Category: Healthcare

• In previously untreated patients, Daiichi Sankyo and AstraZeneca’s datopotamab deruxtecan plus pembrolizumab with or without platinum chemotherapy demonstrated objective response rates of 57% and 50%, respectively, with a disease control rate of 91% across cohorts
• Three ongoing pivotal trials are evaluating datopotamab deruxtecan and immune checkpoint inhibitor combinations in first-line non-small cell lung cancer

TOKYO & MUNICH & BASKING RIDGE, N.J. — (BUSINESS WIRE) — Updated results from the TROPION-Lung02 phase 1b trial showed that with additional enrollment and follow-up from the initial presentation datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum-based chemotherapy demonstrated promising clinical activity and no new safety signals in both previously untreated or pretreated patients with advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs). Results will be presented on June 6 during an oral presentation (#9004) at the American Society of Clinical Oncology Annual Meeting (#ASCO23).

Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) being jointly developed by Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN).

More than one million people are diagnosed with NSCLC at an advanced stage each year.^1,2 While first-line treatment with immune checkpoint inhibitors with or without chemotherapy has improved outcomes for patients with NSCLC without AGAs, like EGFR or ALK, most patients eventually experience disease progression.^3,4,5 TROP2 is a protein expressed in more than 90% of NSCLC tumors.⁶ There are currently no TROP2 directed ADCs approved for the treatment of lung cancer.^7,8

Across previously untreated and pretreated patients, an objective response rate (ORR) of 38% was observed (95% confidence interval [CI]: 26-51) in patients receiving doublet datopotamab deruxtecan plus pembrolizumab (Merck & Co., Inc., Rahway, NJ, USA), an anti-PD-1 therapy. In patients receiving triplet datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy, an ORR of 49% was observed (95% CI: 37-61). Disease control rates (DCR) of 84% and 87% were observed in the doublet and triplet cohorts, respectively. Median duration of response (DoR) was not reached across cohorts. Although immature, median progression-free survival (PFS) was 8.3 months (95% CI: 6.8-11.8) in the doublet cohort and 7.8 months (95% CI: 5.6-11.1) in the triplet cohort. Response rates were highest in previously untreated patients with ORRs of 50% (95% CI: 32-68) and 57% (95% CI: 42-70) observed in the doublet and triplet cohorts, respectively, with a consistent DCR of 91% observed across cohorts.

“Nearly all patients with advanced non-small cell lung cancer experience disease progression following initial therapy, underscoring the need for novel therapeutic approaches across treatment lines,” said Yasushi Goto, MD, Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. “The updated results from TROPION-Lung02 signal the potential for datopotamab deruxtecan combinations to improve outcomes for patients with non-small cell lung cancer and are a promising development in the pursuit of a new standard treatment option beyond immunotherapy.”

The safety profiles of datopotamab deruxtecan-based combinations were consistent with previous data with no new safety signals observed. Grade 3 or greater treatment-related adverse events (TRAEs) occurred in 31% of patients receiving doublet therapy and 58% of patients receiving triplet therapy. The most frequent adverse events of any grade in the doublet and triplet cohorts, respectively, were stomatitis (56% and 35%), nausea (41% and 47%), anemia (21% and 48%) and fatigue (31% and 37%). Across treatment cohorts, there were 27 interstitial lung disease (ILD) or pneumonitis events adjudicated as drug-related by an independent committee. The percentage of ILD or pneumonitis events was similar across cohorts. The majority of ILD or pneumonitis events were low grade with 23 grade 1 or grade 2 and four grade 3 events. No grade 4 or grade 5 ILD or pneumonitis events or grade 5 TRAEs were observed.

“We continue to be encouraged by the findings from TROPION-Lung02, the first trial to evaluate the combination of a TROP2 directed antibody drug conjugate and an immune checkpoint inhibitor with or without platinum chemotherapy in patients with advanced non-small cell lung cancer,” said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. “These data, alongside previous results for datopotamab deruxtecan combined with an immune checkpoint inhibitor, reinforce the potential of these combinations to improve outcomes for patients with different advanced cancers.”

“With more patients and nearly a year of additional follow-up, the updated TROPION-Lung02 results show that datopotamab deruxtecan continues to elicit promising and durable responses in a diverse subset of patients with non-small cell lung cancer,” said Cristian Massacesi, MD, Chief Medical Officer and Chief Development Officer, Oncology, AstraZeneca. “These early data give us confidence in the ongoing phase 3 development program evaluating datopotamab deruxtecan combinations as potential first-line treatment options for patients with advanced lung cancer across tumor histologies and PD-L1 expression levels.”

