Additional analyses from phase III ECHELON-1 clinical trial of Adcetris in newly diagnosed advanced Hodgkin lymphoma.- Seattle Genetics.

Seattle Genetics, Inc. highlighted data from the phase III ECHELON-1 clinical trial evaluating Adcetris (brentuximab vedotin) in combination with chemotherapy in newly diagnosed stage III or IV classical Hodgkin lymphoma (HL) at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting being held June 1-5 in Chicago, Illinois. In March 2018, the FDA approved Adcetris in combination with chemotherapy for the treatment of adult patients with previously untreated stage III or IV classical HL based on the positive results of the phase III ECHELON-1 clinical trial. Adcetris is being evaluated globally as the foundation of therapy for HL in more than 50 ongoing clinical trials, including trials led by Seattle Genetics and its development and commercialization partner, Takeda, as well as by independent investigators.

Three poster presentations highlight analyses from the ECHELON-1 phase III clinical trial evaluating Adcetris in combination with AVD (Adriamycin, vinblastine and dacarbazine) compared to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) in stage III or IV frontline classical HL patients. The ECHELON-1 poster presentations include the results of the North American patient population, optimizing therapy with the use of primary prophylactic growth factors (G-CSF) and improvement of modified progression-free survival (PFS) outcomes in patients who received Adcetris plus AVD regardless of cycle 2 PET (PET2) status. In addition, long-term follow-up from an ongoing phase II clinical trial in newly diagnosed older HL patients was reported.

Poster 1: "Brentuximab Vedotin plus Chemotherapy in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: North American Results (Abstract #7541 " poster presentation on Monday, June 4, 2018) . Of the 1,334 advanced stage classical HL patients who participated in the ECHELON-1 clinical trial, 497 patients were treated in North America, with 250 patients in the Adcetris plus AVD arm and 247 patients in the ABVD control arm. 1.Per Independent Review Facility (IRF) assessment, the two-year modified PFS rate for patients in the Adcetris plus AVD arm was 84.3 percent compared to 73.7 percent in the control arm (HR 0.596; p-value=0.012), which corresponds to a difference of 10.6 percent.2. Per investigator assessment, the two-year modified PFS rate for patients in the Adcetris plus AVD arm was 86.4 percent compared to 73.6 percent in the control arm (HR 0.516; p-value=0.002), which corresponds to a difference of 12.8 percent. 3. Per investigator assessment, the two-year PFS rate for patients in the Adcetris plus AVD arm was 88.1 percent compared to 76.4 percent in the control arm (HR 0.500; p-value=0.002), which corresponds to a difference of 11.7 percent. 3.Consistent improvement in modified PFS per IRF was observed among patients treated with Adcetris plus AVD compared with ABVD across all pre-specified subgroups, including age, disease stage, International Prognostic Score and baseline ECOG score. 5. On the Adcetris plus AVD arm, peripheral neuropathy events were observed in 80 percent of patients compared to 56 percent on the ABVD arm. In the Adcetris plus AVD arm, the majority of peripheral neuropathy events were Grade 1 or 2 (41 percent and 21 percent, respectively). Grade 3 events were reported in 17 percent of patients. In the ABVD arm, Grade 3 events were reported in less than one percent of patients. There were no Grade 4 events on either arm. Across both arms of the study, approximately 75 percent of the patients with peripheral neuropathy reported resolution or improvement at last follow-up. 6.Febrile neutropenia during treatment was reported in 20 percent of patients in the Adcetris plus AVD arm compared with nine percent in the ABVD arm. In the Adcetris plus AVD arm, 35 patients received primary prophylactic G-CSF within five days of starting treatment and nine percent (three patients) reported febrile neutropenia. 7.Pulmonary toxicity was reported in three percent of patients in the Adcetris plus AVD arm versus ten percent of patients in the ABVD arm. Grade greater than 3 events were reported in two percent versus six percent of patients, in theAdcetrisplus AVD and ABVD arms, respectively.

