Seattle Genetics Highlights Additional Analyses from ECHELON-1 Phase 3 Clinical Trial of ADCETRIS® (Brentuximab Vedotin) in Newly Diagnosed Advanced Hodgkin Lymphoma at ASH Annual Meeting

SAN DIEGO, Calif.--(BUSINESS WIRE)-- Seattle Genetics, Inc. (Nasdaq:SGEN) today highlighted data from the ECHELON-1 phase 3 clinical trial evaluating ADCETRIS (brentuximab vedotin) in combination with AVD (Adriamycin^®, vinblastine and dacarbazine) in newly diagnosed stage III or IV classical Hodgkin lymphoma (HL) at the 60^th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in San Diego, Calif., December 1-4, 2018. In March 2018, the U.S. Food and Drug Administration (FDA) approved ADCETRIS in combination with AVD for the treatment of adult patients with previously untreated stage III or IV classical HL based on the positive results of the ECHELON-1 phase 3 clinical trial. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL that plays a role in tumor growth and survival.

“Prior to the FDA approval of ADCETRIS in combination with AVD, up to 30 percent of patients with advanced stage classical Hodgkin lymphoma would not respond or would relapse following frontline treatment with ABVD, demonstrating a need for more effective treatment options,” said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. “Additional analyses from the ECHELON-1 phase 3 clinical trial show that with an additional 18 months of follow-up, the benefit of ADCETRIS plus AVD was maintained compared to ABVD. Select presentations at the ASH Annual Meeting underscore the benefit of ADCETRIS plus AVD in frontline advanced stage HL.”

Three poster presentations highlight analyses from the ECHELON-1 phase 3 clinical trial evaluating ADCETRIS in combination with AVD compared to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) in stage III or IV frontline classical HL patients. The ECHELON-1 poster presentations include an analysis of efficacy benefit for ADCETRIS plus AVD regardless of the inclusion of modified events and progression-free survival (PFS) outcomes in patients per investigator, as well as results of the adolescents and young adults (AYA) trial participants. In addition, data will be presented on peripheral neuropathy resolution and improvement for patients treated with ADCETRIS plus AVD or ABVD after 30 months of follow-up.

Brentuximab Vedotin plus Chemotherapy in Patients with Advanced-Stage Classical Hodgkin Lymphoma: Evaluation of Modified Progression-Free Survival and Traditional PFS in the Phase 3 ECHELON-1 Study (Abstract #2904, poster presentation on Sunday, December 2, 2018)

As previously reported, the ECHELON-1 trial achieved its primary endpoint with the combination of ADCETRIS plus AVD resulting in a statistically significant improvement in modified PFS versus the control arm of ABVD as assessed by independent review facility (IRF; HR 0.77; p-value=0.035). Modified PFS was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy per IRF followed by subsequent anticancer therapy. An analysis was conducted to examine PFS outcomes at three-years and evaluate how the inclusion of subsequent therapy as modified events affected efficacy outcomes in the ECHELON-1 study. Key findings will be presented in a poster presentation by Joseph M. Connors, M.D., FRCPC, Clinical Director, Center for Lymphoid Cancer at BC Cancer in Vancouver, Canada, and include:

• After a median follow-up time of 37.1 months, the three-year PFS rate per investigator for patients in the ADCETRIS plus AVD arm was 83.1 percent compared to 76.0 percent in the control arm (HR 0.704; p-value=0.005).
• After a median follow-up time of 24.7 months, the assessment of two-year PFS per investigator, including subsequent chemotherapy (but not radiotherapy) in patients who were not in a complete response at the end of frontline treatment, in the ADCETRIS plus AVD arm was 84.0 percent compared to 77.3 percent in the control arm (HR 0.687; p-value=0.003).
• After a median follow-up time of 24.7 months, the assessment of two-year traditional PFS per investigator in the ADCETRIS plus AVD arm was 84.2 percent compared to 78.0 percent in the control arm (HR 0.701; p-value=0.006).
• 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. As previously reported, the most common clinically relevant adverse events of any grade that occurred in at least 15 percent of patients in the ADCETRIS plus AVD and ABVD arms were: neutropenia, constipation, vomiting, fatigue, peripheral sensory neuropathy, diarrhea, pyrexia, peripheral neuropathy, abdominal pain and stomatitis. In both the ADCETRIS plus AVD and ABVD arms, the most common Grade 3 or 4 events were neutropenia, febrile neutropenia and neutrophil count decrease.