In the doublet cohort of TROPION-Lung02, 58% of patients were previously untreated and 42% were previously treated with platinum chemotherapy (38%) or immunotherapy (19%). In the triplet cohort, 75% of patients were previously untreated and 25% were previously treated with platinum chemotherapy (24%) or immunotherapy (25%). Eighty percent of patients in the doublet cohort and 73% of patients in the triplet cohort had PD-L1 tumor proportion scores of less than 50%, including 36% and 40% of patients who had PD-L1 tumor proportion scores of less than 1% in the doublet and triplet cohorts, respectively. As of the April 7, 2023 data cut-off, 36% and 46% of patients remained on the doublet and triplet therapy, respectively.

Summary of Efficacy Results

Daiichi Sankyo and AstraZeneca have three phase 3 trials evaluating datopotamab deruxtecan as a potential first-line treatment option for patients with advanced or metastatic NSCLC without AGAs compared to the respective standard of care for the patient population of each study. TROPION-Lung07 is evaluating datopotamab deruxtecan plus pembrolizumab with or without chemotherapy in patients with non-squamous disease and PD-L1 expression of less than 50%. TROPION-Lung08 is evaluating datopotamab deruxtecan plus pembrolizumab in patients with PD-L1 expression of 50% or greater. AVANZAR is evaluating datopotamab deruxtecan plus durvalumab and platinum chemotherapy in patients regardless of PD-L1 expression or tumor histology.

About TROPION-Lung02

TROPION-Lung02 is an ongoing global, open-label, six-cohort phase 1b trial evaluating the safety and efficacy of datopotamab deruxtecan at two dose levels (4 mg/kg and 6 mg/kg) in combination with pembrolizumab (200 mg) with or without four cycles of platinum chemotherapy (carboplatin or cisplatin) in patients with previously untreated or pretreated advanced or metastatic NSCLC without AGAs (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET, MET or other known AGAs).

The primary endpoints of TROPION-Lung02 are dose-limiting toxicities and treatment-emergent adverse events. Secondary endpoints include ORR, DoR, PFS as assessed by investigator, overall survival, pharmacokinetics and anti-drug antibodies for datopotamab deruxtecan and pembrolizumab.

TROPION-Lung02 is one of three clinical trials, alongside TROPION-Lung07 and TROPION-Lung08, in a collaboration and supply agreement between Daiichi Sankyo, AstraZeneca and a subsidiary of Merck & Co., Inc., Rahway, NJ., USA to evaluate the combination of datopotamab deruxtecan and pembrolizumab.

About Non-Small Cell Lung Cancer

More than one million people are diagnosed with advanced stage NSCLC each year.^1,2 While targeted therapies and immune checkpoint inhibitors have improved patient outcomes, advanced NSCLC has a poor prognosis and is associated with worsening outcomes after each line of subsequent therapy.^3,4,5

Most patients with NSCLC have tumors that do not express a known AGA (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET or MET).^9,10,11 The current first-line standard of care for these patients is immune checkpoint inhibitors with or without platinum-based chemotherapy. Approximately 40% to 60% of tumors will not respond to this initial treatment and while these therapies may improve survival for patients whose tumors do respond, most will experience disease progression.^5,7

TROP2, a transmembrane glycoprotein, is expressed in more than 90% of NSCLC tumors.⁶ There are currently no TROP2 directed ADCs approved for the treatment of lung cancer.

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 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 Datopotamab Deruxtecan (Dato-DXd)

Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of the three lead ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads, an exatecan derivative, via tetrapeptide-based cleavable linkers.

A comprehensive development program called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumors, including NSCLC, triple negative breast cancer and hormone receptor positive, HER2 low or negative breast cancer. Beyond the TROPION program, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials.

About the DXd ADC Portfolio of Daiichi Sankyo

The DXd ADC portfolio of Daiichi Sankyo currently consists of five ADCs in clinical development across multiple types of cancer. The company’s clinical trial stage DXd ADCs include ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Two additional ADCs including ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd; DS-6000), a CDH6 directed ADC, are being developed through a strategic early-stage research collaboration with Sarah Cannon Research Institute.

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 and raludotatug deruxtecan are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo

Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 17,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.” For more information, please visit: www.daiichisankyo.com.

References
¹ Siegel R, et al. CA Cancer J Clin. 2021;71:7-33.

² World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Accessed June 2023.

³ Shields MD, et al. Am Soc Clin Oncol Educ Book. 2021;41:1-23.

⁴ Walsh RJ, et al. Ther Adv Med Oncol. 2020;12:1758835920937902.

⁵ Paz-Ares L, et al. J Thorac Oncol. 2020 Oct;15(10):1657-1669.

⁶ Mito R, et al. Pathol Int. 2020;70(5):287-294.

⁷ Rodríguez-Abreu D et al. Ann Onc. 2021 Jul;32(7):881-895.

⁸ American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer. Accessed June 2023.

⁹ Chen R, et al. J Hematol Oncol. 2020;13(1):58.

¹⁰ Majeed U, et al. J Hematol Oncol. 2021;14(1):108.

¹¹ Adib E, et al. Genome Med. 2022;14(1):39.

Contacts

Global:
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

• Daiichi Sankyo and AstraZeneca’s ENHERTU showed an objective response rate of 37.1% in the overall population of the DESTINY-PanTumor02 phase 2 trial
• ENHERTU is the first therapy to show broad activity across HER2 expressing advanced solid tumors where there are currently no approved HER2 directed therapies
• DESTINY-CRC02 phase 2 trial also demonstrated positive antitumor activity and consistent safety in patients with previously treated HER2 positive metastatic colorectal cancer

TOKYO & MUNICH & BASKING RIDGE, N.J. — (BUSINESS WIRE) — Positive results from an interim analysis of the ongoing DESTINY-PanTumor02 phase 2 trial showed that ENHERTU^® (trastuzumab deruxtecan) demonstrated clinically meaningful and durable responses across a broad range of HER2 expressing advanced solid tumors in previously treated patients. These results will be presented today as a late-breaking oral presentation (abstract #LBA3000) at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

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 trial, previously treated patients (n=267) with HER2 expressing advanced solid tumors including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancers or other tumors were treated with ENHERTU. The results showed a confirmed objective response rate (ORR) of 37.1% as assessed by investigator at an interim analysis. Complete response (CR) was achieved in 5.6% (n=15) of patients, 31.5% (n=84) achieved a partial response (PR) and 46.1% (n=123) had stable disease. The disease control rate (DCR) in the overall trial population was 68.2% as assessed by investigator at an interim analysis. The highest response rates were seen in patients with tumor HER2 expression of immunohistochemistry (IHC) 3+ as confirmed by central testing, where ENHERTU demonstrated a confirmed ORR of 61.3%.

Nearly half (49.6%) of all patients in DESTINY-PanTumor02 who achieved a response remained in response at one year. Median duration of response (DoR) was 11.8 months (95% confidence interval [CI]: 9.8-NE) in the overall trial population and 22.1 months (95% CI: 9.3-NE) in patients with IHC 3+ expression.

“The DESTINY-PanTumor02 data showed encouraging and durable response rates across a broad range of HER2 expressing solid tumors where there are currently no approved HER2 targeted treatments,” said Funda Meric-Bernstam, MD, Chair of the Department 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 benefit specific patients with HER2 expressing advanced disease who currently have limited options and may face a poor prognosis.”

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 related treatment emergent adverse events (TEAEs) occurred in 38.6% of patients. The most common grade 3 or higher treatment related TEAEs occurring in ≥5% of patients were neutropenia (19.1%), anemia (8.6%), fatigue (6.0%) and thrombocytopenia (5.2%). In DESTINY-PanTumor02, 7.5% of patients experienced interstitial lung disease (ILD) or pneumonitis related to treatment with ENHERTU as determined by an independent adjudication committee. The majority of ILD or pneumonitis events were low grade (grade 1 or 2) with one grade 3 event, no grade 4 events and one grade 5 event observed.

“Nearly half of patients who achieved a response with ENHERTU as a late-line treatment for HER2 expressing advanced solid tumors in DESTINY-PanTumor02 remained in response at one year, demonstrating the potential of this important medicine to provide benefit to patients with hard-to-treat cancers in need of new options,” said Mark Rutstein, MD, Global Head, Oncology Development, Daiichi Sankyo. “The results further reinforce the important role of antibody drug conjugates like ENHERTU to provide potential new solutions to advance current standards of care in areas of high unmet need and improve the outcomes of patients.”

