Author: Michelle Dryden

— Interim results of tisotumab vedotin plus pembrolizumab from Phase 1b/2 innovaTV 205 trial, showing 41% objective response rate in first-line patients with recurrent or metastatic cervical cancer (r/mCC), to be presented in an oral session —

— Additional poster presentations to include debut of web-based tool for identifying geographical areas across the country in high need of cervical cancer intervention —

 

BOTHELL, Wash. & COPENHAGEN, Denmark — (BUSINESS WIRE) — Seagen Inc. (Nasdaq: SGEN) and Genmab A/S (Nasdaq: GMAB) today announced interim data from the innovaTV 205 trial, which included data evaluating tisotumab vedotin (TIVDAK®) in combination with pembrolizumab (Cohort E) in patients with recurrent or metastatic cervical cancer (r/mCC) who have not received prior systemic therapy, with a confirmed objective response rate (ORR) of 41% (95% Confidence Interval [CI]: 24% to 59%) and median durability of response that was not reached within almost 19 months of median follow up. Data were presented during an oral session at the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting on June 6.

 

“These data showed encouraging and durable anti-tumor activity and provide rationale for the continued development of tisotumab vedotin (TV) in front-line recurrent or metastatic cervical cancer, including its potential use as part of triplet or quadruplet combination therapy,” said Domenica Lorusso, M.D., Ph.D., a gynecologic oncologist working at the Gynaecology Oncology Unit of Policlinico Gemelli IRCCS of Rome and an investigator of the innovaTV 205 clinical trial. “These early results from multiple expansion cohorts of innovaTV 205 support our continued efforts to investigate TV as part of combination therapy to further improve treatment response and durability for this group of patients with high unmet need.”

Dose expansion Cohort E enrolled 33 patients with recurrent or metastatic cervical cancer who had not received any prior systemic therapy. At the time of data cutoff, the confirmed ORR among 32 evaluable patients was 41% (95% Confidence Interval [CI], range 24% to 59%), with 16% of patients (n=5) achieving complete responses and 25% of patients (n=8) achieving partial responses. Median duration of response (DOR) was not reached. Median progression-free survival (PFS) was 5.3 months (95% CI: 4.0 to 12.2).

 

Building on data presented at the European Society for Medical Oncology (ESMO) Congress 2021, additional longer-term follow-up data from Cohorts D (tisotumab vedotin in combination with carboplatin in previously untreated patients) and Cohort F (tisotumab vedotin in combination with pembrolizumab in previously treated patients) of the innovaTV 205 trial were also included in the ASCO 2022 oral presentation.

 

In Cohort E, the most common treatment-emergent adverse events (TEAEs) were alopecia (61%), diarrhea (55%), epistaxis (49%), conjunctivitis (45%), and nausea (46%). Prespecified adverse events (AEs) of interest (grade 1-2/grade ≥3) with tisotumab vedotin included ocular (58%/9%), peripheral neuropathy (49%/3%), and bleeding (61%/6%).

 

Tisotumab vedotin in combination with pembrolizumab across lines of treatment (Cohorts E/F), and with carboplatin (Cohort D) in first-line, demonstrated a tolerable and manageable safety profile. Across all three cohorts, no new safety signals were reported outside of known adverse events associated with the individual agents.

 

Tisotumab vedotin is approved for treatment of patients with previously treated recurrent or metastatic cervical cancer in the US and is commercialized under the tradename TIVDAK. See TIVDAK U.S. Important Safety Information, including Boxed Warning, below.

 

“With Genmab, we will continue to investigate tisotumab vedotin in combination with other therapies because there is still an unmet need for more effective first-line treatment for advanced cervical cancer patients,” said Marjorie Green, M.D., Senior Vice President and Head of Late-Stage Development, Seagen. “We’re also researching innovative new tools to help increase awareness of the disparities and unmet needs that cervical cancer patients experience in order to better support this community in the future.”

 

One highlight of real-world studies presented is a poster discussion on the Cervical Cancer Geographical Burden Analyzer. This is an open access, web-based, interactive tool to visualize geographical areas in the US where cervical cancer education or healthcare resource needs are high.

 

“The Cervical Cancer Geographical Burden Analyzer has potential to help expand understanding of cervical cancer disease burden across different communities,” said Tara Castellano, M.D., Gynecologic Oncologist at Louisiana State University’s Department of Gynecologic Oncology and lead investigator for research and development of the Cervical Cancer Geographical Disease Burden Analyzer. “This tool may be particularly useful for researchers, policy makers, and advocacy groups to inform allocation of healthcare resources.”

