- Oral presentation highlighting extended follow-up data from phase 1 study in patients with locally advanced or metastatic TKI-resistant, EGFR-mutated NSCLC shows promising clinical activity
- Data from this study informed the design of the recently initiated pivotal HERTHENA-Lung01 trial in similar patient population
New data from Daiichi Sankyo Company, Limited (hereafter, patritumab deruxtecan (HER3-DXd), a HER3 directed antibody drug conjugate (ADC), demonstrated preliminary evidence of clinically meaningful and durable tumor response in patients with locally advanced or metastatic TKI-resistant, EGFR-mutated non-small cell lung cancer
These extended follow-up data from the dose escalation portion and one expansion cohort of a phase 1 study of patritumab deruxtecan were presented today during an oral presentation (Abstract #9007) at the 2021 American Society of Clinical Oncology (#ASCO21) Virtual Scientific Program.
While the efficacy of targeted therapy with EGFR TKIs is well-established in the treatment of patients with advanced EGFR-mutated NSCLC, the development of a broad range of resistance mechanisms commonly leads to disease progression. Subsequent salvage therapies after EGFR TKI and platinum-based chemotherapy have limited efficacy with progression-free survival (PFS) of approximately 2.8 to 3.2 months. New treatment approaches are needed to overcome resistance and improve survival in these patients.
An objective response rate (ORR), as assessed by blinded central review, was 39% (CI 95%; 26-52%) in 57 evaluable patients treated with patritumab deruxtecan (5.6 mg/kg). One confirmed complete response and 21 partial responses were observed. The disease control rate was 72% (CI 95%; 59-83%). After a median follow-up of 10.2 months (range, 5.2-19.9 months), the estimated median duration of response was 6.9 months (CI 95%; range, 3.1-NE months) and the estimated median PFS was 8.2 months (CI 95%; range, 4.4-8.3 months). Confirmed responses were observed in patients across a spectrum of baseline tumor HER3 membrane expression levels, EGFR activating mutations and EGFR TKI resistance mechanisms, including EGFR activating mutations (Ex19del, L858R, G719Y), other EGFR mutations (T790M, C797S, Ex20ins), amplifications (EGFR, CCNE1, MET) and non-EGFR mutations and fusions (MET, KRAS). A subgroup of patients treated with osimertinib and platinum-based chemotherapy (n=44) prior to enrollment in the study demonstrated similar efficacy. An ORR of 39% (CI 95%; 24-55%) and PFS of 8.2 months (CI 95%; 4.0-NE) was observed in this subgroup. Additionally, the confirmed ORR and median PFS were similar in patients with or without a history of brain metastases.
“EGFR TKIs are the standard of care for patients with advanced EGFR-mutated NSCLC. However, the
activity of these agents is limited by the development of acquired resistance mechanisms,” said Pasi A.
Jänne, MD, PhD, Director, Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute. “In this
study, where patients were heavily pre-treated, efficacy was observed in patients with and without known
EGFR TKI resistance mechanisms in a population that is often difficult to treat. Targeting HER3 with
patritumab deruxtecan may be a novel and promising strategy, and we look forward to further evaluating
clinical activity and safety in the pivotal HERTHENA-Lung01 trial.”
The safety profile of patritumab deruxtecan in patients treated with the 5.6 mg/kg dose (n=57) is consistent
with that seen across all patients (n=81) in both the dose escalation and dose expansion cohort 1 of the study
(doses range from 3.2 to 6.4 mg/kg). Grade 3 or higher treatment emergent events (TEAEs) occurred in 64%
of all patients (n=81). TEAEs grade 3 or higher severity occurring in ≥ 5% of all patients were platelet count
decreased, neutrophil count decreased, fatigue, anemia, dyspnea, febrile neutropenia, hypoxia, white blood
cell count decreased, hypokalemia and lymphocyte count decreased. There were four cases of treatment related interstitial lung disease (ILD) reported, as determined by an independent adjudication committee, including two of grade 1 severity, one grade 2, and one grade 3. The median time to adjudicated onset of treatment-related ILD was 53 days (range, 13-130 days). There were five TEAEs associated with death including two cases of disease progression, two cases of respiratory failure and one case of shock. All TEAEs associated with death were considered not related to the study drug.
“Treatment options that provide meaningful therapeutic benefit for patients with EGFR-mutated non-small
cell lung cancer with disease progression following standard treatment with EGFR TKIs and platinum-based
chemotherapy are limited,” said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head,
Oncology Development, Oncology R&D, Daiichi Sankyo. “HER3 represents a novel target for therapeutic
development as it is broadly expressed in non-small cell lung cancer. These results are encouraging since the
safety profile was consistent with previous findings and response to patritumab deruxtecan was seen
irrespective of the level of HER3 expression or mechanism of resistance to prior therapies.”
Patients receiving 5.6 mg/kg (n=57) of patritumab deruxtecan were pre-treated with a median of four prior
lines of therapy (range, 1-9), including EGFR TKIs (100%), platinum-based chemotherapy (91%) and immunotherapy (40%). A majority (86%) were previously treated with osimertinib. Of the 57 patients, 27
patients had brain metastases at baseline. As of data cut-off on September 24, 2020, 32% of patients remain
on treatment with patritumab deruxtecan.