then subsequently, as consolidation therapy after autoHSCT in patients who are at high risk for relapse. However, the role of BV in the treatment of HL is evolving. BV has shown promising efficacy as a salvage treatment in the second-line setting prior to autoHSCT. Most recently, the ECHELON-1 trial demonstrated that BV combined with AVD for the treatment of newly diagnosed advanced stage HL improved modified progression-free survival (mPFS) compared with standard ABVD. Based on these results, the US FDA has approved BV as part of the initial treatment of advanced stage HL. With the approval of BV as front-line therapy, depending on how widely the use of BV plus AVD is adopted, the role of BV in the treatment of patients with relapsed or refractory (rel/ref) HL may need to be redefined. BV retreatment can be effective, and studies of rational BV-based combination regimens may help to improve response rates and overcome BV resistance. Furthermore, BV has been demonstrated to be effective in the initial treatment of elderly or unfit patients, and ongoing studies are evaluating the addition of BV to initial chemotherapy in patients with early stage HL.

Introduction

The development of curative treatment with combination chemotherapy for Hodgkin lymphoma (HL) in the 1960s is thought of as one of the greatest achievements in oncology in the last 50 years.¹ In the current treatment era, 75–90% of patients diagnosed with HL are cured.^2–6 Over the years, considerable effort has been devoted to modifying the treatment of HL in order to decrease the acute and long-term toxicities of therapy, while maintaining the high cure rate. These efforts include the introduction of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine), more targeted radiotherapy, omission of radiation in low risk early stage HL, and the use of positron emission tomography (PET) to risk stratify patients who may benefit from de-escalated or more intensive treatment.^2,7–9 Most recently, the use of immunotherapy marks a new era in the treatment of HL. In 2011, brentuximab vedotin (BV), an antibody-drug conjugate (ADC) that targets CD30 on the surface of Reed–Sternberg cells, became the first United States Food and Drug Administration (US FDA)-approved immunotherapy for the treatment of HL. In 2016 and 2017, the anti-programmed cell death 1 (PD1) antibodies, nivolumab and pembrolizumab, were also approved for the treatment of relapsed or refractory (rel/ref) HL. After initial approval, subsequent studies have studied the use of BV earlier in a patient’s course of treatment, with the ECHELON-1 trial demonstrating an improved mPFS with BV added to front-line chemotherapy compared with standard ABVD in patients with stage III or IV HL. In this article, we review the evolving role of BV in the current era of HL treatment.

Hodgkin lymphoma

HL is a lymphoproliferative disorder characterized by the Hodgkin Reed–Sternberg tumor cell, a rare binucleated cell, within an infiltrate of inflammatory cells including T lymphocytes, eosinophils, neutrophils, macrophages, plasma cells, and fibroblasts. It accounts for 10% of all lymphomas and is the most common lymphoma among adolescents and young adults.¹⁰ Hodgkin Reed–Sternberg cells express CD30, a transmembrane glycoprotein that facilitates both cellular proliferation and survival, as well as apoptosis and other antiproliferative behaviors.¹¹ Initial studies using anti-CD30 monoclonal antibodies alone showed a favorable toxicity profile, but only modest antitumor activity.¹² To improve upon the antitumor activity of the CD30-specific antibody, an ADC was created.

Initial approval of BV for the treatment of relapsed or refractory HL

BV is a chimeric CD30-specific immunoglobulin (Ig)G1 antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE), by an enzyme-cleavable linker. Upon the binding of BV to CD30 on the Hodgkin Reed–Sternberg cell, the ADC is internalized and lysosomal enzymes cleave the linker allowing for the release of MMAE inside the cell. MMAE then binds to tubulin, resulting in cell cycle arrest and subsequent apoptosis of CD30-expressing cells.^13,14 In an initial phase I, dose-escalation study of 45 patients with rel/ref CD30 positive lymphoma, 93% with HL and 7% with anaplastic large-cell lymphoma (ALCL), 50% of patients showed an objective response (OR). A total of 80% of responses occurred within the first 2.8 months (or four cycles) and responses lasted a median of 9.6 months. The maximum tolerated dose of BV was 1.8 mg/kg given intravenously every 3 weeks. The most common adverse events (mostly grade 1 or 2) were fatigue, pyrexia, gastrointestinal symptoms, neutropenia, and peripheral neuropathy. The reported dose-limiting toxicities were grade 4 thrombocytopenia, grade 3 hyperglycemia and febrile neutropenia.¹⁵ In another phase I trial, BV was given weekly for 3 weeks, followed by a week break to 38 patients with HL and 5 patients with ALCL. Overall, 54% of the patients with HL had an OR and dose-limiting toxicities in this study included grade 3 gastrointestinal symptoms and grade 4 hyperglycemia.¹⁶

