– ADCETRIS in Combination with Nivolumab, Doxorubicin and Dacarbazine Delivers 88% Complete Response (CR) Rate in Advanced-Stage cHL and 92% CR Rate in Early-Stage cHL –
– 95% of Advanced-Stage Patients Remain Progression Free at 12 Months with 17 Months Median Follow-Up –
– Regimen Was Well-Tolerated in Both Cohorts with No Treatment-Related Deaths and Less Than Half of Patients in Either Group Developed Any Grade Peripheral Sensory Neuropathy –
Seagen Inc. (Nasdaq: SGEN) today announced results from two parts of a phase 2 trial (SGN35-027) evaluating ADCETRIS® (brentuximab vedotin) in combination with the PD-1 inhibitor nivolumab and standard chemotherapy agents doxorubicin and dacarbazine (AN+AD) for the frontline treatment of patients with classical Hodgkin lymphoma (cHL). Part B of the trial evaluated patients with advanced-stage disease and was presented as an oral presentation, and Part C evaluated patients with early-stage disease and was presented as a poster at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans.
Results demonstrated a complete response (CR) rate of 88% and an overall response rate (ORR) of 93% in patients with advanced-stage disease (Part B), and a CR rate of 92% and an ORR of 95% in patients with early-stage disease (Part C). The data showed that the combination was well-tolerated, with no new safety signals observed.
“We are encouraged that ADCETRIS in combination with the immunotherapy nivolumab and standard chemotherapy agents showed promising efficacy and safety as a first-line treatment in patients with early- and advanced-stage classical Hodgkin lymphoma,” said Marjorie Green, M.D., Senior Vice President and Head of Late-Stage Development at Seagen. “These agents with complementary mechanisms of action warrant further investigation as a potential frontline treatment option for patients with Hodgkin lymphoma.”
Part B Phase 2 Study of Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Advanced Stage Classic Hodgkin Lymphoma (Abstract #314)
Part B of SGN35-027 is evaluating the novel ADCETRIS combination in 57 patients with advanced-stage cHL (Stage II with bulky disease, Stage III or IV). Results showed:
- An 88% CR rate (95% Confidence Interval [CI]: 76.3, 94.9) and 93% ORR (95% CI: 83.0, 98.1) at the end of treatment.
- The estimated 12-month progression-free survival (PFS) rate was 95% (median follow-up 17.2 months [95% CI: 15.5, 17.5]).
- The most frequently reported treatment-related treatment-emergent adverse events (TEAEs) occurring in more than 40% of patients were nausea at 65% (37/57), fatigue at 47% (27/57) and peripheral sensory neuropathy at 44% (25/57).
- Peripheral sensory neuropathy was primarily low grade (4% Grade ≥3), and no patients discontinued due to peripheral sensory neuropathy.
Part C Phase 2 Study of Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Early-Stage Classic Hodgkin Lymphoma (Abstract #4230)
Part C of SGN35-027 is evaluating the novel ADCETRIS combination in 125 patients with early-stage (non-bulky Stage I or II) cHL. Of 125 patients in the study, 76 were included at the time of efficacy assessment. Results showed:
- A 92% CR rate (95% CI: 83.6, 97.0) and a 95% ORR (95% CI: 87.1, 98.5) at end of treatment (N=76).
- Follow up is ongoing and PFS results are not yet available.
- The most frequently reported treatment-related TEAEs occurring in more than 30% of patients were nausea at 68% (85/125), peripheral sensory neuropathy at 42% (53/125), and fatigue at 38% (47/125).
- Peripheral sensory neuropathy was primarily low grade (2% Grade ≥3), and no patients discontinued due to peripheral sensory neuropathy.
About the SGN35-027 Clinical Study
SGN35-027 is an ongoing open-label, multiple part, multicenter, phase 2 clinical trial evaluating two brentuximab vedotin treatment combinations in patients with advanced and early-stage cHL. The trial includes three parts (Parts A, B, and C). Part A includes a combination of brentuximab vedotin and doxorubicin, vinblastine and dacarbazine (A+AVD), while Parts B and C include brentuximab vedotin in combination with nivolumab, doxorubicin, and dacarbazine (AN+AD). The primary endpoint for Part A is the proportion of patients with treatment-emergent febrile neutropenia. The primary endpoint for Parts B and C is the proportion of participants with complete response at end of treatment according to the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). Incidence of adverse events is a secondary endpoint for Parts B and C.
About Hodgkin Lymphoma
According to the American Cancer Society, approximately 8,540 cases of Hodgkin lymphoma will be diagnosed in 2022 and more than 900 people will die from the disease.1
ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of cHL and expressed on the surface of several types of lymphomas. It is approved in seven indications in the U.S.:
- Adult patients with previously untreated Stage III/IV cHL, in combination with doxorubicin, vinblastine, and dacarbazine.
- Pediatric patients 2 years and older with previously untreated high risk cHL, in combination with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide.
- Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.
- Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.
- Adult patients with 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.
- Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.
- Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.
Seagen and Takeda jointly develop ADCETRIS. Under the terms of the collaboration agreement, Seagen has U.S. and Canadian commercialization rights, and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seagen recognizes royalty revenues from Takeda based on a percentage of Takeda's net sales of ADCETRIS in its licensed territories based on annual net sales tiers. Seagen 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.
ADCETRIS® (brentuximab vedotin) for injection U.S. Important Safety Information
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.
Contraindicated with concomitant 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. Patients experiencing new or worsening PN may require a delay, change in dose, or discontinuation of ADCETRIS.
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 beginning with Cycle 1 for adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL.
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 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 infections.
Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk. Monitor closely and take appropriate measures.
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. 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. 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 have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors 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 pre-existing GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.
Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of this potential risk, and to avoid pregnancy during ADCETRIS treatment and for 6 months after the last dose of ADCETRIS.
The most common adverse reactions (≥20% in any study) are peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, mucositis, thrombocytopenia, and febrile neutropenia.
Concomitant use of strong CYP3A4 inhibitors has the potential to affect the exposure to monomethyl auristatin E (MMAE). Closely monitor adverse reactions.
USE IN SPECIAL POPULATIONS
Lactation: Breastfeeding is not recommended during ADCETRIS treatment.
Females and Males of Reproductive Potential: Advise females to report pregnancy immediately and advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 6 months after the last dose of ADCETRIS.
Please see full Prescribing information, including BOXED WARNING, for ADCETRIS here.
Seagen Inc. is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people’s lives. Seagen is headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland and the European Union. For more information on our marketed products and robust pipeline, visit www.seagen.com and follow @SeagenGlobal on Twitter.
Certain statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of ADCETRIS alone or in combination, its possible safety, efficacy and therapeutic uses, the SGN35-027 clinical trial and the potential for further investigation in the referenced treatment settings. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include without limitation the risk of delays, setbacks or failures in product development activities, even after encouraging results in earlier-stage trials, for a variety of reasons, including without limitation the difficulty and uncertainty of pharmaceutical product development and the potential for adverse events or safety signals, failure of clinical results to support continued development or regulatory approvals, and adverse regulatory actions. More information about the risks and uncertainties faced by Seagen is contained under the caption “Risk Factors” included in Seagen’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2022, and subsequent periodic reports, filed with the Securities and Exchange Commission. Seagen disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise except as required by applicable law.
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Douglas Maffei, Ph.D.