“While HER2 is an established biomarker in breast, gastric, lung and colorectal cancers, data from the DESTINY-PanTumor02 trial validate HER2 as an actionable biomarker across a broad range of tumor types,” said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. “ENHERTU is the first treatment to demonstrate broad activity across HER2 expressing solid tumors where there are currently no approved HER2 directed therapies. These data will support our ongoing conversations with global health authorities as we look to bring ENHERTU to as many patients as possible.”

In DESTINY-PanTumor02, patients had received a median of two prior cancer therapies (range: 0-13). Of the 267 patients that had received treatment, 75 were IHC 3+ and 125 were IHC 2+ as determined by central testing. As of data cut-off on November 16, 2022, 44 patients remained on treatment.

Summary of DESTINY-PanTumor02 Results

DESTINY-CRC02 Primary Results

Primary results from the DESTINY-CRC02 phase 2 trial, which evaluated ENHERTU at the 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated locally advanced, unresectable or metastatic HER2 positive (IHC 3+ or IHC 2+/in-situ hybridization [ISH]+) colorectal cancer of BRAF wild-type, RAS wild-type or RAS mutant tumor types, also were presented at ASCO.

Analysis of the primary endpoint showed that ENHERTU achieved a confirmed ORR of 37.8% (95% CI: 27.3-49.2) in patients treated with the 5.4 mg/kg dose (n=82) and 27.5% (95% CI: 14.6-43.9) in patients treated with the 6.4 mg/kg dose (n=40) as assessed by blinded independent central review (BICR). All responses were partial (n=31 [5.4 mg/kg]; n=11 [6.4 mg/kg]) with 48.8% of patients in the 5.4 mg/kg arm and 57.5% of patients in the 6.4 mg/kg arm achieving stable disease. Greater efficacy was observed in patients with the highest levels of HER2 expression (IHC 3+) (46.9% ORR [95% CI: 34.3-59.8]) compared to those with IHC 2+/ISH+ HER2 status in the 5.4 mg/kg treatment arm (5.6% ORR [95% CI: 0.1-27.3]). Antitumor efficacy was observed regardless of RAS mutation status (39.7% ORR with RAS mutations; 28.6% ORR without RAS mutations) and in those with prior HER2 directed therapy (41.2% ORR) in the 5.4 mg/kg arm.

With a median duration of follow-up of 8.9 months and 10.3 months in the 5.4 mg/kg and 6.4 mg/kg arms respectively, ENHERTU also demonstrated a median DoR of 5.5 months in both the 5.4 mg/kg (95% CI: 4.2-8.1) and 6.4 mg/kg (95% CI: 3.7-NE) arms. Median progression-free survival (PFS) was 5.8 months (95% CI: 4.6-7.0) in the 5.4 mg/kg arm and 5.5 months (95% CI: 4.2-7.0) in the 6.4 mg/kg arm. Median overall survival (OS) was 13.4 months (95% CI: 12.5-16.8) in the 5.4 mg/kg arm and not reached (95% CI: 9.9-NE) in the 6.4 mg/kg arm.

The safety profile observed in DESTINY-CRC02 at the 5.4 mg/kg and 6.4 mg/kg dose levels was consistent with other clinical trials of ENHERTU, with no new safety signals identified at either dose. A more favorable benefit-risk profile was observed in patients treated with ENHERTU 5.4 mg/kg resulting in its selection as the recommended dose. Grade 3 or higher treatment related TEAEs were numerically higher with ENHERTU 6.4 mg/kg versus 5.4 mg/kg. Grade 3 or higher treatment related TEAEs occurred in 41.0% and 48.7% of patients receiving ENHERTU 5.4 mg/kg or 6.4 mg/kg, respectively. The most common grade 3 or higher TEAEs occurring in ≥10% of patients receiving ENHERTU were neutropenia (16.9% [5.4 mg/kg]; 28.2% [6.4 mg/kg]), anemia (9.6% [5.4 mg/kg]; 23.1% [6.4 mg/kg]) and thrombocytopenia (6.0% [5.4 mg/kg]; 12.8% [6.4 mg/kg]). There were 12 cases of treatment related ILD or pneumonitis reported as determined by an independent adjudication committee (8.4% [n=7/83] in the 5.4 mg/kg arm; 12.8% [n=5/39] in the 6.4 mg/kg arm). The majority of ILD or pneumonitis events (8.4% [5.4 mg/kg]; 10.2% [6.4 mg/kg]) were low grade (grade 1 or 2) with no grade 3, no grade 4 and one grade 5 event observed (2.6% [6.4 mg/kg]).

