ADCETRIS™ (brentuximab vedotin) for the Treatment of Relapsed/Refractory Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma

Epidemiology and Burden of Disease

Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) are relatively uncommon lymphatic system cancers. Each year in the United States, an estimated 8500 patients are diagnosed with HL and 1300 patients are diagnosed with ALCL.¹ Of the two malignancies, HL has a better overall survival rate, and advances in the use of combined chemotherapy and radiotherapy have resulted in durable remission rates of approximately 80%.² However, the multiagent regimens used to treat these cancers can have serious side effects, including secondary malignancies and infertility.²

In HL, there remains a stubbornly refractory population, and 15% to 30% of patients do not achieve long-term remission after conventional treatment.³ Patients with refractory HL are normally treated with autologous hematopoietic stem cell transplantation (SCT); however, SCT is only effective in approximately 50% of these patients.^4,5 Among patients who have a relapse after SCT, overall survival is relatively poor, with only 55% surviving at 2 years and 32% at 5 years.⁶ HL claims 1000 lives each year in the Unites States, and because the median age of this patient population is the mid 30s, many of these patients die at a young age.^7,8 While there is a clear unmet need for therapeutic advances for refractory HL patients, prior to 2011, the FDA had not approved any new therapies for HL in the last 30 years.

ALCL, which is less common than HL, can manifest as a localized cutaneous form of lymphoma, known as primary cutaneous ALCL (cALCL), or as systemic disease (primary systemic ALCL, or sALCL). cALCL is highly treatable, with 5-year survival rates greater than 90%.⁹ sALCL, categorized as either ALK-positive or ALK-negative depending on the expression or absence of anaplastic lymphoma kinase (ALK) fusion proteins, is often difficult to treat, with 5-year survival rates ranging from 49% to 70%.⁹ At present, there is no standard treatment regimen for sALCL. More toxic chemotherapeutic regimens such as fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, metho trexate, cytarabine (hyper- CVAD) have been studied, but these agents have not shown superiority over cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).^10,11

The Promise of Antibody-Drug Conjugates

In HL, malignant Hodgkin Reed-Sternberg (HRS) cells strongly express CD30, a cell membrane protein and tumor marker.¹² CD30 also has high rates of expression in ALCL.³ The disproportionate rate of CD30 expression in malignant cell lines makes this surface antigen a particularly attractive target for selective immunotherapies to treat hematological malignancies.² However, early clinical studies of “naked” monoclonal antibodies targeting CD30 in HL were disappointing, with low overall response rates and few patients achieving complete response.¹² Researchers postulated that these limitations were due to the unique tumor biology of CD30 malignancies, whereby immune effector cells limited the ability of naked monoclonal antibodies to effectively exert their therapeutic effects on malignant cells^.2

In response to these initial shortcomings, researchers began to investigate a number of new therapeutic approaches, including the use of antibody-drug conjugates (ADCs) as anticancer agents to treat refractory or relapsing HL and ALCL. ADCs combine highly potent cytotoxic molecules with the tumor selectivity of monoclonal antibodies. Since ADCs mediate antitumor effects independently of inflammatory cells, it is believed that their action is not limited by the immune evasion mechwww anisms that are abundant in HL.² Because their cytotoxic payload is not released until inside target cells, ADCs allow for prolonged drug exposure compared to chemotherapeutic regimens, obviating the need for frequent recovery periods between treatment cycles.²

Introducing ADCETRIS™, a Novel Antibody-Drug Conjugate

ADCETRIS™ (brentuximab vedotin), a new CD30- directed ADC, was approved by the FDA on August 19, 2011, for the treatment of patients with HL after failure of autologous stem cell transplant (ASCT) or after failure of at least 2 prior multiagent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is also indicated for the treatment of patients with sALCL after failure of at least 1 prior multiagent chemotherapy regimen.¹³ ADCETRIS is composed of cAC10, an anti-CD30 monoclonal antibody, attached by an enzyme-cleavable linker to monomethyl auristan E (MMAE), a strong cytotoxic agent.^12,14 When ADCETRIS selectively binds to the CD30 antigen on the cell surface, it causes the ADC-CD30 complex to be internalized into the cell. Once inside the cell, the complex migrates to the lysosomal compartment, where proteolytic enzymes cleave the linker and activate the cytotoxic antitubulin agent MMAE. Subsequent binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest and results in death of the CD30-expressing tumor cell.^12,14 Refer to Figure 1 for a depiction of the mechanism of action of ADCETRIS.

