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A HER3-targeted therapy has demonstrated clinically meaningful and durable efficacy in heavily pretreated patients with EGFR-mutant non–small cell lung cancer, according to results of a phase 1 study.
Patritumab deruxtecan, an antibody-drug conjugate targeting HER3, had an overall response rate (ORR) of 39% and median progression-free survival (PFS) of 8.2 months in a phase 1 study that included patients previously treated with tyrosine kinase inhibitors (TKIs) and chemotherapy, the results show.
The efficacy was seen across EGFR TKI resistance mechanisms in this very difficult-to-treat patient population, according to investigator Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute, Boston.
“There is not one category of individuals that are having a response, or not having a response,” Dr. Jänne said in a presentation at the annual meeting of the American Society of Clinical Oncology (Abstract 9007).
“Responses are observed in patients with identifiable resistance mechanisms, and in patients that do not have an identifiable resistance mechanism, but have progressed on prior EGFR TKI therapy,” he added.
More than 80% of non–small cell lung cancer (NSCLC) tumors express HER3, and of note, HER3 alterations do not appear to confer resistance to EGFR TKIs in patients with EGFR-mutant NSCLC, according to Dr. Jänne.
Study details
Also known as HER3-DXd, patritumab deruxtecan consists of a fully human anti-HER3 monoclonal antibody linked to a topoisomerase inhibitor payload by a tetrapeptide-based cleavable linker.
The antibody-drug conjugate is also being evaluated in metastatic breast cancer and colorectal cancer, Dr. Jänne said.
In the present phase 1 dose escalation and dose expansion study, a total of 57 patients were treated with patritumab deruxtecan at 5.6 mg/kg, the recommended dose for the expansion phase.
The median age of these patients was 65 years, and the majority (63%) were women, Dr. Jänne reported. About half had a history of central nervous system metastases.
The median number of prior lines of systemic therapy was four, making this a heavily pretreated patient population, Dr. Jänne said. All patients had received prior EGFR TKI therapy, and 86% specifically had prior osimertinib. Ninety-one percent had prior platinum-based chemotherapy, and 40% had received immunotherapy.
Spectrum of responses
The confirmed ORR of 39% included 1 complete response (2%) and 21 partial responses (37%), Dr. Jänne reported. The disease control rate was 72%, and median duration of response was 6.9 months at a median follow-up of 10.2 months.
The median PFS was 8.2 months in 57 patients overall and in a subset of 44 patients who had received prior osimertinib and platinum-based chemotherapy, according to the report.
Activity of patritumab deruxtecan was seen not only across patients with diverse mechanisms of EGFR TKI resistance, but also regardless of prior number of treatments, and regardless of history of brain metastases, the investigator said.
In addition, clinical responses were seen across a spectrum of baseline HER3 expression by immunohistochemistry, the investigator added.
Safety was assessed in 81 patients treated at a range of doses in the phase 1 trial. The most common grade 3 or greater treatment-emergent adverse events, observed in 5% or more of patients, included thrombocytopenia, neutropenia, and anemia, while other side effects such as fatigue and dyspnea were observed, Dr. Jänne said. About 9% of the adverse events led to treatment discontinuation in the safety cohort.
Interstitial lung disease was observed in four patients, or 5% of the safety cohort. Three of these were grade 1-2 and one was grade 3, according to the report.
Questions to explore
The efficacy of patritumab deruxtecan was “high” in this phase 1 study, based on the reported response rate and median PFS, said discussant Nicolas Girard, MD, PhD, of Institut Curie in Paris.
However, the most striking finding of the study was the efficacy of the antibody-drug conjugate across all reported resistance mechanisms, Dr. Girard said in his remarks.
Questions that remains to be explored, according to Dr. Girard, include the impact of previous treatment sequencing with TKIs and chemotherapy on patient outcomes with patritumab deruxtecan, as well as the assessment of intracranial response and PFS for patients treated with the agent.
In addition, antitumor activity was seen across a wide range of baseline HER3 expression levels in this study, suggesting that a predictive biomarker remains to be identified, according to Dr. Girard.
“HER3 immunohistochemistry does not seem to be the candidate in this setting,” he said.
The study was sponsored by Daiichi Sankyo. Dr. Jänne reported disclosures related to Daiichi Sankyo, as well as Araxes Pharma, Astellas Pharma, AstraZeneca, and multiple other pharmaceutical companies. Dr. Jänne is also coinventor on a Dana Farber Cancer Institute–owned patent on EGFR mutations licensed to Labcorp and receives postmarketing royalties from this invention.
Dr. Girard reported disclosures related to AbbVie, AstraZeneca, Boehringer Ingelheim, and multiple other pharmaceutical companies.
