Tag: Business

• Daiichi Sankyo and AstraZeneca’s ENHERTU showed a median progression-free survival of 6.9 months and median overall survival of 13.4 months in the overall trial population
• Results reaffirm potential role of ENHERTU as a tumor agnostic therapy for previously treated patients with HER2 expressing solid tumors and support ongoing discussions with global regulatory authorities

 

 

TOKYO & BASKING RIDGE, N.J. — (BUSINESS WIRE) — Positive results from the ongoing DESTINY-PanTumor02 phase 2 trial showed that ENHERTU^® (trastuzumab deruxtecan) continued to demonstrate clinically meaningful and durable responses, leading to a clinically meaningful survival benefit in previously treated patients across multiple HER2 expressing advanced solid tumors.

 

These results, which include the first progression-free survival (PFS) and overall survival (OS) findings reported from the trial, will be presented today as a late-breaking mini-oral session (LBA34) at the European Society for Medical Oncology (#ESMO23) 2023 Congress and simultaneously published in the Journal of Clinical Oncology.

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 analysis, ENHERTU continued to show a confirmed objective response rate (ORR) of 37.1% (95% confidence interval [CI]: 31.3-43.2) as assessed by investigator in the overall population of previously treated patients (n=267) with HER2 expressing advanced solid tumors, including either biliary tract, bladder, cervical, endometrial, ovarian, pancreatic or other tumors. A median duration of response (DOR) of 11.3 months (95% CI: 9.6-17.8) was seen with a median PFS of 6.9 months (95% CI: 5.6-8.0) and median OS of 13.4 months (95% CI: 11.9-15.5). Median follow-up was 12.75 months as of the data cut-off of June 8, 2023.

 

The highest response rates continued to be seen in the exploratory analysis of patients with tumor HER2 expression of immunohistochemistry (IHC) 3+ (n=75) as confirmed by central testing, where ENHERTU demonstrated a confirmed ORR of 61.3% (95% CI: 49.4-72.4). A median DOR of 22.1 months (95% CI: 9.6-NR) was achieved in this population of patients with HER2 IHC 3+ expression, with ENHERTU demonstrating a median PFS of 11.9 months (95% CI: 8.2-13.0) and a median OS of 21.1 months (95% CI: 15.3-29.6). These clinically meaningful outcomes affirm the interim DESTINY-PanTumor02 results presented earlier this year at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

 

“These primary analysis results confirm the efficacy shown at an interim analysis of the DESTINY-PanTumor02 trial, with responses leading to clinically meaningful survival outcomes across a broad range of HER2 expressing solid tumors,” said Funda Meric-Bernstam, MD, Chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and Principal Investigator for the trial. “Based on these results, ENHERTU has the potential to change the course of disease for certain patients with HER2 expressing advanced cancers who have limited treatment options and currently no approved HER2 directed therapies.”

 

The safety profile observed in DESTINY-PanTumor02 was consistent with previous clinical trials of ENHERTU with no new safety concerns identified. Grade 3 or higher treatment emergent adverse events (TEAEs) occurred in 40.8% of patients. The most common grade 3 or higher TEAEs occurring in ≥5% of patients were neutropenia (19.1%), anemia (10.9%), fatigue (7.1%) and thrombocytopenia (5.6%). In DESTINY-PanTumor02, 10.5% of patients (n=28) experienced interstitial lung disease (ILD) or pneumonitis of any grade related to treatment with ENHERTU as determined by an independent adjudication committee. The majority of ILD or pneumonitis events were low grade (grade 1 [n=7; 2.6%] or grade 2 [n=17; 6.4%]) with one grade 3 (0.4%), zero grade 4 (0%) and three grade 5 (1.1%) events observed.

 

“Improving survival outcomes for patients is one of the primary goals of cancer treatment and the clinically meaningful progression-free and overall survival results seen in DESTINY-PanTumor02 are encouraging,” said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. “These results provide additional evidence for ENHERTU to potentially become the first antibody drug conjugate approved in a tumor agnostic setting in patients whose tumors express HER2.”

