HER2 and HER3 in NSCLC: The Latest ADC Data and NCCN Guideline Updates

As antibody-drug conjugates (ADCs) gain momentum in the treatment landscape of non-small cell lung cancer (NSCLC), a growing body of evidence is reshaping how HER2- and HER3-targeted therapies are used in clinical practice. In an interview with Pharmacy Times®, Penn Medicine oncology clinical pharmacists Corrine Stahura, PharmD; and Sophia Gilardone, PharmD, BCOP, discuss key findings from pivotal trials, including DESTINY-Lung01, DESTINY-Lung02, and HERTHENA-Lung01, and explore how these data are influencing current National Comprehensive Cancer Network (NCCN) guideline recommendations. They offer insight into differences in efficacy and safety between trastuzumab deruxtecan (T-DXd; Enhertu; Daiichi Sankyo and AstraZeneca) and trastuzumab emtansine (T-DM1; Kadcyla; Genentech), the role of HER2 mutation vs HER2 overexpression in guiding ADC use, and the emerging relevance of HER3-directed therapies for patients with EGFR-mutated NSCLC.

Pharmacy Times: Can you summarize the most recent clinical trial data that inform the use of HER2 or HER3-directed ADCs in NSCLC?

Sophia Gilardone, PharmD, BCOP: I'm going to start by talking about the DESTINY-Lung trials. The 2 main ones I want to focus on are DESTINY-Lung01 and DESTINY-Lung02. DESTINY-Lung01 was a phase 2, open-label, single-arm trial that enrolled patients with HER2 mutations. There was also a cohort within this trial that included patients with HER2 IHC 3+ overexpression, which I’ll discuss shortly. In the trial, T-DXd was administered at 6.4 mg/kg IV every 3 weeks. The objective response rate [ORR] assessed by independent central review was 55%, with a median progression-free survival [PFS] of 8.2 months. Median overall survival (OS) was just under 18 months. Importantly, interstitial lung disease [ILD] occurred in 26% of patients, with 2% experiencing fatal ILD—something we've discussed in more detail earlier.

Lung cancer cells. Image Credit: © Goody ART - stock.adobe.com

Corrine Stahura, PharmD; and Sophia Gilardone, PharmD, BCOP, discuss recent clinical trial data and evolving guideline recommendations for HER2- and HER3-directed antibody-drug conjugates in non–small cell lung cancer, highlighting differences in efficacy, safety, and patient selection criteria.

DESTINY-Lung02 was also conducted in a similar patient population but evaluated 2 doses of T-DXd: 5.4 mg/kg and 6.4 mg/kg, again administered every 3 weeks. This was a randomized study. The ORR at the 5.4-mg/kg dose was 49%, compared to 56% at the 6.4-mg/kg dose. Median PFS was 9.9 months at the lower dose and 8.3 months at the higher dose—very close to what we saw in DESTINY-Lung01. Most notably, ILD incidence dropped to 11.9% in the lower dose group, with no fatal ILD cases, compared with 2% fatal ILD at the higher dose. This supports the 5.4-mg/kg dose as preferable, maintaining efficacy with a better safety profile.

The HER2 IHC overexpression cohort in DESTINY-Lung01 included 49 patients with either IHC 3+ or IHC 2+ expression. The ORR in this group was around 25%, with a disease control rate of 70%. Median PFS was just over 5 months, and median OS was 11.3 months. ILD occurred in 19% of patients, with about 4% experiencing grade 3 or higher ILD, and fatal ILD was around 2%. While response rates were lower compared with the HER2-mutant population, HER2 IHC 3+ overexpression still showed clinically meaningful benefit, leading to approval for T-DXd in this subset. However, there are limited data for IHC 2+ expression.

