Patritumab Deruxtecan Looks to Make an Impact in NSCLC Treatment Paradigm with HERTHENA-Lung02

Julia Rotow, MD

Investigators have set their sights on confirming the viability of HER3 as a clinically actionable therapeutic target for the treatment of patients with EGFR-mutant advanced non–small cell lung cancer (NSCLC), with the initiation of the phase 3 HERTHENA-Lung02 trial (NCT05338970) evaluating patritumab deruxtecan.¹

“For patients with EGFR-mutant lung cancer, we know that once they have received first- or second-line targeted therapies, at some point resistance is developed to oncogene-targeted agents,” said Julia Rotow, MD, a medical oncologist in the Thoracic (Lung) Cancer Treatment Center at Dana-Farber Cancer Institute in Boston, Massachusetts, in an interview with OncologyLive^®. “For patients who are receiving first-line osimertinib [Tagrisso], the challenge of how to manage resistance in the clinical setting remains difficult. For many patients, the genomic mechanism of resistance is not clear.”

Most patients with advanced NSCLC harboring an EGFR mutation will experience disease progression after treatment with an EGFR-directed tyrosine kinase inhibitor (TKI) in an early line of therapy. Treatment with platinum-based chemotherapy in later lines following failure with an EGFR TKI has shown modest efficacy and is often accompanied by an unfavorable safety profile.^1-3

Patritumab deruxtecan is an investigational, first-in-class antibody-drug conjugate (ADC) consisting of a fully humanized anti-HER3 IgG11 monoclonal antibody, which is covalently linked to a topoisomerase I inhibitor payload via a tetrapeptide cleavable linker.¹

“[The mechanism of action of patritumab deruxtecan] is relevant in EGFR-mutant lung cancer because we know that almost all patients with EGFR-mutant NSCLC will be positive, at some level, for HER3 on the cell surface,” Rotow said. “Interestingly, for this ADC, it does not look like there is a strong correlation between the level of HER3 and response to the ADC. So any degree of expression in the tumor or around the tumor seems to be adequate to have the opportunity to generate an antitumor effect.”

In December 2021, the FDA granted patritumab deruxtecan a breakthrough therapy designation for the treatment of patients with metastatic or locally advanced NSCLC harboring an EGFR mutation, following disease progression after treatment with a TKI and platinum-based chemotherapy.⁴

Patritumab Deruxtecan Shows Early Efficacy in NSCLC

Patritumab deruxtecan is under examination in the phase 1 U31402-A-U102 study (NCT03260491), which enrolled patients with locally advanced or metastatic NSCLC with and without identified driver genomic alterations. The dose-escalation and dose-expansion study enrolled patients with EGFR-mutant disease, as well as patients with non-EGFR oncogenic alterations if they had received at least 1 prior treatment with targeted therapy, if available.⁵

In the dose-escalation portion of the trial, patients received intravenous patritumab deruxtecan once every 3 weeks at a dose of 3.2 mg/kg (n = 4), 4.8 mg/kg (n = 15), 5.6 mg/kg (n = 12), or 6.4 mg/kg (n = 5). The recommended dose level for the dose-expansion portion was determined to be 5.6 mg/kg.

In a pooled analysis of efficacy-evaluable patients with disease harboring an EGFR mutation who received the recommended dose in the dose-expansion or dose-escalation portion of the trial (n = 57), the overall response rate (ORR) was 39% (95% CI, 26%-52.4%), including 1 complete response. The disease control rate (DCR) was 72% (95% CI, 58.5%-83%). Nine percent of patients experienced disease progression and 19% achieved stable disease.

