The treatment of patients with epidermal growth factor receptor (EGFR)-mutated lung cancer that progresses on EGFR-targeted tyrosine kinase inhibitors has been challenging. In the phase II HERTHENA-Lung01 trial, the topoisomerase-1 HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd) yielded clinically meaningful and durable responses in this population, including intracranial responses, and thus is considered an emerging treatment option.
At the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer, Helena Yu, MD, Associate Attending Physician at Memorial Sloan Kettering Cancer Center, New York, presented an analysis of the most recent data,1 which were concurrently published in the Journal of Clinical Oncology.2
Helena Yu, MD
“HER3-DXd has emerged as a promising therapy for patients with EGFR-mutated NSCLC after failure of EGFR tyrosine kinase inhibitors and platinum-based chemotherapy, for whom available treatment options provide only limited efficacy,” Dr. Yu said. “The results from HERTHENA-Lung01 provide compelling evidence of efficacy.”
The current standard of care after disease progression in this population is platinum-based chemotherapy. Salvage therapies yield very low response rates and median progression-free survival.
HERTHENA-Lung01 is a global, multicenter, open-label, two-arm phase II trial evaluating the safety and efficacy of patritumab deruxtecan in patients with EGFR-mutated locally advanced or metastatic NSCLC following disease progression with an EGFR tyrosine kinase inhibitor and platinum-based chemotherapy. It enrolled 275 patients in Asia, Europe, North America, and Oceania, of whom 63% had an EGFR exon 19 deletion and 36% had an exon 21 L858R mutation; one patient had both. Brain metastases were seen in 32%, and liver metastases were seen in 33%.
Patients were heavily pretreated, having received a median of three prior lines of systemic therapy in the locally advanced or metastatic setting (range, 1–11 lines). This prior treatment included platinum-based chemotherapy (100%), third-generation EGFR tyrosine kinase inhibitors (93%), and immunotherapy (40%). The 225 patients in this analysis all received 5.6 mg/kg (n = 225) intravenously of HER3-DXd every 3 weeks. The primary endpoint was objective response rate by blinded independent central review.
In 225 patients, the confirmed objective response rate was 29.8% in patients with prior EGFR tyrosine kinase inhibitor and platinum-based chemotherapy (any lines) and 29.2% in patients who received a third-generation EGFR tyrosine kinase inhibitor and platinum-based chemotherapy. For each group, stable disease plus partial response was attained in approximately 73%, median duration of response was 6.4 months, median progression-free survival was 5.5 months, and median overall survival was 11.9 months, Dr. Yu reported.
Antitumor activity with HER3-DXd was seen across diverse mechanisms of EGFR tyrosine kinase inhibitor resistance—including patients with EGFR-dependent, EGFR-independent, and unidentified mechanisms of resistance—and across a broad range of pretreatment tumor HER3 membrane expression, she said.
“This study provides the first report of HER3-DXd efficacy in the central nervous system [CNS],” Dr. Yu added, citing a 33% intracranial response rate among 30 patients with brain metastases and no prior radiotherapy. Outcomes in these patients included 9 intracranial complete responses, 1 intracranial partial response, and 13 cases of stable disease. A CNS duration of response of 8.4 months was achieved. The vast majority of patients had some degree of tumor shrinkage, and all prespecified subgroups appeared to derive benefit from this treatment, Dr. Yu said.
The safety profile of HER3-DXd observed in HERTHENA-Lung01 was consistent with previous clinical trials, with a low rate (7.1%) of treatment discontinuation from treatment-emergent adverse events. Grade ≥ 3 adverse events occurred in 64.9% of patients, most commonly thrombocytopenia (21%), neutropenia (19%), anemia (14%), leukopenia (10%), fatigue (6%), hypokalemia (5%), and asthenia (5%). A total of 12 patients (5.3%) had confirmed treatment-related interstitial lung disease, mostly low grade, although there was one death related to interstitial lung disease.
“The clinically meaningful efficacy observed across a broad range of HER3 expression and diverse mechanisms of EGFR tyrosine kinase inhibitor resistance as well as the antitumor activity seen in patients with brain metastases underscore the potential of patritumab deruxtecan to become an important treatment option for a population of patients with lung cancer who have limited treatment options,” Dr. Yu concluded.
Ongoing trials include the phase III HERTHENA-Lung02 study, evaluating HER3-DXd vs platinum-based tyrosine kinase inhibitor in EGFR-mutant NSCLC after disease progression on third-generation EGFR tyrosine kinase inhibitor, and a phase I study of HER3-DXd in combination with osimertinib in EGFR-mutated NSCLC after disease progression on first-line osimertinib and in previously untreated patients.
DISCLOSURE: Dr. Yu has served as a consultant for or received honoraria from AstraZeneca, Cullinan, Takeda, Black Diamond, Daiichi, Blueprint Medicine, Janssen Oncology, and Amgen.
1. Yu HA, Goto Y, Hayashi H, et al: Patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC following EGFR TKI and platinum-based chemotherapy: HERTHENA-Lung01. 2023 World Conference on Lung Cancer. Abstract OA05.03. Presented September 10, 2023.
2. Yu HA, Goto Y, Hayashi H, et al: HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor-mutated non-small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. September 10, 2023 (early release online).
Helena Linardou, MD, PhD
Helena Linardou, MD, PhD, Director of the 4th Department of Oncology and the Comprehensive Clinical Trials Center, Metropolitan Hospital, Athens, served as discussant of the session on antibody-drug conjugates at the 2023 World Conference on Lung Cancer. Calling...