New data presented at this year’s annual meeting of the American Society of Clinical Oncology, held online June 4 – 8, 2021, confirms promising clinical activity for patritumab deruxtecan (HER3-DXd, previously known as U3-1402; Daiichi Sankyo), a potential first-in-class HER3 directed Antibody-drug Conjugate or ADC for the treatment of patients with a form of metastatic non-small cell lung cancer (NSCLC).
In an oral session (Abstract #9007), researchers reported extended follow-up data from the dose-escalation portion and one expansion cohort phase 1 trial (NCT04619004) of patritumab deruxtecan in patients with locally advanced or metastatic tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated NSCLC.
The results 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 (NSCLC). Preliminary data from this trial informed the recently initiated pivotal HERTHENA-Lung01 phase 2 trial, which was also highlighted as a trial-in-progress poster presentation (Abstract #TPS9139).
Designed using Daiichi Sankyo’s proprietary DXd ADC technology, patritumab deruxtecan is comprised of a human anti-HER3 antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.
Treatment of advanced EGFR-mutated NSCLC
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.[1][2] 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.[3] 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 (Tagrisso®; AstraZeneca) 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.
Standard of care
“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, Ph.D., 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,” Jänne added.
Safety profile
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, Ph.D., 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,” Gallant further added.
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.
Trial design
The dose escalation part of the study evaluated patients with EGFR-mutated disease either with progression on osimertinib or T790M-negative after progression on erlotinib, gefitinib or afatinib. The primary objective of this part of the study was to assess the safety and tolerability of patritumab deruxtecan and determine the recommended dose for expansion (RDE).
The dose expansion part of the study is evaluating patritumab deruxtecan at the RDE (5.6 mg/kg every three weeks) in three cohorts. Cohort 1 includes patients with locally advanced or metastatic EGFR-mutated NSCLC who experienced disease progression after taking one or more EGFR TKIs and one or more platinum based chemotherapy regimens. Cohort 2 includes patients with squamous or non-squamous NSCLC without EGFR-activating mutations following platinum-based chemotherapy and following an anti-PD-1 or anti-PD-L1 antibody regimen. Cohort 3 includes patients with NSCLC with EGFR-activating mutations including any histology other than combined small cell and non-small cell lung cancer; patients in Cohort 3 are randomized 1:1 to receive the 5.6 mg/kg RDE regimen (Cohort 3a) or an escalating up-titration regimen of patritumab deruxtecan (Cohort 3b).
Lung cancer is the most common cancer and the leading cause of cancer mortality worldwide. There were an estimated 2.2 million new cases of lung cancer and 1.8 million deaths in 2020. [4] Most lung cancers are diagnosed at an advanced or metastatic stage. [5] Non-small cell lung cancer (NSCLC) accounts for 80 to 85% of all lung cancers.[6]
The introduction of targeted therapies and checkpoint inhibitors in the past decade has improved the treatment landscape for patients with advanced or metastatic NSCLC; however, the prognosis is particularly poor among patients who have progressed after treatment with standard therapies. For patients who are not eligible for current treatments, or whose cancer continues to progress, new therapeutic approaches are needed.[7]
The mutationally-activated EGFR tyrosine kinase is a well-established oncogenic driver and molecular target for management of advanced stage NSCLC.[8]For patients with advanced EGFR-mutated NSCLC, targeted therapy with EGFR TKIs offer higher response rates and progression-free survival compared to chemotherapy. [7] However, most patients eventually develop resistance to these therapies, and standard treatment options are limited. [9] Treatment options used in this setting historically have demonstrated limited efficacy with progression free survival of up to 6.4 months for platinum-based chemotherapy and 3.2 months for other salvage therapies. [3][10] New treatment approaches are needed to overcome resistance and improve survival in these patients.
About HER3
HER3 is a member of the EGFR family of receptor tyrosine kinases, which are associated with aberrant cell proliferation and survival [11] Approximately 25 to 30% of lung cancers worldwide have an EGFR-activating mutation, and it is estimated that about 83% of all NSCLC tumors express the HER3 protein, which can be associated with an increased incidence of metastases, reduced survival and resistance to standard of care treatment. [12][13][14]
Currently, no HER3 directed medicines are approved for the treatment of cancer.
