This phase III trial compares standard therapy given after surgery (adjuvant) to standard therapy given before and after surgery (perioperative) in treating patients with stage II-IIIB non-small cell lung cancer (NSCLC) that can be removed by surgery (resectable). The usual approach for patients with resectable NSCLC is chemotherapy and/or immunotherapy before surgery, after surgery, or both before and after surgery. This study is being done to find out which approach is better at treating patients with lung cancer. Treatment will be administered according to the current standard of care at the time of enrollment. Chemotherapy options may include cisplatin, carboplatin, pemetrexed, gemcitabine, docetaxel, and vinorelbine at standard doses according to the treating physician. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by stopping cells from using folic acid to make deoxyribonucleic acid (DNA) and may kill tumor cells. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill tumor cells. Docetaxel is in a class of medications called taxanes. It stops tumor cells from growing and dividing and may kill them. Other chemotherapy drugs, such as vinorelbine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading . Immunotherapy with monoclonal antibodies, such as nivolumab, pembrolizumab, and atezolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Starting treatment with chemotherapy and immunotherapy prior to surgery and continuing treatment after surgery may be a more effective treatment option than adjuvant therapy alone in patients with stage II-IIIB resectable NSCLC.

Start Date30 May 2025

Sponsor / Collaborator

Alliance for Clinical Trials in Oncology

[+1]

NCT06692491

/ Not yet recruitingPhase 2IIT

A Phase II Clinical Study on Precision Treatment of Rare Tumours in China Guided by Patient-Derived Tumor Organoids (PDO) and Next-Generation Sequencing (NGS)

The objective of this Phase II, open-label, multicenter, non-randomised controlled clinical trial is to guide precision treatment for patients with rare tumours based on Patient-Derived Organoids/Next-Generation Sequencing drug screening.

Start Date01 Jan 2025

Sponsor / Collaborator

Peking University Shenzhen Hospital

NCT06690840

/ Not yet recruitingPhase 2IIT

A Phase II Study of Atezolizumab, Vinorelbine and Weekly Cyclophosphamide as T-cell Activators in First Line Metastatic Triple Negative Breast Cancer Patients Pre-treated With Anti-PD-L1/PD-1

Triple-negative breast cancer (TNBC) is among the most aggressive and lethal types of breast cancer, and currently available therapies have an unsatisfactory impact on patients' survival.
The primary aim of this clinical trial is to evaluate efficacy in terms of Overall Response Rate (ORR) of atezolizumab plus cyclophosphamide and vinorelbine in first line patients with unresectable locally advanced or metastatic TNBC patients, previously treated with anti-programmed cell death ligand-1 (PD-L1) or anti-programmed cell death-1 (PD-1) - containing regimens, in the neoadjuvant/adjuvant setting.

Start Date01 Dec 2024

Sponsor / Collaborator

Istituto Europeo di Oncologia SRL

100 Clinical Results associated with Vinorelbine Tartrate

100 Translational Medicine associated with Vinorelbine Tartrate

100 Patents (Medical) associated with Vinorelbine Tartrate

4,255

Literatures (Medical) associated with Vinorelbine Tartrate

01 Feb 2025·Current Computer-Aided Drug Design

Computer-aided Drug Discovery Approaches in the Identification of Anticancer Drugs from Natural Products: A Review

Review

Author: Priya, Muthiah Gnana Ruba ; Manisha, Jessica ; Lazar, Lal Prasanth Mercy ; Solomon, Viswas Raja ; Rathore, Seema Singh

Natural plant sources are essential in the development of several anticancer drugs, such as vincristine, vinblastine, vinorelbine, docetaxel, paclitaxel, camptothecin, etoposide, and teniposide. However, various chemotherapies fail due to adverse reactions, drug resistance, and target specificity. Researchers are now focusing on developing drugs that use natural compounds to overcome these issues. These drugs can affect multiple targets, have reduced adverse effects, and are effective against several cancer types. Developing a new drug is a highly complex, expensive, and time-consuming process. Traditional drug discovery methods take up to 15 years for a new medicine to enter the market and cost more than one billion USD. However, recent Computer Aided Drug Discovery (CADD) advancements have changed this situation. This paper aims to comprehensively describe the different CADD approaches in identifying anticancer drugs from natural products. Data from various sources, including Science Direct, Elsevier, NCBI, and Web of Science, are used in this review. In-silico techniques and optimization algorithms can provide versatile solutions in drug discovery ventures. The structure-based drug design technique is widely used to understand chemical constituents' molecular-level interactions and identify hit leads. This review will discuss the concept of CADD, in-silico tools, virtual screening in drug discovery, and the concept of natural products as anticancer therapies. Representative examples of molecules identified will also be provided.

06 Dec 2024·Hematology-American Society of Hematology Education Program

Has PD-1 blockade changed the standard of care for cHL?

Review

Author: Kuczmarski, Thomas M. ; Lynch, Ryan C.