These promising results prompted a multicenter, open label, pivotal phase II study of BV for the treatment of rel/ref HL. In this study, 102 patients with were treated with BV at 1.8 mg/kg every 3 weeks for a maximum of 16 cycles. Patients had received a median of 3.5 prior regimens, and all patients had received prior autologous hematopoietic stem cell transplant (autoHSCT). A total of 75% of patients responded, including 35% who had a complete response (CR) (Table 1).¹⁷ Based on these results, in 2011 the US FDA granted BV accelerated approval for the treatment of rel/ref HL after failure of at least two prior lines of multiagent chemotherapy in patients who are not transplant candidates or patients with HL who progressed after autoHSCT. Long-term follow up showed durable remissions, with 41% of patients still alive at 5 years. Additionally, of the patients who achieved a CR, the 5-year overall survival (OS) and progression-free survival (PFS) were 64% and 52% respectively.^18,19

Table 1.

Initial phase I and II studies of single-agent BV.

Regimen	Phase	Number of patients	Average number of prior lines of therapy	Patients with prior ASCT (%)	ORR (%)	CR (%)	Median PFS (months)	Reference
BV 1.8 mg/kg given every 3 weeks	1	42	3	73	50	35	9.7	15
BV 1.2 mg/kg given weekly	1	44 (86% with HL, 11% with PTCL)	3	68	59	34	7.2	16
BV 1.8 mg/kg given every 3 weeks	2	102	3.5	100	75	34	5.6	17

ASCT, autologous stem cell transplantation; BV, brentuximab vedotin; CR, complete response; HL, Hodgkin lymphoma; ORR, overall response rate; PFS, progression-free survival; PTCL, peripheral T-cell lymphoma.

BV was also studied as consolidation therapy after autoHSCT. Although most HL patients are cured with multiagent chemotherapy, up to 20–25% will relapse after or be refractory to initial therapy. The standard of care for these patients is high dose chemotherapy followed by autoHSCT.^4,5 Despite a 50% durable remission rate, about 50% will still relapse after autoHSCT.^20–22 Since BV had been shown to be safe and tolerable after autoHSCT, the AETHERA trial examined the use of BV as consolidation therapy to improve PFS post-autoHSCT. In this trial, patients with high risk features, including primary refractory disease, relapse within 12 months of initial therapy, or extranodal involvement, were given BV 1.8 mg/kg for 16 cycles following autoHSCT. For those who received BV maintenance, median PFS was 42.9 months compared with 24.1 months for those who received placebo. The estimated 2-year PFS in patients who received BV consolidation was 65% compared with 45% in patients who received placebo.²³ As a result, the US FDA granted BV additional approval as consolidation therapy after autoHSCT in patients who are at high risk for relapse.

BV-based second-line therapy in HL patients prior to autoHSCT

The effectiveness and tolerability of BV in patients with rel/ref HL after autoHSCT prompted efforts to utilize BV in the second-line setting as first salvage therapy prior to autoHSCT. In one study, single-agent BV dosed at 1.2 mg/kg was given on days 1, 8, and 15 for two 28-day cycles followed by a PET scan. Those who were PET-negative proceeded to autoHSCT. Those who were PET-positive received two cycles of augmented ICE (ifosfamide, carboplatin and etoposide) chemotherapy followed by autoHSCT. Of the 65 patients enrolled, 64 patients ultimately proceed to transplant. A total of 28% were PET-negative and proceeded to autoHSCT after the two cycles of BV. Overall, 69% were PET-positive (1 patient had dropped out) and received two cycles of augmented ICE followed by autoHSCT. The 3-year OS and event-free survival were 95% and 82% respectively (Table 2).²⁴

Table 2.