A HER3-targeted therapy has demonstrated clinically meaningful and durable efficacy in heavily pretreated patients with EGFR-mutant non–small cell lung cancer, according to results of a phase 1 study.
Patritumab deruxtecan, an antibody-drug conjugate targeting HER3, had an overall response rate (ORR) of 39% and median progression-free survival (PFS) of 8.2 months in a phase 1 study that included patients previously treated with tyrosine kinase inhibitors (TKIs) and chemotherapy, the results show.
The efficacy was seen across EGFR TKI resistance mechanisms in this very difficult-to-treat patient population, according to investigator Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute, Boston.
“There is not one category of individuals that are having a response, or not having a response,” Dr. Jänne said in a presentation at the annual meeting of the American Society of Clinical Oncology (Abstract 9007).
“Responses are observed in patients with identifiable resistance mechanisms, and in patients that do not have an identifiable resistance mechanism, but have progressed on prior EGFR TKI therapy,” he added.
More than 80% of non–small cell lung cancer (NSCLC) tumors express HER3, and of note, HER3 alterations do not appear to confer resistance to EGFR TKIs in patients with EGFR-mutant NSCLC, according to Dr. Jänne.
Study details
Also known as HER3-DXd, patritumab deruxtecan consists of a fully human anti-HER3 monoclonal antibody linked to a topoisomerase inhibitor payload by a tetrapeptide-based cleavable linker.
The antibody-drug conjugate is also being evaluated in metastatic breast cancer and colorectal cancer, Dr. Jänne said.
In the present phase 1 dose escalation and dose expansion study, a total of 57 patients were treated with patritumab deruxtecan at 5.6 mg/kg, the recommended dose for the expansion phase.
The median age of these patients was 65 years, and the majority (63%) were women, Dr. Jänne reported. About half had a history of central nervous system metastases.
The median number of prior lines of systemic therapy was four, making this a heavily pretreated patient population, Dr. Jänne said. All patients had received prior EGFR TKI therapy, and 86% specifically had prior osimertinib. Ninety-one percent had prior platinum-based chemotherapy, and 40% had received immunotherapy.
Spectrum of responses
The confirmed ORR of 39% included 1 complete response (2%) and 21 partial responses (37%), Dr. Jänne reported. The disease control rate was 72%, and median duration of response was 6.9 months at a median follow-up of 10.2 months.
The median PFS was 8.2 months in 57 patients overall and in a subset of 44 patients who had received prior osimertinib and platinum-based chemotherapy, according to the report.
Activity of patritumab deruxtecan was seen not only across patients with diverse mechanisms of EGFR TKI resistance, but also regardless of prior number of treatments, and regardless of history of brain metastases, the investigator said.
In addition, clinical responses were seen across a spectrum of baseline HER3 expression by immunohistochemistry, the investigator added.
Safety was assessed in 81 patients treated at a range of doses in the phase 1 trial. The most common grade 3 or greater treatment-emergent adverse events, observed in 5% or more of patients, included thrombocytopenia, neutropenia, and anemia, while other side effects such as fatigue and dyspnea were observed, Dr. Jänne said. About 9% of the adverse events led to treatment discontinuation in the safety cohort.
Interstitial lung disease was observed in four patients, or 5% of the safety cohort. Three of these were grade 1-2 and one was grade 3, according to the report.
Questions to explore
The efficacy of patritumab deruxtecan was “high” in this phase 1 study, based on the reported response rate and median PFS, said discussant Nicolas Girard, MD, PhD, of Institut Curie in Paris.
However, the most striking finding of the study was the efficacy of the antibody-drug conjugate across all reported resistance mechanisms, Dr. Girard said in his remarks.
Questions that remains to be explored, according to Dr. Girard, include the impact of previous treatment sequencing with TKIs and chemotherapy on patient outcomes with patritumab deruxtecan, as well as the assessment of intracranial response and PFS for patients treated with the agent.
In addition, antitumor activity was seen across a wide range of baseline HER3 expression levels in this study, suggesting that a predictive biomarker remains to be identified, according to Dr. Girard.
“HER3 immunohistochemistry does not seem to be the candidate in this setting,” he said.
The study was sponsored by Daiichi Sankyo. Dr. Jänne reported disclosures related to Daiichi Sankyo, as well as Araxes Pharma, Astellas Pharma, AstraZeneca, and multiple other pharmaceutical companies. Dr. Jänne is also coinventor on a Dana Farber Cancer Institute–owned patent on EGFR mutations licensed to Labcorp and receives postmarketing royalties from this invention.
Dr. Girard reported disclosures related to AbbVie, AstraZeneca, Boehringer Ingelheim, and multiple other pharmaceutical companies.
