Merck & Gilead Halt Phase III Study on Non-Small Cell Lung Cancer Treatment
On June 8, Gilead Sciences, Inc. (Foster City, CA, Nasdaq: GILD) and Merck & Co., Inc. (Rahway, NJ, NYSE: MRK) announced the discontinuation of their Phase III clinical trial, KEYNOTE-D46/EVOKE-03, which was evaluating the combination therapy of Gilead's Trodelvy® (sacituzumab govitecan) and Merck's Keytruda® (pembrolizumab). This decision comes after an analysis of pre-defined endpoints suggested that the combination therapy did not demonstrate statistically significant improvements in progression-free survival (PFS) compared to Keytruda monotherapy. While there was numerical improvement in PFS, expected results from the final overall survival (OS) analysis were not anticipated to be statistically significant.
The external data monitoring committee (DMC) had verified the results based on final PFS and interim OS analyses. The safety profile of the combination therapy remained consistent with known profiles of each agent, and no new safety signals were identified during the trial. Further details from the study are anticipated to be presented at an upcoming academic conference.
Notifications have been completed with regulatory authorities, and Merck has advised the principal investigator to inform participating patients to discuss treatment options with their healthcare providers. Ongoing studies of Trodelvy or other Merck trials will continue unaffected.
Both companies expressed gratitude to patients, families, and healthcare professionals who participated in the KEYNOTE-D46/EVOKE-03 study, acknowledging their contribution to this important research.
Lung cancer remains one of the most common cancers globally, with approximately 2.5 million new cases reported in 2022. Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of lung cancer cases. Many patients diagnosed with NSCLC face limited treatment options and low long-term survival rates upon initial diagnosis, especially at the metastatic stage. Despite advancements in treatment, the five-year survival rate for metastatic NSCLC is below 10%. Immunotherapy, with or without chemotherapy, is considered the standard first-line treatment, yet there remains a critical need for new treatment options as not all patients respond effectively.
The KEYNOTE-D46/EVOKE-03 trial specifically targeted patients with previously untreated metastatic NSCLC with high PD-L1 expression (Tumor Proportion Score [TPS] of 50% or more) lacking the sensitizing EGFR, ALK, or ROS1 mutations. This international, non-blinded, randomized Phase III study aimed to assess the safety and efficacy of combining Trodelvy and Keytruda compared to Keytruda alone. Approximately 620 patients across global clinical settings were enrolled in the study.
Participants in the study were randomized in a 1:1 ratio to receive either the combination therapy of Trodelvy (administered intravenously at a dosage of 10 mg/kg on Day 1 and Day 8 of a 21-day cycle) and Keytruda (200 mg IV on Day 1 of each 21-day cycle) or Keytruda monotherapy. Keytruda was allowed for up to 35 cycles, while Trodelvy could continue until disease progression, death, unacceptable toxicity, or meeting termination criteria.
The primary endpoints of the trial were progression-free survival (PFS) assessed independently by blinded central review (BICR) according to RECIST v1.1, and overall survival (OS). Secondary endpoints included the objective response rate (ORR), duration of response (DOR), patient-reported outcomes (PRO), and safety assessments. More information regarding the study can be found on ClinicalTrials.gov (NCT05609968).
Trodelvy® (sacituzumab govitecan) is a first-in-class antibody-drug conjugate targeting TROP-2, a cell surface antigen overexpressed in more than 90% of various cancers, including breast cancer and lung cancer. It is designed to deliver a payload of the topoisomerase I inhibitor SN-38 via a proprietary hydrolysable linker. This enables Trodelvy to exert powerful activity through a bystander effect on both TROP-2 expressing cells and the tumor microenvironment.
Trodelvy is currently approved in over 60 countries as a treatment for metastatic or recurrent triple-negative breast cancer (TNBC) following at least two prior therapies, and in more than 50 countries for HR+/HER2- breast cancer with earlier treatment history. Its application is already established among healthcare providers, demonstrating consistent outcomes in over 75,000 breast cancer patients across clinical trials and real-world settings.
Trodelvy is under evaluation in multiple ongoing Phase III trials targeting various cancers with high TROP-2 expression. These investigations are exploring both monotherapy and combination therapy with pembrolizumab, targeting TNBC and HR+/HER2- cancer early treatment, along with previously recognized clinical activity in small cell lung cancer and gynecological tumors.
Trodelvy may cause severe neutropenia and diarrhea. Patients experiencing neutrophil counts below 1500/mm3 or febrile neutropenia should discontinue Trodelvy. Patients must have regular blood counts monitored during treatment. Patients at high risk for febrile neutropenia should consider primary prophylaxis with G-CSF. Severe diarrhea can occur, requiring observation and electrolyte supplementation when necessary.