 

“These updated data from DESTINY-PanTumor02 continue to illustrate the importance of HER2 as an actionable biomarker across a range of studied solid tumor types,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. “ENHERTU has the potential to offer improved outcomes for specific patients with previously treated HER2 expressing cancers and we hope to bring this important medicine to patients as quickly as possible.”

 

In DESTINY-PanTumor02, 40.8% of patients (n=109) had received three or more prior lines of therapy. As of the data cut-off of June 8, 2023, a total of 267 patients had received treatment and of those 75 (28.1%) were IHC 3+ as determined by central testing.

 

Summary of DESTINY-PanTumor02 Primary Analysis Results

Efficacy Measure	All Patients	Endometrial	Cervical	Ovarian	Bladder	BTC	Pancreatic	Otheri
All IHC Expression Levels
(n)	267	40	40	40	41	41	25	40
Confirmed ORR (%) (Investigator Assessed) (95% CI)ii	37.1% (31.3-43.2)	57.5% (40.9-73.0)	50.0% (33.8-66.2)	45.0% (29.3-61.5)	39.0% (24.2-55.5)	22.0% (10.6-37.6)	4.0% (0.1-20.4)	30.0% (16.6-46.5)
Median DOR (months) (95% CI)iii	11.3 (9.6-17.8)	NR (9.9-NR)	14.2 (4.1-NR)	11.3 (4.1-22.1)	8.7 (4.3-11.8)	8.6 (2.1-NR)	5.7 (NR-NR)	22.1 (4.1-NR)
Median PFS (months) (95% CI)	6.9 (5.6-8.0)	11.1 (7.1-NR)	7.0 (4.2-11.1)	5.9 (4.0-8.3)	7.0 (4.2-9.7)	4.6 (3.1-6.0)	3.2 (1.8-7.2)	8.8 (5.5-12.5)
Median OS (months) (95% CI)	13.4 (11.9-15.5)	26.0 (12.8-NR)	13.6 (11.1-NR)	13.2 (8.0-17.7)	12.8 (11.2-15.1)	7.0 (4.6-10.2)	5.0 (3.8-14.2)	21.0 (12.9-24.3)
IHC 3+
(n)	75	13	8	11	16	16	2	9
Confirmed ORR (%) (95% CI)ii	61.3% (49.4-72.4)	84.6% (54.6-98.1)	75.0% (34.9-96.8)	63.6% (30.8-89.1)	56.3% (29.9-80.2)	56.3% (29.9-80.2)	0.0%	44.4% (13.7-78.8)
Median DOR (months) (95% CI)iii	22.1 (9.6-NR)
Median PFS (months) (95% CI)	11.9 (8.2-13.0)	NR (7.3-NR)	NR (3.9-NR)	12.5 (3.1-NR)	7.4 (3.0-11.9)	7.4 (2.8-12.5)	5.4 (2.8-NR)	23.4 (5.6-NR)
Median OS (months) (95% CI)	21.1 (15.3-29.6)	26.0 (18.9-NR)	NR (3.9-NR)	20.0 (3.8-NR)	13.4 (6.7-19.8)	12.4 (2.8-NR)	12.4 (8.8-NR)	24.3 (11.1-NR)
IHC 2+
(n)	125	17	20	19	20	14	19	16
Confirmed ORR (%) (95% CI)ii	27.2% (19.6-35.9)	47.1%	40.0%	36.8%	35.0%	0.0%	5.3%	18.8%
Median DOR (months) (95% CI)iii	9.8 (4.3-12.6)
Median PFS (months) (95% CI)	5.4 (4.2-6.0)	8.5 (4.6-15.1)	4.8 (2.7-5.7)	4.1 (2.3-12.6)	7.8 (2.6-11.6)	4.2 (2.8-6.0)	2.8 (1.4-9.1)	5.5 (2.8-8.7)
Median OS (months) (95% CI)	12.2 (10.7-13.5)	16.4 (8.0-NR)	11.5 (5.1-NR)	13.0 (4.7-21.9)	13.1 (11.0-19.9)	6.0 (3.7-11.7)	4.9 (2.4-15.7)	14.6 (6.8-22.4)
BTC, biliary tract cancer; CI, confidence interval; DOR, duration of response; IHC, immunohistochemistry; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival
iResponses in extramammary Paget disease, head and neck cancer, oropharyngeal neoplasm, and salivary gland cancer.
iiAnalysis of ORR by investigator was performed in patients who received ≥1 dose of ENHERTU; all patients (n=267; including 67 patients with IHC 1+ [n=25], IHC 0 [n=30], or unknown IHC status [n=12] by central testing) and patients with centrally confirmed HER2 IHC 3+ (n=75) or IHC 2+ (n=125) status.
iiiAnalysis of DOR was performed in patients with objective response who received ≥1 dose of ENHERTU; all patients (n=99; including 19 patients with IHC 1+ [n=6], IHC 0 [n=9], or unknown IHC status [n=4] by central testing) and patients with centrally confirmed HER2 IHC 3+ (n=46) or IHC 2+ (n=34) status.