Single-agent and combination BV as second-line therapy in HL patients prior to autoHSCT.

Regimen	Phase	Number of patients	Average number of prior lines of therapy	Patients with prior ASCT (%)	ORR (%)	CR (%)	Reference
Sequential BV -ICE	2	46	1	0	96	75	24
BV	2	56	1	0	75	43	25
BV-nivolumab	1/2	62	1	0	82	61	26
BV-bendamustine	1/2	93	1	0	93	74	27
BV-ESHAP	1/2	66	1	0	96	70	28
BV-ICE	1/2	16	1	0	94	69	29
BV-DHAP	1/2	12	1	0	100	100	30

ASCT, autologous stem cell transplantation; BV, brentuximab vedotin; CR, complete response; DHAP, dexamethasone, AraC and cisplatin; ESHAP, etoposide, solumedrol, high dose AraC, and cisplatin; HL, Hodgkin lymphoma; ICE, ifosfamide, carboplatin, and etoposide; ORR, overall response rate.

In another phase II study of patients with HL who were rel/ref after initial therapy, 56 patients were treated with BV as first salvage. Patients in CR after the first two cycles of 1.8 mg/kg BV administered in 3-week cycles were given an additional two cycles of standard dose BV and then proceeded to autoHSCT. Overall, two cohorts of patients were enrolled. In one cohort, patients who had stable disease (SD) or partial response (PR) after the two cycles of BV were eligible to continue standard dose BV for two additional cycles and in a second cohort, patients in SD or PR were given an escalated dose of BV at 2.4 mg/kg for two additional cycles. Patients not in CR after four cycles of standard dose or escalated dose BV were eligible to receive alternative salvage therapy or proceed with autoHSCT at the discretion of the investigator. Among the 56 evaluable patients, the overall response rate (ORR) was 75% and 43% achieved a CR. BV escalation was well tolerated but did not increase conversion to CR, and is not recommended. Overall, 88% of patients proceeded to autoHSCT with half of patients proceeding to autoHSCT without additional salvage chemotherapy. The two-year PFS and OS in patients who underwent autoHSCT were 67% and 93%, respectively.²⁵

Although single-agent BV shows an OR rate of >70%, the achievement of CR prior to autoHSCT is the strongest prognostic factor of outcome, therefore, BV-based combination salvage regimens have been evaluated to improve the CR rate and durability of responses. One study looked at the combination of BV with nivolumab in 62 patients with HL who were relapsed after or refractory to front-line therapy. Patients received BV and nivolumab in 21-day cycles for four cycles, with BV on day 1 and nivolumab on day 8 of cycle 1 and both drugs administered on day 1 in subsequent cycles. Overall, 82% of patients had an OR, including 61% who achieved a CR. A total of 87% of patients proceed to autoHSCT, with 68% proceeding directly to autoHSCT without any need for alternative salvage therapy. At the 6 months follow up, the median PFS had not been reached for these patients. Aside from a high rate of infusion-related reactions (44%), the regimen was well tolerated with <10% of patients requiring systemic steroids for the treatment of immune-related adverse events.²⁶

In another study, the combination of bendamustine with BV was given to 55 patients with ref/rel HL after front-line therapy. These patients received the standard dose of BV on day 1 with bendamustine 90 mg/m² on days 1 and 2 every 3 weeks for up to six cycles. A total of 93% of patients had an OR including 74% who had a CR. Of the 93% of patients who were able to undergo autoHSCT, 80% were still alive and without disease at 1 year.²⁷

