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HER2/HER3/TROP2 in NSCLC
My Take on Emerging Agents Targeting HER2, HER3, and TROP2 in NSCLC

Released: November 23, 2020

Expiration: November 22, 2021

Sandip P. Patel
Sandip P. Patel, MD
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The list of actionable targets in non-small-cell lung cancer (NSCLC) continues to expand, with corresponding FDA approvals and promising data emerging on targeted therapies. Below, I provide a focused overview of investigational therapeutics targeting HER2, HER3, and TROP2 in NSCLC.

Targeting HER2
Up to 4% of patients with NSCLC exhibit HER2 amplification or activating mutations. Thus, an important targeted agent currently under investigation is trastuzumab deruxtecan (T-DXd, formerly DS-8201), an antibody–drug conjugate consisting of a HER2-directed antibody linked to a topoisomerase inhibitor. T-DXd has already been approved by the FDA for adults with unresectable or metastatic HER2-positive breast cancer previously treated with ≥ 2 anti–HER2-based regimens.

The international, open-label, multicohort phase II DESTINY-Lung01 trial is evaluating T-DXd in patients with unresectable or metastatic NSCLC that is HER2 overexpressing or harbors a HER2-activating mutation; patients must be relapsed/refractory to standard therapy and cannot have received previous HER2-targeted agents. T-DXd is administered at 6.4 mg every 3 weeks in both cohort 1, which consists of patients with HER2-expressing NSCLC, and cohort 2, which consists of patients with HER2-mutated NSCLC.

We are still awaiting results for cohort 1 (HER2-overexpressing NSCLC), but we now have data for cohort 2 (HER2-mutated NSCLC). At ASCO 2020, Smit and colleagues reported that in an interim analysis of patients with HER2-mutated NSCLC, T-DXd was associated with a confirmed ORR of 62%. Many of these responses were durable in otherwise refractory disease. I consider these findings to be a high watermark for the treatment of HER2-mutated NSCLC.

It is important to be cognizant of the risk of interstitial lung disease with the use of T-DXd, as this adverse event has been observed in trials of T-DXd in other tumor types, including breast, gastric, and colorectal cancers. The interim analysis of the DESTINY-Lung01 trial reported only grade 2 cases of interstitial lung disease with no related deaths. Interstitial lung disease is managed depending on its severity, with asymptomatic grade 1 events requiring corticosteroids and withholding T-DXd, whereas symptomatic grade ≥ 2 events necessitate corticosteroids and permanent discontinuation.

Targeting HER3
Approximately 3% of NSCLC cases have gene fusions in NRG1, which encodes the HER3 ligand neuregulin, part of the EGF family. Detecting NRG1 fusions optimally requires RNA-based sequencing because traditional, amplicon-based sequencing of DNA will often miss gene fusions. Currently, CLIA-validated laboratories only perform RNA-based sequencing using tissue.

We have early data from an ongoing dose-escalation/dose-expansion phase I trial of the investigational antibody–drug conjugate patritumab deruxtecan (US-1402), which targets HER3. At ESMO 2020, Yu and colleagues reported that patritumab deruxtecan was associated with an ORR of 25% in 49 patients with heavily pretreated EGFR-mutated NSCLC.

We also have early data from 3 patients with NRG1 fusion–positive solid cancers with MCLA-128, a bispecific HER2/HER3-directed antibody that prevents NRG1 fusions from binding to HER2 and also prevents HER2 from interacting with HER3. In the single patient with lung cancer, who had been treated with 6 previous lines of therapy, MCLA-128 was associated with a 41% reduction in tumor size.

Although research is still needed for understanding the clinical utility of targeting HER3, it is important to consider testing appropriate patients to determine if they might be eligible for a clinical trial of these or other HER3-targeting agents.

Targeting TROP2
TROP2 is highly expressed in multiple cancers, including lung cancer and triple-negative breast cancer. In April 2020, the FDA approved the anti-TROP2 antibody–drug conjugate sacituzumab govitecan for treatment of adults with metastatic triple-negative breast cancer previously treated with ≥ 2 previous therapies; sacituzumab govitecan was associated with impressive efficacy (ORR of 33.3%) in this difficult-to-treat population.

The success of anti-TROP2 therapy in triple-negative breast cancer spurred investigation of this approach in NSCLC. At ASCO 2020, Lisberg and colleagues presented data from an ongoing first-in-human phase I trial evaluating datopotamab deruxtecan (DS-1062), a TROP2-targeted antibody–drug conjugate, in patients with advanced NSCLC that is relapsed or refractory to standard treatment. TROP2 expression was not required for enrollment. The ORR was 27% in 85 evaluable patients, with the major adverse events being fatigue, stomatitis, and mucosal inflammation.

Datopotamab deruxtecan will be further studied in the single-arm phase II TROPION Lung05 trial (NCT04484142), which is not yet enrolling. This trial will recruit patients with advanced or metastatic NSCLC that harbors actionable genomic alterations and who have received ≤ 3 previous lines of therapy, which must include a kinase inhibitor and platinum-based chemotherapy with or without immune checkpoint inhibition. The primary endpoint is ORR.

Your Thoughts?
Are you assessing rare actionable driver mutations such as HER2 mutations in your patients with advanced NSCLC? I encourage you to answer the polling question and post your thoughts and questions in the discussion box below.
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