 

Additional updates from the tisotumab vedotin clinical development program were presented at the ASCO 2022 Annual Meeting, including trial-in-progress overviews for innovaTV 205/ENGOT-cx8/GOG-3024 evaluating first-line tisotumab vedotin in combination with pembrolizumab, carboplatin and bevacizumab in first-line r/mCC; and for innovaTV 207 Part D evaluating tisotumab vedotin in combination with pembrolizumab and platinum in squamous cell carcinoma of the head and neck (HNSCC) and squamous cell non-small cell lung cancer (sqNSCLC).

 

“The collective data presented for tisotumab vedotin at the ASCO 2022 Annual Meeting are reflective of our commitment to investigating this therapy across treatment lines and in combination with other therapies,” said Jan van de Winkel, Ph. D., Chief Executive Officer, Genmab. “With Seagen, we are continuing to advance clinical trials in order to explore future treatment options for recurrent or metastatic cervical cancer patients.”

 

About the innovaTV 205 Trial

The innovaTV 205 trial (also known as ENGOT-cx8/GOG-3024) is a Phase 1b/2 open-label, multi-center trial of tisotumab vedotin monotherapy and in combination with bevacizumab, pembrolizumab, or carboplatin in patients with recurrent or metastatic cervical cancer. The study consists of two parts: dose escalation (Cohorts A, B, and C) and dose expansion (Cohorts D, E, F, G and H). Patients enrolled in the dose escalation cohorts have progressed during or after standard of care therapy or are intolerant or ineligible to receive standard of care treatments. The primary objective is to identify and establish the maximum tolerated dose and Recommended Phase 2 Dose (RP2D) of tisotumab vedotin as combination therapy. Within the dose expansion cohorts, patients with recurrent or metastatic cervical cancer who have not previously received prior systemic therapy are treated in Cohorts D, E and H, with patients who have progressed on or after standard of care treatments evaluated in Cohorts F and G. For more information about the innovaTV 205 clinical trial and the study collaborators, please visit www.clinicaltrials.gov (Identifier: NCT03786081).

 

About Tisotumab Vedotin

Tisotumab vedotin-tftv (TIVDAK®) is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Seagen’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Nonclinical data suggests that the anticancer activity of tisotumab vedotin is due to the binding of the ADC to TF expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

 

In September 2021, the U.S. Food and Drug Administration granted accelerated approval for tisotumab vedotin-tftv (TIVDAK) in adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TIVDAK is the first and only approved ADC for the treatment of these patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The ongoing clinical trial innovaTV 301, an open-label, randomized, global trial, is intended as the confirmatory trial for use in verifying and describing the clinical benefit and as support for US and global regulatory applications.

 

Indication

TIVDAK is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

 

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

 

Important Safety Information

BOXED WARNING: OCULAR TOXICITY

TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during, and after infusion. Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity.

Warnings and Precautions

Ocular Adverse Reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8 % of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose. In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.

 

Refer patients to an eye care provider for an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold dose, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction.

 

Peripheral Neuropathy (PN) occurred in 42% of cervical cancer patients treated with TIVDAK across clinical trials; 8% of patients experienced Grade 3 PN. PN adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain- Barre syndrome. Monitor patients for signs and symptoms of neuropathy. For new or worsening PN, withhold, dose reduce, or permanently discontinue TIVDAK based on the severity of PN.

 

Hemorrhage occurred in 62% of cervical cancer patients treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients. Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue TIVDAK. For Grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue TIVDAK.

 

Pneumonitis: Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody-drug conjugates containing vedotin, including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.

 

Monitor patients for pulmonary symptoms of pneumonitis. Infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations.

 

Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis.

 

Embryo-Fetal Toxicity: TIVDAK can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.

 

Adverse Reactions

In the innovaTV 204 clinical trial (n=101), serious adverse reactions occurred in 43% of patients; the most common (≥3%) were ileus (6%), hemorrhage (5%), pneumonia (4%), PN, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock, pneumonitis, sudden death, and multisystem organ failure (each 1%).

 

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) were PN (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (≥3%) were PN (8%), conjunctival adverse reactions (4%), and hemorrhage (4%). Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

 

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), PN (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%).

 

Drug interactions

Strong CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for TIVDAK adverse reactions.

 

Use in Specific Populations

Moderate or Severe Hepatic Impairment: MMAE exposure and adverse reactions are increased. Avoid use.