Abstract:

The treatment paradigm for classic Hodgkin lymphoma (CHL) continues to evolve, particularly in light of the incorporation of programmed cell death protein 1 (PD-1) inhibitors into a variety of therapeutic settings. PD-1 inhibitors have demonstrated high efficacy and a favorable toxicity profile when added to a doxorubicin, vinblastine, dacarbazine chemotherapy backbone in patients with untreated CHL. PD-1 inhibitors are also effective treatment options in the relapsed/refractory setting. For patients who are pursuing autologous stem cell transplant (ASCT), pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin has shown marked efficacy and is an effective treatment regimen to administer prior to transplant. For patients who either are not eligible for ASCT or have relapsed after ASCT, pembrolizumab or nivolumab monotherapy have been well studied and demonstrate high efficacy even when patients have been exposed to numerous lines of prior therapy. As data from previous trials continue to mature and new clinical trials are conducted, PD-1 inhibitors will continue to become an integral component for successful management of CHL.

06 Nov 2024·Journal of Translational Internal Medicine

Inetetamab for injection in combination with vinorelbine weekly or every three weeks in HER2-positive metastatic breast cancer: A multicenter, randomized, phase II clinical trial

Article

Author: Zheng, Yabing ; Wang, Xiaojia ; Chen, Zhanhong ; Xie, Ning ; Gan, Lu ; Yang, Xiuli ; Wang, Xinshuai ; Huang, Jian ; Chen, Yuru ; Ouyang, Quchang ; Yang, Hua ; Chen, Shaoping ; Cao, Wenming ; Shao, Xiying

Abstract:

Objective:

We aimed to investigate the pharmacokinetics, safety, efficacy, and immunogenicity of different dosing regimens (weekly and every three weeks) of inetetamab in combination with vinorelbine in human epidermal growth factor receptor 2 (HER2)+ patients with metastatic breast cancer who had received one or more chemotherapy regimens.

Methods:

HER2+ patients with metastatic breast cancer who had received one or more chemotherapy regimens were included. Eligible patients received inetetamab administered weekly or every three weeks in combination with vinorelbine injection chemotherapy. Pharmacokinetics, safety, efficacy, and immunogenicity were compared between the groups.

Results:

Sixty HER2+ patients were randomized into a single-week administration group ( n = 29) and a three-week administration group ( n = 31). After the final dose in the single-week administration group and the three-week administration group, the mean Cmax values were 79.773 μg/mL and 146.083 μg/mL; the mean Cmin values were 30.227 μg/mL and 11.926 μg/mL; the mean AUCtau values were 7328.443 μg·h/mL and 22647.101 μg·h/mL; and the mean Cav values were 43.622 μg/ mL and 44.935 μg/mL, respectively. The best overall response (BOR) rates at 24 weeks and unconfirmed BOR rates at 24 weeks were both 40.7% in the single-week dosing group and 40.7% in the three-week dosing group, and the 24-week confirmed disease control rates (DCRs) were 88.9% and 81.5%, respectively. The incidence of adverse events (AEs) was generally consistent across all levels.

Conclusion:

There were slight differences in the mean Cmax, Cmin, AUCtau and Cav between the three-week dosing group and the single-week dosing group, and the mean steady-state concentrations of Cav were comparable; however, there were no differences in efficacy, safety or immunogenicity between the two groups.

News (Medical) associated with Vinorelbine Tartrate

23 Sep 2024

·www.businesswire.com

Datopotamab deruxtecan final overall survival results reported in patients with metastatic HR-positive, HER2-low or negative breast cancer in TROPION-Breast01 Phase III trial

