Unlocking the Potential: The Evolution of ADCs in HER2+ NSCLC

Joshua K. Sabari, MD

Ongoing studies are aiming to evaluate the use of the notable antibody-drug conjugates (ADCs) fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and patritumab deruxtecan, which target HER2 and HER3, respectively, in further settings as well as subtypes of non–small cell lung cancer (NSCLC).

“T-DXd is a humanized anti-HER2 IgG1 monoclonal antibody. It’s the same amino acid sequence as trastuzumab [Herceptin] which is approved in breast cancer. It has a tetrapeptide-based cleavable linker to the warhead, which is a topoisomerase 1 inhibitor, also known as DXd or an exatecan-derivative,deruxtecan,” Joshua K. Sabari, MD, detailed.

In an interview with OncLive^®, Sabari delved into an explanation of the utility of ADCs in patients with NSCLC, expanded on specific ADCs in the space and their benefit in each respective patient subgroup, and highlighted previous and ongoing clinical trials that are taking place to treat patients with EGFR-, ALK-, or HER2-mutant NSCLC. Sabari is an assistant professor in the Department of Medicine at New York University (NYU) Grossman School of Medicine and the director of High Reliability Organization Initiatives at Perlmutter Cancer Center, NYU Langone Health.

OncLive: How have ADCs evolved to treat HER2-positive disease?

Sabari: ADCs are an extremely exciting therapeutic class of medicines. Some of the key principles of ADCs are that they are chemotherapies attached with a linker to an antibody. We’re looking at tumor antigens that are highly expressed in tumors and minimally expressed in normal tissues. We are also looking for chemotherapeutic warheads that are potent, active payloads that can internalize in cancer cells causing cancer cell death as well as potential microenvironment damage or this bystander effect.

[ADCs give us the] ability to give high doses of chemotherapy in a targeted fashion. We’ve seen broad indications across all solid tumors in this setting, particularly in NSCLC.

What is T-DXd’s current place in the treatment paradigm? What are the key findings of the clinical trials that have examined this agent?

What’s interesting about this agent is that it has a high drug-to-antibody ratio, a very stable linker payload, and the tumor is selectable—the linker can be cleaved in the tumor microenvironment hopefully leading to tumor death due to the bystander effect. This drug has broad FDA indications and it’s approved in the second-line for HER2-positive metastatic breast cancer, the third-line for HER2-low metastatic breast cancer, and in the third-line for HER2-positive gastric cancer. Most recently, there’s an accelerated approval in the second-line setting in lung cancer for HER2-mutant NSCLC post-progression on first-line therapy with chemotherapy or chemotherapy and immunotherapy.

What is even more exciting is that there is an ongoing frontline study examining T-DXd vs chemotherapy and immunotherapy. If positive, this will lead to a broad indication in the frontline setting for HER2 exon 20 insertion-mutant NSCLC.

The data from the phase 2 DESTINY-Lung01 trial [NCT03505710] were quite impressive. Initially, we were looking at HER2 overexpression, and that hasn’t panned out. We finally settled on HER2 mutations, looking at the 6.4 mg/kg dose [of T-DXd] initially and then in the phase 2 DESTINY-Lung02 trial [NCT04644237], the 5.4 mg/kg dose. In these early studies in patients with HER2 exon 20 insertion-mutant lung cancers, we’re seeing a [beneficial] response rate and very robust durability of response.

We know that there are some toxicities with these agents, particularly inflammatory or interstitial lung disease [ILD]. We need to monitor those very closely as well as the common hematologic toxicities seen with some of these ADCs, typically [seen with] the deruxtecan chemotherapeutic warhead. This includes anemia, thrombocytopenia, and leukopenia. Overall, this is a well tolerated medicine. Alopecia and diarrhea have also been seen, but it is well managed in clinical practice.

How does the HER3-directed ADC, patritumab deruxtecan differ from T-DXd?

Patritumab deruxtecan is a HER3-directed ADC with a similar linker and payload. We initially saw data from the phase 2 HERTHENA-Lung01 trial [NCT04619004] of impressive response rates. These are in patients with EGFR-mutant lung cancer post-progression on a third-generation EGFR TKI, most commonly osimertinib [Tagrisso].

We initially saw a 39% response rate presented at the 2023 World Conference on Lung Cancer, that has since come down a bit. However, what is particularly exciting about this agent is that we’re seeing central nervous system activity, intracranial activity. In a small subset of patients, 30 patients, treated with patritumab deruxtecan those who had brain metastasis at baseline with no prior radiotherapy experienced a confirmed response rate of 33.3% with some complete responses in this patient population.

This is quite interesting and exciting to see that these ADCs not only have activity extracranially, but also importantly, intracranially. There are ongoing phase 1 studies combining the HER3 ADC patritumab deruxtecan with osimertinib in the frontline setting. These studies are ongoing and hopefully may change practice in the future.

Looking to phase 3 TROPION-Lung01 trial (NCT04656652), how did this trial fair in comparison with other approaches?

The Trop-2 ADCs are a huge opportunity. We know that Trop-2 is highly overexpressed in NSCLC and in many epithelial cancers. The idea here is that you can target or give high doses of chemotherapy using a Trop-2–targeted agent. The TROPION-Lung01 study evaluated datopotamab deruxtecan [Dato-DXd; DS-1062a]. This is a Trop-2 ADC with a deruxtecan derivative chemotherapy payload and it’s a cleavable linker.

We know that this drug has been studied in a phase 1 dose escalation study, with impressive activity [but] some ILD risk and some stomatitis [were seen]. However, in this study oncologists studied this agent in the second-line of a NSCLC population with both squamous and non-squamous patients. Overall, the data was somewhat disappointing vs docetaxel. The median PFS was 4.4 months for Dato-DXd in the second line vs 3.7 months for docetaxel. There was a 3-week benefit in median PFS and the HR was 0.75.

How does a patient’s squamous vs non-squamous status impact treatment?

It’s interesting if you look at groups broken up by squamous vs non-squamous histology—if you look at the squamous histology it seems that there is a decrease in PFS in those patients receiving Dato-DXd. However, if you look at non-squamous [population] which is mostly adenocarcinoma and specifically if you look at the actionable genomic alteration population, there does seem to be a significant benefit with this Trop-2 ADC. There is a 2-month improvement in median PFS. We’ll need to see what the median OS is as it is still immature.

What is also reassuring in the [data from the] phase 2 TROPION-Lung05 study [NCT04484142], which was presented at the 2023 ESMO Congress, evaluating Dato-DXD in patients with driver mutation-positive NSCLC, such as EGFR and ALK. In those who are t790m-positive we saw a 49.1% response rate.Therefore, there may be a story emerging in the driver-mutant patient population.

The non-driver mutant or the squamous-cell population seems to[experience] less efficacy [with Dato-DXd]. There’s a rationale here that maybe there is differences in self trafficking in patients who have driver alterations. With T-DXd, targeting HER2, you see very nice response rates; in HER3 in the EGFR mutant population and now here in the TROPION-Lung05 study, you’re selecting for better, durable responses in the EGFR and ALK mutant population.

Reference

FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. August 11, 2022. Accessed February 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan