A potential central nervous system niche for trastuzumab deruxtecan in patients with HER2-expressing non-small cell lung cancer
Editorial Commentary

A potential central nervous system niche for trastuzumab deruxtecan in patients with HER2-expressing non-small cell lung cancer

Anna-Maria Lazaratos1,2, David J. H. Bian3, Kevin Petrecca4, Marie-Christine Guiot4, Matthew Dankner2,3 ORCID logo

1Department of Medicine, Université de Montreal, Montreal, QC, Canada; 2Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada; 3Department of Internal Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada; 4Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada

Correspondence to: Matthew Dankner, MD, PhD. Rosalind and Morris Goodman Cancer Institute, McGill University, 1160 Pine Ave. West, Montreal, QC H3A 1A3, Canada; Department of Internal Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada. Email: matthew.dankner@mail.mcgill.ca.

Comment on: Smit EF, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol 2024;25:439-54.

Keywords: Trastuzumab deruxtecan (TDXd); non-small cell lung cancer (NSCLC); central nervous system metastases (CNS metastases); DESTINY-Lung01

Submitted Sep 20, 2024. Accepted for publication Dec 04, 2024. Published online Dec 27, 2024.

doi: 10.21037/tlcr-24-856

Trastuzumab deruxtecan (TDXd) is an antibody-drug conjugate that has become a component of the treatment armamentarium for a subset of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing and HER2-mutated solid tumors, including those with brain metastases (1). HER2 is amplified, mutated, or overexpressed in approximately 2–5%, 1–4%, and 8–23% of non-small cell lung cancer (NSCLC) specimens, respectively (2-4). For this reason, trials that employed the HER2-targeted therapies trastuzumab, pertuzumab and trastuzumab emtansine (T-DM1), as well as tyrosine kinase inhibitors, notably afatinib, poziotinib, neratinib and pyrotinib, have been performed for this subgroup of patients, albeit with limited success (5) (Table 1).

Table 1

Clinical trial data of HER2-targeted therapies in patients with HER2-overexpressing or mutated NSCLC