WILMINGTON, Del.--( BUSINESS WIRE )--High-level results from the TROPION-Breast01 Phase III trial of datopotamab deruxtecan (Dato-DXd) compared to investigator’s choice of chemotherapy, which previously met the dual primary endpoint of progression-free survival (PFS), did not achieve statistical significance in the final overall survival (OS) analysis in patients with inoperable or metastatic hormone receptor (HR)-positive, HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer previously treated with endocrine-based therapy and at least one systemic therapy. This analysis follows positive PFS results presented at the 2023 European Society for Medical Oncology Congress which showed datopotamab deruxtecan demonstrated a statistically significant and clinically meaningful improvement in PFS. An improvement in patient-reported outcomes was also seen. 1 The PFS data and additional results for key secondary endpoints were published this month in the Journal of Clinical Oncology. The safety profile of datopotamab deruxtecan was consistent with that observed in the previous analysis including lower rates of Grade 3 or higher treatment-related adverse events compared to chemotherapy, and no new safety concerns identified. All grade interstitial lung disease (ILD) rates remained low with no new Grade 3 or higher ILD events observed. With multiple antibody drug conjugates (ADCs) approved during the course of the trial, including ENHERTU ® (fam-trastuzumab deruxtecan-nxki), subsequent treatment following patients’ disease progression or treatment discontinuation is likely to have affected survival results. Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “ The metastatic HR-positive breast cancer treatment landscape has advanced remarkably in the last several years to benefit patients. Based on the TROPION-Breast01 results, there is evidence of the clinical value of datopotamab deruxtecan in this setting. We will continue discussions with regulatory authorities and apply insights from these results to our clinical development program for datopotamab deruxtecan in breast cancer.” Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: “ Datopotamab deruxtecan has previously shown a statistically significant progression-free survival benefit in TROPION-Breast01, a result supported by multiple meaningful secondary measures including patient-reported outcomes. We are proud to have brought forth a new standard of care for patients with metastatic breast cancer with ENHERTU and we remain committed to making datopotamab deruxtecan another potential option for patients who can benefit.” Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd ADC discovered by Daiichi Sankyo and being jointly developed by AstraZeneca and Daiichi Sankyo. The data will be presented at a forthcoming medical meeting and shared with regulatory authorities currently reviewing applications for this indication. In addition to TROPION-Breast01, AstraZeneca and Daiichi Sankyo are evaluating datopotamab deruxtecan alone and with immunotherapy as treatment for patients with triple-negative or HR-low, HER2-negative breast cancers in the TROPION-Breast02 , TROPION-Breast03 , TROPION-Breast04 and TROPION-Breast05 Phase III trials. 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 (IHC 3+ or ISH 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 (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen Unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. 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. 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. HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. HER2-Positive 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 10 9 /L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 10 9 /L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 10 9 /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. HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 63% of patients. Seventeen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1% of patients. HER2-Positive 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. HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.8% of patients, of which 0.6% were Grade 3. HER2-Positive 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 10 9 /L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 10 9 /L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level. Adverse Reactions HER2-Positive and HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 1799 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 65% were exposed for >6 months and 38% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (73%), decreased white blood cell count (70%), decreased hemoglobin (66%), decreased neutrophil count (63%), decreased lymphocyte count (58%), fatigue (56%), decreased platelet count (48%), increased aspartate aminotransferase (47%), increased alanine aminotransferase (43%), vomiting (40%), increased blood alkaline phosphatase (38%), alopecia (34%), constipation (33%), decreased appetite (32%), decreased blood potassium (31%), diarrhea (29%), musculoskeletal pain (24%), and abdominal pain (20%). HER2-Positive Metastatic Breast Cancer DESTINY-Breast03 The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg intravenously once every three weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30). Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each). ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), decreased blood potassium (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), headache (22%), respiratory infection (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%). HER2-Low Metastatic Breast Cancer DESTINY-Breast04 The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU. Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each). ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (70%), decreased hemoglobin (64%), decreased neutrophil count (64%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (44%), alopecia (40%), vomiting (40%), increased aspartate aminotransferase (38%), increased alanine aminotransferase (36%), constipation (34%), increased blood alkaline phosphatase (34%), decreased appetite (32%), musculoskeletal pain (32%), diarrhea (27%), and decreased blood potassium (25%). HER2-Mutant Unresectable or Metastatic NSCLC (5.4 mg/kg) DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis. The safety of ENHERTU was evaluated in 101 patients with HER2-mutant unresectable or metastatic NSCLC who received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity in DESTINY‑Lung02. Nineteen percent of patients were exposed for >6 months. Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%). ENHERTU was permanently discontinued in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, decreased blood potassium, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (61%), decreased white blood cell count (60%), decreased hemoglobin (58%), decreased neutrophil count (52%), decreased lymphocyte count (43%), decreased platelet count (40%), decreased albumin (39%), increased aspartate aminotransferase (35%), increased alanine aminotransferase (34%), fatigue (32%), constipation (31%), decreased appetite (30%), vomiting (26%), increased alkaline phosphatase (22%), and alopecia (21%). HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m 2 biweekly or paclitaxel (N=7) 80 mg/m 2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) for patients who received ENHERTU. Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%). ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (75%), decreased white blood cell count (74%), decreased neutrophil count (72%), decreased lymphocyte count (70%), decreased platelet count (68%), nausea (63%), decreased appetite (60%), increased aspartate aminotransferase (58%), fatigue (55%), increased blood alkaline phosphatase (54%), increased alanine aminotransferase (47%), diarrhea (32%), decreased blood potassium (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%). HER2-Positive (IHC3+) Unresectable or Metastatic Solid Tumors The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. The median duration of treatment was 8.3 months (range 0.7 to 30.2). Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock. ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (75%), nausea (69%), decreased hemoglobin (67%), decreased neutrophil count (66%), fatigue (59%), decreased lymphocyte count (58%), decreased platelet count (51%), increased aspartate aminotransferase (45%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (36%), vomiting (35%), decreased appetite (34%), alopecia (34%), diarrhea (31%), decreased blood potassium (29%), constipation (28%), decreased sodium (22%), stomatitis (20%), and upper respiratory tract infection (20%). Use in Specific Populations Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU. Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose. Females and Males of Reproductive Potential: Pregnancy testing : Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception : Females : ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males : 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. Infertility : ENHERTU may impair male reproductive function and fertility. Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients. Geriatric Use: Of the 1287 patients with HER2-positive or HER2-low breast cancer treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years and 3.8% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (59%) as compared to younger patients (49%). Of the 101 patients with HER2-mutant unresectable or metastatic NSCLC treated with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01, or DESTINY-CRC02, 39% were 65 years or older and 9% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min). Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST). To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch. Please see accompanying full Prescribing Information , including Boxed WARNINGS, and Medication Guide . Notes HR-positive breast cancer Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide. 2 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally. 2 While survival rates are high for those diagnosed with early breast cancer, less than 35% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis. 3 Approximately 70% of diagnosed cases are considered what has been historically called HR-positive, HER2-negative breast cancer (measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-). 3 Endocrine therapies are widely given consecutively in the early lines of treatment for HR-positive metastatic breast cancer; however, after two lines of treatment, further efficacy from endocrine therapy is often limited. 4 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes. 4-7 TROP2 is a protein broadly expressed in HR-positive, HER2-negative breast cancer and is associated with increased tumor progression and poor survival. 8,9 TROPION-Breast01 TROPION-Breast01 is a global, randomized, multicenter, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0mg/kg) versus investigator’s choice of single-agent chemotherapy (eribulin, capecitabine, vinorelbine or gemcitabine) in adult patients with unresectable or metastatic HR-positive, HER2-low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have progressed on and are not suitable for endocrine therapy per investigator assessment and have received at least one additional systemic therapy for unresectable or metastatic disease. Following disease progression or discontinuation of datopotamab deruxtecan or chemotherapy, patients had the option to receive subsequent treatment at the discretion of their physician. Crossover between trial arms was not permitted. The dual primary endpoints of TROPION-Breast01 are PFS as assessed by blinded independent central review and OS. Key secondary endpoints include objective response rate, duration of response, investigator-assessed PFS, disease control rate, time to first subsequent therapy and safety. TROPION-Breast01 enrolled more than 700 patients in Africa, Asia, Europe, North America and South America. For more information visit ClinicalTrials.gov . 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 six DXd 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, DXd) via tetrapeptide-based cleavable linkers. A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple-negative breast cancer (TNBC) and HR-positive, HER2-negative breast cancer. The program includes seven Phase III trials in lung cancer and five Phase III trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings. Daiichi Sankyo collaboration AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialize fam-trastuzumab deruxtecan-nxki 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 fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan. AstraZeneca in breast cancer Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death. AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumor environment. With fam-trastuzumab deruxtecan-nxki, a HER2-directed ADC, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive and HER2-low metastatic breast cancer and are exploring its potential in earlier lines of treatment and in new breast cancer settings. In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines goserelin and aims to reshape the HR-positive space with first-in-class AKT inhibitor, capivasertib, and next-generation SERD and potential new medicine camizestrant. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting. PARP inhibitor olaparib is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research olaparib in these settings and to explore its potential in earlier disease. To bring much-needed treatment options to patients with TNBC, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan alone and in combination with immunotherapy durvalumab, capivasertib in combination with chemotherapy, and durvalumab in combination with other oncology medicines, including olaparib and fam-trastuzumab deruxtecan-nxki. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 125 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca . References Pernas S, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer: Patient-reported outcomes (PROs) from the TROPION-Breast01 study. Presented at: ASCO Congress 2024; 31 May - 4 June, 2024; Chicago, IL. Abstract 1006. Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 Apr 4. doi: 10.3322/caac.21834. National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html . Accessed August 2024 Manohar P, et al. Updates in endocrine therapy for metastatic breast cancer. Cancer Biol Med . 2022 Feb 15; 19(2):202–212. Cortes J, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377:914-923. Yuan P, et al. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer . 2019;112:57–65. Jerusalem G, et al. Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor–Positive, HER2-Negative Advanced Breast Cancer. JAMA Oncol . 2018;4(10):1367–1374. Goldenberg D, et al. The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018;9(48): 28989-29006. Vidula N, et al. Trophoblast Cell Surface Antigen 2 gene (TACSTD2) expression in primary breast cancer. Breast Cancer Res Treat . 2022 Aug;194(3):569-575. US-93959 Last Updated 9/24

