Seattle Genetics, Inc., presented promising data on Adcetris (brentuximab vedotin), alone and in combination with other drugs, in ongoing clinical tests involving Hodgkin lymphoma (HL) patients. The data were given during the recent 57^th Annual Meeting and Exposition of the American Society of Hematology (ASH) in Orlando, Florida.

Adcetris is an antibody-drug conjugate (ADC) directed to the protein CD30 expressed in classical Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). The drug is being assessed worldwide as a key treatment for HL in over 45 ongoing clinical trials, including trials led by Seattle Genetics, its partner Takeda, and independent researchers.

“For the past decade, we have been committed to improving the therapeutic options for HL patients, and we have made tremendous progress with ADCETRIS, which is now FDA-approved for two HL indications and is being evaluated broadly in multiple settings and combinations across more than 45 ongoing clinical trials,” Jonathan Drachman, MD, chief medical officer and executive vice president, Research and Development at Seattle Genetics, said in a news release. “The data presented at the ASH annual meeting continue to support our goal to establish ADCETRIS as the foundation of care for HL. Notably, final results from the pivotal HL clinical trial demonstrate that some patients remain free from recurrence after more than five years of follow-up. We continue to explore novel ADCETRIS combinations in the salvage setting and in older frontline HL patients, with data from ongoing phase 1/2 and phase 2 clinical trials demonstrating objective response rates greater than 90 percent, supporting further follow-up and evaluation of therapeutic strategies.”

One of the studies, titled “Five-Year Survival Data Demonstrating Durable Responses from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma,” revealed the results of a pivotal, single-arm clinical trial, which supported Adcetris approval by the FDA in 2011 for relapsed/refractory Hodgkin lymphoma. The trial was conducted in 102 patients, previously treated with an autologous stem cell transplant (ASCT) and three chemotherapy regimens, to evaluate the safety and efficacy of Adcetris as a monotherapy. Additionally, the trial assessed the progression-free survival (PFS), overall survival (OS) and duration of response.  After five years of follow-up the results showed that:

• The estimated median OS was of 40.5 months, while the estimated five-year survival rate was of 41%.
• Of all the patients who received treatment (N=102), 15 patients remained in disease remission with a median observation time of 69.5 months and may potentially be cured. Of these, nine patients received no further treatment and six patients received consolidative allogeneic stem cell transplant.
• Of the 34 patients with a complete remission, the median OS and PFS had not yet been reached.
• Overall, patients were treated for a median of nine Adcetris cycles, and patients who achieved complete remission were treated for a median of 13.5 cycles.
• The most common adverse events (AEs) of any grade were fatigue, neutropenia, diarrhea, peripheral sensory, neuropathy, and nausea. Fifty-six patients (55%) had treatment emergent peripheral neuropathy. Of these patients, 88% patients improved their symptoms, with 73% achieving complete symptom resolution.
• The most usual Grade 3 or higher adverse events in at least 5% of the patients were peripheral sensory neuropathy (8%), thrombocytopenia (8%), neutropenia (20%), and anemia (6%).

Another study, titled “Updated Efficacy and Safety Data from the AETHERA Trial of Consolidation with Brentuximab Vedotin after Autologous Stem Cell Transplant (ASCT) in Hodgkin Lymphoma Patients at High Risk of Relapse,” presented results of a Phase 3 clinical trial that assessed the potential of Adcetris as monotherapy to prolong PFS following ASCT in HL patients who were at high risk of disease progression or relapse. The study enrolled 329 patients with HL, of which 165 received Adcetris and 164 receive a placebo control. Results of a three-year follow-up study concerning safety and efficacy included:

• A three-year PFS rate of 61% in patients who received Adcetris compared to a PFS rate of 43% in those who received placebo. Median PFS was not yet reached in the Adcetris group versus 15.8 months in the placebo group of patients.
• An analysis of PFS evaluating subgroups, including disease characteristics, number of risk factors, and initial response to salvage therapy revealed that patients with more risk factors for relapse post-ASCT seemed to benefit the most from the Adcetris consolidation therapy.
• In the Adcetris-treated group of patients who did not experience disease progression, PFS rates were higher in patients who remained longer on therapy.
• In the Adcetris-treated group, 67% (112 patients) experienced peripheral neuropathy. Eighty-eight percent had improvement or resolution in peripheral neuropathy symptoms, and 66% experienced complete symptom resolution. Patients remain in long-term follow-up until 2020.

Christopher Yasenchak, MD, Willamette Valley Cancer Institute and Research Center/US Oncology Research, presented an additional study titled “Brentuximab Vedotin in Combination with Dacarbazine or Bendamustine for Frontline Treatment of Hodgkin Lymphoma in Patients Aged 60 Years and Above: Interim Results of a Multi-Cohort Phase 2 Study,” which included the results of an interim analysis of an ongoing Phase 2 trial assessing the effects of Adcetris plus dacarbazine or bendamustine as a frontline treatment for patients with HL age 60 or older. At time of diagnosis, 70% of patients in each group had stage III/IV disease and most patients had multiple comorbidities.

Results revealed that:

• All 21 patients (100%) in the dacerbazine combo group had an objective response, including 14 patients (67%) with a complete remission and seven patients (33%) with a partial remission.
• All 16 patients (100%) in the bendamustine combo group had an objective response, including 13 patients (81%) with a complete remission and three patients (19%) with a partial remission.
• In the dacarbazine combo group, the median observation time was of 13.4 months and PFS at six months was 95%, at nine months was 89%, and at one year was 66%. In the bendamustine combo group, the median observation time was too short to specify a PFS.
• The most common AEs of any grade experienced by at least 25% of patients in the dacarbazine combo group were peripheral sensory n europathy (77%), constipation (45%), fatigue (41%), nausea (41%), joint pain (32%), and peripheral edema (32%).
• The most common AEs of any grade experienced by at least 25% of patients in the bendamustine combo group were diarrhea (75%), nausea (60%), fatigue (55%), decreased appetite (40%), and fever (40%). Within 30 days of the last dose, two patients died for reasons not related related to the drug.
• Conclusion of patient enrollment in the bendamustine group was because the tolerability of the combination treatment did not meet the clinical trial aims. All the patients in this group continue to receive Adcetris as monotherapy.

Finally, in a poster titled “Brentuximab Vedotin Plus Bendamustine: A Highly Active Salvage Treatment Regimen for Patients with Relapsed or Refractory Hodgkin Lymphoma,” the results of an open-label, Phase 1/2 single-arm study that assessed the tolerability and efficacy of Adcetris combined with bendamustine in HL patients who had relapsed or were refractory to frontline therapy were presented.

The combined treatment was given to patients every three weeks, for up to six treatment cycles, which was then followed by a supplementary treatment with Adcetris alone. After patients had been administered with at least two combo cycles, they could opt to pause treatment to receive an ASCT and then recommence the therapy with Adcetris as a monotherapy for treatment consolidation. At time of initial diagnosis, most patients (53%) had their disease in stages III/IV. Twenty-eight (51%) had primary refractory HL and 27 (49%) had relapsed HL following frontline treatment, mainly involving the ABVD chemotherapy regimen (Adriamycin, bleomycin, vinblastine and dacarbazine).

Updated results from this Phase 1/2 clinical trial were:

• Of the 53 examined patients, 49 (93%) had an objective response to brentuximab vedotin combined with bendamustine. This included 40 patients (76%) with complete remission and nine patients (17%) with partial remission. The rate of complete remission was 88% in relapsed patients and 64% in primary refractory patients.
• For all of the 53 patients, the median OS, involving the 40 patients who were treated with ASCT, had not yet been attained.
• The estimated rate of PFS at 18 months was of 75% for the 53 examined patients and 83% for those 40 patients who received ASCT.
• For those patients who attained complete remission with the combined treatment, the percentage of progression events was identical whether patients did or did not have an ASCT (21% versus 17%, respectively).
• Those patients who were not treated with Adcetris as consolidation experienced a superior amount of PFS events when compared to those patients who were treated with consolidation therapy (29% versus 15%).
• Most AEs experienced from the combination therapy were infusion-related reactions (IRRs), observed in 58% of patients. The most common symptoms related with IRRs experienced in about 15% of patients were nausea, chills, fever, flushing and dyspnea. The clinical trial protocol was revised to involve corticosteroids and antihistamines as premedication, which diminished IRRs severity.

Adcetris for intravenous injection has been given U.S. Food and Drug Administration (FDA) approval or accelerated approval for three indications: 1) treatment of patients with classical HL after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not auto-HSCT candidates; 2) regular approval for the treatment of classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation; and 3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one previous multiagent chemotherapy regimen. The sALCL indication is under accelerated approval based on overall response rate.

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