Brahmer Highlights Practice-Changing Data in HER2-Mutated NSCLC

Results from the phase 2 DESTINY-Lung01 trial, which utilized fam-trastuzumab deruxtecan-nxki (Enhertu) in the treatment of patients with HER2-mutated metastatic non–small cell lung cancer (NSCLC), could have a potentially practice-changing impact on the field, explained Julie R. Brahmer, MD.

Updated findings from DESTINY-Lung01, which were presented at the 2020 ASCO Virtual Scientific Program, showed an encouraging objective response rate (ORR) and duration of response (DOR) in the 42 enrolled patients who were treated with the antibody-drug conjugate (ADC). Byindependent central review, the ORR was 61.9% (95% CI, 45.6%-76.4%), and the median DOR was not yet reached at data cutoff (95% CI, 5.3 months–not evaluable [NE]). Additionally, the median progression-free survival (PFS) was found to be 14.0 months (95% CI, 6.4-14).

Regarding safety, all patients experienced treatment-emergent adverse effects (TEAE). Approximately, 64.3% of TEAEs were grade 3 or higher (52.4% drug-related). There were 5 cases (11.9%) of drug-related interstitial lung disease (ILD), all of which were grade 2 aside from a single case of grade 1 ILD that is pending. TEAEs led to dose interruptions in 59.5% of patients, dose reductions in 38.1% of patients, and treatment discontinuations in 23.8% of patients.

In May 2020, the FDA granted a breakthrough therapy designation to trastuzumab deruxtecan for patients with metastatic NSCLC whose tumors have a HER2 mutation and have experienced disease progression on or after platinum-based therapy. The designation is based on earlier findings from the DESTINY-Lung01 trial, as well as data from a phase 1 study.

In an interview with OncLive, Brahmer, co-director of the Upper Aerodigestive Department in the Bloomberg-Kimmel Institute for Cancer Immunotherapy, director of Thoracic Oncology, and professor of oncology at Johns Hopkins Medicine, discussed the details of the DESTINY-Lung01 trial, as well as remaining questions that could be answered with further research.

OncLive: Could you provide an overview of the DESTINY-Lung01 trial?

Brahmer: For patients with HER2-mutated, NSCLC, [the DESTINY-Lung01 trial] is a game-changer for these patients. Response rates were nearly 70%. Obviously, this is a single-arm study and there are caveats. The next step is to try to figure out when to give this type of drug to patients with HER2 mutations? Obviously, we all treat patients with HER2 mutations, even though they're rare. We have been giving ado-trastuzumab emtansine (T-DM1; Kadcyla) in the past, based on the National Comprehensive Cancer Network (NCCN) guidelines. However, based on data [with trastuzumab deruxtecan] that came out of the breast cancer world, we're excited to potentially use this drug for these patients in the future.

Could you provide background on the goals of the trial and what the results were?

Trastuzumab deruxtecan is an ADC that is directed towards HER2 and the payload is a topoisomerase 1 inhibitor; there is also a cleavable linker to this ADC. Certainly, in lung cancer, we don't use these types of drugs very often, except for T-DM1 in HER2-mutated disease, as well.

Now, this drug is being studied in various cohorts, including a HER2-overexpressing [cohort], which was immunohistochemistry (IHC) 3+ or 2+, or HER2-mutated NSCLC. This trial included previously treated patients, but they could not have had any prior HER2-targeted therapy except for pan-HER TKIs. [A total of] 42 patients were enrolled and the most exciting data were the response rate, which was approximately 62%. There was also 1 patient who had a complete response.

The waterfall plot that Egbert F. Smit, MD, [of Vrije Universiteit Medical Centre in Amsterdam], presented was quite impressive. Again, it comprises a small number of patients, but the response over time and the median OS in this heavily pretreated group has not been reached yet. [There was a] median PFS of 14.0 months. These are impressive results for a small number of patients because HER2 mutations are not very common, but [us and our patients] are looking for drugs that work this well.

In general, besides a drop in blood counts, trastuzumab deruxtecan was quite tolerable. The rate of TEAEs that led to discontinuation [of the regimen] was only about 19%; it's a pretty well-tolerated drug. One thing to look for in this study is ILD. That is an AE of special interest. There is about a 12% rate of ILD that occurred, and trying to figure out how to monitor patients [with this AE while on] this drug will be worth looking at in the future. Certainly, the co-authors should be commended for this trial, and these amazing results will, down the road, make a huge difference for this group of patients.

Are there any remaining questions regarding the use of this ADC in lung cancer that you would like to see answered with further data?

The big question is, “How does this compare in this group of patients to immunotherapy plus chemotherapy in the first-line treatment setting?” Also, “Is this a group of patients who should receive this first because of the very amazing response rate, as well as the PFS? Should these patients receive immunotherapy plus chemotherapy upfront?” Those are big questions that need to be answered.

It's going to be hard to answer [those questions] depending on how this will play out in guidelines or [if there is an] FDA approval for this group of patients. Also, the questions that need to be answered are really surrounding ILD. Again, it is not very common, but in our patients with lung cancer, a lot of patients will have interstitial changes that we're not quite sure what to make of. Do we see a higher rate of ILD in patients who received immunotherapy up front? There are a lot of questions regarding this particular AE. But just as with immunotherapy, the key thing will be figuring out how to identify those patients who are at risk for this, as well as identify those patients for when they do develop it as early as possible.

Reference

1. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504