Trial/study/NCT Patient population HER2-targeted treatment ORR, mPFS and mOS
All patients Patients with brain metastases
Monoclonal antibody targeting HER2
   Lara et al., no NCT ID, PMID: 14967075 HER2-positive (2+ or 3 by immunohistochemistry) NSCLC Trastuzumab N=4, mOS: 5.7 months Patients with active BM were excluded. Inactive/treated BM were eligible but data not described
   Gatzemeier et al., no NCT ID, PMID: 14679114 Patients with untreated advanced or metastatic HER2-positive (2+ or 3 by immunohistochemistry) NSCLC Trastuzumab, gemcitabine, and cisplatin N=51, ORR: 36%, mPFS: 6.1 months, mOS: 12.2 months Patients with BM were excluded
   Van Berge Henegouwen et al., NCT02925234, PMID: 35716537 Advanced pre-treated HER2-mutant NSCLC Trastuzumab and pertuzumab N=24, ORR: 8.3%, mOS: 10 months Patients with active BM were excluded. Inactive/treated BM were eligible, but data not described
Antibody-drug conjugate targeting HER2
   Hotta et al., no NCT ID, PMID: 29313813 HER2-overexpressing (2+ or 3+ by immunohistochemistry) relapsed NSCLC T-DM1 N=15, ORR: 20%, mPFS: 2 months, mOS: 10.9 months Not described
   Peters et al., NCT02289833, PMID: 30206164 HER2-overexpressing (2+ or 3 by immunohistochemistry) previously treated advanced NSCLC T-DM1 N=49, ORR: 6.7%, mPFS: 2.6 months, mOS: 12.2 months Patients with BM were excluded
   Li et al., NCT02675829, PMID: 29989854 HER2-mutant locally advanced, recurrent, or metastatic NSCLC T-DM1 N=18, ORR: 44%, mPFS: 5 months 2 patients had active untreated BM at enrollment, but both patients had progression of disease systemically and in the brain at first response assessment
   Iwama et al., JapicCTI-194620, PMID: 34959152 HER2-mutant (HER2 exon 20 insertion mutations) locally advanced, recurrent, or metastatic NSCLC T-DM1 N=22, ORR: 38.1%, mPFS: 2.8 months, mOS: 8.1 months N=9 but BM-specific data not described
   Li et al., NCT02675829, PMID: 32213539 HER2-mutant or amplified lung cancer T-DM1 N=49, ORR: 51%, mPFS: 5 months Not described
   Smit et al., Destiny-Lung01, HER2 overexpression cohort, NCT03505710, PMID: 38547891 HER2-overexpressing (2+ or 3+ by immunohistochemistry) unresectable or metastatic NSCLC TDXd 5.4 and 6.4 mg/kg 5.4 mg/kg: N=41, ORR: 34.1%, mPFS: 6.7 months, mOS: 11.2 months; 6.4 mg/kg: N=49, ORR: 26.5%, mPFS: 5.7 months, mOS: 12.4 months 5.4 mg/kg: N=12, ORR: 50%, mPFS: 7.1 months, mOS: 13.5 months; 6.4 mg/kg: N=17, ORR: 29%, mPFS: 4.6 months, mOS: not reached
   Li et al., Destiny-Lung01, HER2 mutant cohort, NCT03505710, PMID: 34534430 Metastatic HER2-mutant NSCLC that was refractory to standard treatment TDXd 6.4 mg/kg N=91, ORR: 55%, mPFS: 8.2 months, mOS: 17.8 months N=33, ORR: 54.5%, mPFS: 7.1 months, mOS: 13.8 months
   Goto et al., Destiny-Lung02, NCT04644237, PMID: 37694347 Patients with previously treated HER2-mutant metastatic NSCLC TDXd 5.4 and 6.4 mg/kg 5.4 mg/kg: N=102, ORR: 49%, mOS: 19.5 months; 6.4 mg/kg: N=50, ORR: 56%, mOS: NE 5.4 mg/kg: N=35, ORR: 60%; 6.4 mg/kg: N=22, ORR: 45.5%
   Planchard et al., Destiny-Lung03, NCT04686305, no PMID (conference abstract) Pretreated HER2-overexpressing unresectable, locally advanced or metastatic, nonsquamous NSCLC TDXd 5.4 mg/kg N=36, ORR: 44.4%, mPFS: 8.2 months, mOS: 14.7 months N=9 but BM-specific data not described
Anti-HER2 tyrosine kinase inhibitors
   Dziadziuszko et al., NCT02369484, PMID: 30825613 Advanced NSCLC harboring HER2 exon 20 mutations Afatinib N=13, mPFS: 15.9 months, mOS: 56 months N=1 but BM-specific data not described
   Elamin et al., NCT03066206, PMID: 34550757 HER2 exon 20 mutant advanced NSCLC Poziotinib N=30, ORR: 43%, mPFS: 5.5 months, mOS: 15 months Inactive/treated BM were eligible, but data not described
   Le et al., NCT03318939, PMID: 34843401 Advanced or metastatic NSCLC Poziotinib N=90, ORR: 27.8 months, mPFS: 5.5 months N=14, ORR: 28.6%, mPFS: 7.4 months
   Heymach et al., NCT03066206, DOI: 10.1016/j.jtho.2018.08.243 HER2 exon 20 mutant NSCLC Poziotinib N=12, ORR: 50% Not described
   Hyman et al., NCT01953926, PMID: 29420467 HER2-mutant lung cancer Neratinib N=26, ORR: 3.8%, mPFS: 5.5 months Not described
   Gandhi et al., NCT00838539, PMID: 24323026 HER2-mutant advanced NSCLC Neratinib + temsirolimus N=43, ORR: 16.2%, mPFS: 4.1 months, mOS: 15.8 months Inactive/treated BM were eligible, but data not described
   Zhou et al., NCT02834936, PMID: 32614698 Stage IIIB or IV HER2-mutant lung adenocarcinoma who were previously treated with platinum-based chemotherapy Pyrotinib N=60, ORR: 30%, mPFS: 6.9 months, mOS: 14.4 months N=12, ORR: 25.0%, mPFS: 5.5 months, mOS: 6.9 months

HER2, human epidermal growth factor receptor 2; NSCLC, non-small cell lung cancer; NCT, National Clinical Trial Identifier Number; ORR, overall response rate; mPFS, median progression-free survival; mOS, median overall survival; BM, brain metastases; T-DM1, trastuzumab emtansine; TDXd, trastuzumab deruxtecan; NE, not evaluable; PMID, PubMed Identifier.

TDXd has emerged as an effective treatment option for breast cancer and other solid tumors with HER2 overexpression or mutation (6). The phase II DESTINY-Lung01 trial enrolled patients with HER2-overexpressing (characterized by an immunohistochemistry (IHC) score of 2+ or 3+) or HER2-mutated unresectable or metastatic NSCLC, and treated them with TDXd administered at a dose of 5.4 or 6.4 mg/kg (Table 1) (7,8). Importantly, patients with stable brain metastases were eligible in this trial, but responses to treatment were determined systemically with no intracranial response data presented.