 

About DESTINY-PanTumor02

DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label phase 2 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) for the treatment of previously treated HER2 expressing tumors, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancer or other tumors. The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator. Secondary endpoints include DOR, disease control rate, PFS, OS, safety, tolerability and pharmacokinetics. DESTINY-PanTumor02 has enrolled 267 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

 

About HER2 Expression in Solid Tumors

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tissue cells throughout the body and is involved in normal cell growth.^1,2 In some cancers, HER2 expression is amplified or the cells have activating mutations.^1,3 HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis.⁴

 

While HER2 directed therapies have been used to treat breast, gastric, lung and colorectal cancers, more research is needed evaluating their potential role in treating other HER2 expressing solid tumor types.^2,5,6

 

HER2 is an emerging biomarker in solid tumor types including biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers.³ Testing is not routinely performed in these additional tumor types and as a result, available literature is limited. HER2 overexpression (IHC 3+) has been observed at rates from 1% to 28% in these solid tumors.^7,8

 

There is an unmet need for effective therapies for certain HER2 expressing solid tumors, particularly for those who have progressed on or are refractory to standard of care therapies as there are currently no approved HER2 directed therapies for these cancers.^2,9

 

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 number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

 

ENHERTU (5.4 mg/kg) is approved in more than 55 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a (or one or more) 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 the results from the DESTINY-Breast03 trial.

 

ENHERTU (5.4 mg/kg) is approved in more than 40 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/in-situ hybridization (ISH)-) 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 from the DESTINY-Breast04 trial.

 

ENHERTU (5.4 mg/kg) is approved in more than 30 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

 

ENHERTU (6.4 mg/kg) is approved in more than 30 countries worldwide 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 and/or DESTINY-Gastric02 trials.

 

About the ENHERTU Clinical Development Program

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

 

About the Daiichi Sankyo and AstraZeneca Collaboration

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 for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

 

About the DXd ADC Portfolio of Daiichi Sankyo

The DXd ADC portfolio of Daiichi Sankyo currently consists of six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc., Rahway, N.J. USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.

 

Designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan and DS-3939 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

 

ENHERTU U.S. Important Safety Information

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

• Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
• Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy

  This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

• 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. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. 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 and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. Median time to first onset was 5 months (range: 0.9 to 23).

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In 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).

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, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 10⁹/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Sixteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 664). Febrile neutropenia was reported in 1.1% of patients.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In 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 and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.6% of patients, of which 0.4% were Grade 3.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In 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. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.

Additional Dose Modifications

Thrombocytopenia

For Grade 3 thrombocytopenia (platelets <50 to 25 x 10⁹/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 10⁹/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level.

Adverse Reactions

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 984 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, and DESTINY-Lung02. Among these patients 65% were exposed for >6 months and 39% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (71%), decreased hemoglobin (66%), decreased neutrophil count (65%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (47%), increased aspartate aminotransferase (48%), vomiting (44%), increased alanine aminotransferase (42%), alopecia (39%), increased blood alkaline phosphatase (39%), constipation (34%), musculoskeletal pain (32%), decreased appetite (32%), hypokalemia (28%), diarrhea (28%), and respiratory infection (24%).

Contacts

Media:

Global/US:

Jennifer Brennan

Daiichi Sankyo, Inc.

jbrennan2@dsi.com
+1 908 900 3183 (mobile)

Japan:
Koji Ogiwara

Daiichi Sankyo Co., Ltd.

ogiwara.koji.ay@daiichisankyo.co.jp
+81 3 6225 1126 (office)

Investor Relations Contact:
DaiichiSankyoIR@daiichisankyo.co.jp

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KEYTRUDA plus enfortumab vedotin significantly prolonged overall survival (OS) by 53% – an improvement in median OS of more than 15 months – compared to chemotherapy in the total patient population

Late-breaking results from the Phase 3 KEYNOTE-A39/EV-302 trial were selected for the official Press Briefing and presentation during a Presidential Symposium session at the European Society for Medical Oncology Congress 2023

RAHWAY, N.J. — (BUSINESS WIRE) — $MRK #MRK — Merck (NYSE: MRK), known as MSD outside of the United States and Canada, on Sunday announced results from the Phase 3 KEYNOTE-A39 trial (also known as EV-302), which was conducted in collaboration with Seagen and Astellas, evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, plus Padcev (enfortumab vedotin-ejfv), an antibody-drug conjugate, compared to chemotherapy (gemcitabine plus cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC).

 

Findings from its first pre-specified analysis showed that KEYTRUDA plus enfortumab vedotin significantly improved overall survival (OS), reducing the risk of death by 53% compared to chemotherapy (median OS, 31.5 months vs. 16.1 months, respectively), an improvement in median OS of more than 15 months; (HR=0.47 [95% CI, 0.38-0.58]; p<0.00001). KEYTRUDA plus enfortumab vedotin also achieved a significant improvement in progression-free survival (PFS), reducing the risk of disease progression or death by 55% (median PFS, 12.5 months vs. 6.3 months, respectively); (HR=0.45 [95% CI, 0.38-0.54]; p<0.00001). Results were consistent across all predefined subgroups, including patients who may or may not be eligible for treatment with cisplatin-based chemotherapy, patients whose tumors expressed both high (Combined Positive Score [CPS] ≥10) or low (CPS <10) levels of PD-L1, and patients with or without liver metastases. These late-breaking data are being presented for the first time today during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2023 (abstract #LBA6) and are included in the official ESMO Press Briefing.

 

“As an investigator in this trial and a physician who treats patients with advanced urothelial cancer, I can attest to the challenging nature of this diagnosis for patients and their families,” said Dr. Thomas Powles, KEYNOTE-A39 primary investigator, professor of Genitourinary Oncology and director, Barts Cancer Center. “These results, showing a 53% reduction in the risk of death for the combination compared to chemotherapy, are striking and may open a new chapter for the treatment of these patients diagnosed with advanced urothelial carcinoma, who face an urgent need for new therapies.”

 

“Our goal is to extend the lives of patients with cancer, and these unambiguous survival findings from KEYNOTE-A39 showing that KEYTRUDA plus enfortumab vedotin reduced the risk of death by half when compared to chemotherapy are important to patients and the medical community alike,” said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “These results – the first positive Phase 3 results combining a PD-1 inhibitor and an antibody-drug conjugate in this patient population – have the potential to change the treatment paradigm for previously untreated patients with advanced urothelial cancer regardless of whether patients are eligible or ineligible for cisplatin.”

