On June 13, 2023 Seagen Inc. (NASDAQ: SGEN) reported updated efficacy and safety results from Part C of a phase 2 single-arm trial (SGN35-027) evaluating the antibody-drug conjugate 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 early-stage classical Hodgkin lymphoma (cHL) (Press release, Seagen, JUN 13, 2023, View Source [SID1234632668]). Data results will be presented at the 17th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland June 13-17.
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Also, to be presented in a late-breaking session, are three-year results from a 1,500-patient phase 3 trial from the German Hodgkin Study Group (HD21) evaluating non-inferiority efficacy and potential for reduced toxicity of an ADCETRIS regimen (BrECADD) compared to the highly efficacious yet chemotherapy intensive escalated BEACOPP regimen, commonly used outside of the U.S. The study will be presented on June 17, 2023.
ADCETRIS + AVD chemotherapy (Adriamycin, vinblastine, dacarbazine) is a U.S. standard of care in advanced-stage cHL based on national treatment guidelines and is the only targeted therapy inclusive regimen that has a proven statistically significant overall survival benefit at 6-years of follow-up, reducing risk of death by 41% for these patients.i,ii ADCETRIS is approved for seven indications in the U.S. and five indications in Europe, where Takeda has commercialization rights.
"With teens and young adults primarily impacted by Hodgkin lymphoma, our goal is to develop curative treatments that improve survival while also reducing toxicity," said Jeremy Abramson, MD, Director, Jon and Jo Ann Hagler Center for Lymphoma at Massachusetts General Hospital and principal investigator of the trial. "The targeted agents of brentuximab vedotin and nivolumab have distinct mechanisms of action and demonstrated promising activity and safety in this early study; the omission of bleomycin and vinblastine chemotherapy likely contributed to the absence of certain adverse events."
"We are encouraged by the promising clinical outcomes of an ADCETRIS plus nivolumab combination with reduced chemotherapy as we seek to maximize efficacy and improve tolerability in both early- and late-stage classical Hodgkin lymphoma," said Roger Dansey, President of Research and Development and Chief Medical Officer at Seagen.
New Results Presented from SGN35-027
Of 154 patients with early-stage disease in Part C of the study, 150 were included at the time of efficacy assessment, showing:
A 98% ORR (95% CI: 94.3, 99.6) and a 93% CR rate (95% CI: 87.3, 96.3) at end of treatment (EOT).
Follow-up is ongoing and progression-free survival (PFS) results are not yet available.
The most frequently reported treatment-related treatment-emergent adverse events (TRAEs) of any grade occurring in more than 30 percent of patients were nausea (65%), peripheral sensory neuropathy (47%) and fatigue (44%).
Peripheral sensory neuropathy was primarily low grade (3% Grade ≥3).
There were no cases of febrile neutropenia.
Immune-mediated AEs observed to date are consistent with the individual safety profile of nivolumab.
There were no grade 5 adverse events.
Updated data results from Part B of the study in patients with advanced-stage disease (n=57) were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2023 Congress in Frankfurt, Germany June 8-11, which showed an estimated 95% 12-month PFS rate and 93% 18-month PFS rate, an ORR of 95% and CR rate of 89% at EOT. The most frequently reported TRAEs of any grade occurring in more than 30 percent of patients were nausea (65%), fatigue (49%), peripheral sensory neuropathy (44%) and alopecia (35%).
Please see Important Safety Information, including a BOXED WARNING for progressive multifocal leukoencephalopathy (PML), for ADCETRIS below.
About the SGN35-027 Clinical Study
SGN35-027 is an ongoing open-label, multiple part, multicenter, phase 2 clinical trial evaluating two different brentuximab vedotin treatment combinations in patients with advanced and early-stage cHL. The trial includes three parts (Parts A, B, and C). Part A is evaluating the combination of brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine (A+AVD) with primary granulocyte-colony stimulating factor (G-CSF) prophylaxis, while Parts B and C are evaluating brentuximab vedotin in combination with nivolumab, doxorubicin, and dacarbazine (AN+AD) as a first-line treatment in advanced and early-stage disease, respectively. Part B is evaluating the combination in patients with stage II bulky (mediastinal mass ≥10 cm), stage III or IV cHL. Part C is evaluating the combination in patients with stage I or II cHL without bulky mediastinal disease (<10 cm). 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
Lymphoma is a general term for a group of cancers that originate in the lymphatic system affecting a type of white blood cell called lymphocytes. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished by the presence of Reed-Sternberg cells that usually have a protein called CD30 on their surface. Approximately 8,830 cases of classical Hodgkin lymphoma will be diagnosed in the United States during 2023 and 900 people will die from the disease.iii According to the International Agency for Research on Cancer in 2020, over 83,000 people worldwide were diagnosed with Hodgkin lymphoma and approximately 23,000 people died from this cancer.iv
About ADCETRIS
ADCETRIS is an antibody-drug conjugate (ADC) comprised of a CD30-directed monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seagen’s 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-positive tumor cells.
ADCETRIS 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 (2018)
Pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (2022)
Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation (2015)
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 (2011)
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 (2018)
Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. (2011)
Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) after prior systemic therapy (2017)
ADCETRIS has marketing authorization in more than 70 countries for relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. ADCETRIS received conditional marketing authorization from the European Commission in October 2012. Its approved indications in Europe are for:
Adult patients with previously untreated CD30-positive Stage IV Hodgkin lymphoma in combination with AVD
Adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT
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
Adult patients with relapsed or refractory sALCL
Adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one 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 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
BOXED WARNING
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.
CONTRAINDICATION
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.
ADVERSE REACTIONS
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.
DRUG INTERACTIONS
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 the full Prescribing Information, including BOXED WARNING, for ADCETRIS here .