 

Lactation: Advise lactating women not to breastfeed during TIVDAK treatment and for at least 3 weeks after the last dose.

 

Please see full prescribing information, including BOXED WARNING for TIVDAK here.

 

About Seagen

Seagen 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 the company’s marketed products and robust pipeline, visit www.seagen.com and follow @SeagenGlobal on Twitter.

 

About Genmab

Genmab is an international biotechnology company with a core purpose to improve the lives of people with cancer. For more than 20 years, Genmab’s vision to transform cancer treatment has driven its passionate, innovative and collaborative teams to invent next-generation antibody technology platforms and leverage translational research and data sciences, fueling multiple differentiated cancer treatments that make an impact on people’s lives. To develop and deliver novel therapies to patients, Genmab has formed 20+ strategic partnerships with biotechnology and pharmaceutical companies. Genmab’s proprietary pipeline includes bispecific T-cell engagers, next-generation immune checkpoint modulators, effector function enhanced antibodies and antibody-drug conjugates.

 

Genmab is headquartered in Copenhagen, Denmark with locations in Utrecht, the Netherlands, Princeton, New Jersey, U.S. and Tokyo, Japan. For more information, please visit Genmab.com and follow us on Twitter.com/Genmab.

 

About the Seagen and Genmab Collaboration

Tisotumab vedotin is being co-developed by Genmab and Seagen, under an agreement in which the companies share costs and profits for the product on a 50:50 basis.

 

Seagen Forward-Looking Statements

Certain statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of tisotumab vedotin, its possible efficacy, safety and therapeutic uses, the referenced clinical trials, and the tisotumab vedotin development program, including the potential for development of tisotumab vedotin in a first-line treatment setting and/or as part of a combination therapy, as well as other planned clinical trial activities. 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 the inability of tisotumab vedotin to show sufficient activity in ongoing or future trials, the risk of adverse events or safety signals, difficulties and delays in planned clinical trial initiations, enrollment and conduct or in obtaining data from clinical trials, in each case for a variety of reasons, including the difficulty and uncertainty of pharmaceutical product development, unexpected adverse events and/or adverse regulatory action, and the possibility that clinical results may fail to support continued development. More information about the risks and uncertainties faced by Seagen is contained under the caption “Risk Factors” included in the company’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2022 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 law.

 

Genmab Forward-Looking Statements

This Media Release contains forward-looking statements. The words “believe,” “expect,” “anticipate,” “intend” and “plan” and similar expressions identify forward-looking statements. Actual results or performance may differ materially from any future results or performance expressed or implied by such statements. The important factors that could cause our actual results or performance to differ materially include, among others, risks associated with pre-clinical and clinical development of products, uncertainties related to the outcome and conduct of clinical trials including unforeseen safety issues, uncertainties related to product manufacturing, the lack of market acceptance of our products, our inability to manage growth, the competitive environment in relation to our business area and markets, our inability to attract and retain suitably qualified personnel, the unenforceability or lack of protection of our patents and proprietary rights, our relationships with affiliated entities, changes and developments in technology which may render our products or technologies obsolete, and other factors. For a further discussion of these risks, please refer to the risk management sections in Genmab’s most recent financial reports, which are available on www.genmab.com and the risk factors included in Genmab’s most recent Annual Report on Form 20-F and other filings with the U.S. Securities and Exchange Commission (SEC), which are available at www.sec.gov. Genmab does not undertake any obligation to update or revise forward looking statements in this Media Release nor to confirm such statements to reflect subsequent events or circumstances after the date made or in relation to actual results, unless required by law.

 

Genmab A/S and/or its subsidiaries own the following trademarks: Genmab^®; the Y-shaped Genmab logo^®; Genmab in combination with the Y-shaped Genmab logo^®; HuMax^®; DuoBody^®; DuoBody in combination with the DuoBody logo^®; HexaBody^®; HexaBody in combination with the HexaBody logo^®; DuoHexaBody^® and HexElect.^®

 

Contacts

INVESTOR & MEDIA CONTACTS

Seagen Contacts:
For Media:
David Caouette

Vice President, Corporate Communications

(310) 430-3476

dcaouette@seagen.com

For Investor Relations:
Peggy Pinkston

Senior Vice President, Investor Relations

(425) 527-4160

ppinkston@seagen.com

Genmab A/S Contacts:
For Media:
David Freundel

Director, Product Communications

(609) 613-0504

dafr@genmab.com

For Investor Relations:
Andrew Carlsen

Vice President, Head of Investor Relations

+45 3377-9558

acn@genmab.com

KEYNOTE-716 is the first Phase 3 trial with an anti-PD-1/L1 to significantly improve distant metastasis-free survival (DMFS) and recurrence-free survival (RFS) for these patients