The results of DESTINY-CRC02 support 5.4 mg/kg as the optimal dose of ENHERTU monotherapy in patients with HER2 positive metastatic colorectal cancer.

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 cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer and other tumors. The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator. Secondary endpoints include DoR, DCR, 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 DESTINY-CRC02

DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter phase 2 trial evaluating the efficacy and safety of two doses (5.4 mg/kg or 6.4 mg/kg) of ENHERTU in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, or RAS wild-type and RAS mutant tumor types previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (n=80) were randomized 1:1 to receive either 5.4 mg/kg or 6.4 mg/kg of ENHERTU. In the second stage, additional patients (n=42) were enrolled in the 5.4 mg/kg arm. The primary endpoint is confirmed ORR as assessed by BICR. Secondary endpoints include DoR, DCR, investigator-assessed confirmed ORR, clinical benefit ratio, PFS, OS and safety. DESTINY-CRC02 enrolled 122 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 tumor types.^2,5,6

HER2 is an emerging biomarker in 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

Colorectal cancer is the third most common and second most common cause of cancer deaths worldwide with more than 1.9 million patients diagnosed and more than 935,000 deaths globally in 2020.¹⁰ Approximately 25% of patients have metastatic disease at diagnosis, meaning the disease has spread to distant organs and about 50% of patients with colorectal cancer will eventually develop metastases.¹¹ For patients with metastatic disease, approximately 2% to 3% are HER2 overexpressing.^6,12

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 more than 50 countries 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 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 Israel and under accelerated approval in the U.S. for the treatment of adult patients with 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 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 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 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 five ADCs in clinical development across multiple types of cancer. The company’s clinical trial stage DXd ADCs include ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Two additional ADCs including ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd; DS-6000), a CDH6 directed ADC, are being developed through a strategic early-stage research collaboration with Sarah Cannon Research Institute.

Designed using Daiichi Sankyo’s proprietary DXd ADC technology, each ADC targets and delivers 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 and raludotatug deruxtecan 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

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.

Contacts

Media:
Global:
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:
DaiichiSankyoIR@daiichisankyo.co.jp

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In Phase 3 CCTG IND.227/KEYNOTE-483 trial, KEYTRUDA plus chemotherapy also demonstrated statistically significant improvements in PFS and ORR compared to chemotherapy alone

RAHWAY, N.J. & KINGSTON, Ontario — (BUSINESS WIRE) — $MRK #MRK — Merck (NYSE: MRK), known as MSD outside of the United States and Canada, and the Canadian Cancer Trials Group (CCTG) today announced results from the Phase 3 CCTG IND.227/KEYNOTE-483 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, plus chemotherapy as first-line treatment for patients with unresectable advanced pleural mesothelioma. At the final analysis of the study, KEYTRUDA plus chemotherapy significantly improved overall survival (OS), reducing the risk of death by 21% (HR=0.79 [95% CI, 0.64-0.98]; two-sided p value=0.0324), with a median OS of 17.3 months (95% CI, 14.4-21.3) versus 16.1 months (95% CI, 13.1-18.2) for chemotherapy alone. These late-breaking data are being presented today during an oral abstract session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA8505) and are being discussed with regulatory authorities worldwide.

“Patients with pleural mesothelioma are usually diagnosed at an advanced stage, when the five year survival rate is only 12% and curative surgery is not an option,” said Dr. Lesley Seymour, Director of the Investigational New Drug program at CCTG, and Senior Investigator for IND.227. “The addition of pembrolizumab to platinum-pemetrexed in our study resulted in significantly improved overall survival, progression-free survival and objective response rates compared to platinum-pemetrexed alone, regardless of PD-L1 expression. This regimen represents a potential new treatment option for patients with advanced pleural mesothelioma.”

“These results support the potential of KEYTRUDA plus chemotherapy as a new first-line option for patients with advanced pleural mesothelioma, who currently have limited treatment options,” said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck Research Laboratories. “These data demonstrate our commitment to improving outcomes for patients with different types of thoracic cancer through our expansive clinical development program and research evaluating KEYTRUDA in new, difficult-to-treat tumors.”