BV has also been studied as second-line therapy in combination with multidrug chemotherapy in rel/ref HL patients prior to autoHSCT. The regimens evaluated include BV combined with ESHAP (etoposide, solumedrol, high dose AraC, and cisplatin), ICE, or DHAP (dexamethasone, AraC and cisplatin). A phase I/II dose-escalation study of BV with ESHAP is being conducted by GELTAMO and has enrolled 66 patients and 61 were able to proceed to autoHSCT after either the first, second, or third cycle of BV with ESHAP. Overall, 96% of patients responded, including a CR in 70%. The 1-year PFS after autoHSCT was 87%. There were two deaths, one due to non-neutropenic sepsis and one due to a pulmonary embolus. Grade 3/4 adverse events were noted in 22 patients including neutropenia (18 patients), thrombocytopenia (12 patients), and anemia (5 patients).²⁸ The preliminary results of a study evaluating BV administered concomitantly with ICE have been presented. Patients received BV on days 1 and 8, ifosfamide, mesna, and carboplatin on day 2, and etoposide on days 1 through 3. BV was given at a dose of 1.2–1.5 mg/kg based on a standard 3 + 3 dose-escalation design. Preliminary results of the16 patients enrolled thus far demonstrated an OR in 94% and CR in 88% of patients by investigator review (69% CR by central independent review). A total of 75% of patients proceeded directly to autoHSCT.²⁹ Preliminary results of a phase I dose-escalation trial of BV in combination with DHAP in 12 patients with rel/ref HL showed a CR rate of 100% with a median follow up of 15.4 months.³⁰

Studies of BV in the initial treatment of advanced stage HL

Based on the promising efficacy and tolerability of BV in patients with rel/ref HL, BV was evaluated in the front-line setting in patients with previously untreated HL. A phase I trial that included 51 patients with newly diagnosed stage IIA bulky or stage IIB–IV HL compared BV added to standard ABVD (A-ABVD) and BV added to AVD without bleomycin (A-AVD). The CR rate was 95% in patients who received A-ABVD compared with 96% of patients who received A-AVD. However, in the A-ABVD cohort there was an unacceptably high rate of adverse pulmonary events (44%); therefore, it is recommended that BV not be given in combination with bleomycin.³¹ A 5-year follow up of this study showed a failure-free survival of 92% and OS of 100%.³² Based on these findings, the ECHELON-1 trial, a randomized phase III trial of front-line A-AVD compared with non-PET-adapted ABVD was conducted in patients with previously untreated advanced stage HL. The study met its primary endpoint, the 2-year modified PFS (with events defined as death, disease progression, or lack of CR at the end of therapy followed by administration of a subsequent antilymphoma therapy) was 82.1% in the A-AVD group versus 77.2% in the ABVD group. In the intent-to-treat population, 73% of patients in the A-AVD arm were in CR compared with 70% in the ABVD arm. Using the Deauville score (DS), 86% of patients in the A-AVD arm had a DS of 1–3 at the end of front-line therapy compared with 82% in the ABVD arm. In secondary analyses, the subgroups that appeared to particularly benefit from the inclusion of BV into front-line therapy were younger patients, patients with more than one site of extranodal involvement, and those with stage IV disease. Patients in either arm who were switched to an alternative front-line regimen prior to the completion of the randomized regimen without evidence of disease progression were not considered to have a mPFS event, but this was not commonly done. Notable adverse events included neutropenia in 58% of the patients receiving A-AVD and in 45% of those receiving ABVD. Febrile neutropenia occurred in 21% of those treated with A-AVD, prompting the common use of prophylactic granulocyte colony-stimulating factor (GCSF). In those who were then given prophylactic GCSF, the rate of febrile neutropenia decreased to 11%. Peripheral neuropathy occurred in 67% of patients in the A-AVD group and in 43% of patients in the ABVD group. Grade 2 and 3 peripheral neuropathy occurred in 20% and 11% in the A-AVD group and in 9% and 2% of the ABVD group respectively. Of those who developed peripheral neuropathy in the A-AVD group, 67% had resolution of symptoms and 24% had improvement by at least one grade at the time of last follow up. At the time of last follow up, 92% of ongoing peripheral neuropathy was grade 1 or 2. Pulmonary toxicity of grade 3 or higher was reported in <1% of patients receiving A-AVD and in 3% of those receiving ABVD.³³