Based on KEYNOTE-716, KEYTRUDA received US FDA approval and a positive EU CHMP opinion for the adjuvant treatment of patients aged 12 and older with completely resected stage IIB and IIC melanoma

 

RAHWAY, N.J. — (BUSINESS WIRE) — $MRK #MRK–Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced distant metastasis-free survival (DMFS) results from the Phase 3 KEYNOTE-716 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, versus placebo as adjuvant therapy for patients with resected stage IIB or IIC melanoma. With a median follow-up of 27.4 months, KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in DMFS versus placebo (HR=0.64 [95% CI, 0.47-0.88]; p=0.0029). Median DMFS was not reached in either arm. These late-breaking data are being presented for the first time today at 10:45 a.m. ET during an oral abstract session at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA9500).

Additionally, at the median 27.4-month follow-up, KEYTRUDA continued to show a reduction in the risk of recurrence versus placebo (HR=0.64 [95% CI, 0.50-0.84]). According to Kaplan-Meier estimates, 81.2% of patients in the KEYTRUDA arm were recurrence-free at two years compared to 72.8% of patients in the placebo arm. A prespecified exploratory analysis of health-related quality of life (HRQoL) from KEYNOTE-716 will also be presented at ASCO 2022 on Monday, June 6 (abstract #9581), showing HRQoL was similar between the KEYTRUDA and placebo arms based on EORTC Quality of Life Questionnaire Core 30 or EQ-5D-5L VAS scores.

 

“Patients with stage IIB and IIC melanoma are at risk of seeing their cancer return and spread to distant sites,” said Dr. Georgina Long, co-medical director, Melanoma Institute Australia (MIA), and chair, Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney. “The latest results from KEYNOTE-716 show the potential of pembrolizumab to help reduce distant recurrence in patients with resected stage IIB and IIC melanoma, and further highlight the important role of adjuvant therapy for these patients.”

 

In the study, the safety profile of KEYTRUDA was consistent with previously reported studies in patients with solid tumors, and no new safety signals were observed at the time of DMFS analysis. Treatment-related adverse events Grade 3 or higher were observed in 17% of patients receiving KEYTRUDA versus 5% of patients receiving placebo. Immune-mediated events and infusion reactions were higher with KEYTRUDA (38% vs 9%, respectively).

 

“Based on survival data, we know that patients with stage IIB and IIC melanoma have similar five-year outcomes as those with stage IIIB melanoma,” said Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories. “In KEYNOTE-716, treatment with KEYTRUDA after surgery improved both distant metastasis-free survival and recurrence-free survival compared to placebo in patients with stage IIB or IIC melanoma. These data are encouraging for the melanoma community and add to results from six positive pivotal studies for KEYTRUDA-based regimens in earlier stages of cancer.”

 

In addition to KEYNOTE-716, the five other pivotal trials evaluating a KEYTRUDA-based regimen in patients with earlier stages of cancer met their primary endpoint(s). These trials include: KEYNOTE-091 in stage IB (≥4 centimeters) to IIIA non-small cell lung cancer; KEYNOTE-054 in stage III melanoma; KEYNOTE-564 in renal cell carcinoma; KEYNOTE-522 in triple-negative breast cancer; and KEYNOTE-057 in Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer.

 

Based on RFS results from KEYNOTE-716, the U.S. Food and Drug Administration approved KEYTRUDA for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB or IIC melanoma following complete resection in December 2021. With the approval, KEYTRUDA became the first anti-PD-1 adjuvant treatment option for patients (12 years and older) across completely resected stage IIB, IIC and III melanoma. The European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a positive opinion based on KEYNOTE-716 in May 2022, and the data will be shared with additional health authorities globally.

 

A compendium of Merck’s presentations and posters is available here. Please visit https://www.merck.com/media/merck-at-asco-2022 and @Merck on Twitter to keep up to date with ASCO news and updates.

 

KEYNOTE-716 study design and additional data

KEYNOTE-716 (ClinicalTrials.gov, NCT03553836) is a randomized, double-blind Phase 3 trial that enrolled 976 adult and pediatric patients (12 years and older) with resected stage IIB or IIC melanoma. Following complete surgical resection, patients were randomized to KEYTRUDA 200 mg for adult patients and 2 mg/kg (up to 200 mg) for pediatric patients or placebo every three weeks for approximately one year until disease recurrence or unacceptable toxicity. The primary endpoint was RFS, and secondary endpoints included DMFS and overall survival. Overall survival will continue to be followed for upcoming analyses.