Brentuximab Vedotin with Chemotherapy in Adolescents and Young Adults (AYA) with Stage III or IV Hodgkin Lymphoma: a Subgroup Analysis From the Phase 3 ECHELON-1 Study (Abstract #1647, poster presentation on Saturday, December 1, 2018)

Of the 1,334 advanced stage classical HL patients who participated in the ECHELON-1 clinical trial, 771 patients (57.8 percent) were AYA defined as age 15 to 39 years, with 396 patients in the ADCETRIS plus AVD arm and 375 patients in the ABVD control arm. To participate in the ECHELON-1 study, trial participants had to be 18 years or older. The median age of patients in the ADCETRIS plus AVD arm compared to the control arm was 27 years and 28 years, respectively. Key findings were presented in a poster presentation by Howland Crosswell, M.D., Pediatric Hematology-Oncology at the Bon Secours Hematology Oncology in Greenville, S.C., and include:

• Per IRF, AYA treated with ADCETRIS plus AVD showed a positive trend towards improved modified PFS and consistent benefit across all age subgroups compared with patients in the ABVD arm (<25 years, HR 0.724; <30 years, HR 0.587; <40 years, HR 0.697).
• The two-year modified PFS per IRF for patients age 40 or less who received ADCETRIS plus AVD (396 patients) was 84.6 percent compared to 78.6 percent who received ABVD (375 patients). Patients age 30 or less who received ADCETRIS plus AVD (244 patients) had improved modified PFS compared with patients treated with ABVD (224 patients; 86.7 percent versus 74.4 percent, respectively).
• Traditional PFS by investigator was consistent with the modified PFS outcomes across all age subgroups.
• The rate of adverse events in patients receiving ADCETRIS plus AVD or ABVD was similar across age groups and consistent with the previously reported rate of adverse events for the ECHELON-1 intent to treat population. The rate of any adverse events in the patients age 40 or younger in both the ADCETRIS plus AVD and ABVD arms was 98 percent. The rate of any adverse events in the patients age 30 or younger in the ADCETRIS plus AVD arm was 98 percent and in the ABVD arm was 99 percent. The rate of any adverse events in the patients age 25 or younger in both the ADCETRIS plus AVD and ABVD arms was 99 percent. The AYA patients in the ADCETRIS plus AVD arm experienced more Grade 3 or higher adverse events (80 percent versus 63 percent) but had similar rates of treatment discontinuation as patients receiving ABVD (nine percent versus 10 percent, respectively).

Resolution of Peripheral Neuropathy (PN) in Patients Who Received A+AVD or ABVD in the Phase 3 ECHELON-1 Trial (Abstract #2921, poster presentation on Sunday, December 2, 2018)

As previously reported in the ECHELON-1 study, the incidence of peripheral neuropathy of any grade was 67 percent (442 of 662 patients) and 43 percent (286 of 659 patients) in the ADCETRIS plus AVD and ABVD arms of the study, respectively. At the time of primary analysis and with a median follow-up time of approximately 21 months, 67 percent of patients treated with ADCETRIS plus AVD had either complete resolution or improvement of peripheral neuropathy events by at least one grade at the time of last follow-up. An updated analysis of peripheral neuropathy outcomes from the ECHELON-1 study at a median follow-up time of 30 months will be presented in a poster presentation by John Radford, M.D., Manchester Academic Health Centre in Manchester, United Kingdom, and include:

