Trastuzumab deruxtecan yields promising results in HER2-positive breast cancer patients pretreated with TDM-1

Dr Ian Krop - Dana Farber Cancer Institute, Boston, USA

Good morning, thanks for the opportunity to discuss this phase II trial of trastuzumab deruxtecan, the DESTINY-Breast01 study.  These are my disclosures.

Trastuzumab deruxtecan is a novel antibody-drug conjugate. It consists of a HER2 specific monoclonal antibody with the same amino acid sequence as trastuzumab. It’s conjugated to a topoisomerase-1 inhibitor payload via a peptide based cleavable linker. Now, trastuzumab deruxtecan has several distinctive features: one is that, as I mentioned, its payload is a potent topoisomerase-1 inhibitor. This is a kind of chemotherapy that is not typically used in HER2 positive breast cancer so it’s less likely the cancers will have developed resistance to this agent. There are about eight of these payload molecules per antibody and this is a higher drug to antibody ratio than is typically seen with current antibody conjugates. Lastly, the payload is membrane permeable so in pre-clinical studies it allows it to diffuse out of the targeted cell and kill neighbouring tumour cells, regardless of their HER2 expression.

This study enrolled patients with centrally confirmed HER2 positive advanced breast cancer. All patients had had prior T-DM1. Patients who had significant history of interstitial lung disease were excluded and patients with stable treated brain metastases were eligible. In part 1 of the study, which was designed to identify the recommended phase II dose of the drug, patients who had T-DM1 resistant advanced cancers were randomised to one of several different concentrations of trastuzumab deruxtecan. After review of the safety and efficacy of this part, 5.4mg/kg was established as a recommended phase II dose and an additional 130 patients were treated at that dose in part II of the study. A small cohort of four patients who were intolerant of T-DM1 also was included at 5.4mg/kg.

This presentation will focus on the protocol specified analysis of all 184 patients treated at the recommended phase II dose. The primary objective was confirmed response rate by central imaging review and the data cut-off was August 1st where about 43% of patients are still ongoing.

This was a very heavily pre-treated population with a median of six prior lines of therapy in the advanced disease setting. All patients had had prior trastuzumab and T-DM1, two-thirds had had prior pertuzumab and the majority had other HER2 directed therapies as well.

Now for the efficacy analysis. The primary endpoint of objective response rate by independent review was 60.9%, 6% were complete responses 54.9% were partial responses. The clinical benefit rate at six months was 76%. The median duration of response was 14.8 months and the median time to response was 1.6 months, essentially the time of the first restaging. The disease control rate was 97%. There were less than 2% of patients who had progressive disease at time of first restaging and this uniformity of activity of trastuzumab deruxtecan is reflected in this waterfall plot shown here.
We also looked at how the response varied by subgroup and, as you can see in this forest plot, the activity of trastuzumab deruxtecan was relatively consistent across all major subgroups, including those patients who had had prior pertuzumab where the response rate was about 65%.

The progression free survival Kaplan-Meier curve is shown on the left. The median progression free survival was 16.4 months and in the important subgroup of those patients who had had prior brain metastases the PFS was 18 months. I should point out that this was a small subgroup and the confidence intervals are wide. On the right side is the overall survival. At this data cut-off the median follow-up was only 11 months so the data are immature and the median overall survival is not yet reached.

Turning to the safety analysis, 57% of patients had at least one grade 3 adverse event. 15% of patients discontinued the study drug because of an adverse event and the most common reason for discontinuation was pneumonitis or interstitial lung disease.

This is a summary of the most common adverse events. This was similar to what was seen with the phase I study of this agent – nausea, vomiting and fatigue were the most common adverse events but these were almost all low grade.

Alopecia was seen in 48% of patients, neutropenia was in 35% of patients but febrile neutropenia, which is what is most clinically relevant, was rare, less than 2% of patients.

Because we knew that interstitial lung disease was a risk of trastuzumab deruxtecan from the phase I study, all patients in this study who had evidence of pulmonary toxicity were adjudicated by an independent expert panel. This panel identified 25 patients, or 13.6% of the population, who had interstitial lung disease that was felt to be drug related. 20 of the 25 were low grade but unfortunately 4 patients had fatal ILD that was felt to be drug related. Of the total 25 patients who had had ILD of any grade the median time to onset was 193 days or about six months after starting study therapy. Of the 20 patients who had grade 2 or higher ILD, so that’s symptomatic ILD, 13 of them, so just over half, had received steroids as part of their treatment. In the patients who had non-fatal ILD, seven had recovered, two were in the process of recovering at the time of the data cut-off and twelve either had unknown outcomes or were not followed until resolution. Of the four fatal cases the onset ranged from 63 to 148 days after starting study therapy. Three of those patients had received steroids as part of the treatment for ILD and the deaths occurred between 9 and 60 days after their initial ILD diagnosis.

This expert panel, after looking over these data, their advice was for future studies of trastuzumab deruxtecan that patients be monitored closely for symptoms of ILD and that trastuzumab deruxtecan be held and the steroids started as soon as ILD was suspected.

In conclusion, trastuzumab deruxtecan demonstrated a confirmed response rate of 60.9% and durable benefit in a very heavily pre-treated population. The median progression free survival was 16.4 months and the activity seemed relatively consistent across clinical subgroups. The overall safety profile was consistent with what’s previously been reported with trastuzumab deruxtecan where low grade GI and hematologic toxicities were most common. But ILD is confirmed as an important risk of trastuzumab deruxtecan, it can be severe and requires careful monitoring and prompt intervention.

These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2 positive breast cancer. There are several phase III studies of this agent underway, both in HER2 over-expressing cancer as well as HER2 low expressing cancer.