Study design and additional data from IND.227/KEYNOTE-483

IND.227/KEYNOTE-483 is a randomized, open-label Phase 2/3 trial (ClinicalTrials.gov, NCT02784171) sponsored and conducted by CCTG in collaboration with National Cancer Institute of Naples (NCIN) and Intergroupe Francophone de Cancérologie Thoracique (IFCT). Merck provided KEYTRUDA and support for the trial. The trial evaluated KEYTRUDA plus chemotherapy versus chemotherapy alone for the treatment of patients with unresected advanced pleural mesothelioma. The primary endpoint of the study is OS, and secondary endpoints include progression-free survival (PFS) and objective response rate (ORR) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) modified for mesothelioma, safety and quality of life. The Phase 3 part of the trial enrolled 440 patients who were randomized to receive:

• KEYTRUDA (200 mg intravenously [IV] every three weeks [Q3W] for up to 35 cycles) plus pemetrexed (500 mg/m2 Q3W for six cycles) and cisplatin (75 mg/m2 Q3W for six cycles; carboplatin substitution [AUC 5-6 Q3W for six cycles] was permitted), or
• Pemetrexed and cisplatin (carboplatin substitution was permitted) alone.

PFS was also significantly improved for KEYTRUDA plus chemotherapy compared to chemotherapy alone (HR=0.80 [95%CI, 0.65-0.99], two-sided p value = 0.0372; median PFS 7.13 months versus 7.16 months respectively). At 12 months, the estimated PFS rate was 26% for KEYTRUDA plus chemotherapy versus 17% for chemotherapy alone. The ORR was significantly higher for KEYTRUDA plus chemotherapy versus chemotherapy alone (62% versus 38%, p<0.0001).

The safety profile of KEYTRUDA plus chemotherapy in this study was consistent with previously reported studies. Adverse events related to study treatment of grade 3 or 4 occurred in 27% of patients in the KEYTRUDA plus chemotherapy arm, and 15% of patients on the chemotherapy-alone arm. The most common grade ≥3 adverse events in the KEYTRUDA arm were fatigue (7%), nausea (5%) and febrile neutropenia (5%); the corresponding values for the chemotherapy arm were 6%, 1% and 1%. KEYTRUDA-related adverse events resulting in discontinuation of KEYTRUDA occurred in 16% of patients receiving KEYTRUDA plus chemotherapy.

About mesothelioma

Mesothelioma is a type of cancer that starts in the linings of certain parts of the body, including the chest, abdomen, heart and testicles. Worldwide, it is estimated there were more than 30,000 new cases of mesothelioma diagnosed and more than 26,000 deaths from the disease in 2020. Pleural mesothelioma, which develops in the lining of the lungs, is the most common form of mesothelioma, accounting for about 75% of all cases. Pleural mesothelioma often progresses rapidly, and the five-year survival rate is only 12%. Although incidence of mesothelioma has gradually declined in the U.S., continued use of and exposure to asbestos around the world has resulted in increasing global rates of this aggressive disease.

About the Canadian Cancer Trials Group

The Canadian Cancer Trials Group (CCTG) is a cancer clinical trials research cooperative that develops, conducts and analyses phase I-III trials to test anti-cancer and supportive therapies at over 85 hospitals and cancer centres across Canada and internationally. From their operations centre at Queen’s University, CCTG has supported more than 600 trials enrolling 100,000 patients from 40 countries on 6 continents through a global network of 20,000 investigators and clinical trial staff. CCTG is a national program of the Canadian Cancer Society (CCS) and their aim is to improve survival and quality of life for all people with cancer. CCTG IND.227 was supported by a grant from CCS (707213). For further information, please visit the CCTG website: www.cctg.ca.

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.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

• stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
• metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC.

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 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.

Pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. In adult patients who received adjuvant therapy for NSCLC, 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.

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:

Julie Cunningham

(617) 519-6264

Sienna Choi

(908) 873-4311

Investor Contacts:

Peter Dannenbaum

(732) 594-1579

Damini Chokshi

(732) 594-1577

CCTG Media Contacts:

Lisa Callahan

CCTG Communications Leader

lcallahan@ctg.queensu.ca
(343) 363-7158

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