Trastuzumab Deruxtecan Shakes Up HER2-Mutated NSCLC Treatment Paradigm

The data reported with the novel antibody-drug conjugate trastuzumab deruxtecan (Enhertu) are a gamechanger for patients with HER2-mutated non–small cell lung cancer (NSCLC), according to Solange Peters, MD, PhD, who added that the agent might show even more efficacy if examined in the frontline setting.

“Prior to this trial, we were trying to target HER2 mutations, but with a very low level of success, I must say. For me, the DESTINY-Lung01 trial is, for the first time, paving the way to first-line targeted therapy in patients with HER2-mutated NSCLC,” said Peters. “Of course, we still need larger numbers, but the results have been absolutely amazing. This trial will potentially result in new treatment strategies that we have been underestimated in the past. I’m very excited about this trial for our patients with HER2 mutations.”

Results from an interim analysis of the phase 2 DESTINY-Lung01 trial reported during the 2020 ASCO Virtual Scientific Program indicated that the ADC showed favorable clinical activity, inducing durable responses in patients with HER2-mutated NSCLC.

Treatment with trastuzumab deruxtecan was shown to lead to a confirmed objective response rate (ORR) of 61.9% (95% CI, 45.6%-76.4%) via independent central review, a disease control rate of 90.5% (95% CI, 77.4%-97.3%), and an estimated median progression-free survival (PFS) of 14 months. The median duration of response was not reached at the time of data cutoff.

The safety profile of the agent in the HER2-mutant cohort proved to be consistent with what has previously been reported with the ADC. Treatment-emergent adverse events (AEs) reported in 15% or more of patients included nausea, alopecia, anemia, reduced appetite, a decrease in neutrophil count, vomiting, and diarrhea. Most of the events were grade 1 or 2.

“Many trials have been done, but [the data seen with the agents] have not been convincing enough to be considered in the frontline –or even as standard second line; nothing could challenge chemotherapy or chemoimmunotherapy,” said Peters. “For the first time though, I think this can be challenged.”

In an interview with OncLive, Peters, head of the Medical Oncology Service and Chair of Thoracic Oncology at Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, discussed the promising clinical activity observed with trastuzumab deruxtecan in patients with HER2-mutated NSCLC, next steps for research, and other exciting lung cancer data.

OncLive: Could you shed light on the DESTINY-Lung01 trial?

Peters: The DESTINY-Lung01 trial is trying to address the question of how to target HER2 mutations. HER2 mutations consist most often in exon 20 insertion mutations, which were the subject of many previous clinical tria attempts with targeted therapy. We have tried to deliver a trial of afatinib (Gilotrif) with a response rate of less than 10%. We have been trying to deliver dacomitinib (Vizimpro) with a response rate of approximately 11%. Recently, some data have emerged with poziotinib with around a 50% response rate in a very small number of patients. As such, this has been a very frustrating area of research.

Results with ado-trastuzumab emtansine (T-DM1; Kadcyla) in this disease [have also been published]. We tried to address this in all expressions of HER2, but colleagues from the United States have delivered T-DM1 in patients with HER2-mutated and they showed a response rate of 44% in a small subset of patients, which would deserve additional investigation.

The new compound, the antibody-drug conjugate from the DESTINY-Lung01 trial, is very specific because of the payload, a topoisomerase-1 inhibitor, present in high concentrations (8 molecules). It targets the transcellular domain of the HER2 protein. The ADC has been tested in breast cancer and colorectal cancer. In this trial, investigators treated the largest number of patients with HER2 mutations to date, a total of 42. The overall response rate [reported with the agent] was approximately 61% and the progression-free survival was 14 months. The 14-month PFS is very interesting in the frontline and the response rate is challenging chemotherapy.

Are there any questions left by this research? What are your thoughts on its safety profile?

We need more data to truly understand how this drug works in HER2 mutations. In the trial, there was an arm investigating HER2 overexpression. How does the agent work in this disease when HER2 is expressed at a low level, and there are no rearrangements or mutations? These data are still awaited but, more importantly, we need more information on toxicity.

This drug has shown some inflammatory lung disease, pneumonitis-like toxicity. It appears as though this phenomenon has been manageable, but we still need to know more about management, outcome, and treatment decisions around potential toxicities. How to prevent and how to react are very important things to know before we are fully convinced. But again, these data are a game changer in the field of HER2-mutated NSCLC.

If the follow-up data are positive, how might this agent impact the treatment paradigm?

So far, we have seen data for a total of 42 patients, but investigators are now expanding this cohort. This is very important, again, because we need to be able to describe the granularity, the different components of this response rate. Another important factor, and this is also based on the experience with other oncogenetic NSCLC, is to see how the drug works in the first-line setting. What we have been seeing with EGFR, with ALK in particular, is that response rate is always pretty interesting with EGFR and ALK inhibitors. The main difference between first and second-line therapy is PFS; we have been seeing a better PFS when the compounds are given in the first-line setting. So, if 14 months are met in the second-line setting, I would be very interested to see the efficacy profile of this agent in these patients receiving treatment in the first-line setting.

On the other hand, if you think about first-line strategies, you might have a cleaner vision of the toxicity. Nowadays, when you use any compound second-line, you need to remember that there may be an overlap between the toxicity of the current compound and toxicities of previous treatments.Here, I’m thinking about immunotherapy because most of the patients receive some type of immunotherapy before, which has a long-term pharmacology; this might overlap in toxicity with the new compounds that are given.

Did any other lung cancer trials presented during this year’s ASCO meeting interest you?

I found the ADAURA trial to be very interesting. I was, at first, very reluctant to discuss any data in the curative setting when the OS data were not available. However, after seeing the magnitude of difference between osimertinib in the adjuvant setting versus placebo, there must be some biological rational behind this. I would love to know more about what is happening in patients not receiving osimertinib. Where exactly do they relapse? Is it in the brain, bone, or the liver? When and how do they relapse?

On the contrary of my initial thought, I might be convinced by such a magnitude of difference between the 2 arms. I need to wait a bit more, but I was certainly surprised by these data.

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: Interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504