BOTHELL, Wash.--(BUSINESS WIRE)--
Seattle Genetics, Inc. (SGEN) today highlighted data from the phase 3 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 U.S. Food and Drug Administration (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 3 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.
“For over 40 years, the standard of care for the treatment of frontline HL in North America has been combination chemotherapy with ABVD. Unfortunately, approximately 30 percent of advanced stage HL patients will not respond or relapse to this therapy,” said Radhakrishnan Ramchandren, M.D., Barbara Ann Karmanos Cancer Center. “The ECHELON-1 phase 3 clinical trial is the first trial to demonstrate superior clinical activity utilizing a novel therapeutic agent, ADCETRIS, in combination with AVD in comparison to ABVD. At ASCO 2018, we presented outcomes specifically evaluating the North American population, which demonstrated a two-year modified progression-free survival benefit of approximately 11 percent over ABVD. Importantly, an analysis of traditional progression-free survival at two years also demonstrated a benefit for ADCETRIS plus AVD versus ABVD with a difference of 11.7 percent, a Hazard Ratio of 0.500 and a p-value of 0.002. These findings represent a significant and meaningful difference in outcomes for these patients.”
“Our goal is to establish ADCETRIS as the foundation of care for CD30-expressing lymphomas, including HL, and the data presented at ASCO continue to support this goal,” said Nancy Whiting, Pharm.D., Senior Vice President, Clinical Affairs at Seattle Genetics. “Multiple posters featuring additional analyses from the ECHELON-1 trial for ADCETRIS combination use in the treatment of patients with stage III or IV classical HL demonstrate superior efficacy benefit when compared with ABVD. In addition, data from an ongoing phase 2 study evaluating frontline use of ADCETRIS in older HL patients demonstrate a durable efficacy benefit with both monotherapy and combination therapy. Our data at ASCO highlight the substantial potential for ADCETRIS to address the needs of patients with lymphoma.”
Three poster presentations highlight analyses from the ECHELON-1 phase 3 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 2 clinical trial in newly diagnosed older HL patients was reported.
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. The North American results presented by Dr. Radhakrishnan Ramchandren, Barbara Ann Karmanos Cancer Center, are included below and a video summary of the poster presentation can be found here:
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 ≥3 events were reported in two percent versus six percent of patients, in the ADCETRIS plus AVD and ABVD arms, respectively.
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:
- 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).
- 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.
- There was no evidence of an association between use of G-CSF primary prophylaxis and pulmonary toxicity.
- In the ADCETRIS plus AVD arm, incidence of peripheral neuropathy was 57 percent in patients with G-CSF primary prophylaxis versus 68 percent without.
- Lastly, use of G-CSF primary prophylaxis was associated with a lower rate of ADCETRIS dose delays and dose reductions compared to those without.
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. 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:
- 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 plus AVD arm had superior results compared to historical controls.
- 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 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 2 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:
- 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.
- 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.
- Treatment-emergent peripheral neuropathy of any grade was observed in 24 patients (89 percent) in the ADCETRIS 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.
- 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). 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.
ECHELON-1 is a randomized, open-label, two-arm, multi-center phase 3 study designed to compare ADCETRIS plus (Adriamycin, vinblastine and dacarbazine) to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) as frontline therapy in patients with previously untreated advanced classical HL. The primary endpoint is modified progression-free survival (PFS) per Independent Review Facility (IRF). Modified PFS is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy per IRF followed by subsequent anticancer therapy. The study enrolled 1,334 patients who had histologically-confirmed diagnosis of Stage III or IV Hodgkin lymphoma and had not been previously treated with systemic chemotherapy or radiotherapy.
About Classical Hodgkin Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.
According to the American Cancer Society, approximately 8,500 cases of Hodgkin lymphoma will be diagnosed in the United States during 2018 and more than 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.
About ADCETRIS (brentuximab vedotin)
ADCETRIS is being evaluated broadly in more than 70 clinical trials, including two ongoing phase 3 studies: the ECHELON-2 trial in frontline mature T-cell lymphomas (also known as peripheral T-cell lymphoma) and the CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.
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 regular approval for five indications in adult patients with: (1) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with chemotherapy, (2) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (3) 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, (4) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (5) 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 71 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 or planned 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 immune-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) U.S. Select Important Safety Information
BOXED WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.
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. Administer G-CSF primary prophylaxis starting with Cycle 1 for previously untreated patients who receive ADCETRIS in combination with chemotherapy for Stage III or IV HL. Monitor complete blood counts prior to each ADCETRIS dose. Consider more frequent monitoring 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 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%) Adverse Reactions: Neutropenia, anemia, peripheral sensory neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and pyrexia.
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, 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.
Certain of the statements made in this press release are forward looking, such as those, among others, relating to the potential utilization of ADCETRIS (brentuximab vedotin) for patients with previously untreated Stage III or IV classical Hodgkin lymphoma and other possible uses. 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 March 31, 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.