 

As of data cutoff for the third interim analysis (Jan. 4, 2022), the median study follow-up was 27.4 months. Distant metastasis-free survival was defined as time from randomization to the first diagnosis of distant metastasis. In the KEYTRUDA arm, 12.9% (n=63/487) of patients experienced a DMFS event versus 19.4% (n=95/489) of patients in the placebo arm. The estimated two-year DMFS rates were 88.1% with KEYTRUDA versus 82.2% with placebo.

 

As previously announced, the study met the primary endpoint of RFS at the first interim analysis (HR=0.65 [95% CI, 0.46-0.92]; p=0.00658). At the third interim analysis, 19.5% (n=95/487) of patients who received KEYTRUDA experienced an RFS event versus 28.4% (n=139/489) of patients who received placebo. At two years, the estimated RFS rates were 81.2% with KEYTRUDA versus 72.8% with placebo.

 

About Merck’s research in melanoma

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The rates of melanoma have been rising over the past few decades, with nearly 325,000 new cases diagnosed worldwide in 2020. In the U.S., skin cancer is one of the most common types of cancer diagnosed, and melanoma accounts for a large majority of skin cancer deaths. It is estimated there will be nearly 100,000 new cases of melanoma diagnosed and almost 8,000 deaths resulting from the disease in the U.S. in 2022.

 

The recurrence rates for resected melanoma are estimated to be 32-46% for patients with stage IIB and stage IIC disease and 39-74% for patients with stage III disease. The five-year survival rates (AJCC eighth edition) are estimated to be 87% for stage IIB, 82% for stage IIC, 93% for stage IIIA, 83% for stage IIIB, 69% for stage IIIC and 32% for stage IIID.

 

Merck is committed to delivering meaningful advances for patients with melanoma with KEYTRUDA and to continuing research in skin cancers through a broad clinical development program across investigational and approved medicines. KEYTRUDA has been established as an important treatment option for the adjuvant treatment of adult patients with resected stage III melanoma and is approved in over 90 countries based on the results from EORTC1325/KEYNOTE-054. KEYTRUDA is also approved worldwide for the treatment of patients with unresectable or metastatic melanoma.

 

About Merck’s early-stage cancer clinical program

Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

 

About KEYTRUDA^® (pembrolizumab) injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

 

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,700 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

 

Selected KEYTRUDA^® (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.

See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.

 

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

 

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

 

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

 

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

 

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

 

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

 

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

 

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

 

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

 

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

 

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

 

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

 

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

 

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

 

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

 

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

 

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

 

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause).

Contacts

Media Contacts:

Melissa Moody

(215) 407-3536

Ayn Wisler

(917) 691-6218

Investor Contacts:

Peter Dannenbaum

(908) 740-1037

Damini Chokshi

(908) 740-1807

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• Daiichi Sankyo and AstraZeneca’s ENHERTU also improved median overall survival by more than 6 months vs. chemotherapy in all patients evaluated in DESTINY-Breast04
• ENHERTU met the primary endpoint of progression free survival in patients with HR positive disease, reducing the risk of disease progression or death by 49% vs. chemotherapy
• ENHERTU is the first HER2 directed therapy to demonstrate a survival benefit in this population, potentially redefining treatment for approximately half of all patients with breast cancer

 

TOKYO & MUNICH & BASKING RIDGE, N.J. — (BUSINESS WIRE) — Detailed positive results from the pivotal DESTINY-Breast04 phase 3 trial showed that ENHERTU^® (trastuzumab deruxtecan) demonstrated superior and clinically meaningful progression-free survival (PFS) and overall survival (OS) in previously treated patients with HER2 low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridization (ISH)-negative) unresectable and/or metastatic breast cancer with hormone receptor (HR) positive or HR negative disease versus standard of care physician’s choice of chemotherapy. Results will be presented during the Plenary Session (#LBA3) today at the American Society of Clinical Oncology (#ASCO22) Annual Meeting and have been simultaneously published in The New England Journal of Medicine.

ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN).

 

In the primary endpoint analysis for DESTINY-Breast04, ENHERTU demonstrated a 49% reduction in the risk of disease progression or death versus physician’s choice of chemotherapy in patients with HER2 low metastatic breast cancer with HR positive disease (hazard ratio [HR] = 0.51; 95% confidence interval [CI]: 0.40-0.64; p<0.001). A median PFS of 10.1 months (9.5-11.5) was seen in patients treated with ENHERTU compared to 5.4 months (4.4-7.1) with chemotherapy, as assessed by blinded independent central review (BICR).