BV has also been studied in combination with modified escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for initial treatment of advances stage HL. In this phase II study, 104 patients with newly diagnosed advanced stage HL were randomized to either BrECAPP (BV, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) or BrECADD (BV, etoposide, doxorubicin, cyclophosphamide, vincristine, dacarbazine, and dexamethasone). The co-primary endpoints were CR to chemotherapy and complete remission status as their final treatment outcome. A total of 86% of patients who received BrECAPP achieved a CR after treatment with 94% achieving a complete remission at the end of treatment. In patients who received BrECADD, 88% achieved both a CR after treatment and complete remission at the end of treatment.³⁴ BreCADD was associated with a more favorable toxicity profile (i.e. fewer grade 3–4 organ toxicities) and is being evaluated against eBEACPP in the randomized phase III HD21 trial [ClinicalTrials.gov identifier: NCT02661503].

Studies of BV as front-line therapy in early stage HL

The addition of BV to front-line treatment has also been studied in patients with early stage HL. The current standard of care for early stage HL is 2–4 cycles of ABVD with radiation or six cycles of ABVD without radiation depending upon the stage and the presence of favorable or unfavorable disease characteristics. With combined modality therapy, the prognosis of HL is favorable, with survival generally exceeding 90%.^3,8 These outcomes are obtained at the cost of long-term sequelae of radiation; therefore, studies such as the RAPID trial have studied the omission of radiotherapy using a PET-adapted approach. Indeed, the RAPID trial demonstrated that in early stage HL, excellent outcomes can still be obtained despite the omission of radiotherapy in patients with a negative interim PET.³⁵ A phase II multicenter study evaluated the addition of BV to initial therapy and omission of radiation in patients with nonbulky stage I and II HL. Patients received BV 1.2 mg/kg on days 1 and 15 followed by PET-CT. Patients then received 4–6 cycles of BV-AVD pending the interim PET-CT results. A total of 36 patients were enrolled, including 62% with favorable and 38% with unfavorable features. After two doses of lead-in BV monotherapy, 53% of patients were in a CR, and after two cycles of BV-AVD, 97% of patients achieved CR. At the end of treatment 88% of all patients were in CR, two patients had progressive disease and two patients discontinued therapy due to toxicity. At a median follow up of 14 months, the PFS was 90% and OS was 97%. Overall, 38% of patients required a dose reduction of BV, primarily for peripheral neuropathy.³⁶

Another study evaluated the addition of BV consolidation after initial chemotherapy and omission of radiation in patients with previously untreated early stage, nonbulky HL. Patients received ABVD for 2–6 cycles based on clinical characteristics and interim PET-CT results followed by consolidation BV given at 1.8 mg/kg every 3 weeks for 6 cycles. The primary goal of the study was to assess the proportion of patients who were PET-negative after consolidation BV. A total of 41 patients were enrolled; 45% had unfavorable disease and 40 were evaluable for response (one patient died due to sepsis and hepatic failure). Among evaluable patients, 72.5% were PET-negative (DS 1-2) after two cycles of ABVD and 95% of patients were PET-negative after six cycles of BV. The 2-year estimated PFS was 92% and 2-year OS was 97%. The 2-year PFS was 100% in the 37 patients who were PET-negative at the end of BV consolidation.³⁷

In another study, previously untreated, early stage unfavorable HL patients were treated with BV 1.2 mg/kg with AVD every 2 weeks for four cycles and then patients with a negative PET scan received involved site radiation therapy (ISRT). Patients treated in an initial cohort received 30 Gy ISRT and then a decreased dose of radiation to 20 Gy was studied in a second cohort. In the 30 Gy cohort, 30 patients were enrolled, 29 patients completed four cycles of BV-AVD, and 25 patients completed BV-AVD plus 30 Gy of ISRT. A total of 90% achieved a negative PET-CT after two cycles of study therapy and 93% achieved a negative PET-CT after four cycles of BV-AVD. All 25 patients who completed the combined modality therapy had a CR at the end of treatment. The 1-year PFS was 93% at a median follow up of 18.8 months. There were no unexpected toxicities, and no significant pulmonary adverse effects. Results were similar in the 20 Gy cohort, with 90% and 93% of the 29 enrolled patients achieving a PET-negative CR after two and four cycles of BV-AVD, respectively. Overall, 28 patients completed BV-AVD + 20 Gy ISRT and all had CR with no relapses having occurred at the time of interim analysis presentation.^38,39

