The human epidermal growth factor (HER) family of receptors are a well-established therapeutic target. Indeed, seminal studies conducted nearly 2 decades ago identified a key association between activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR, also known as HER1) gene and sensitivity to EGFR tyrosine kinase inhibitors.1,2 These pivotal studies catalyzed a sea change that vaulted precision medicine to the forefront of management of metastatic non–small cell lung cancer (NSCLC).
This was not the first success targeting this family of receptors, as trastuzumab, a monoclonal antibody that binds to the extracellular domain of HER2, had gained U.S. Food and Drug Administration (FDA) approval years earlier for the treatment of breast cancers harboring HER2 overexpression/amplification.3 Trastuzumab’s approval was eventually extended to include HER2-amplified metastatic gastric cancers.4 Although copy number gain was the initial focus of HER2-directed therapies, subsequent studies have identified activating mutations in the kinase, transmembrane, and extracellular domains of HER2.5
Ibiayi Dagogo-Jack, MD
HER2 Alterations in NSCLC and Activity of Trastuzumab and Tyrosine Kinase Inhibitors
In NSCLC, HER2 mutations and amplifications largely occur independently, with each alteration present in approximately 1% to 3% of tumors.5,6 Among the diverse HER2 mutations, insertions in exon 20 of the kinase domain predominate in NSCLC.5 HER2 exon 20 insertions are enriched in adenocarcinomas arising in patients with a minimal smoking history and are associated with a lifetime incidence of developing brain metastases that exceeds 40%.7-9
To date, attempts to target HER2-mutant NSCLC have employed several distinct approaches, including tyrosine kinase inhibitors, monoclonal antibodies, and antibody-drug conjugates.10 Unlike breast and gastric cancers, where trastuzumab-based chemotherapy combinations have proved to be efficacious,3,4 these combinations have demonstrated modest to moderate antitumor activity in NSCLC.11-13
Similarly, the experience with tyrosine kinase inhibitors for HER2-mutant NSCLC has been clouded by underwhelming results. Specifically, nonselective, irreversible pan-HER inhibitors (eg, neratinib, afatinib, lapatinib, dacomitinib) borrowed from breast cancer and EGFR-mutant NSCLC have been associated with limited activity and non-negligible toxicity across studies of HER2-mutant NSCLC.11,14-16 Newer exon 20–specific HER2 tyrosine kinase inhibitors (eg, poziotinib, pyrotinib) have yielded more encouraging results, though efficacy has fallen short of the standard set by targeted therapies for other molecular indications, partly due to toxicities that preclude dosing at optimal therapeutic concentrations.17-19
HER2 Antibody-Drug Conjugates in Lung Cancer: T-DM1 and T-DXd
In contrast to the experience with HER2 tyrosine kinase inhibitors and trastuzumab, antibody-drug conjugates with proven activity in HER2-amplified breast cancer have demonstrated crossover efficacy in HER2-mutant NSCLC. For example, in a phase II study, ado-trastuzumab emtansine (T-DM1) induced responses in 50% of patients with HER2-mutant NSCLC, with a median progression-free survival of 5 to 6 months.20 The encouraging initial results with T-DM1 have been backed by recent findings from the DESTINY-Lung01 phase II study of fam-trastuzumab deruxtecan-nxki (T-DXd), reported by Li et al21 and summarized in this issue of The ASCO Post.
The DESTINY-Lung01 trial evaluated the next-generation HER2 antibody-drug conjugate T-DXd in patients with HER2-mutant NSCLC.21 T-DXd contains an identical HER2 monoclonal antibody as T-DM1 but has a twofold higher drug-to-antibody ratio and a different payload, which can traffic to neighboring cells via a unique “bystander” function.22 In DESTINY-Lung01, objective responses and disease control were observed in 55% and 92% of patients, respectively, who had experienced disease progression on standard therapies and had not received prior HER2 monoclonal antibody therapy.21 Responses to T-DXd were durable, with a median duration of response of approximately 9 months. Furthermore, responses were observed irrespective of the location of the HER2 mutation, level of HER2 expression, presence of concurrent HER2 amplification, and prior treatment with HER2 tyrosine kinase inhibitors. In addition, systemic responses were seen among the 33 patients with baseline asymptomatic brain metastases, though formal central nervous system (CNS) surveillance was not incorporated into the study design.
The toxicity profile of T-DXd in DESTINY-Lung01 was not inconsequential, with grade ≥ 3 adverse events occurring in 46% of patients, including two patients with fatal respiratory events. The overall frequency of interstitial lung disease was striking at 26%, with the majority (83%) of events categorized as grade ≥ 2.21 Treatment-related toxicities necessitated dose reduction for 34% of patients and treatment discontinuation for 25% of patients, in most cases due to interstitial lung disease, fatigue, and gastrointestinal effects.