Clinical ResultPhase 3Accelerated ApprovalADCImmunotherapy

23 Sep 2024

·pipelinereview.com

Datopotamab Deruxtecan Final Overall Survival Results Reported in Patients with Metastatic HR Positive, HER2 Low or Negative Breast Cancer in TROPION-Breast01 Phase 3 Trial

TOKYO, Japan & BASKING RIDGE, NJ, USA I September 23, 2024 I Topline results from the TROPION-Breast01 phase 3 trial of datopotamab deruxtecan (Dato-DXd) compared to investigator’s choice of chemotherapy, which previously met the dual primary endpoint of progression-free survival (PFS), did not achieve statistical significance in the final overall survival (OS) analysis in patients with inoperable or metastatic hormone receptor (HR) positive, HER2 low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer previously treated with endocrine-based therapy and at least one systemic therapy. Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN). This analysis follows the positive PFS results presented at the 2023 European Society for Medical Oncology Congress which showed datopotamab deruxtecan demonstrated a statistically significant and clinically meaningful improvement in PFS. An improvement in patient-reported outcomes was also seen. 1 The PFS data and additional results for key secondary endpoints were published this month in the Journal of Clinical Oncology . The safety profile of datopotamab deruxtecan was consistent with that observed in the previous analysis, including lower rates of grade 3 or higher treatment-related adverse events compared to chemotherapy, and no new safety concerns identified. All grade interstitial lung disease (ILD) rates remained low with no new grade 3 or higher ILD events observed. With ADCs approved during the course of the trial, including ENHERTU ® (trastuzumab deruxtecan), subsequent treatment following patients’ disease progression or treatment discontinuation is likely to have affected survival results. “Datopotamab deruxtecan has previously shown a statistically significant progression-free survival benefit in TROPION-Breast01, a result supported by multiple meaningful secondary measures including patient-reported outcomes,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “We are proud to have brought forth a new standard of care for patients with metastatic breast cancer with ENHERTU and we remain committed to making datopotamab deruxtecan another potential option for patients who can benefit.” “The metastatic HR positive breast cancer treatment landscape has advanced remarkably in the last several years to the benefit of patients,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “Based on the TROPION-Breast01 results, there is evidence of the clinical value of datopotamab deruxtecan in this setting. We will continue discussions with regulatory authorities and apply insights from these results to our clinical development program for datopotamab deruxtecan in breast cancer.” The data will be presented at an upcoming medical meeting and shared with regulatory authorities currently reviewing applications for this indication. In addition to TROPION-Breast01, Daiichi Sankyo and AstraZeneca are evaluating datopotamab deruxtecan alone and with immunotherapy as treatment for patients with triple negative or HR low, HER2 negative breast cancers in the TROPION-Breast02 , TROPION-Breast03 , TROPION-Breast04 and TROPION-Breast05 phase 3 trials. About TROPION-Breast01 TROPION-Breast01 is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) versus investigator’s choice of single-agent chemotherapy (eribulin, capecitabine, vinorelbine or gemcitabine) in adult patients with unresectable or metastatic HR positive, HER2 low or negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have progressed on and are not suitable for endocrine therapy per investigator assessment and have received at least one additional systemic therapy for unresectable or metastatic disease. Following disease progression or discontinuation of datopotamab deruxtecan or chemotherapy, patients had the option to receive subsequent treatment at the discretion of their physician. Crossover between trial arms was not permitted. The dual primary endpoints of TROPION-Breast01 are PFS as assessed by blinded independent central review and OS. Key secondary endpoints include objective response rate, duration of response, investigator-assessed PFS, disease control rate, time to first subsequent therapy and safety. TROPION-Breast01 enrolled more than 700 patients in Africa, Asia, Europe, North America and South America. For more information visit ClinicalTrials.gov . About Hormone Receptor Positive Breast Cancer Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide. 2 More than two million breast cancer cases were diagnosed in 2022, with more than 665,000 deaths globally. 2 While survival rates are high for those diagnosed with early breast cancer, less than 35% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis. 3 Approximately 70% of diagnosed cases are considered what has been historically called HR positive, HER2 negative breast cancer (measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-). 3 Endocrine therapies are widely given consecutively in the early lines of treatment for HR positive metastatic breast cancer. 4 However, following two lines of endocrine therapy, further efficacy with additional endocrine treatment is often limited. 4 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes. 4,5,6,7 TROP2 is a protein broadly expressed in HR positive, HER2 negative breast cancer and is associated with increased tumor progression and poor survival. 8,9 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 six DXd 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, DXd) via tetrapeptide-based cleavable linkers. A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including non-small cell lung cancer, triple negative breast cancer and HR positive, HER2 negative breast cancer. The program includes seven phase 3 trials in lung cancer and five phase 3 trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings. 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 ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where 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. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which 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. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 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: Please see accompanying full Prescribing Information , including Boxed WARNINGS, and Medication Guide . About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com . References: 1 Pernas S, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer: Patient-reported outcomes (PROs) from the TROPION-Breast01 study. Presented at: ASCO Congress 2024; 31 May – 4 June, 2024; Chicago, IL. Abstract 1006. 2 Bray F, et al. CA Cancer J Clin . 2024; 10.3322/caac.21834. 3 National Cancer Institute. SEER Cancer Stat Facts: Female Breast Cancer Subtypes . Accessed September 2024. 4 Manohar P, et al. Cancer Biol Med . 2022 Feb 15; 19(2):202–212. 5 Cortes J, et al. Lancet . 2011;377:914-923. 6 Yuan P, et al. Eur J Cancer . 2019;112:57-65. 7 Jerusalem G, et al. JAMA Oncol . 2018;4(10):1367–1374. 8 Goldenberg D, et al. Oncotarget . 2018;9(48): 28989-29006. 9 Vidula N, et al. Breast Cancer Res Treat . 2022 Aug;194(3):569-575. SOURCE: Daiichi Sankyo

Phase 3Clinical ResultADCLicense out/in

09 Sep 2024

·www.prnewswire.com

Three Study Results Abstracts From Kelun-Biotech's TROP2-ADC SKB264 (sac-TMT) At 2024 ESMO Released Today