BV as front-line therapy in elderly or frail patients, or patients with multiple comorbidities

BV has also been studied as a front-line option for HL patients who are considered elderly or frail, or have comorbidities that may limit the use of chemotherapy. Overall, 20% of all HL patients are over the age of 60 years of age and have inferior outcomes when compared with younger patients. In a prior study comparing ABVD with Stanford V, patients aged 60 years or above had poorer FFS and OS when compared with younger patients irrespective of treatment regimen.⁴⁰ A study of BV monotherapy in patients with HL over the age of 60 resulted in a ORR of 92% and a CR rate of 73%. All patients achieved at least SD. At the time of analysis, the median duration of response was 9.1 months and the median PFS was 10.5 months. Peripheral sensory neuropathy occurred in 78% of patients, including 30% with grade 3 neuropathy.⁴¹

In the BREVITY study, HL patients who were deemed unsuitable for chemotherapy due to age, frailty, or comorbidities, were given four doses of BV 1.8 mg/kg. Patients with OR to BV based on PET-CT continued to receive BV for up to 16 cycles. Patients either had bulky disease of any stage, stage II to IV disease with cardiorespiratory compromise, or were 60 years or older with Eastern Cooperative Oncology Group (ECOG) performance status of three or higher and were considered unfit for standard chemotherapy. A total of 38 patients were enrolled with a median age of 76 years. Overall, 31 patients were evaluable for response, and patients received a median of four cycles of BV. Median PFS in these patients was 7.4 months and 26% had a CR. Overall, 84% of patients responded. Dose reductions were needed in about half of the patients due to toxicity, most commonly infection, myelosuppression, or neuropathy. About one third of patients stopped therapy due to adverse events.⁴²

BV combination regimens are also being studied in previously untreated elderly patients. One study looked at both the combination of BV given with dacarbazine (DTIC) and the combination of BV given with bendamustine in previously untreated HL patients over the age of 60. A total of 22 patients received standard dose BV combined with DTIC at 375 mg/m² for up to six cycles (BV monotherapy could be continued after completion of combined therapy). The ORR was 100% with a CR rate of 62%. The median PFS was 17.9 months. It was planned for 30 patients to receive standard dose BV with bendamustine 90 or 70 mg/m² for up to six cycles, however serious adverse events were noted in 65% of patients, including two deaths, leading to the discontinuation of enrollment into the bendamustine cohort. The ORR to BV plus bendamustine was 100% with a CR rate of 88%. All patients experienced a treatment-emergent adverse event with 90% having a grade 3–4 adverse event. Diarrhea, nausea, and fatigue were the most common treatment-emergent adverse events overall. The most common grade 3–4 treatment-emergent adverse events were fatigue, peripheral neuropathy, urinary tract infection, and hypotension. Although the median PFS and OS were not reached, this regimen was deemed not to be tolerable for this patient population given the high rate of serious adverse events.⁴³ The HALO study also examined BV given in combination with bendamustine in previously untreated elderly patients with advanced HL. These patients were given BV 1.2 mg/kg on day 1 and bendamustine 90 mg/m² on day 1 and day 2 every 3 weeks for up to six cycles. A total of 60 patients were enrolled in the study with a median age of 77.3 years. The OR rate was 78%. Serious adverse events included 14% with grade 3 lung infection and 25% with neutropenia.^44,45 BV combined with nivolumab is also being studied in previously untreated HL patients who are either 60 years of age or older or considered unsuitable for standard chemotherapy [ClinicalTrials.gov identifier: NCT02758717].

Sequential BV with ABVD has also been assessed in elderly HL patients. In a phase II study, 48 patients over the age of 60 with previously untreated stage III or IV HL were given two cycles of single-agent BV (1.8 mg/kg every 3 weeks) followed by six cycles of AVD. The OR rate was 88% with 81% achieving a CR. PFS was 85% and OS was 94% at a median follow up of 2 years. Overall, 42% of patients experienced a serious adverse event, with the most common being neutropenia or infection (Table 3).⁴⁶

Table 3.

