Distinctions Between Alteration Types, Therapeutic Classes Could Drive Optimal Treatment Selection in HER2-Mutant NSCLC

Tailoring treatment approaches for patients with HER2-mutant non–small cell lung cancer (NSCLC) requires identifying the specific type of HER2 alteration at diagnosis, understanding distinctions between HER2-directed TKIs and antibody-drug conjugates (ADCs), and using data from ongoing research to elucidate appropriate sequencing of these therapeutic classes, according to Nicolas Girard, MD.

“The ultimate objective is to expose patients to all the mechanisms of action that we have in our hands [between various classes of drugs]. In the end, the overall survival of patients is related not only to the efficacy of first-line [treatment], but also of subsequent lines, and how you best individualize the treatment strategy,” said Girard, a professor of respiratory medicine at Versailles Saint Quentin University, head of Curie-Montsouris Thorax Institute, and chair of the Medical Oncology Department at Institut Curie in France.

In an interview with OncLive®, Girard emphasized the importance of distinguishing between HER2 alterations; explained how prognostic and predictive values, drug sensitivity, and mechanisms of action differ between HER2-targeted TKIs vs ADCs; and discussed the need for data regarding the optimal sequencing of HER2-directed therapies to maximize efficacy and minimize toxicities for patients with HER2-mutant NSCLC.

OncLive: Why is it important to distinguish between the types of HER2 alterations when talking about drug development in lung cancer?

Girard: It's important because, ultimately, there are several alterations. There may be some EGFR exon 20 insertions as well as point mutations, and the sensitivity to the available drugs may be different from 1 mutation to another, and between mutations and EGFR exon 20 insertion mutations. There is also some high variability in the frequency of each of these alterations. In the end, [this variance] is probably more important for the TKIs as opposed to the ADCs, which might be more potent.

How do the prognostic and predictive values differ between the various HER2 alterations?

It's clear that the prognostic and predictive values of each mutation and alteration are different. [These values] may also be different from 1 compound to another, especially in terms of mechanism of action. It [also important] to distinguish between TKIs and ADCs. With TKIs, it's a matter of confirmation of the tyrosine kinase domain, and the impact of 1 mutation or another may be very important regarding the efficacy in inhibiting the kinase activity. With ADCs, we are moreso targeting the extracellular part of HER2; the type of intracellular alterations may actually be lower.

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What is the general breakdown of HER2 de novo and resistance alterations within tumor types?

We know that HER2 may be activated after exposure to a TKI, especially in patients with common EGFR mutations. For example, a patient may develop acquired resistance related to the proliferation of cancer cells with HER2 amplification or pathway activation. This is a very different situation compared with that of patients with de novo HER2 alterations for whom the objective is to start with HER2-directed treatment. In NSCLC, de novo HER2 mutations are present in approximately 2% to 3% of patients. Next-generation sequencing [NGS] is required to identify those mutations. If we use PCR-based assays, there is a high risk to miss some of these alterations.

The other point is that there are multiple ways to investigate HER2 [alterations]. Mutations [can be detected] with NGS; amplifications may require RNA-based NGS or fluorescent in situ hybridization. We also have HER2 expression, which may be associated with mutations or amplifications, but [expression] may also be independent from mutations and amplifications. When looking at HER2 expression in patients with NSCLC, it's important to look at the methods that were used to assess HER2 alterations.

How do the mechanisms of action differ for HER2-targeted TKIs vs ADCs?

With TKIs, we are inhibiting the intracellular domain of HER2—the kinase domain—which is associated with the activation of those pathways involved in cell proliferation and resistance to apoptosis. TKIs are binding to this ATP binding pocket in the intracellular part of HER2. If [a patient] has a HER2 mutation in the ATP domain, some TKIs may not work, and we would need TKIs with a different conformation that will work and bind to the ATP pocket. The advantage of TKIs is that they’re usually oral drugs with a known safety profile; however, the sensitivity of each mutation may differ from one TKI to another.

With ADCs, it's a completely different strategy, where you have drugs that [comprise] an antibody targeting the extracellular part of HER2 [and] a cytotoxic payload. The idea is to inhibit signaling pathways through the inhibition of the extracellular domain and also let this cytotoxic payload enter specifically into cancer cells, leading to a higher specificity for the cancer cells compared with systemic, cytotoxic chemotherapy. [There is] also an opportunity to have efficacy [irrespective of] the type of alteration, including HER2 mutations, amplifications, or even overexpression.

What are some relevant clinical features commonly observed among patients with HER2-mutant NSCLC?

A majority of [these] patients are never smokers, but you also have some smokers who develop lung cancer associated with HER2 mutations. Therefore, it's important to look for those alterations in all patients, usually using NGS. It's important to obtain HER2 status at [a patient’s initial] diagnosis because many clinical trials and potentially the standard of care in the future will likely [be to deliver HER2-directed therapies] in the first-line setting. Usually, the clinical radiological presentation is variable; [however,] in many patients [with NSCLC harboring HER2 alterations], there are multiple nodules and lymphangitis. [These patients have] quite extensive and aggressive disease with frequent metastases, especially in the brain.

Going forward, how might efficacy and safety considerations influence the selection and sequencing of ADCs and TKIs in NSCLC?

All those new drugs are of interest, including the ADCs and TKIs. The key question for me as a clinician is: ‘What is the best treatment sequence?’ I want to expose my patients with HER2-mutant NSCLC to ADCs, cytotoxic chemotherapy, and dedicated TKIs. Perhaps the best sequence may be to start with ADCs, and if progression occurs, the HER2-directed TKIs may work. Maybe it will be the reverse, starting with an oral drug and then [addressing] resistance with an ADC. [Sequencing choices will be] a matter of efficacy. We need to see the data, especially in the first-line setting, for ADCs and HER2-directed TKIs.

The adverse effects [AEs] also [need to be considered]. With ADCs, there may be some AEs that are quite similar to that of cytotoxic chemotherapy, [including] hematological toxicity, low blood pressure, nausea, vomiting, and possibly interstitial lung disease. With TKIs, [these AEs may include] more digestive tract–related toxicities with diarrhea. There may be some rash and cutaneous toxicities. Balancing the efficacy with the safety profile [is critical].