Dosing and Administration

The required dose and number of vials of ADCETRIS should be calculated prior to reconstitution. ADCETRIS single- use vials contain 50 mg of brentuximab vedotin as a white to off-white lyophilized cake or powder. Each 50 mg vial of ADCETRIS should be reconstituted with 10.5 mL of Sterile Water for Injection, USP, to yield a single-use solution containing 5 mg/mL brentuximab vedotin.¹⁴ For patients weighing more than 100 kg, calculate the dose to 100 kg.⁴ Add to an infusion bag containing 0.9% Sodium Chloride Injection (5% Dextrose Injection or Lactated Ringer’s Injection can also be used) to achieve a final concentration of 0.4-1.8 mg/mL brentuximab vedotin and gently invert the bag to mix the solution.¹⁴ If not used immediately, the reconstituted solution may be stored at 2-8°C (36-46°F), but it should never be frozen. Because ADCETRIS contains no bacteriostatic preservatives, it should always be infused within 24 hours of vial reconstitution.¹⁴

The maximum tolerated dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.¹⁴ ADCETRIS should never be administered as an intravenous push or bolus, and treatment should be continued until disease progression or unacceptable toxicity. Health professionals should be careful to use appropriate aseptic technique when reconstituting and preparing ADCETRIS.¹⁴

ADCETRIS Clinical Trial Program

ADCETRIS demonstrated durable objective response and measurable tumor remission with moderate adverse effects in phase 1 and 2 clinical trials.^3,15,16 In a phase 1 dose-escalation study of 45 patients with CD30-positive hematological malignancies, brentuximab vedotin was administered every 3 weeks in doses ranging from 0.1 to 3.6 mg/kg.³ The study population included 42 HL patients and 2 ALCL patients. Overall, tumor regression was reported for 36 of 42 patients (86%) who could be evaluated.³ Of the 16 patients with disease-related symptoms at baseline, 13 (81%) had resolution of symptoms during treatment, regardless of response status. For patients who received the maximum tolerated dose (1.8 mg/kg), the objective response rate was 50% (6 of 12 patients). Remissions were durable in this population of patients, with a median duration of at least 9.7 months.³

ADCETRIS for Hodgkin Lymphoma

The safety and efficacy of ADCETRIS was evaluated in a pivotal phase 2, open-label, single-arm, multicenter study in 102 patients with relapsed or refractory HL after receiving autologous SCT.15 Participating patients were treated with ADCETRIS 1.8 mg/kg administered intravenously over 30 minutes, repeated every 3 weeks.¹⁵ The 102 patients ranged in age from 15 to 77 years, with a median age of 31 years. Slightly more than half (53%) of the patients were female. Patients had received a median of 3.5 prior therapies, and 58% of patients were relapsed and 42% of patients were refractory to their most recent prior therapy.¹⁵ Efficacy results for this study are summarized in Table 1.

Results were also compelling for the additional parameters evaluated in the study. Perhaps most notably, 96 of the 102 patients (94%) had a measurable reduction in tumor volume.¹⁷ Of the 35 patients achieving a complete response (CR), the median time to CR was 12.0 weeks, and of the 76 patients achieving an overall objective response (ORR) in the study, the median time to ORR was 5.7 weeks.¹⁴ For the 27 patients entering the clinical trial with baseline B symptoms, symptom resolution was achieved in a median time of 3.1 weeks.¹⁴ In a subanalysis of progression-free survival, patients treated with ADCETRIS did not exhibit disease progression for a median of 34 weeks compared to a median of 18 weeks for patients’ most recent prior therapy.^14,15

ADCETRIS for Systemic Anaplastic Large Cell Lymphoma

The efficacy of ADCETRIS in 58 patients with relapsed or refractory sALCL after prior therapy was evaluated in one phase 2 open label, single-arm, multicenter study.^14,16 Patients were treated with ADCETRIS 1.8 mg/kg administered intravenously over 30 minutes, repeated every 3 weeks.^14,16 Participating patients ranged in age from 14 to 76 years (median 52 years), and the majority were male (57%) and white (83%). Patients had received a median of 2 prior therapies, and 26% had received prior autologous SCT.^14,16 Fifty percent of patients were relapsed and 50% of patients were refractory to their most recent prior therapy.^14,16 The efficacy results for this study are summarized in Table 2.

