Pfizer’s ADCETRIS® Regimen Produces Clinically Meaningful Improvement in Overall Survival in Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)
Pfizer's Phase 3 ECHELON-3 study on ADCETRIS® (brentuximab vedotin) in combination with lenalidomide and rituximab for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) showed significant results. The regimen reduced the risk of death by 37% compared to chemotherapy alone, with a median overall survival of 13.8 months versus 8.5 months. The study included 230 patients and will be presented at the 2024 ASCO Annual Meeting. ADCETRIS demonstrated consistent benefits across different levels of CD30 expression and is a standard of care in several lymphomas. Median progression-free survival was 4.2 months for the ADCETRIS regimen compared to 2.6 months for the placebo group. The overall response rate was 64.3% versus 41.5%, and complete response rate was 40.2% versus 18.6%. Adverse events included higher rates of neutropenia, thrombocytopenia, and anemia in the ADCETRIS group.
- ADCETRIS regimen reduced the risk of death by 37% compared to chemotherapy alone.
- Median overall survival was 13.8 months for ADCETRIS versus 8.5 months for chemotherapy.
- Improved progression-free survival of 4.2 months for ADCETRIS regimen compared to 2.6 months for placebo.
- Overall response rate for ADCETRIS was 64.3% versus 41.5% for the placebo group.
- Complete response rate for ADCETRIS was 40.2% versus 18.6% for the placebo group.
- Consistent benefits across different levels of CD30 expression.
- The study will be presented at the high-profile ASCO Annual Meeting.
- High rates of neutropenia (43% vs 28%), thrombocytopenia (25% vs 19%), and anemia (22% vs 21%) were reported for ADCETRIS.
- Peripheral sensory neuropathy, although infrequent, had Grade 3 events of 4% in the ADCETRIS group.
Insights
The Phase 3 ECHELON-3 study showcasing a 37% reduction in risk of death for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) using the ADCETRIS regimen is a significant medical advancement. This marks the third Phase 3 trial where ADCETRIS has shown improved overall survival for lymphoma patients, validating its potential as a robust treatment option. For patients who have exhausted other treatment methods, including CAR-T therapy or bispecific antibodies, this regimen offers a potential lifeline, particularly given the aggressive nature of DLBCL. Median overall survival extending from 8.5 to 13.8 months is substantial, especially in a population with limited options. The consistent benefit irrespective of CD30 expression further broadens its applicability. However, the adverse events, such as neutropenia and thrombocytopenia, necessitate careful patient monitoring. This data could transform treatment protocols and patient outcomes, providing hope where few alternatives exist.
From a research perspective, the ECHELON-3 study’s robust p-value of 0.0085 and statistically significant hazard ratio (HR 0.63) underpin the reliability of these findings. The improvement in median progression-free survival (PFS) from 2.6 to 4.2 months is also notable as it indicates not just prolonged survival but potentially better quality of life. The overall response rate (ORR) of 64.3% versus 41.5% is a critical indicator of the regimen’s efficacy. It’s worth noting that the complete response rate of 40.2% significantly surpasses the 18.6% in the control group. These figures suggest that ADCETRIS in combination with lenalidomide and rituximab could be a game-changer in the relapsed/refractory DLBCL landscape. Given the extensive clinical data supporting its use, this regimen is likely to gain traction in clinical settings, potentially impacting future guidelines and standards of care.
From an investor’s viewpoint, the consistent clinical success of ADCETRIS in multiple Phase 3 trials positions Pfizer favorably in the oncology market. The significant 37% reduction in mortality risk and the median overall survival benefit demonstrated in the ECHELON-3 trial align with industry benchmarks for breakthrough therapies. Investors should note the broad applicability of ADCETRIS across different lymphomas, which could translate into expanded market share and a strong revenue stream. However, attention should be paid to the incidence of adverse events, including neutropenia and thrombocytopenia, as these could impact patient adoption and satisfaction. Additionally, the presentation of these results at the ASCO Annual Meeting will likely draw significant attention, potentially driving stock performance. A keen eye on the FDA’s stance on these findings will also be pivotal, as approval for expanded indications can catalyze significant market growth.