In the HER2-mutated cohort of the DESTINY-Lung01 study wherein patients were treated exclusively with the 6.4 mg/kg dose, TDXd resulted in an overall response rate (ORR) of 55%, a median progression-free survival (PFS) of 8.2 months and a median overall survival (OS) of 17.8 months (7). Thirty-three patients in the HER2-mutated cohort with stable brain metastases exhibited an ORR of 54.5%, a median PFS of 7.1 months, and a median OS of 13.8 months (7). The DESTINY-Lung02 trial subsequently evaluated the efficacy of TDXd administered at a dose of 5.4 vs. 6.4 mg/kg in patients with advanced HER2-mutated NSCLC and found an ORR of 49% and 56% in the cohort of patients receiving TDXd at a dose of 5.4 and 6.4 mg/kg respectively (9). Thirty-five patients with stable brain metastases exhibited an ORR of 60% when receiving TDXd at a dose of 5.4 mg/kg, while 22 patients with stable brain metastases displayed an ORR of 45.5% when receiving TDXd at a dose of 6.4 mg/kg (9).

In the HER2-overexprresing cohort of the DESTINY-Lung01 study, the authors describe 39 patients with a HER2 IHC score of 2+ and 10 patients with a HER2 IHC score of 3+ in the cohort of patients receiving TDXd at a dose of 6.4 mg/kg, as well as 24 patients with a HER2 IHC score of 2+ and 17 patients with a HER2 IHC score of 3+ in the cohort of patients receiving TDXd at a dose of 5.4 mg/kg (8). Patients with HER2-overexpressing NSCLC receiving TDXd at a dose of 5.4 mg/kg exhibited an ORR of 34.1%, a median PFS of 6.7 months and a median OS of 11.2 months, while those receiving TDXd at a dose of 6.4 mg/kg exhibited an ORR of 26.5%, a median PFS of 5.7 months and a median OS of 12.4 months (8). Patients receiving TDXd at a dose of 5.4 mg/kg with a HER2 IHC score of 2+ or 3+ exhibited an ORR of 21% and 53%, a median PFS of 4.5 and 7.5 months, and a median OS of 10.6 and 12.5 months respectively (8). When TDXd was administered at a dose of 6.4 mg/kg, patients with a HER2 IHC score of 2+ or 3+ exhibited an ORR of 28% and 20%, a median PFS of 5.9 and 4.2 months, and a median OS of 16.8 and 11.7 months respectively (8). Twelve patients with stable brain metastases receiving TDXd at a dose of 5.4 mg/kg exhibited an ORR of 50%, a median PFS of 7.1 months and a median OS of 13.5 months, while the 17 receiving TDXd at a dose of 6.4 mg/kg exhibited an ORR of 29%, a median PFS of 4.6 months, and a median OS of that was not reached.

Recently, the first results from the TDXd single-agent arm of the DESTINY-Lung03 trial were presented and build upon these results (10,11). This study enrolled patients with unresectable or metastatic non-squamous NSCLC with HER2 2+ or 3+ and treated them with TDXd at 5.4 mg/kg (10,11). ORR was 44.4%, median duration of response (DOR) was 12.2 months, median PFS was 8.2 months, and median OS was 14.7 months (10,11). Among patients with HER2 3+ status, ORR was 56.3% and mDOR was 12.5 months (10,11). Importantly, response rates were higher in patients who received prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (68.4% vs. 17.8%) (10,11).

Together, the conclusion of these studies posits that TDXd is more effective in patients with HER2-mutated NSCLC compared to patients with HER2-overexpressing tumors. However, it is difficult to fully understand the differences in outcomes in the HER2-overexpression cohorts of DESTINY-Lung01 and DESTINY-Lung03 without full publication of the DESTINY-Lung03 results, where outcomes in patients with HER2 3+ was closer to what was seen in patients with HER2-mutations (7). If indeed TDXd is more effective in NSCLC patients with HER2− mutations compared to HER2-overexpresion, this may be explained by the fact that pre-clinical data has shown that in NSCLC, HER2 activating mutations drive rapid recycling of HER2 receptors, leading to more rapid internalization and cleavage of DXd from the trastuzumab antibody (12).