Several additional measures were assessed in the phase 2 ALCL study. Nearly all (97%) patients had a reduction in tumor volume.^14,16 In patients who achieved an objective response, the median time to objective response was 5.9 weeks and the median time to CR was 11.7 weeks.¹⁴ Seventeen patients entered the clinical trial with baseline B symptoms, and 82% of these patients experienced resolution of their B symptoms on treatment in a median time of 3.1 weeks.^14,16 Moreover, 14 of 15 patients (93%) had complete resolution of malignant cutaneous lesions.^14,16

Safety Profile

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 studies. Across both studies, the most common adverse events (≥20%) in rank order of frequency were peripheral sensory neuropathy, fatigue, nausea, diarrhea, pyrexia, upper respiratory tract infection, neutropenia, and vomiting.^14-17 ADCETRIS-induced peripheral neuropathy (PN) was typically cumulative and generally reversible.¹⁴ The majority of PN events were grade 1 and 2 (79%; N=67), and there were no grade 4 events.^16,17 Eighty-one percent of PN cases resolved or showed some improvement, and 49% of all PN cases completely resolved.1,16 In the phase 2 studies, the median time to PN resolution or improvement for patients with HL was 13.2 weeks,17 compared to 9.9 weeks for ALCL patients.¹⁶

Ninety percent of patients completing their course of treatment in the phase 2 studies remained at the recommended dose of 1.8 mg/kg for the duration of therapy.¹⁴ Some adverse events, however, required management with dose delays and/or dose reductions to 1.2 mg/kg. Adverse events that led to dose delays in more than 5% of patients were neutropenia (14%) and peripheral sensory neuropathy (11%).¹⁴

The adverse event that led to a dose reduction in more than 5% of patients was peripheral sensory neuropathy (8%).14 Adverse events led to treatment discontinuation in 19% of patients. Adverse events that led to treatment discontinuation in 2 or more HL or sALCL patients were peripheral sensory neuropathy (6%) and peripheral motor neuropathy (2%).¹⁴

Management Considerations

In clinical trials, ADCETRIS 1.8 mg/kg was administered every 21 days via outpatient intravenous infusion over 30 minutes. ^15,16 In a phase 1 dose-finding study, dose-limiting toxicities such as neutropenia and hyperglycemia were observed at doses higher than 1.8 mg/kg.⁸

Patients should be counseled regarding potential side effects seen with ADCETRIS in clinical trials.

According to the product full prescribing information, infusion- related reactions can occur with ADCETRIS and therefore patients should be carefully monitored for the duration of the infusion. In the phase 2 studies, infusion-related reactions were primarily mild to moderate and were reported for 17 patients (11%).¹⁴ If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated with acetaminophen, an antihistamine, or a corticosteroid for subsequent infusions.¹⁴ Anaphylaxis has been reported with ADCETRIS. If anaphylaxis occurs, ADCETRIS administration should immediately be discontinued and appropriate medical therapy administered. ¹⁴

Patients should be advised that ADCETRIS may cause PN, and they should report to their physician any numbness and tingling of the hands or feet.¹⁴ Patients should be monitored for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness.¹⁴ New or worsening PN may require a dose delay, a change in dose of ADCETRIS, or ADCETRIS discontinuation. ¹⁴ For new or worsening grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to grade 1 or baseline and then restarted at 1.2 mg/kg. In the event of a grade 4 PN, ADCETRIS should be discontinued.¹⁴

Severe prolonged neutropenia can occur with ADCETRIS. Therefore, patients should be advised to contact their physician if fever of 100.5°F or greater or other evidence of potential infection such as chills, cough, or burning or pain on urination develops.¹⁴ Complete blood counts should be monitored prior to each dose of ADCETRIS.¹⁴ Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome. These patients should be monitored closely and appropriate measures taken.¹⁴ Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.¹⁴

ADCETRIS can cause fetal harm. As a result, women should be advised to not be pregnant during treatment and for 30 days after ADCETRIS therapy has stopped.¹⁴ Furthermore, female patients should avoid nursing while receiving ADCETRIS. Patients should be advised to report pregnancy immediately. ¹⁴ Due to the possible effect on spermatogenesis, men receiving ADCETRIS should use reliable contraception during therapy and for 6 months after ADCETRIS therapy has stopped.¹⁴

Conclusion

Targeted immunotherapies incorporating ADC technology are rapidly emerging and hold the promise of delivering effective cancer therapy with modest toxicity.² ADCETRIS, a novel CD30-directed ADC, enables selective delivery of the potent cytotoxic agent MMAE to patients with relapsed or refractory HL and relapsed or refractory sALCL.2,^12,14

The encouraging findings observed in phase 1 dose-escalation studies, including tumor remission in 86% of patients, generated a strong rationale for future clinical development of ADCETRIS.³ In phase 2 studies, ADCETRIS demonstrated outstanding efficacy, with overall response rates of 75% in relapsing or refractory HL patients and 87% in relapsing or refractory sALCL patients.^15,16 Overall, ADCETRIS was well tolerated and side effects were manageable.^14,15 Now commercially available¹³, ADCETRIS is a promising new treatment option for heavily pretreated HL and ALCL patients for whom alternatives have been extremely limited.

References

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