Next, I’ll discuss patritumab deruxtecan, evaluated in the HERTHENA-Lung01 trial—a global, multicenter phase 2 study of over 200 patients with advanced EGFR-mutated NSCLC who had progressed on EGFR TKIs and platinum-based chemotherapy. The ORR was around 30%, and the CNS ORR was about 33%. Median PFS was 5.5 months, and median OS was 11.9 months. In terms of safety, 65% of patients experienced grade 3 or higher treatment-related adverse events, with thrombocytopenia, neutropenia, and anemia being most common, alongside fatigue and some lab abnormalities. About 7% of patients discontinued therapy due to adverse effects. ILD was observed in 5% of patients. This suggests patritumab deruxtecan may be a promising option for patients who have limited remaining therapies after targeted and chemotherapy regimens.

Pharmacy Times: How have response rates and progression-free survival outcomes evolved with newer ADCs in HER2- and HER3-expressing NSCLC subtypes?

Corrine Stahura, PharmD: T-DM1 was first approved for metastatic breast cancer in 2013 based on the EMILIA study, while T-DXd was first approved in 2020 based on DESTINY-Breast01. However, these agents have not been directly compared in lung cancer. While T-DM1 is listed in the NCCN guidelines for NSCLC, it is not FDA-approved for this indication. Separate trials have assessed PFS for both agents individually. In DESTINY-Lung01, T-DXd showed a median PFS of 8.2 months. For T-DM1 in HER2-positive NSCLC, median PFS was only 2.6 months. While both are included in guidelines, T-DXd is the preferred regimen, and these data demonstrate that newer ADCs offer improved efficacy in this setting.

Sophia already reviewed HERTHENA-Lung01, where patritumab deruxtecan demonstrated a PFS of 5.5 months—somewhere between what we saw with T-DM1 and T-DXd. Importantly, its indication is different; it's approved for advanced EGFR-mutated NSCLC rather than HER2-positive disease.

Pharmacy Times: What are the current NCCN or American Society of Clinical Oncology guideline recommendations for the use of HER2- and HER3-targeting ADCs in NSCLC? Have there been any recent changes?

Gilardone: In the NCCN guidelines, both T-DXd and T-DM1 are recommended as subsequent therapy for ERBB2 [HER2] mutation–positive NSCLC. Additionally, for HER2 IHC 3+ overexpression, T-DXd is also included. The most recent updates include a recommendation to test specifically for HER2 IHC status in addition to ERBB2 mutations. They now define what constitutes HER2 IHC 3+ expression. Another addition to the guidelines is zenocutuzumab, a HER2/HER3 bispecific antibody used for NRG1 fusions. Though it’s not an ADC, this reflects the expanding role of HER2-targeted agents in NSCLC.

Pharmacy Times: How does HER2 mutation status impact eligibility or response to ADC therapy in NSCLC compared to HER2 overexpression or amplification?

Stahura: The type of HER2 status definitely impacts ADC eligibility. Patients with HER2 mutations may receive either T-DXd or T-DM1. T-DXd is approved for both HER2-mutant and HER2 IHC 3+ NSCLC. However, T-DM1 is not approved for HER2 IHC-positive disease, making those patients ineligible for that therapy. It's also worth noting that HER2-mutant patients do not respond well to immune checkpoint inhibitors (ICIs) alone in the first-line setting. Therefore, it is important that these patients receive combination therapy with chemotherapy and ICIs in the frontline setting.

Pharmacy Times: Given the emerging data on HER3 as a therapeutic target in NSCLC, what is the clinical relevance of HER3 expression testing, and how might it influence treatment decisions?

Gilardone: HER3 testing is not currently standard. HER3 overexpression occurs in about 80% of NSCLC tumors and is even more common in those with EGFR mutations. HER3 can also function as a resistance mechanism to EGFR TKIs. In the HERTHENA-Lung01 trial, HER3 expression was assessed retrospectively but was not required for enrollment. Although evaluating HER3 could inform future treatment strategies, it is not currently a requirement for drug eligibility. As with HER2, we’ll likely continue learning more about how HER3 expression may impact treatment response over time.