For the time being, TDXd has begun to gain acceptance for use in patients with metastatic NSCLC whose tumors harbor HER2-mutations in the absence of randomized data (13-15). However, the same cannot be said for HER2-overexpressing NSCLC, where outcomes with TDXd appear to be closer to what may be expected with standard of care chemoimmunotherapy in these patients (16). Furthermore, rare but well-described cases of lethal toxicities with TDXd represent an additional drawback of using TDXd in the absence of definitive data showing superiority compared to other therapeutic agents (17). Notably, TDXd has been associated with interstitial lung disease in a minority of patients but poses a risk of severe outcomes. A recent meta-analysis reported interstitial lung disease in 11.6% of patients receiving TDXd, with 6.4% of these events being grade 5 (17). These findings underscore the importance of careful patient monitoring and early intervention when administering TDXd.

Despite this, it is possible that patients with HER2-overexpressing NSCLC with central nervous system (CNS) metastases represent a population uniquely poised to derive benefit from TDXd compared to other agents, with further study. The results of the DESTINY-Lung01 and DESTINY-Lung02 trials suggest that TDXd exhibits comparable activity in NSCLC patients with stable brain metastases compared to the rest of the cohort at large. These findings are similar to what has been observed in other cancer types, such as breast cancer, where TDXd has demonstrated robust intracranial activity (1,18-21). This distinguishes TDXd from other anti-cancer therapies that possess limited intracranial activity. Therefore, patients with NSCLC harboring HER2-overexpression may stand to benefit from TDXd compared to alternative agents, exclusively if they have CNS metastases.

In order to better understand the subset of patients with NSCLC brain metastases who may be able to derive benefit from treatment with TDXd, we performed IHC on a tissue microarray containing 109 lung cancer brain metastasis specimens, with representative images shown in Figure 1A. When applying the IHC staining criteria used in the DESTINY-Lung01 study, we found that 6% of patients with lung cancer brain metastases exhibit HER2 2+ (4%) or 3+ (2%) staining (Figure 1B). Thus, this represents a significant patient population who may stand to derive clinical benefit from TDXd. Furthermore, an additional 18% of patients had 1+ HER2 staining. While these patients were not included in the DESTINY-Lung studies, it is possible that TDXd may possess meaningful activity in these patients as well, as it does in HER2-low and HER2-ultralow breast cancer (22,23).

Figure 1 Immunohistochemistry for HER2 on lung cancer brain metastasis specimens. (A) Representative images of 0, 1+, 2+ and 3+ HER2 staining in NSCLC brain metastases. (B) Proportion of NSCLC brain metastases with 0, 1+, 2+ and 3+ HER2 staining. NSCLC, non-small cell lung cancer; HER2, human epidermal growth factor receptor 2.

Together, it is apparent that additional studies are required to better understand TDXd’s role in HER2-overexpressing NSCLC. This includes the publication of intracranial response outcomes of patients with brain metastases included in the DESTINY-Lung01, 02 and 03 studies, new studies with robust pharmacodynamics specifically for patients with CNS metastases that uses reproducible criteria to define intracranial response, and trials that combine TDXd with other agents to augment HER2 expression or receptor recycling. Furthermore, such studies for patients with brain metastases should be performed in a multidisciplinary context that considers radiotherapy and surgical modalities, and also take into consideration the fact that HER2 expression levels may change in intracranial compared to extracranial lesions in the same patient (24).

Methods

HER2 immunohistochemistry was performed using anti-HER2 clone 790-2991 (Roche) using Ventana Benchmark Ultra Autostainer, on a tissue microarray derived from 109 surgically resected lung cancer brain metastases, in duplicate 1.5 mm cores from each patient, arranged across two tissue blocks. Operations performed on all patients occurred at the Montreal Neurological Institute-Hospital between 2007 and 2019. HER2 scoring was performed by a board-certified pathologist according to the recommendations of Bartley et al. (25), as was performed in the DESTINY-Lung01 trial. An immunohistochemistry score of 3+ was defined as strong complete, basolateral, or lateral membranous reactivity in at least 10% of tumour cells, an immunohistochemistry score of 2+ was defined as weak-to-moderate complete, basolateral, or lateral membranous reactivity in at least 10% of tumour cells, and an immunohistochemistry score of 1+ was defined as faint/barely perceptible membranous reactivity in ≥10% of tumor cells; cells are reactive only in part of their membrane.

Acknowledgments

We thank the patients who generously consented to provide their brain metastasis specimens.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-856/prf

Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-856/coif). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics board of McGill University and the Montreal Neurological Institute-Hospital (IRB Nos. 2018-4150 and NEU-10-066) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Lazaratos AM, Bian DJH, Petrecca K, Guiot MC, Dankner M. A potential central nervous system niche for trastuzumab deruxtecan in patients with HER2-expressing non-small cell lung cancer. Transl Lung Cancer Res 2024;13(12):3824-3830. doi: 10.21037/tlcr-24-856

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