 

Results also showed a 36% reduction in the risk of death with ENHERTU compared to chemotherapy in patients with HR positive disease (HR = 0.64; 95% CI: 0.48-0.86; p=0.003) with a median OS of 23.9 months with ENHERTU (95% CI: 20.8-24.8) versus 17.5 months with chemotherapy (95% CI: 15.2-22.4), meeting a key secondary endpoint of the trial. Confirmed objective response rate (ORR) more than tripled in the ENHERTU arm versus the chemotherapy arm (52.6% [n=175/333; 95% CI: 47.0-58.0%] versus 16.3% [n=27/166; 95% CI: 11.0-22.8%], respectively). Twelve (3.6%) complete responses (CR) and 164 (49.2%) partial responses (PR) were observed in patients with HR positive disease treated with ENHERTU compared to one (0.6%) CR and 26 (15.7%) PRs in those treated with chemotherapy. Median duration of response was 10.7 months for ENHERTU versus 6.8 months for chemotherapy.

 

“The results of DESTINY-Breast04 show for the first time that a HER2 directed therapy can provide a survival benefit to patients with low HER2 expression, indicating we must reconsider the way we categorize patients with metastatic breast cancer,” said Shanu Modi, MD, medical oncologist, Memorial Sloan Kettering Cancer Center and principal investigator for the trial. “The efficacy seen with ENHERTU also reinforces the potential to establish a new standard of care for more than half of all patients with breast cancer currently categorized as having HER2 negative disease, but who actually have tumors with low HER2 expression.”

 

Additionally, data showed consistent efficacy for ENHERTU in the overall trial population of patients with HER2 low metastatic breast cancer with HR positive or HR negative disease and across levels of HER2 expression (both IHC1+ and IHC 2+/ISH-). In the key secondary endpoint analysis of PFS by BICR in all patients, a similar 50% reduction in the risk of disease progression or death was observed between ENHERTU and chemotherapy (HR = 0.50; 95% CI:0.40-0.63; p<0.001), with a median PFS of 9.9 months (9.0-11.3) for ENHERTU versus 5.1 months (4.2-6.8) in those treated with chemotherapy. Results of the key secondary endpoint of OS in all patients also showed a median OS of 23.4 months (20.0-24.8) for ENHERTU versus 16.8 months (14.5-20.0) with chemotherapy (HR=0.64; 95% CI: 0.49-0.84; p=0.001), with confirmed ORR more than tripled in the ENHERTU arm (52.3% [n=195/373; 95% CI: 47.1-57.4%]) versus those treated with chemotherapy (16.3% [n=30/184; 95% CI: 11.3-22.5%]).

 

In an exploratory analysis of patients with HR negative disease, median PFS was 8.5 months (4.3-11.7) with ENHERTU versus 2.9 months (1.4-5.1) with chemotherapy (HR=0.46; 95% CI: 0.24-0.89). Median OS was 18.2 months (13.6-NE) with ENHERTU versus 8.3 months (5.6-20.6) with chemotherapy (HR=0.48; 95%CI: 0.24-0.95). Confirmed ORR was 50% with ENHERTU (n=20/40; 95% CI: 33.8-66.2%) versus 16.7% with chemotherapy (n=3/18; 95% CI: 3.6-41.4%).

 

The safety profile of ENHERTU was consistent with previous clinical trials with no new safety concerns identified. The most common grade 3 or higher treatment emergent adverse events were neutropenia (13.7%), anemia (8.1%), leukopenia (6.5%), fatigue (7.5%), thrombocytopenia (5.1%), nausea (4.6%), increased aminotransferase (3.2%), decreased appetite (2.4%), vomiting (1.3%) and diarrhea (1.1%). Interstitial lung disease (ILD) or pneumonitis rates were consistent with that observed in late-line HER2 positive breast cancer trials of ENHERTU with a lower rate of grade 5 ILD observed, as determined by an independent adjudication committee. Overall, 12.1% of patients had confirmed ILD or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (10%) were primarily low grade (grade 1 (3.5%) or grade 2 (6.5%)) with five grade 3 (1.3%), no grade 4 and three grade 5 (0.8%) events reported.