Where Does T-DXd Fit in the Treatment Paradigm for HER2-Mutant NSCLC?
The emergence of HER2-directed antibody-drug conjugates represents a turning point in the ongoing mission to develop selective approaches for treating HER2-mutant NSCLC. Although long-awaited initial strides have been made, the path forward is not fully paved, as there are outstanding questions regarding the ideal time for deploying HER2 antibody-drug conjugates, and the toxicity profile of T-DXd warrants additional scrutiny.
In current practice, the standard first-line therapy for metastatic HER2-mutant NSCLC consists of platinum-doublet chemotherapy combined with immunotherapy. Although the efficacy of T-DXd in pretreated patients with NSCLC in DESTINY-Lung01 exceeded the anticipated efficacy of first-line chemotherapy plus immunotherapy,23 we do not yet have prospective data comparing these approaches.
The emergence of HER2-directed antibody-drug conjugates represents a turning point in the ongoing mission to develop selective approaches for treating HER2-mutant NSCLC.— Ibiayi Dagogo-Jack, MD
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In other molecular subsets (eg, EGFR-mutant NSCLC), administering immunotherapy in close sequence to targeted therapy increases the risk of developing pneumonitis.24 As two-thirds of patients in DESTINY-Lung01 had received immunotherapy,21 it will be informative to determine the incidence of interstitial lung disease in those with and without prior checkpoint inhibitor exposure. If pulmonary toxicity is found to be enriched after checkpoint inhibitor exposure, this may support prioritizing T-DXd in the first-line setting. Interestingly, the incidence of interstitial lung disease is similar in patients with breast cancer treated with T-DXd as monotherapy compared with those who received T-DXd in combination with nivolumab, suggesting interstitial lung disease events may not be modulated by immunotherapy.25
The limited studies of the pathogenesis of T-DXd–related interstitial lung disease suggest that the toxicity is dose-dependent and driven by target-independent uptake in alveolar macrophages.26,27 At an identical dose of T-DXd, the incidence of interstitial lung disease is twofold lower in patients with gastric cancer and colorectal cancer than in those with NSCLC.21,28,29 Thus, it is worth exploring whether the alveolar reticuloendothelial cells may be more dysregulated and more abundant in the lungs of patients with pulmonary malignancies and whether prior immunotherapy exacerbates this disparity.
The Future of HER2-Selective Therapies for HER2-Mutant NSCLC
As exon 20–specific HER2 tyrosine kinase inhibitors continue to be refined, decisions regarding sequencing of HER2-directed therapies will likely become more complex. Although it is reassuring that benefit from T-DXd was observed in tyrosine kinase inhibitor–pretreated patients in DESTINY-Lung01, the activity of T-DXd is more impressive than the activity of existing exon 20-specific tyrosine kinase inhibitors.17,19,21 As such, it is likely that T-DXd will be prioritized over these drugs if both options receive FDA approval.
In addition to considering efficacy when selecting between different HER2-targeting strategies, the CNS tropism of HER2-mutant NSCLC will likely also factor into future decision-making.9 To this end, it is imperative that forthcoming clinical trials of novel HER2-directed therapies not overlook the value and relevance of CNS-specific endpoints.
Finally, the dramatic improvements in prognosis that patients and providers seek require therapies that can achieve durable responses that are ideally measured in years. Thus, it will be important to build upon the early successes we are now witnessing in the HER2 therapeutic space by developing additional therapies and exploring novel combinations, as informed by preclinical models and future studies of acquired resistance to existing HER2-directed therapies.20
Dr. Dagogo-Jack is a thoracic oncologist practicing at Massachusetts General Hospital Cancer Center and in the Department of Medicine, Massachusetts General Hospital, Harvard Medical School.
DISCLOSURE: Dr. Dagogo-Jack has received honoraria from Foundation Medicine, Creative Education Concepts, DAVA Pharmaceuticals, The ASCO Post, OncLive, Medscape, and the American Lung Association; has served as a consultant to Guidepost, AstraZeneca, Bayer, Boehringer Ingelheim, BostonGene, Catalyst, Genentech, Janssen, Novocure, Pfizer, Sanofi/Genzyme, Syros Pharmaceuticals, and Xcovery; has received research funding from Array BioPharma, Genentech, Novartis, Pfizer, and Guardant Health; and has received travel support from Array BioPharma and Pfizer.
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