 

The Phase 3 KEYNOTE-A39 trial is intended to serve as the basis for global regulatory submissions and as the confirmatory trial for the current U.S. accelerated approval of KEYTRUDA plus enfortumab vedotin as first-line treatment for patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy. The accelerated approval is based on data from the KEYNOTE-869 trial (also known as EV-103) dose escalation cohort, Cohort A and Cohort K.

 

As announced, data spanning more than 15 types of cancer are being presented from Merck’s broad oncology portfolio and investigational pipeline at the ESMO Congress 2023.

Study design and additional data from KEYNOTE-A39 (EV-302)

The KEYNOTE-A39 trial (ClinicalTrials.gov, NCT04223856) is an open-label, randomized, controlled Phase 3 trial evaluating KEYTRUDA plus enfortumab vedotin compared to chemotherapy (gemcitabine plus cisplatin or carboplatin) for the treatment of patients with previously untreated la/mUC. The trial enrolled patients who may or may not be eligible for treatment with cisplatin-based chemotherapy, regardless of PD-L1 status. The dual primary endpoints are PFS as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and OS. Secondary endpoints include objective response rate (ORR) per RECIST v1.1 by BICR, time to pain progression and duration of response (DOR) per RECIST v1.1 by BICR. The study enrolled 886 patients, randomized to receive either:

• KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle for a maximum of 35 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first) plus enfortumab vedotin (125 mg/m² by IV on Days 1 and 8 of each three-week cycle for an unlimited number of cycles until a protocol defined reason for study discontinuation occurs); or
• Gemcitabine (administered as IV infusion on Days 1 and 8 of each three-week cycle) plus platinum-containing chemotherapy (either carboplatin [administered by IV on Day 1 of each three-week cycle] or cisplatin [administered by IV on Day 1 of each three-week cycle]) for a maximum of six cycles or a protocol-defined reason for study discontinuation occurs, whichever is first.

 

In KEYNOTE-A39, KEYTRUDA plus enfortumab vedotin demonstrated statistically significant and clinically meaningful improvements in the secondary endpoints of ORR and DOR. Confirmed ORR by BICR was 67.7% (95% CI, 63.1%-72.1%) in the KEYTRUDA plus enfortumab vedotin arm and 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (p<0.00001). Median DOR was not reached in the KEYTRUDA plus enfortumab vedotin arm; in the chemotherapy arm, median DOR was seven months.

 

59% of patients in the chemotherapy arm received a PD-1/PD-L1 inhibitor as first subsequent systemic therapy, either as maintenance or second-line therapy.

 

The safety profile for KEYTRUDA plus enfortumab vedotin was consistent with results observed in the Phase 1/2 KEYNOTE-869/EV-103 trial. Treatment-related adverse events of any grade occurring in ≥20% of patients include peripheral sensory neuropathy, pruritus, alopecia, maculo-papular rash, fatigue, diarrhea, decreased appetite, and nausea.

 

About bladder and urothelial cancer

Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis and some other organs. In the U.S., it is estimated that approximately 82,300 people will be diagnosed with bladder cancer in 2023. Globally, it is estimated that approximately 573,000 new cases of bladder cancer are reported annually. Approximately 12% of cases are la/mUC at diagnosis. Many patients with advanced urothelial carcinoma face a poor prognosis and experience disease progression following initial treatment with chemotherapy.

 

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 1,600 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.

Urothelial Carcinoma

KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing 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 the confirmatory trials.

 

KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma:

• who are not eligible for any platinum-containing chemotherapy, or
• who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

 

KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

See additional selected indications for KEYTRUDA 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 programmed death receptor-1 (PD-1) or the programmed death ligand 1 (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.

 

Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% 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. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) 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.

Contacts

Media Contacts:

Julie Cunningham

(617) 519-6264

Chrissy Trank

(640) 650-0694

Investor Contacts:

Peter Dannenbaum

(732) 594-1579

Damini Chokshi

(732) 594-1577

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