- Detailed data from Phase 3 ECHELON-3 study demonstrate investigational ADCETRIS regimen reduced risk of death by 37 percent compared to chemotherapy alone, resulting in median overall survival of 13.8 months versus 8.5 months
- Third Phase 3 trial in third type of lymphoma to show improvement in overall survival with an ADCETRIS-containing regimen
The ECHELON-3 results will be presented as a late-breaker (LBA7005) in an oral session at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting along with four-year results from the Phase 3 HD21 trial in advanced classical Hodgkin lymphoma (cHL) (LBA7000).
“ECHELON-3 is one of the first randomized, placebo-controlled Phase 3 studies to demonstrate an overall survival benefit in patients with relapsed/refractory DLBCL after two or more prior lines of systemic therapy,” said principal investigator Dr. Jeung-A Kim, College of Medicine, The Catholic University of
ADCETRIS is approved in the
“Three Phase 3 trials in three different types of lymphoma have now demonstrated that an ADCETRIS-containing regimen improved overall survival,” said Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer. “ADCETRIS is a standard of care medicine in its approved indications today, and these impressive results from an interim analysis highlight its potential to benefit people with relapsed/refractory DLBCL regardless of CD30 expression.”
DLBCL is the most common lymphoma and is aggressive and difficult to treat, with up to 40 percent of patients experiencing disease progression after initial therapy.1,2
Among 230 randomized patients in the trial, the interim analysis showed that median OS in patients randomized to receive ADCETRIS, lenalidomide and rituximab was 13.8 months (
Median progression-free survival (PFS) was 4.2 months (
The most frequently reported treatment-emergent adverse events (TEAEs) Grade 3 or higher for the ADCETRIS versus placebo arms were: neutropenia (
About ECHELON-3
ECHELON-3 is an ongoing, randomized, double-blind, multicenter Phase 3 study evaluating ADCETRIS plus lenalidomide and rituximab versus lenalidomide and rituximab plus placebo in adult patients with relapsed/refractory DLBCL, regardless of CD30 expression, who have received two or more prior lines of therapy and are ineligible for stem cell transplant or CAR-T therapy. In this global study, 230 patients were randomized across
About Diffuse Large B-cell Lymphoma
DLBCL is the most frequent type of lymphoma and is aggressive and difficult to treat.1,2 More than 25,000 cases of DLBCL are diagnosed each year in
About ADCETRIS
More than 55,000 patients have been treated with ADCETRIS in the
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 Pfizer'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
- Adult patients with previously untreated Stage III/IV classical Hodgkin lymphoma (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)
Pfizer and Takeda jointly develop ADCETRIS. Under the terms of the collaboration agreement, Pfizer has
ADCETRIS® (brentuximab vedotin) for injection
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-
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 use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS.
ADVERSE REACTIONS
The most common adverse reactions (≥
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.
Please see the full Prescribing Information, including BOXED WARNING, for ADCETRIS here.
About Pfizer Oncology
At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and bispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives.
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Disclosure Notice
The information contained in this release is as of June 1, 2024. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.
This release contains forward-looking information about Pfizer Oncology and ADCETRIS (brentuximab vedotin), including its potential benefits, its potential for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and the ongoing investigational trial for ADCETRIS in combination with lenalidomide and rituximab, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, uncertainties regarding the commercial success of ADCETRIS; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed in particular jurisdictions for ADCETRIS with lenalidomide and rituximab or as a single agent for any potential indication; whether and when any applications that may be pending or filed for ADCETRIS may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the product's benefits outweigh its known risks and determination of the product's efficacy and, if approved, whether ADCETRIS with lenalidomide and rituximab or as a single agent will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of ADCETRIS with lenalidomide and rituximab or as a single agent; uncertainties regarding the impact of COVID-19 on Pfizer’s business, operations and financial results; and competitive developments.
A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the
1 National Library of Medicine. Diffuse Large B-Cell Lymphoma. https://www.ncbi.nlm.nih.gov/books/NBK557796/. Updated April 24, 2023.
2 Leukemia & Lymphoma Society. Diffuse Large B-Cell Lymphoma (DLBCL). https://www.lls.org/research/diffuse-large-b-cell-lymphoma-dlbcl
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FAQ
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