ADCs Redefine HER2+ NSCLC Landscape With Potential to Shift to the Frontline Setting

Noman Ashraf, MD

The HER2-directed antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) is currently under evaluation in the frontline setting following promising data seen in patients with previously treated HER2-mutated and -overexpressing non–small cell lung cancer (NSCLC), according to Noman Ashraf, MD. However, T-DXd yielded higher objective response rates (ORRs) in patients with HER2-mutated disease.

“The phase 2 DESTINY-Lung01 study [NCT03505710] had 2 cohorts—patients who overexpressed HER2 and patients who had HER2 mutations—and both cohorts of patients seemed to benefit from T-DXd,” Ashraf said in an interview with OncLive® following an OncLive State of the Science Summit™ on lung cancer, which he chaired. “It seemed like the patients who had HER2 mutations experienced a bit more of a benefit [with a confirmed] ORR of 55% and median progression-free survival of 8.2 months [observed]. [Further], the median overall survival was 17.8 months.”

Findings also revealed that patients overexpressing HER2 treated with 6.4 mg/kg of T-DXd in cohort 1 experienced an ORR of 26.5%. The ORR was 34.1% among those in cohort 1a who received the agent at 5.4 mg/kg. Further, patients experienced reduced toxicity when administered T-DXd at the lower dose.¹

“The patients in [DESTINY-Lung01 and the phase 2 DESTINY-Lung02 trial (NCT04644237) received T-DXd] in the second line and beyond setting,” Ashraf noted. “[However], ADCs are making a move towards the upfront setting for these same patient populations, whether it’s in HER2 overexpressed or HER2-mutated [disease].”

In the interview, Ashraf discussed the current status of treatment with the HER2-directed ADC T-DXd and highlighted data from trials that have supported the use of the agent. Ashraf is a hematologist-oncologist at Tampa General Hospital and an associate professor of medicine in the Division of Hematology/Oncology at the University of South Florida Health Morsani College of Medicine in Florida.

OncLive: What notable data were seen with T-DXd in patients with HER2-overexpressing NSCLC?

Ashraf: When looking at different doses—which were also studied in DESTINY-Lung02 trial—the lower dose of 5.4 mg/kg had much less toxicity but almost equal efficacy. That is the dose that was approved by the FDA in 2022. The cohort of patients [with] HER2-overexpressing disease by IHC included patients who had [a HER2 status of] 2+ or 3+ by IHC and response rates were a bit lower than [seen in] the HER2-mutated cohort at [approximately] 35%.

In DESTINY-Lung01, the 2 cohorts [for patients with] HER2 overexpressing disease [were] already built in, with approximately 40 patients in each cohort. One cohort received the lower dose of 5.4 mg/kg and the other the 6.4 mg/kg dose. The efficacy was about the same with both the doses, but the toxicity was significantly less with the lower dose. As far as toxicity, ADCs have toxicities that are similar to chemotherapy [including] the usual cytopenias and alopecia. However, the unique toxicity with them is interstitial lung disease [ILD], and that was fatal in some patients, so it’s important to minimize toxicity.

What are some of the promises and challenges seen when combining ADCs with additional agents?

If the ADC is working, then why not combine it with something else….There are several studies [now] looking at upfront T-DXd. For example, the phase 2 DESTINY-Lung05 trial [NCT05246514] is examining [frontline] T-DXd in combination with standard of care treatment whether it’s immunotherapy or chemoimmunotherapy.

When combining 2 drugs, you have to worry about the overlapping toxicities. ADCs have the toxicity of cytopenia and that’s something we will watch for. Additionally, ILD is not so much a problem with chemotherapy itself, but immunotherapy can cause pneumonitis by itself, so we must [diligently monitor patients to see] if that’s going to increase the toxicity of ILD when we combine [the drugs].

We [also] have data from the phase 2 NeoCOAST-2 trial [NCT05061550], which was presented the 2024 IASLC World Conference on Lung Cancer, [demonstrating that it appears] safe to combine some of these ADCs with chemotherapy. Although that was not for HER2-[targeted ADCs] specifically, it was for TROP2, it does seem like there is some data [showing] that you can safely combine ADCs. We’ll know more once we have more studies.

What is important for colleagues to know about the shifting treatment paradigm with ADCs?

ADCs are making huge progress in NSCLC. We’ve been a bit behind [with] ADCs in NSCLC compared with our breast cancer colleagues. However, as we go along, we are getting more targets and are going to see more ADCs, which are effective not only in the second line setting but may turn out to be effective in the first line setting as well.

HER2 has also [very much] become a target in NSCLC, whether it’s HER2 mutations or overexpression. Additionally, some TKIs [are] coming out that seem very effective.

Reference

Smit EF, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol. 2024;25(4):439-454. doi:10.1016/S1470-2045(24)00064-0