Clinical trials
HERTHENA-Lung01: Patritumab Deruxtecan in Subjects With Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer – NCT04619004
A Study to Evaluate U3-1402 in Subjects With Advanced or Metastatic Colorectal Cancer – NCT04479436
Phase I/II Study of U3-1402 in Subjects With Human Epidermal Growth Factor Receptor 3 (HER3) Positive Metastatic Breast Cancer – NCT02980341
Patritumab Deruxtecan in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic EGFR-mutated Non-Small Cell Lung Cancer – NCT04676477
U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer – NCT03260491
Highlights of prescribing information
Osimertinib (Tagrisso®; AstraZeneca)[{Prescribing Information]
References
[1] Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Jänne PA. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007 May 18;316(5827):1039-43. doi: 10.1126/science.1141478. Epub 2007 Apr 26. PMID: 17463250.[Article]
[2] Schoenfeld AJ, Yu HA. The Evolving Landscape of Resistance to Osimertinib. J Thorac Oncol. 2020 Jan;15(1):18-21. doi: 10.1016/j.jtho.2019.11.005. PMID: 31864549.[Article]
[3] Yang CJ, Tsai MJ, Hung JY, Lee MH, Tsai YM, Tsai YC, Hsu JF, Liu TC, Huang MS, Chong IW. The clinical efficacy of Afatinib 30 mg daily as starting dose may not be inferior to Afatinib 40 mg daily in patients with stage IV lung Adenocarcinoma harboring exon 19 or exon 21 mutations. BMC Pharmacol Toxicol. 2017 Dec 13;18(1):82. doi: 10.1186/s40360-017-0190-1. PMID: 29237484; PMCID: PMC5729426.[Article]
[4] World Health Organization. GLOBOCAN 2020. Lung Cancer Fact Sheet. Online. Last accessed on June 2, 2021.
[5] American Cancer Society. Lung Cancer Early Detection, Diagnosis. Online. June 2, 2021.
[6] American Cancer Society. Types of Non-Small Cell Lung Cancer. Onlinr. Last accessed on June 2, 2021.
[7] Economopoulou P, Mountzios G. The emerging treatment landscape of advanced non-small cell lung cancer. Ann Transl Med. 2018 Apr;6(8):138. doi: 10.21037/atm.2017.11.07. PMID: 29862227; PMCID: PMC5952023.[Article]
[8] Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, Reck M, Van Schil PE, Hellmann MD, Peters S; ESMO Guidelines Committee. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29(Suppl 4):iv192-iv237. doi: 10.1093/annonc/mdy275. Erratum in: Ann Oncol. 2019 May;30(5):863-870. PMID: 30285222.[Article]
[9] Morgillo F, Della Corte CM, Fasano M, Ciardiello F. Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open. 2016 May 11;1(3):e000060. doi: 10.1136/esmoopen-2016-000060. PMID: 27843613; PMCID: PMC5070275. [Article]
[10] Han B, Yang L, Wang X, Yao L. Efficacy of pemetrexed-based regimens in advanced non-small cell lung cancer patients with activating epidermal growth factor receptor mutations after tyrosine kinase inhibitor failure: a systematic review. Onco Targets Ther. 2018 Apr 12;11:2121-2129. doi: 10.2147/OTT.S157370. PMID: 29695919; PMCID: PMC5905532. [Article]
[11] Mishra R, Patel H, Alanazi S, Yuan L, Garrett JT. HER3 signaling and targeted therapy in cancer. Oncol Rev. 2018 May 16;12(1):355. doi: 10.4081/oncol.2018.355. PMID: 30057690; PMCID: PMC6047885.[Article]
[12] Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR, Threapleton D, Yang ZY, Mao C, Tang JL. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016 Nov 29;7(48):78985-78993. doi: 10.18632/oncotarget.12587. PMID: 27738317; PMCID: PMC5346692.[Article]
[13] Müller-Tidow C, Diederichs S, Bulk E, Pohle T, Steffen B, Schwäble J, Plewka S, Thomas M, Metzger R, Schneider PM, Brandts CH, Berdel WE, Serve H. Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer. Cancer Res. 2005 Mar 1;65(5):1778-82. doi: 10.1158/0008-5472.CAN-04-3388. PMID: 15753374. [Article]
[14] Scharpenseel H, Hanssen A, Loges S, Mohme M, Bernreuther C, Peine S, Lamszus K, Goy Y, Petersen C, Westphal M, Glatzel M, Riethdorf S, Pantel K, Wikman H. EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients. Sci Rep. 2019 May 15;9(1):7406. doi: 10.1038/s41598-019-43678-6. PMID: 31092882; PMCID: PMC6520391.[Article] 2019;9:7406.
Featured Image: 3D illustration of Lungs. Courtesy: © 2017 – 2021. Fotolia/Adobe. Used with permission.