Novel BV combination regimens in heavily pretreated, rel/ref HL patients.

Regimen	Phase	Number of patients	Average number of prior lines of therapy	Patients with prior ASCT (%)	ORR (%)	CR (%)	Reference
BV-ibrutinib	2	39			69	46	49
BV-bendamustine	1/2	65 (98% HL, 2% ALCL)			78		50
BV-ipilimumab	1	12	4	67	67	42	51
BV-nivolumab	1	12	4	67	67	42	52

ALCL, anaplastic large-cell lymphoma; ASCT, autologous stem cell transplantation; BV, brentuximab vedotin; CR, complete response; HL, Hodgkin lymphoma; ORR, overall response rate; rel/ref, relapsed or refractory.

The current role of BV in HL and future directions

With the US FDA approval of BV (with AVD) for the initial treatment of advanced stage HL in March 2018, the role of BV in the treatment of HL is being redefined. One critical question is whether BV-AVD should be the new standard regimen for all patients with advanced stage HL. The ECHELON-1 trial met its primary endpoint, with a statistically significant mPFS improvement over standard ABVD. However, one important limitation of the study was the lack of PET-adapted therapy in the control arm, which might have impacted the mPFS in the control arm and thus whether BV-AVD was truly significantly better than the current standard. Also, in the time that the ECHELON-1 was conducted, the RATHL study demonstrated the non-inferiority of omitting bleomycin after two cycles of ABVD in PET-negative patients, which minimizes the toxicity of the standard approach. Importantly, there was no OS advantage conferred by the addition of BV to initial therapy, but the follow up is not long enough to truly assess this at the present time. One important difference between BV-AVD and a standard approach was the significant neutropenia observed in the BV-AVD arm that necessitated the use of prophylactic GCSF. The subgroup analyses offer some clues about who might benefit most from the BV-AVD approach, as it appeared that BV-AVD was especially advantageous in younger and higher risk patients (e.g. stage IV disease and multiple extranodal sites). However, it is important to remember that the study was not powered to show differences in these subgroups. In the end, treating physicians must balance the incremental disease-free survival benefit conferred by front-line incorporation of BV with the increased toxicity that has been observed. On a different note, the requirement for growth factors and the incorporation of an expensive drug like BV may potentially increase the financial burden of initial treatment of advanced stage HL, but formal cost-effectiveness analyses will weigh these costs against the potentially reduced costs of subsequent therapies needed for disease progression when using a BV-AVD approach. At the present time, BV-AVD is approved for use in front-line advanced stage HL and is an important option to consider in any patient with advanced stage HL, but particularly in younger or higher risk patients.

Currently, in patients with early stage disease who did not receive BV during initial therapy who now have rel/ref HL, BV-based therapy clearly still has a role. Similarly, in patients who have advanced stage disease at diagnosis who do not receive BV, the traditional roles of BV for use as an effective agent for refractory disease or post-autoHSCT relapse, or as post-autoHSCT maintenance are still applicable. However, in advanced stage HL patients who ultimately have rel/ref disease after initial treatment with BV-AVD, the role of BV may need to be redefined as the role of subsequent BV is unclear. There is evidence that retreatment with BV in patients with HL who were previously BV-sensitive is effective. In 21 patients with HL who had previously experienced a CR or PR with BV and had a median of 11.4 months since last BV therapy, the OR rate to BV retreatment was 60%, and 30% of patients had a CR. Of the patients with a CR, the duration of response lasted an average of 6 months.⁴⁷ Aside from retreatment with single-agent BV, strategies to counter or overcome BV resistance could be utilized and are currently being studied. There is evidence that resistance to BV in HL can be mediated by increased expression of multidrug resistance 1 (MDR1) drug exporter by the Hodgkin Reed–Sternberg cells, which allows MDR1 to actively pump MMAE out of the cells and rescue the cell from cell cycle arrest and apoptosis.⁴⁸ Possible strategies to overcome this resistance mechanism include conjugating the CD30 antibody to a different drug that is not a substrate for MDR1 transport, or to give BV in combination with another drug that prevents the export of MMAE out of the tumor cell. A phase I trial examining BV given with cyclosporine or verapamil, which are both substrates for MDR1 that can be administered to overwhelm the transporter, is currently ongoing [ClinicalTrials.gov identifier: NCT03013933].