CHENGDU, China, Sept. 9, 2024 /PRNewswire/ -- The European Society for Medical Oncology (ESMO) Congress 2024 will be held in Barcelona, Spain from September 13 to 17, 2024. Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd（"Kelun-Biotech", 6990.HK）will present the following results of its anti-TROP2 ADC sacituzumab tirumotecan (sac-TMT, formerly SKB264/MK-2870). Continue Reading 1.Efficacy and safety of sac-TMT plus pembrolizumab (KEYTRUDA®) in patients with recurrent or metastatic cervical cancer (CC), to be presented in a mini oral session on September 15, 2024, 14:55-15:00, local time (presentation number: 716MO); 2.Safety and efficacy of sac-TMT monotherapy in patients with previously treated advanced endometrial carcinoma (EC) and ovarian cancer (OC) from a phase 2 study, to be presented in a mini oral session on September 15, 2024, 14:50-14:55, local time (presentation number: 715MO); and 3.Exploratory analysis of patients with or without prior PD-(L)1 inhibitors in phase 3 OptiTROP-Breast01 study of sac-TMT versus chemotherapy for previously treated advanced triple-negative breast cancer (TNBC), to be presented as a poster on September 16, 2024, local time (presentation number: 386P). The abstracts for the above studies were published on the official website of the ESMO Congress on September 9, 2024, local time. The study results are summarized as follows: CC Patients with recurrent or metastatic (R/M) CC who had progressed on or after platinum-doublet chemotherapy and received no more than 2 systemic therapies (PD-(L)1 inhibitor allowed) for R/M disease were enrolled in this study. Sac-TMT at 3 or 5 mg/kg Q2W plus pembrolizumab at 400 mg Q6W was assessed in safety run-in period and the doses deemed well tolerated were explored in expansion period. As of data cutoff of March 25, 2024, 38 patients were treated and followed up for at least 17 weeks or 2 tumor assessments (3 received sac-TMT at 3 mg/kg, 35 received sac-TMT at 5 mg/kg). The median follow-up was 6.2 months. The median age of patients was 52 years. 76.3% had squamous histology, 47.4% had received two prior lines of therapy, 52.6% had received bevacizumab, and 42.1% had received anti-PD-1-based therapy. The ORR was 57.9% (22/38, 19 (50%) confirmed), with 3 complete responses. Median duration of response (DoR) was not reached and the 6-month DoR rate was 82.1%. Responses were also observed in patients who were pre-treated with anti-PD-1 based therapy (ORR 68.8%, 11/16). Median PFS was not reached and the 6-month PFS rate was 65.7%. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 47.4% of patients. The most common Grade ≥3 TRAEs were neutrophil count decreased (23.7%), anemia (21.1%) and white blood cell count decreased (15.8%). TRAEs led to dose reduction of sac-TMT in 44.7% of patients and discontinuation of sac-TMT in 1 pt (2.6%). No TRAEs led to discontinuation of both drugs. A Phase 3 global study sponsored by MSD evaluating sac-TMT monotherapy versus treatment of physician's choice (TPC) as second-line treatment for patients with recurrent or metastatic CC is ongoing (NCT06459180). EC and OC Two cohorts of patients with advanced EC and OC, respectively, who had previously been treated with platinum-based chemo were given sac-TMT at 5 mg/kg Q2W until disease progression, unacceptable toxicity or withdrawal of consent. The TROP2 expression was scored using the semi-quantitative H-score method, and cut-off point was set to 200. As of data cutoff of March 5, 2024, 44 patients were enrolled to the EC cohort and median follow-up time was 7.2 months. 52.3% of patients had received ≥ 2 prior lines of therapy. The objective response rate (ORR) was 34.1% (15/44, 12 confirmed) and the disease control rate (DCR) was 75%. Median progression-free survival (PFS) was 5.7 months (95% CI: 3.7, 9.4) with 6-month PFS rate of 47.5%. For patients with TROP2 IHC H-score > 200 (n=12), the ORR was 41.7% (5/12, 3 confirmed) and for patients with an H-score ≤ 200 (n=28), the ORR was 35.7% (10/28, 9 confirmed). 40 patients were enrolled to the OC cohort and median follow-up time was 28.2 months. All patients had received ≥ 2 prior lines of therapy (with 80% of patients receiving ≥3 prior lines) and 87.5% of patients were platinum-resistant. The ORR was 40% (16/40, 14 confirmed) and DCR was 75%. Median PFS was 6.0 months (95% CI: 3.9, 7.3) and median overall survival (OS) was 16.5 months (95% CI: 10.7, NE). In patients with TROP2 IHC H-score > 200 (n=13), the ORR was 61.5% (8/13, 7 confirmed) and in patients with an H-score ≤ 200 (n=22), the ORR was 27.3% (6/22, 6 confirmed). In the patients who are platinum-resistant (n=35), median PFS was 6.0 months (95% CI: 5.3, 7.3) and median OS was 16.1 months (95% CI: 10.5, NE). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 72.7% and 67.5% of patients with EC and OC, respectively. The most common Grade ≥3 TRAEs (≥15%) (EC and OC) were neutrophil count decreased (43.2% and 30.0%), white blood cell count decreased (40.9% and 22.5%), anemia (29.5% and 35.0%) and stomatitis (13.6% and 15.0%). TRAEs led to discontinuation in 1(2.3%) and 5(12.5%) patients with EC and OC, respectively. A Phase 3 global study sponsored by MSD evaluating sac-TMT as a monotherapy for the treatment of EC who have received prior platinum-based chemotherapy and immunotherapy is ongoing (NCT06132958). TNBC Patients with locally recurrent or metastatic TNBC who had received ≥2 prior therapies, with at least one given in the metastatic setting, were randomized to receive either sac-TMT or treatment of physician's choice (TPC: eribulin, capecitabine, gemcitabine, or vinorelbine). The primary endpoint was PFS by blinded independent central review (BICR). As of Nov 30, 2023, 24.6% (32/130) of patients treated with sac-TMT had received prior PD-(L)1 inhibitors and 27.1% (36/133) treated with TPC had received prior PD-(L)1 inhibitors. Clinical benefit was observed with sac-TMT versus TPC in this subgroup. The median PFS by BICR was 5.6 months versus 2.7 months (HR 0.31; 95% CI 0.17-0.54), and ORR by BICR was 56.3% for those treated with sac-TMT versus 5.6% for those treated with TPC. For those patients who didn't receive prior PD-(L)1 inhibitors, similar improvements in efficacy outcomes were observed with sac-TMT versus TPC. The median PFS was 7.2 versus 2.3 months (HR 0.34; 95% CI 0.23-0.48), and ORR was 41.8% versus 14.4%. Safety data in the sac-TMT arm were similar between patients with prior or without prior PD-(L)1 inhibitor treatment. The results from the Phase 3 OptiTROP-Breast01 study of sac-TMT in patients with previously treated locally recurrent or metastatic TNBC was presented on June 2, 2024 at the 2024 ASCO Annual Meeting, details of which may be found in the Company's 2024 interim result announcement and announcement dated May 24, 2024. A Phase 3 global study sponsored by MSD evaluating sac-TMT plus pembrolizumab versus TPC in patients with TNBC who received neoadjuvant therapy and did not achieve a pathological complete response (pCR) (NCT06393374) and a Phase 3 study sponsored by the Company of sac-TMT in China for 1L treatment for patients with unresectable advanced, recurrent or metastatic TNBC whose tumors are PD-L1 negative or in patients whose tumors are PD-L1 positive and have relapsed after prior anti-PD-(L)1 inhibitor in early setting (NCT06279364) are both ongoing. In May 2022, the Company licensed the exclusive rights to MSD (the tradename of Merck & Co., Inc, Rahway, NJ, USA) to develop, use, manufacture and commercialize sac-TMT in all territories outside of Greater China (which includes Mainland China, Hong Kong, Macao, and Taiwan). KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. The incidence rate of cervical cancer ranks first among the three major malignant tumors in gynecology, and is the fourth leading cause of cancer deaths among women. According to the "China Malignant Tumor Discipline Development Report (2023)", the incidence of gynecological tumors in China continues to show an increasing trend, in which the number of annual incidence cases of cervical cancer is 119,300, and the number of annual death cases is 37,200 [1]. Endometrial cancer (EC), as the second common gynecological malignant tumor after cervical cancer (CC), accounts for 20% to 30% of gynecological malignant tumors, with 77,700 new cases and 13,500 deaths in China in 2022 [2]; surgery is the main treatment for endometrial cancer, and except for the patients who can not tolerate surgery or who can not be operated in advanced stages, they should be operated with the supplement of Radiation therapy, chemotherapy, hormone and immune-targeted therapy and other comprehensive treatments. In addition, as the third common gynecological malignant tumor, the incidence rate of ovarian cancer (OC) is also high, and the number of new patients with OC in China in 2022 was 61,100 [2], with the incidence rate ranking the third of female reproductive system tumors [3]. In addition to the above three common gynecological malignant tumors, breast cancer is also a threat to women's lives and health. Among them, triple-negative breast cancer has unique biobehavioral characteristics, and is also known as the "most toxic" breast cancer. 2022 analysis of China's malignant tumor epidemiology data shows that there are 357,000 new cases of breast cancer and 75,000 deaths in Chinese women annually [4]. In the absence of effective therapeutic targets for triple-negative breast cancer, chemotherapy is the most important systemic treatment in the clinic [5], but it often has poor efficacy and high toxicity and side effects, and the prognosis is different from other subtypes of breast cancer [6], so it is necessary to explore more therapeutic means to improve the clinical benefit. The research results for different indications of sacituzumab tirumotecan (sac-TMT) announced at the ESMO Congress are expected to further meet the therapeutic needs of gynecological oncology including triple-negative breast cancer, and benefit more clinical patients. Dr. Junyou Ge, Chief Executive Officer of Kelun-Biotech, said, "Adhering to source innovation and possessing world-class innovation capabilities of our own are prerequisites for the sustainable development of innovative drug companies. We are very pleased that TROP2 ADC sacituzumab tirumotecan has demonstrated excellent clinical efficacy and safety in a number of studies in gynecologic oncology indications announced at the ESMO Congress. Kelun-Biotech has always been committed to solving unmet medical needs in China and around the world, with patients around the globe in mind, and with patient benefit as its primary goal. With a heart of love for patients, we look forward to providing patients around the world with innovative Chinese ADCs with significant clinical value and excellent cost-effectiveness." Reference SOURCE Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.