 

“As innovative research organizations, extending the survival for patients is one of our primary goals as we seek to identify potentially new treatment options for patients with metastatic breast cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “These potentially practice-changing data show that DESTINY-Breast04 takes us one step closer to achieving this goal, as ENHERTU is the first HER2 directed medicine to demonstrate a survival benefit in patients with HER2 low metastatic breast cancer. We are honored by the recognition these important findings are receiving at one of the world’s most prominent oncology meetings as well as in one of the leading medical journals.”

 

“Today’s results represent a pivotal moment demonstrating the potential for ENHERTU to redefine the treatment of HER2 targetable cancers,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “DESTINY-Breast04 validates targeting the lower end of the spectrum of HER2 expression, since ENHERTU reduced the risk of disease progression or death across all types of patients in the trial by half and reduced the risk of death by over a third. We must now evolve the way we classify and treat metastatic breast cancer to ensure these patients are effectively diagnosed and treated.”

 

All patients in DESTINY-Breast04 received at least one prior cancer therapy, including targeted therapy (ENHERTU = 279; chemotherapy = 140), a CDK4/6 inhibitor (ENHERTU = 239; chemotherapy = 119), endocrine therapy (ENHERTU = 347; chemotherapy = 165), chemotherapy (ENHERTU = 373; chemotherapy = 183). The median lines of prior systemic therapies in the metastatic setting were three (range 1-9). A prior CDK4/6 inhibitor was received by 70% of hormone receptor positive patients (ENHERTU = 233/331; chemotherapy = 115/163). As of data cut-off on January 11, 2022, 58 patients remained on treatment with ENHERTU and 3 patients on chemotherapy.

 

Summary of DESTINY-Breast04 Results

Efficacy Measure	HR Positive (n=494)		All Patients (n=557)		HR Negative (n=58)i
	ENHERTU (5.4 mg/kg) (n=331)	Chemotherapy (n=163)	ENHERTU (5.4 mg/kg) (n=373)	Chemotherapy (n=184)	ENHERTU (5.4 mg/kg) (n=40)	Chemotherapy (n=18)
Median PFS (months) (95% CI)ii	10.1 months (9.5-11.5)	5.4 months (4.4-7.1)	9.9 months (9.0-11.3)	5.1 months (4.2-6.8)	8.5 months (4.3-11.7)	2.9 months (1.4-5.1)
	HR=0.51 (0.40-0.64) p<0.001		HR=0.50 (0.40-0.63) p<0.001		HR=0.46 (0.24-0.89)
Median OS (months) (95% CI)	23.9 months (20.8-24.8)	17.5 months (15.2-22.4)	23.4 months (20.0-24.8)	16.8 months (14.5-20.0)	18.2 months (13.6-NE)	8.3 months (5.6-20.6)
	HR=0.64 (0.48-0.86) p=0.003		HR=0.64 (0.49-0.84) p=0.001		HR=0.48 (0.24-0.95)
Confirmed ORR (%) (95% CI)ii,iii	52.6% (47.0-58.0)	16.3% (11.0-22.8)	52.3% (47.1-57.4)	16.3% (11.3-22.5)	50.0% (33.8-66.2)	16.7% (3.6-41.4)
CR (%)	3.6%	0.6%	3.5%	1.1%	2.5%	5.6%
PR (%)	49.2%	15.7%	49.1%	15.2%	47.5%	11.1%
SD (%)	35.1%	50.0%	34.6%	49.5%	30.0%	44.4%
PD (%) (95% CI)	7.8%	21.1%	8.3%	22.3%	12.5%	33.3%
Median DoR (months)ii	10.7 months	6.8 months	10.7 months	6.8 months	8.6 months	4.9 months
CBR (%)ii,iv	71.2%	34.3%	70.2%	33.7%	62.5%	27.8%
DCR (%)v	88.0%	66.3%	87.1%	65.8%	80.0%	61.1%

CI, confidence interval; CBR, clinical benefit rate; CR, complete response; DCR, disease control rate; DoR, duration of response; HR, hazard ratio; NE, not evaluable; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease

i For the primary endpoint (PFS in the HR positive cohort) and key secondary endpoints (PFS among all patients and OS in the HR positive cohort and among all patients), the HR status is based on data collected with the use of the interactive Web response and voice response system at the time of randomization, which includes patients who were mis-stratified. For the other endpoints, HR status is based on data from the electronic data capture that was corrected for mis-stratification

ii As assessed by BICR

iii ORR is (CR + PR)

iv CBR is CR + PR + SD (≥ 6 months)

v DCR is (CR + PR + SD)

 

About DESTINY-Breast04

DESTINY-Breast04 is a global, randomized, open-label, pivotal phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR positive or HR negative, HER2 low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either ENHERTU or chemotherapy.