At a median follow-up of 10.2 months (range, 5.2-19.9), the median progression-free survival (PFS) was 8.2 months (95% CI, 4.4-8.3) and the median duration of response (DOR) 6.9 months (95% CI, 3.1-not estimable [NE]). The median time to response was 2.6 months (95% CI, 1.2-5.4).⁵

Additionally, a subgroup of efficacy-evaluable patients who had received prior platinum-based chemotherapy and osimertinib (n = 44) achieved an ORR of 39% (95% CI, 24.4%-54.5%), with 1 patient experiencing a complete response. The DCR was 68% (95% CI, 52.4%-81.4%) and the median DOR was 7.0 months (95% CI, 3.1-NE).

The median age of patients included in the efficacy analysis was 65 years (range, 40-80). The population was heavily pretreated, with a median of 4 (range, 1-9) prior lines of therapy. All patients included in the analysis had received prior EGFR TKI therapy. Additionally, most had undergone prior treatment with platinum-based chemotherapy in addition to osimertinib (77%).⁵

Regarding safety, all patients treated at the recommended dose experienced a treatment-emergent adverse effect (TEAE). Common TEAEs of grade 3 or greater included thrombocytopenia (30%), neutropenia (19%), and fatigue (14%). TEAEs associated with treatment discontinuation occurred in 11% of patients, and TEAEs associated with death were reported in 7% of patients.

Grade 3 or greater TEAEs occurred at the recommended dose level at a rate of 74%, and nearly all patients experienced a treatment-related AE (96%). Serious treatment-related AEs were reported in 21% of efficacy-evaluable patients.⁵

Interstitial lung disease, which has been previously identified in studies of the ADC fam-trastuzumab deruxtecan-nxki (Enhertu) as an AE of special interest for this type of agent,⁶ was confirmed by an independent adjudication committee in 5 patients.⁵ Adjudicated treatment-related interstitial lung disease was reported in 4 patients: grade 1 (n = 2), grade 2 (n = 1), and grade 3 (n = 1).

Considering the encouraging findings from preclinical work and the U31402-A-U102 trial, the HERTHENA-Lung program was initiated to further examine the safety and efficacy of patritumab deruxtecan in patients with EGFR-mutant NSCLC.⁷ This includes trials such as HERTHENA-Lung01 (NCT04619004), a randomized, open-label trial that will enroll approximately 420 patients with metastatic or locally advanced NSCLC harboring an activating EGFR mutation. Eligible patients must also have progressed during or after treatment with at least 1 EGFR TKI and at least 1 platinum-based chemotherapy regimen.⁷

Patients will be randomly assigned 1:1 to receive either a fixed-dose regimen of patritumab deruxtecan 5.6 mg/kg or patritumab deruxtecan via an up-titration dose regimen. In the up-titration arm, patients will be treated at a dose of 3.2 mg/kg in cycle 1; 4.8 mg/kg in cycle 2; and 6.4 mg/kg in cycle 3 and beyond.

The primary end point is ORR by blinded independent central review. Secondary end points include DOR, PFS, ORR by investigator assessment, DCR, and time to response. The study is open for enrollment and has an estimated completion date of July 2024.⁷

Details of the HERTHENA-Lung02 Trial

Building on HERTHENA-Lung01’s design, HERTHENA-Lung02 will evaluate the safety and efficacy of patritumab deruxtecan compared with that of platinum-based chemotherapy in patients with locally advanced or metastatic nonsquamous NSCLC with an EGFR-activating mutation. Patients must have progressed on or after treatment with a third-generation TKI to be included in the trial.

“HERTHENA-Lung02 moves [the concept of HERTHENA-Lung01] forward and looks at using this [sequencing] for patients who have had acquired resistance to an EGFR inhibitor and randomly [assigning] them to go straight to the patritumab deruxtecan or to platinum-doublet chemotherapy,” Rotow said. “It is really moving [patritumab deruxtecan] up 1 line of therapy in a randomized fashion. We will be able to see with these data whether we can delay the use of platinum-doublet therapy in this patient population.”

