HER2 Mutations Present Unique Challenges in NSCLC

HER2 mutations recently joined an expanding list of therapeutically actionable alterations in non-small cell lung cancer (NSCLC). Of note, trastuzumab deruxtecan was recently granted accelerated FDA approval in August 2022 for pre-treated advanced NSCLC tumors harboring an activating HER2 mutation and is the only approved therapy to date for this specific marker.

Various classes of agents including antibody-drug conjugates (ADCs), tyrosine kinase inhibitors (TKIs) and monoclonal antibodies in combination with chemotherapy have been studied in the context of HER2 mutations, overexpression, and amplification. 1,2,3,4,5

Given the rarity and heterogeneity of alterations in HER2, which is commonly used to refer to the protein encoded by the erythroblastic oncogene B (ERBB2), in NSCLC, patient selection for HER2-directed treatment remains a significant clinical challenge.

HER2 mutations in NSCLC were first described almost two decades ago by Stephens et al, who identified mutations in the HER2 kinase domain in 4% of 120 NSCLC tumors and proposed ERBB2 inhibitors should be specifically evaluated in patients with HER2 mutations.6 Thereafter, the oncogenicity of HER2 exon 20 insertion mutations was demonstrated in pre-clinical models, although less is known about uncommon HER2 mutations.7,8

While HER2 mutations, especially insertions in exon 20, appear to be the strongest predictor of response to HER2-directed therapy,5 the significance of HER2 amplification and overexpression is less defined. HER2 amplifications have been found to be mutually exclusive with HER2 mutations in NSCLC,9 whereas the association between HER2 overexpression and mutations/amplifications is controversial.9,10,11,12,13,14

Consequently, clinical trials using various HER2-directed therapies have employed different selection criteria, thereby adding to the complexity of HER2 as a biomarker in NSCLC.1,2,3,4,15,16,17 This underscores the need to refine biomarker selection for HER2-directed therapy, in tandem with implementation of HER2 testing in NSCLC.

As HER2-directed therapies have been approved in breast cancer since 1998, the expanding role of HER2 ADCs has revealed new therapeutic opportunities that could impact the NSCLC treatment landscape. HER2-low expression breast cancer has been described in recent years,17,18 with trastuzumab deruxtecan demonstrating significantly longer progression-free survival compared to physician’s choice of chemotherapy in tumors with HER2 immunohistochemistry (IHC) 1+ or IHC 2+ with a negative in situ hybridization result.20

While the exact mechanism of action remains unknown, it has been hypothesized that these ADCs show a higher bystander killer effect through cleavable linkers and a higher drug-to-antibody ratio, thereby resulting in an enhanced treatment effect even in tumors with low HER2 expression.19,21,22

Similarly, responses to trastuzumab deruxtecan have been observed in NSCLC patients with no detectable HER2 expression or HER2 amplification.1 In parallel, whether this bystander effect can also account for the high incidence of interstitial lung disease observed with trastuzumab deruxtecan in NSCLC warrants closer examination.1

Future directions for HER2 alterations in NSCLC will likely focus on biomarker development, as well as rational sequencing and combination strategies. With the anticipated approval of various HER2-directed therapies in NSCLC, standardization of HER2 testing and its incorporation into routine clinical practice are of paramount importance.22 Poziotinib was notably not granted approval by the FDA’s Oncologic Drugs Advisory Committee for metastatic HER2 exon 20 insertion mutation-positive NSCLC in September 2022, because of concerns about limited responses with short durability, drug toxicities, inadequate dose optimization, and because the confirmatory clinical trial was delayed. As such, ADCs are likely to be favoured in view of higher anti-tumor activity.

DESTINY-Lung04 (NCT05048797) is currently ongoing to evaluate trastuzumab deruxtecan in the first-line setting among advanced HER2-mutated NSCLC, while DESTINY-Lung03 (NCT04686305) aims to assess the safety of trastuzumab deruxtecan in combination with durvalumab and chemotherapy in patients with HER2 overexpression. Safety considerations for combination and sequential approaches will need to be carefully deliberated, particularly in light of the risk of interstitial lung disease.23

In conclusion, HER2 alterations in NSCLC represent a diverse population with unique challenges; the ultimate treatment paradigm will likely be distinct from HER2-driven breast cancer. While further insights will no doubt be gleaned from experiences with other tumour types, it is imperative that clinicians appreciate the intricacies of HER2 testing in NSCLC to optimize patient selection. To that end, upfront next generation sequencing should be encouraged as should enrollment into suitable clinical trials where possible.

References

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