 

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR positive disease based on blinded independent central review (BICR). Key secondary endpoints include PFS based on BICR in all randomized patients (HR positive and HR negative disease), OS in patients with HR positive disease and OS in all randomized patients (HR positive and HR negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety.

 

DESTINY-Breast04 enrolled 557 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

 

About Breast Cancer and HER2 Expression

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.¹ More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.¹

 

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers, and is one of many biomarkers expressed in breast cancer tumors.²

 

HER2 expression is currently defined as either positive or negative, and is determined by an IHC test which measures the amount of HER2 protein on a cancer cell, and/or an ISH test, which counts the copies of the HER2 gene in cancer cells.^2,3 HER2 positive cancers are defined as IHC 3+, IHC 2+/ISH+.² HER2 negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.² Approximately half of all patients with breast cancer have tumors with a HER2 IHC score of 1+, or a HER2 IHC score of 2+ in combination with a negative ISH test, an expression level not currently eligible for HER2 targeted therapy.^4,5,6,7 Low HER2 expression occurs in both HR positive and HR negative disease.⁸

 

HER2 testing is routinely used to determine appropriate treatment options for patients with metastatic breast cancer. Targeting the lower range of expression in the HER2 spectrum may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.⁹ Currently, patients with low HER2 expression with HR positive tumors have limited treatment options following progression on endocrine (hormone) therapy.¹⁰ Few targeted options are available for those who are HR negative.¹¹

 

About ENHERTU

ENHERTU^® (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

 

ENHERTU (5.4 mg/kg) is approved in the U.S. and Israel for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy, based on results from the DESTINY-Breast03 trial. ENHERTU is also approved in approximately 40 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

 

ENHERTU (6.4 mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

 

ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity. For more information, please see the accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

 

About the ENHERTU Clinical Development Program

A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

 

Regulatory applications for ENHERTU are currently under review in China, Europe, Japan and several other countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a prior anti-HER2-based regimen based on the results from the DESTINY-Breast03 trial.

 

ENHERTU was granted Breakthrough Therapy Designation in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results of the DESTINY-Breast04 trial. Patients with hormone receptor (HR) positive breast cancer should additionally have received or be ineligible for endocrine therapy.

 

ENHERTU also is currently under review in the U.S. for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have a HER2 (ERBB2) mutation and who have received a prior systemic therapy based on the results from the DESTINY-Lung01 trial, and in Europe for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2 based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

 

About the Daiichi Sankyo and AstraZeneca Collaboration

Daiichi Sankyo Company, Limited (referred to as Daiichi Sankyo) and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

 

U.S. Important Safety Information for ENHERTU

Indications

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

• Unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either:

  – In the metastatic setting, or

  – In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy

• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms. Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications

None.

Warnings and Precautions

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Metastatic Breast Cancer

In clinical studies, of the 491 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 13% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.4% of patients treated with ENHERTU. Median time to first onset was 5.5 months (range: 1.1 to 20.8).

Locally Advanced or Metastatic Gastric Cancer

In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 10⁹/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 10⁹/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 10⁹/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Metastatic Breast Cancer

In clinical studies, of the 491 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 68% of patients. Eighteen percent had Grade 3 or 4 decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 6 to 664). Febrile neutropenia was reported in 1.2% of patients.

Locally Advanced or Metastatic Gastric Cancer

In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Metastatic Breast Cancer

In the 491 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, 13 cases (2.6%) of asymptomatic LVEF decrease were reported.

Locally Advanced or Metastatic Gastric Cancer

In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus.

Contacts

Media Contacts:

Global:
Victoria Amari

Daiichi Sankyo, Inc.

vamari@dsi.com
+1 908 900 3010 (mobile)

US:
Don Murphy

Daiichi Sankyo, Inc.

domurphy@dsi.com
+1 917 817 2649 (mobile)

EU:
Simone Jendsch-Dowé

Daiichi Sankyo Europe GmbH

simone.dowe@daiichi-sankyo.com
+49 (89) 7808437 (office)

+49 176 11780822 (mobile)

Japan:
Masashi Kawase

Daiichi Sankyo Co., Ltd.

kawase.masashi.a2@daiichisankyo.co.jp
+81 3 6225 1126 (office)

Investor Relations Contact:
DaiichiSankyoIR@daiichisankyo.co.jp

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