Finally, it may be possible to administer BV in combination with other agents that might result in synergistic effects to improve the efficacy of BV retreatment. For example, a prospective, multicenter phase II trial is evaluating BV combined with ibrutinib in rel/ref HL patients. Patients received standard dose BV every 3 weeks and ibrutinib 560 mg daily. Of the 16 patients enrolled at the time of presentation, the ORR was 69% with 46% CR and a disease control rate of 100%. There were two patients who received prior BV; one patient had a PR and 1 patient had a CR.⁴⁹ A phase I/II dose-escalation study in rel/ref HL patients tested bendamustine in combination with BV. A total of 65 patients were enrolled, including 64 patients with HL and 1 patient with ALCL. BV was given at 1.8 mg/kg on day 1 and bendamustine 90 mg/kg was administered on days 1 and 2 of a 21-day cycle. The OR rate was 78% with a CR rate of 48% and median duration of response of 3.95 months.⁵⁰ In another phase I/II dose-escalation study, BV was given in combination with ipilimumab to patients with rel/ref HL. Patients received the standard dose of BV every 21 days for 16 cycles and ipilimumab every 21 days for 4 cycles followed by every 3 months for 1 year. Overall, 19 patients with a median of four prior therapies, including 8 who had received HSCT (7 autologous and 1 allogeneic) were enrolled. In the 12 evaluable patients, the OR rate was 67% with a CR rate of 42%. A total of 83% of patients had an overall clinical benefit.⁵¹ As part of the same study, the combination of BV plus nivolumab was studied. Patients received either 1.2 or 1.8 mg/kg according to a 3 + 3 dose-escalation design. A total of 19 patients were enrolled and 17 were evaluable for response at the time of presentation. Overall, 89% of patients had an OR, including 50% with CR. Overall, 2 CRs and 1 PR were observed in patients treated with prior BV. Thus far, the 6 month PFS is 91% (Table 4).⁵²

Table 4.

Front-line BV in elderly patients, or in other patients deemed unsuitable for chemotherapy due frailty or comorbidities.

Regimen	Phase	Number of patients	Average number of prior lines of therapy	Patients with prior ASCT (%)	ORR (%)	CR (%)	Median PFS (months)	Reference
BV in elderly	2	27	0	0	92	73	10.5	41
BV in elderly (BREVITY)	2	38	0	0	84	26	7.4	42
BV-DTIC in elderly	2	22	0	0	100	62	17.5	43
BV-bendamustine in elderly	2	20	0	0	100	88	Not reached	43
BV-bendamustine in elderly (HALO)	½	60	0	0	87	87	At 9 months, 10/15 in ongoing CR	44, 45
Sequential BV-AVD	2	48	0	0	88	81	2y PFS 85% (ITT)	46

ASCT, autologous stem cell transplantation; BV, brentuximab vedotin; CR, complete response; DTIC, dacarbazine; HL, Hodgkin lymphoma; ITT, intention to treat; ORR, overall response rate; PFS, progression-free survival.

Conclusion

The US FDA approval of BV-AVD as front-line therapy for advanced stage HL has necessitated a re-evaluation of the role of BV in the treatment of HL. Based on the ECHELON-1 data, BV-AVD is available for use as an effective front-line regimen for advanced stage HL, and particular consideration of this regimen in younger or higher risk patients is warranted. Ongoing studies continue to evaluate the role of BV in the front-line treatment in early stage HL and elderly HL patients with comorbidities. For patients who do not receive front-line BV, the traditional uses of BV remain applicable. However, for patients with rel/ref HL after receiving prior BV, the role of subsequent BV may need to be redefined. Retreatment with BV can be considered, but BV resistance usually occurs. Rational combinations of BV with agents that have an alternate mechanism of action, including drugs that specifically counter BV resistance mechanisms merit further study and may have a role in the future.