• After continued follow-up at a median of 30 months, peripheral neuropathy was either completely resolved or improved in 335 out of 442 patients (76 percent) in the ADCETRIS plus AVD arm and 234 out of 286 patients (82 percent) in the ABVD arm.
• For patients whose peripheral neuropathy had not resolved by end of treatment (182 patients in ADCETRIS plus AVD arm and 81 patients in ABVD arm), the median time to resolution of all peripheral neuropathy events was 28 weeks for ADCETRIS plus AVD arm and 14 weeks for the ABVD arm.
• In the patients who experienced peripheral neuropathy, 10 percent (44 out of 442 patients) and four percent (11 out of 286 patients) discontinued treatment due to peripheral neuropathy in the ADCETRIS plus AVD arm and ABVD arm, respectively.
• For both study arms, peripheral neuropathy was generally manageable and reversible, and the majority of ongoing peripheral neuropathy was Grade 1/2.

About ADCETRIS (brentuximab vedotin)

ADCETRIS is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas. These include three recently completed phase 3 trials: ECHELON-2 in frontline peripheral T-cell lymphomas (also known as mature T-cell lymphoma), ECHELON-1 in previously untreated Hodgkin lymphoma, and ALCANZA in cutaneous T-cell lymphoma. The phase 3 CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma is ongoing.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, and (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in 72 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

About Seattle Genetics

Seattle Genetics, Inc. is an emerging multi-product, global biotechnology company that develops and commercializes transformative therapies targeting cancer to make a meaningful difference in people’s lives. ADCETRIS^® (brentuximab vedotin) utilizes the company’s industry-leading antibody-drug conjugate (ADC) technology and is currently approved for the treatment of multiple CD30-expressing lymphomas. Beyond ADCETRIS, the company has established a pipeline of novel targeted therapies at various stages of clinical testing, including three in ongoing pivotal trials for solid tumors. Enfortumab vedotin for metastatic urothelial cancer and tisotumab vedotin for metastatic cervical cancer utilize our proprietary ADC technology. Tucatinib, a small molecule tyrosine kinase inhibitor, is in a pivotal trial for HER2-positive metastatic breast cancer. In addition, we are leveraging our expertise in empowered antibodies to build a portfolio of proprietary immuno-oncology agents in clinical trials targeting hematologic malignancies and solid tumors. The company is headquartered in Bothell, Washington, and has a European office in Switzerland. For more information on our robust pipeline, visit www.seattlegenetics.com and follow @SeattleGenetics on Twitter.

ADCETRIS (brentuximab vedotin) Important Safety Information

BOXED WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML):

JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication

ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

• Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly.
• Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
• Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Start primary prophylaxis with G-CSF beginning with Cycle 1 for patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III or IV classical HL or previously untreated PTCL. Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent ADCETRIS doses.
• Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.
• Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
• Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment.
• Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment.
• Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
• PML: Fatal cases of JC virus infection resulting in PML and death have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. Other possible contributory factors other than ADCETRIS include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
• Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
• Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
• Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
• Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Most Common (≥20% in any study) Adverse Reactions: Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia and mucositis.

Drug Interactions

Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations

Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

For additional Important Safety Information, including BOXED WARNING, please see the full Prescribing Information for ADCETRIS at www.seattlegenetics.com or http://www.ADCETRIS.com.

Seattle Genetics Forward Looking Statements

Certain of the statements made in this press release are forward looking, such as those, among others, relating to the potential benefit and use of ADCETRIS (brentuximab vedotin). Actual results or developments may differ materially from those projected or implied in these forward-looking statements due to factors such as utilization and adoption of the approved treatment regimen by prescribing physicians, competitive conditions including the availability of alternative treatment regimens, the availability and extent of reimbursement, the risk of adverse events, and adverse regulatory action. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption “Risk Factors” included in the company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2018 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

 

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