The trial aims to enroll approximately 560 adult patients. Eligible participants must have disease with either an exon 19 deletion or L858R mutation. Patients with stable brain metastases will be permitted and patients must have an ECOG performance status of 1 or less.^1,8

Patients with a history of interstitial lung disease or other clinically severe respiratory compromise will be excluded from the trial. Additionally, patients who have undergone any prior treatment with an agent containing a chemotherapeutic component targeting topoisomerase I or prior treatment with an anti-HER3 antibody, and those with significant cardiovascular disease, are ineligible for the trial.

Once enrolled, patients will be randomly assigned to receive either patritumab deruxtecan 5.6 mg/kg or platinum-based chemotherapy. Patritumab deruxtecan will be given intravenously every 3 weeks. Patients in the chemotherapy arm will be treated with either cisplatin 75 mg/m2 or carboplatin at a dose of target area under the curve 5 every 3 weeks for 4 cycles plus pemetrexed 500 mg/m2 every 3 weeks.^1,8

Patients will be stratified by prior third-generation TKI (osimertinib vs other), region (Asia vs rest of world), line of prior third-generation TKI use (first line vs second line), and presence of stable brain metastases (yes vs no).¹

The primary end point of the study is PFS by blinded independent central review. Secondary end points include OS, ORR, clinical benefit rate, and DCR.

On August 8, 2022, the first patient received their dose as part of the trial. Investigators are actively recruiting patients and the trial has an estimated completion date of August 2026.^8,9

“Right now, our go-to first-line agent for EGFR-mutant lung cancer is osimertinib,” Rotow said. “However, we do not really have our go-to second-line option yet. The approval of an agent that we can use for all patients, regardless of subsequent genomic status, will be clinically quite useful and meaningful to our patients and we hope would improve outcomes.”

References

1. Mok TSK, Wu YL, Nishio M, et al. HERTHENA-Lung02: a randomized phase III study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR TKI. Ann Oncol. 2022;33(suppl 7):S1095. doi:10.1016/j.annonc.2022.07.1318
2. Johnson M, Garassino MC, Mok T, Mitsudomi T. Treatment strategies and outcomes for patients with EGFR-mutant non-small cell lung cancer resistant to EGFR tyrosine kinase inhibitors: focus on novel therapies. Lung Cancer. 2022;170:41-51. doi:10.1016/j.lungcan.2022.05.011
3. Mok TK, Wu YL, Ahn MJ, et al; AURA3 Investigators. Osimertinib or platinum–pemetrexed in EGFRT790M–positive lung cancer. N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674
4. Patritumab deruxtecan granted U.S. FDA breakthrough therapy designation in patients with metastatic EGFR-mutated non-small cell lung cancer. News release. Daiichi Sankyo Company, Limited. December 23, 2021. Accessed September 26, 2022. bit.ly/32A3C62
5. Jänne PA, Baik C, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer. Cancer Discov. 2022;12(1):74-89. Published correction appears in Cancer Discov. 2022;12(6):1598.
6. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2022. Accessed September 26, 2022. bit.ly/3SByOq8
7. Jänne PA, Johnson ML, Goto Y, et al. HERTHENA-Lung01: a randomized phase 2 study of patritumab deruxtecan (HER3-DXd) in previously treated metastatic EGFR-mutated NSCLC. J Clin Oncol. 2021;39(suppl 15):TPS9139. doi:10.1200/JCO.2021.39.15_suppl.TPS9139
8. HERTHENA-Lung02: a study of patritumab deruxtecan versus platinum-based chemotherapy in metastatic or locally advanced EGFRm NSCLC after failure of EGFR TKI therapy. ClinicalTrials.gov. Updated on September 21, 2022. Accessed September 21, 2022. https://clinicaltrials.gov/ct2/show/NCT05338970
9. HERTHENA-Lung02 phase 3 trial of patritumab deruxtecan initiated in patients with EGFR-mutated metastatic non-small cell lung cancer. News release. Daiichi Sankyo. August 8, 2022. Accessed September 21, 2022. bit.ly/3SkV5Iv

Funding from Daiichi Sanyko. Content Developed Independently by OncLive.