The drug should not be used in patients with a history of severe hypersensitivity reaction to Trodelvy. The expected side effects reported in the safety analysis population noted leukopenia (84%), neutropenia (75%), anemia (69%), diarrhea (64%), and nausea (64%) among others, indicating the drug's active effects and its implications for patient management during treatment.
The external data monitoring committee (DMC) had verified the results based on final PFS and interim OS analyses. The safety profile of the combination therapy remained consistent with known profiles of each agent, and no new safety signals were identified during the trial. Further details from the study are anticipated to be presented at an upcoming academic conference.
Notifications have been completed with regulatory authorities, and Merck has advised the principal investigator to inform participating patients to discuss treatment options with their healthcare providers. Ongoing studies of Trodelvy or other Merck trials will continue unaffected.
Both companies expressed gratitude to patients, families, and healthcare professionals who participated in the KEYNOTE-D46/EVOKE-03 study, acknowledging their contribution to this important research.
Background on Non-Small Cell Lung Cancer (NSCLC)
Lung cancer remains one of the most common cancers globally, with approximately 2.5 million new cases reported in 2022. Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of lung cancer cases. Many patients diagnosed with NSCLC face limited treatment options and low long-term survival rates upon initial diagnosis, especially at the metastatic stage. Despite advancements in treatment, the five-year survival rate for metastatic NSCLC is below 10%. Immunotherapy, with or without chemotherapy, is considered the standard first-line treatment, yet there remains a critical need for new treatment options as not all patients respond effectively.
Insights into KEYNOTE-D46/EVOKE-03 Study
The KEYNOTE-D46/EVOKE-03 trial specifically targeted patients with previously untreated metastatic NSCLC with high PD-L1 expression (Tumor Proportion Score [TPS] of 50% or more) lacking the sensitizing EGFR, ALK, or ROS1 mutations. This international, non-blinded, randomized Phase III study aimed to assess the safety and efficacy of combining Trodelvy and Keytruda compared to Keytruda alone. Approximately 620 patients across global clinical settings were enrolled in the study.
Participants in the study were randomized in a 1:1 ratio to receive either the combination therapy of Trodelvy (administered intravenously at a dosage of 10 mg/kg on Day 1 and Day 8 of a 21-day cycle) and Keytruda (200 mg IV on Day 1 of each 21-day cycle) or Keytruda monotherapy. Keytruda was allowed for up to 35 cycles, while Trodelvy could continue until disease progression, death, unacceptable toxicity, or meeting termination criteria.
The primary endpoints of the trial were progression-free survival (PFS) assessed independently by blinded central review (BICR) according to RECIST v1.1, and overall survival (OS). Secondary endpoints included the objective response rate (ORR), duration of response (DOR), patient-reported outcomes (PRO), and safety assessments. More information regarding the study can be found on ClinicalTrials.gov (NCT05609968).
About Trodelvy
Trodelvy® (sacituzumab govitecan) is a first-in-class antibody-drug conjugate targeting TROP-2, a cell surface antigen overexpressed in more than 90% of various cancers, including breast cancer and lung cancer. It is designed to deliver a payload of the topoisomerase I inhibitor SN-38 via a proprietary hydrolysable linker. This enables Trodelvy to exert powerful activity through a bystander effect on both TROP-2 expressing cells and the tumor microenvironment.
Trodelvy is currently approved in over 60 countries as a treatment for metastatic or recurrent triple-negative breast cancer (TNBC) following at least two prior therapies, and in more than 50 countries for HR+/HER2- breast cancer with earlier treatment history. Its application is already established among healthcare providers, demonstrating consistent outcomes in over 75,000 breast cancer patients across clinical trials and real-world settings.
Trodelvy is under evaluation in multiple ongoing Phase III trials targeting various cancers with high TROP-2 expression. These investigations are exploring both monotherapy and combination therapy with pembrolizumab, targeting TNBC and HR+/HER2- cancer early treatment, along with previously recognized clinical activity in small cell lung cancer and gynecological tumors.
Major Safety Information in the United States
Trodelvy may cause severe neutropenia and diarrhea. Patients experiencing neutrophil counts below 1500/mm3 or febrile neutropenia should discontinue Trodelvy. Patients must have regular blood counts monitored during treatment. Patients at high risk for febrile neutropenia should consider primary prophylaxis with G-CSF. Severe diarrhea can occur, requiring observation and electrolyte supplementation when necessary.
The drug should not be used in patients with a history of severe hypersensitivity reaction to Trodelvy. The expected side effects reported in the safety analysis population noted leukopenia (84%), neutropenia (75%), anemia (69%), diarrhea (64%), and nausea (64%) among others, indicating the drug's active effects and its implications for patient management during treatment.
Topics Health）
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