Clinical ResultPhase 3Phase 2Radiation Therapy

100 Deals associated with Vinorelbine Tartrate

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KEGG	Wiki	ATC	Drug Bank
D01935	Vinorelbine Tartrate	L01CA04	DB00361

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Breast Cancer	-	Pierre Fabre SA	01 Jan 1989
Non-Small Cell Lung Cancer	-	Pierre Fabre SA	01 Jan 1989

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced cancer	Phase 3	FR	Pierre Fabre Medicament Information	24 Feb 2016
Hormone receptor positive HER2 negative breast cancer	Phase 3	FR	Pierre Fabre Medicament Information	24 Feb 2016
Locally Advanced Lung Non-Small Cell Carcinoma	Phase 3	DE	Pierre Fabre Medicament Information	01 Apr 2005
Non-small cell lung cancer stage III	Phase 3	DE	Pierre Fabre Medicament Information	01 Apr 2005
Metastatic human epidermal growth factor 2 positive carcinoma of breast	Phase 3	US	GSK Plc	01 Aug 2001
Neoplasms	Phase 2	CN	-	19 Jun 2017
Advanced breast cancer	Phase 2	DE	Pierre Fabre Pharma GmbH	01 Dec 2016
Disease Progression	Phase 2	AR	GSK Plc	01 Nov 2009
Disease Progression	Phase 2	BR	GSK Plc	01 Nov 2009
Disease Progression	Phase 2	PE	GSK Plc	01 Nov 2009