A HER3-targeted therapy has demonstrated clinically meaningful and durable efficacy in heavily pretreated patients with EGFR-mutant non–small cell lung cancer, according to results of a phase 1 study.
Patritumab deruxtecan, an antibody-drug conjugate targeting HER3, had an overall response rate (ORR) of 39% and median progression-free survival (PFS) of 8.2 months in a phase 1 study that included patients previously treated with tyrosine kinase inhibitors (TKIs) and chemotherapy, the results show.
The efficacy was seen across EGFR TKI resistance mechanisms in this very difficult-to-treat patient population, according to investigator Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute, Boston.
“There is not one category of individuals that are having a response, or not having a response,” Dr. Jänne said in a presentation at the annual meeting of the American Society of Clinical Oncology (Abstract 9007).
“Responses are observed in patients with identifiable resistance mechanisms, and in patients that do not have an identifiable resistance mechanism, but have progressed on prior EGFR TKI therapy,” he added.
More than 80% of non–small cell lung cancer (NSCLC) tumors express HER3, and of note, HER3 alterations do not appear to confer resistance to EGFR TKIs in patients with EGFR-mutant NSCLC, according to Dr. Jänne.
Study details
Also known as HER3-DXd, patritumab deruxtecan consists of a fully human anti-HER3 monoclonal antibody linked to a topoisomerase inhibitor payload by a tetrapeptide-based cleavable linker.
The antibody-drug conjugate is also being evaluated in metastatic breast cancer and colorectal cancer, Dr. Jänne said.
In the present phase 1 dose escalation and dose expansion study, a total of 57 patients were treated with patritumab deruxtecan at 5.6 mg/kg, the recommended dose for the expansion phase.
The median age of these patients was 65 years, and the majority (63%) were women, Dr. Jänne reported. About half had a history of central nervous system metastases.
The median number of prior lines of systemic therapy was four, making this a heavily pretreated patient population, Dr. Jänne said. All patients had received prior EGFR TKI therapy, and 86% specifically had prior osimertinib. Ninety-one percent had prior platinum-based chemotherapy, and 40% had received immunotherapy.
Spectrum of responses
The confirmed ORR of 39% included 1 complete response (2%) and 21 partial responses (37%), Dr. Jänne reported. The disease control rate was 72%, and median duration of response was 6.9 months at a median follow-up of 10.2 months.
The median PFS was 8.2 months in 57 patients overall and in a subset of 44 patients who had received prior osimertinib and platinum-based chemotherapy, according to the report.
Activity of patritumab deruxtecan was seen not only across patients with diverse mechanisms of EGFR TKI resistance, but also regardless of prior number of treatments, and regardless of history of brain metastases, the investigator said.
In addition, clinical responses were seen across a spectrum of baseline HER3 expression by immunohistochemistry, the investigator added.
Safety was assessed in 81 patients treated at a range of doses in the phase 1 trial. The most common grade 3 or greater treatment-emergent adverse events, observed in 5% or more of patients, included thrombocytopenia, neutropenia, and anemia, while other side effects such as fatigue and dyspnea were observed, Dr. Jänne said. About 9% of the adverse events led to treatment discontinuation in the safety cohort.
Interstitial lung disease was observed in four patients, or 5% of the safety cohort. Three of these were grade 1-2 and one was grade 3, according to the report.
Questions to explore
The efficacy of patritumab deruxtecan was “high” in this phase 1 study, based on the reported response rate and median PFS, said discussant Nicolas Girard, MD, PhD, of Institut Curie in Paris.
However, the most striking finding of the study was the efficacy of the antibody-drug conjugate across all reported resistance mechanisms, Dr. Girard said in his remarks.
Questions that remains to be explored, according to Dr. Girard, include the impact of previous treatment sequencing with TKIs and chemotherapy on patient outcomes with patritumab deruxtecan, as well as the assessment of intracranial response and PFS for patients treated with the agent.
In addition, antitumor activity was seen across a wide range of baseline HER3 expression levels in this study, suggesting that a predictive biomarker remains to be identified, according to Dr. Girard.
“HER3 immunohistochemistry does not seem to be the candidate in this setting,” he said.
The study was sponsored by Daiichi Sankyo. Dr. Jänne reported disclosures related to Daiichi Sankyo, as well as Araxes Pharma, Astellas Pharma, AstraZeneca, and multiple other pharmaceutical companies. Dr. Jänne is also coinventor on a Dana Farber Cancer Institute–owned patent on EGFR mutations licensed to Labcorp and receives postmarketing royalties from this invention.
Dr. Girard reported disclosures related to AbbVie, AstraZeneca, Boehringer Ingelheim, and multiple other pharmaceutical companies.
REPORTING FROM ASCO 2021