Emerging TROP-2 Directed ADCs Show Promise in Advanced NSCLC

The focus on novel antibody-drug conjugate (ADC) development in non–small cell lung cancer (NSCLC) signifies a fundamental shift in the treatment paradigm, with several anticipated approvals on the horizon, according to Benjamin Philip Levy, MD, who said that continued research is necessary to improve understanding of the clinical activity, safety, and optimal sequencing of these agents.

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) is currently the only ADC to be FDA approved for the treatment of adult patients with unresectable or metastatic NSCLC harboring activating HER2 mutations who have previously received systemic therapy.¹ However, several other ADCs are showing promise in advanced stage disease, including the TROP-2 directed ADCs sacituzumab govitecan-hziy (Trodelvy) and datopotamab deruxtecan (Dato-DXd; DS-1062a). These agents have both demonstrated efficacy in the second line, and smaller datasets signal their potential clinical activity in the first-line setting.

Initial results from the ongoing phase 2 EVOKE-2 trial (NCT05186974) demonstrated that the addition of sacituzumab govitecan to pembrolizumab (Keytruda) produced high response rates in the frontline setting for patients with advanced NSCLC. Across all patients, the overall response rate (ORR) with the combination regimen was 56%, with a disease control rate of 82%. Patients in cohort A, who had a tumor proportion score (TPS) of at least 50% achieved an ORR of 69%, and patients in cohort B with a TPS score below 50% achieved an ORR of 44%. Preliminary data suggest that responses are durable, and the median duration of response was not reached at the time of data cut-off.²

“ADCs are coming [down the pike in NSCLC]. We have T-DXd for patients who harbor HER2 exon 20 mutations, but we're going to have to learn very quickly how to adapt and leverage these other ADCs that may be approved,” said Levy, an associate professor of oncology at Johns Hopkins University School of Medicine and the clinical director of Medical Oncology at Johns Hopkins Sidney Kimmel Cancer Center, part of Sibley Memorial Hospital in Baltimore, Maryland.

In an interview with OncLive®, Levy discussed the current landscape of emerging ADCs and their early activity in advanced lung cancer, the potential utility of oncogene-directed ADCs for patients with driver mutations, and the importance of ongoing investigations of sacituzumab govitecan and datopotamab deruxtecan in the first and second lines.

OncLive: Please discuss the key highlights from your presentation on oncogene-directed ADCs in lung cancer from the 18th Annual New York Lung Cancers Symposium®.

Levy: As these [novel] ADCs roll out, we may start categorizing them as onco[gene]-directed, meaning that some of these ADCs may be efficacious [for patients expressing] driver alterations. My presentation is [focused on] those [agents] that have activity in both EGFR- and HER2-mutant disease as well as patients with MET overexpression. We will be reviewing the data for HER2 exon 20 mutations with T-DXd and the efficacy we've seen in an updated analysis that was presented at the International Associated for the Study of Lung Cancer [IASLC] World Lung Cancer Conference. We'll be reviewing the patritumab deruxtecan (HER3-DXd) data that were also presented at the IASLC World Lung Cancer Conference, and its activity in EGFR-mutant lung cancer. [Lastly], MET-directed ADCs like telisotuzumab vedotin (ABBV-399; Teliso-V) are being looked at for patients with MET overexpression. We know that MET overexpression happens in patients without EGFR mutations, but we also know it happens in the resistant setting for patients who have had received a prior TKI [and who] are EGFR positive. Hopefully [our review of these data will] lay the foundation for where we're heading moving forward.

Please provide an overview of the 2 TROP-2 directed ADCs currently in development for patients with NSCLC.

There are 2 TROP-2 directed ADCs currently in development. One is sacituzumab govitecan. This agent was [investigated for use] in lung cancer back in 2017 and efforts [to utilize it] in the second line and in the first line [are being reignited]. Dato-DXd also has been looked at as a single agent in a highly pretreated group of patients with NSCLC. We now have phase 3 data looking at Dato-DXd versus docetaxel in the second line [from the TROPION-LUNG01 study (NCT04656652)]. These data were presented at the 2023 ESMO Congress and showed a PFS advantage in patients with nonsquamous histology. Both TROP-2 directed ADCs have activity in the second line. Both have [also] been looked at in the first line in small datasets and showed meaningful activity. The question is: could these ADCs replace platinum chemotherapy? I'm not sure that's going to happen, but I'm excited to see the data that roll out in the next 6 to 12 months with these drugs.

How do these 2 agents differ from each other in terms of clinical activity or safety?

If we look at the activity of these 2 drugs, it's too early to tell whether they're the same or not. The settings [in which they have been evaluated] have been a bit different. I think we'll find [that] out from the phase 3 EVOKE-01 trial [NCT05089734] of sacituzumab govitecan vs docetaxel, which will hopefully be presented in the next 6 to 12 months. We will then be able to compare those data with the TROPION-Lung01 data [NCT04656652] of Dato-DXd versus docetaxel. These are 2 similar studies. We already know the data for TROPION-Lung01, but we need to find out the data for EVOKE-01 to see how [the agents perform] with a similar comparator arm of docetaxel. If you look at these agents in the front line, specifically in combination with immunotherapy, they look about the same in terms of their activity.

Toxicities do differ here. We know that there may be more cytopenias with sacituzumab govitecan, and we know that there may be more stomatitis with Dato-DXd. We have to be proactive in managing that. Although these 2 drugs are both TROP-2 directed ADCs, they may have different activity and they do have different toxicities. We'll have to see how they're leveraged in our clinic and how they might get approved.

What is your main message for colleagues based on your presentation?

In my opinion, Dato-DXd will be approved in the next 6 to 12 months. It will be important to look at the data and understand toxicities, how to manage them, and potentially how to sequence these therapies.

This is a whole new class of drugs that [we have] never really had to wrestle with. We've always been in the lane of either targeted therapy, chemotherapy, or immunotherapy. Along comes this new class, and we're going to have to learn about them quickly as they gain approval. We're going to have to try to understand who these drugs work for. Most importantly, [we will have to learn] how to mitigate toxicities for these drugs so that that journey is clean for patients and that we can be proactive in the management of these adverse effects.

References

1. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. August 11, 2022. Accessed November 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung
2. Gilead’s phase 2 EVOKE-02 study of Trodelvy (sacituzumab govitecan-hziy) in combination with Keytruda (pembrolizumab) demonstrates promising clinical activity in first-line metastatic non-small cell lung cancer. News release. Gilead. September 10, 2023. Accessed November 16, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2023/9/gileads-phase-2-evoke02-study-of-trodelvy-sacituzumab-govitecanhziy-in-combination-with-keytruda-pembrolizumab-demonstrates-promising-clinical-activity