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASH2024	Not Applicable	Classical Hodgkin's Lymphoma	-	Pembrolizumab Gemcitabine Vinorelbine and Liposomal Doxorubicin (P-GVD)	rgveebuhdc(plggnewlqw) = inpahnpdmq yswlpkhzzd (gyxpbnknrp ) View more	-	09 Dec 2024
ASH2024	Not Applicable	Refractory Hodgkin Lymphoma	-	Pembrolizumab Maintenance	grrobvgrgj(qdekstwfzd) = ruxhytcebx jhytorowqt (doeqnkyoef, 33 - 80)	-	08 Dec 2024
EUCTR2016-002165-63-DK (NAME, ESMO2024)	Phase 2	Metastatic breast cancer HER2 normal \| Estrogenic receptor (ER) positive \| ER negative	163	Vinorelbine (Navelbine Oralâ) standard treatment	wkrxfzqoql(leuiuvjpum) = qgkfnpgaje zrjchxitpu (jychhnwvkc, 14.66 - 18.61) View more	Negative	16 Sep 2024
				Vinorelbine (Navelbine Oralâ) metronomic treatment	wkrxfzqoql(leuiuvjpum) = wokkjphmtm zrjchxitpu (jychhnwvkc, 12.11 - 18.16) View more
NCT04389073 (Pubmed) Manual	Phase 2	Metastatic HER2-Negative Breast Carcinoma HER2 Negative	97	Anti-angiogenic bevacizumab, vinorelbineipalitoripalimab	aplnmpcbim(quyujhzgkp) = rayxjnetyv sjnovamizp (laepjsvyoh ) View more	Positive	05 Jul 2024
				Conventional cisplatin, vinorelbineipalitoripalimab	aplnmpcbim(quyujhzgkp) = psaaldfgxt sjnovamizp (laepjsvyoh ) View more
ChiCTR2000041217 (ASCO2024) Manual	Phase 4	Metastatic human epidermal growth factor 2 positive carcinoma of breast Third line HER2 Positive	101	Pyrotinib + taxanes or vinorelbine	ahvefutfah(zcygxujuan) = ichayhmter wjozyusqmj (cfuhodndoi, 8.8 - 15.7)	Positive	24 May 2024
				Pyrotinib plus taxanes	ahvefutfah(zcygxujuan) = kfiqpkugfi wjozyusqmj (cfuhodndoi, 9.2 - 18.6) View more
NCT03887130 (CTgov)	Phase 2	Metastatic breast cancer	152	Oral Vinorelbine+capecitabine (Vinorelbine-Capecitabine (Arm A))	accvfmavgc(dbvytigumg) = cbzxwuxyic ddenuxpjax (fgfxvnyykk, qquwssksac - luyaldggok) View more	-	30 Apr 2024
				paclitaxel+Gemcitabine 1250 mg/m² (Gemcitabine-Paclitaxel (Arm B))	accvfmavgc(dbvytigumg) = nkzeagupho ddenuxpjax (fgfxvnyykk, rkwxtzblrd - laublrbqjw) View more
NCT02954055 (METEORA-II, CTgov)	Phase 2	ER-positive/HER2-negative Breast Cancer \| Advanced breast cancer	140	Paclitaxel (Arm A)	pyvqhhqsuy(ftcfbxxuud) = tyeuhihhwt ztcbftvdki (bmmergugai, ywgmqaplbw - gxaksisfbz) View more	-	26 Feb 2024
				CYCLOPHOSPHAMIDE+Vinorelbine+Capecitabine (Arm B)	pyvqhhqsuy(ftcfbxxuud) = csudkrhmci ztcbftvdki (bmmergugai, xdpccphiqo - ehcvznsqwn) View more
NCT02709720 (NORA, CTgov)	Phase 2	Non-Small Cell Lung Cancer \| Locally Advanced Lung Carcinoma	68	Vinorelbine+Cisplatin	bqngfwylie(hnnbmdglny) = ebzmwmgdlr jgtdvvgbzz (jzkqzsgqfa, bxucrazekw - oykbinvltn) View more	-	11 Jan 2024
ESMO 12023 \| ESMO 22023 Manual	Not Applicable	Metastatic human epidermal growth factor 2 positive carcinoma of breast Second line HER2 positive	89	Vinorelbine + Inetetamab + Pyrotinib	exhchsvfjq(sedrcoidox) = atrvzbjqmc lydbnofmgs (hmxswztdqp )	Positive	21 Oct 2023
				Vinorelbine + Inetetamab + Pyrotinib (second-line treatment)	defgdexjdn(jzerfpvgmv) = ydyjoyhbnc rfbqquoemf (vqqtdaoqpi ) View more
UEGW	Not Applicable	-	-	Neoadjuvant chemoradiotherapy (cisplatin and vinorelbine) + surgery	lydzjvtqiy(rmdpsjshds) = jyennjswnz tkbaghmyit (bcxtamylso ) View more	-	15 Oct 2023
				Surgery alone	semvyuqwqd(qkungpqbtb) = jimhktoofn mpatpuepgr (bwjxzvtlls )

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