Poster 2: "Improving Outcomes with Brentuximab Vedotin plus Chemotherapy in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma" (Abstract #7534 ) , poster presentation on Monday, June 4, 2018) During the ECHELON-1 clinical trial, an independent monitoring committee (IDMC) recommended the use of primary prophylactic G-CSF for patients in the Adcetris plus AVD arm of the study due to an increased risk of febrile neutropenia. In the Adcetris plus AVD arm, 83 patients received G-CSF primary prophylaxis (defined as receipt of G-CSF by day five of the first treatment cycle) and 579 patients did not. An analysis of these two patient populations in the ECHELON-1 study presented by Dr. David Straus, Memorial Sloan Kettering Cancer Center, included: 1.The two-year modified PFS rate for patients in the Adcetris plus AVD arm who received G-CSF primary prophylaxis was 84.6 percent compared to 81.7 percent for those who did not (HR 0.737; 95% CI, 0.396 to 1.372) and compared to 77.2 percent in the ABVD control arm (HR 0.586; 95% CI, 0.317 to 1.081). 2. Use of G-CSF primary prophylaxis in the Adcetris plus AVD arm was associated with a decrease in neutropenia (35 percent versus 73 percent), overall febrile neutropenia (11 percent versus 21 percent) and febrile neutropenia in the first treatment cycle (one percent versus 11 percent). Seven of the nine deaths that occurred in the Adcetris plus AVD arm were associated with neutropenia, none of whom had received primary prophylaxis with G-CSF before the onset of neutropenia. 3. There was no evidence of an association between use of G-CSF primary prophylaxis and pulmonary toxicity. 4.In the Adcetris plus AVD arm, incidence of peripheral neuropathy was 57 percent in patients with G-CSF primary prophylaxis versus 68 percent without. 5. Lastly, use of G-CSF primary prophylaxis was associated with a lower rate of Adcetris dose delays and dose reductions compared to those without.

Poster 3-"Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin Lymphoma: Impact of Cycle 2 PET Result on Modified Progression-Free Survival" (Abstract #7539, poster presentation on Monday, June 4, 2018). A post-hoc analysis of the ECHELON-1 clinical trial was conducted to evaluate modified PFS outcomes and clinical characteristics by PET2 status per IRF. 1.In the Adcetris plus AVD arm of the study, 588 patients were PET2-negative (Deauville score ?3) and 47 were PET2-positive (Deauville score ?4). In the ABVD arm of the study, 577 patients were PET2-negative and 58 were PET2-positive. The analysis presented by Dr. Robert Chen, City of Hope National Medical Center, included: 1. Adcetris plus AVD improved modified PFS outcomes in patients regardless of PET2 status. The modified PFS in PET2-negative patients in the Adcetris plus AVD arm was 85.2 percent compared to 80.9 percent in the ABVD arm (HR 0.774; 95% CI, 0.586 to 1.022). The modified PFS in PET2-positive patients in the Adcetris plus AVD arm was 57.5 percent compared to 42.0 percent in the ABVD arm (HR 0.609; 95% CI, 0.341 to 1.088). PET2-positive patients in the Adcetris . 2 The safety profile of Adcetris plus AVD in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen. There were no notable differences in the safety profile between PET2-positive or PET2-negative subgroups in either arm of the study.

Long Term Follow Up report;-"Long-Term Follow-Up of Brentuximab Vedotin +/- Dacarbazine as First-Line Therapy in Elderly Patients with Hodgkin Lymphoma (Abstract #7542, poster presentation on Monday, June 4, 2018) .Long-term follow-up results were presented from an ongoing phase II clinical trial evaluating Adcetris alone or in combination with dacarbazine as frontline therapy for HL patients age 60 years or older. Data were reported from 27 patients treated with Adcetris monotherapy and 22 patients treated with Adcetris in combination with dacarbazine. The median age of patients was 78 years in the Adcetris monotherapy arm and 69 years in the dacarbazine combination arm. Over 60 percent of patients in each arm had stage III/IV disease at the time of diagnosis and the majority were frail with multiple comorbidities. Long-term data highlighted by Dr. Jonathan Friedberg, University of Rochester, included: 1.In the Adcetris monotherapy arm, the median observation time from first dose was 42.6 months. Estimated three-year PFS and overall survival rates were 34 percent and 71 percent, respectively, with no deaths occurring within 30 days of last treatment. Median PFS was 10.48 months and median overall survival had not yet been reached. 2. In the dacarbazine combination arm, the median observation time from first dose was 37.8 months. Estimated three-year PFS and overall survival rates were 52 percent and 90 percent, respectively, with no deaths occurring within 30 days of last treatment. Both median PFS and overall survival had not yet been reached. 3. Treatment-emergent peripheral neuropathy of any grade was observed in 24 patients (89 percent) in the Acetris arm and 19 patients (86 percent) in the dacarbazine combination arm, with most Grade 1 or 2 and sensory in nature. The majority of patients with treatment-emergent peripheral neuropathy had either complete resolution or some resolution or improvement. 3 .Adverse events leading to treatment discontinuation in the Adcetris monotherapy arm were peripheral sensory neuropathy (30 percent), peripheral motor neuropathy (seven percent) and orthostatic hypotension (four percent). 4. Adverse events leading to treatment discontinuation in the dacarbazine combination arm were peripheral sensory neuropathy (36 percent); asthenia, systemic lupus erythematosus, hypotension and non-cardiac chest pain (five percent each). Adcetris in combination with dacarbazine is not approved for use in frontline HL.