Trastuzumab Deruxtecan Continues to Show Safety in Metastatic Breast Cancer

A safety follow-up of the phase 3 DESTINY-Breast03 study (NCT03529110) revealed no new safety signals to be found with fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with HER2-positive unresectable or metastatic breast cancer.¹

Findings of the DESTINY-Breast03 trial were presented at the 2022 American Society of Clinical Oncology (ASCO)Annual Meeting by lead investigator Erika P. Hamilton, MD, and compared the safety of trastuzumab deruxtecan and trastuzumab emtansine (TDM-1) in this patient population.

In the DESTINY-Breast03 study, patients were randomized in a 1:1 ratio to receive either trastuzumab deruxtecan (n = 257) or T-DM1 (n = 261). At the time of the safety update, the median treatment duration was 16.1 months for trastuzumab deruxtecan vs 6.9 months for T-DM1.²

Data from the safety update showed that a total of 54.9% of patients discontinued trastuzumab deruxtecan vs 85.1% who discontinued T-DM1. The rates of treatment-emergent adverse events (TEAEs), any-grade, grade 3 or higher, or serious AEs, were similar between arms. Any-grade TEAEs were experienced by 99.6% of those given trastuzumab deruxtecan regimen and 95.4% of those treated with T-DM1. Grade 3 or greater TEAEs were experienced by 53.3% and 49.8% for each arm, respectively.¹

Serious TEAEs of any grade were experienced by 21.0% of patients in the trastuzumab deruxtecan arm and 19.2% of those in the T-DM1 arm. Grade 3 or greater serious TEAEs were also seen in 15.2% and 14.6% of patients for each treatment, respectively.

Further, the most common TEAEs of any grade for both treatments included nausea (73.5% vs 27.6%), fatigue (45.9% vs 29.1%), vomiting (44.4% vs 5.7%), neutropenia (43.2% vs 11.5%), alopecia (37.7% vs 2.7%), anemia (31.9% vs 14.2%), leukopenia (30.7% vs 8.0%), decreased appetite (26.5% vs 13.0%), thrombocytopenia (25.3% vs 52.5%), diarrhea (23.7% vs 4.2%), and constipation (23.3% vs 9.6%). Grade 3 or greater drug-related TEAEs that were the most common included neutropenia (19.8% vs 3.1%), thrombocytopenia (7.4% vs 24.9%), leukopenia (6.6% vs 0.8%), nausea (6.6% vs 0.4%), anemia (6.2% vs 4.2%), and fatigue (6.2% vs 0.8%).

In an interview with Targeted Oncology^TM, Hamilton, lead investigator and director of the Breast and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute/Tennessee Oncology, discussed the key takeaways of the updated safety analysis of the DESTINY-Breast03 trial.

Targeted Oncology^TM: Can you discuss what you presented in regard to the DESTINY-Breast03 trial at ASCO this year?

Hamilton: This was the safety update for DESTINY-Breast03. As you recall, trastuzumab deruxtecan was initially approved based on DESTINY-Breast01 [NCT03248492]. DESTINY-Breast03 was a study that brought it up into an earlier-line setting, so patients that had seen trastuzumab and/or a taxane in the metastatic setting or relapsed within 6 months of neoadjuvant or adjuvant therapy. Based on DESTINY-Breast03, trastuzumab deruxtecan got a new expanded indication in earlier-line settings in May 2022.

What has the evolution of trastuzumab deruxtecan looked like over the years?

DESTINY-Breast03 was the trial that really moved trastuzumab deruxtecan into the so-called second-line space. What the safety update aimed to do was to quantify the safety and also look at some special things like exposure-adjusted incidence rates now that we've had longer follow-up for the patients that were receiving trastuzumab deruxtecan. Essentially at this safety update, our patients that are receiving trastuzumab deruxtecan had now been on treatment for a median of 16 months, so quite a while.

What we saw is that grade 3 serious AEs were similar between trastuzumab deruxtecan and T-DM1 at about 53% or 50%, respectively. There were a few more discontinuations of trastuzumab deruxtecan of a little over 14% compared with a little over 7% with T-DM1, but it was largely ILD [interstitial lung disease]/pneumonitis [at] about 8%, that was driving most of those 14% discontinuations for trastuzumab deruxtecan.

This special parameter that we looked at, exposure-adjusted incidence rate, is a new one. It's essentially a measure of risk per patient year that is commonly used to describe the safety in long-term studies where the follow-up duration may differ between the 2 arms. When we looked at serious AEs, grade 3 or greater, with all of these with exposure-adjusted incidence rates, they were lower with trastuzumab deruxtecan compared with T-DM1, except 1. The 1 exception was an AE leading to a treatment discontinuation and, again, it was the ILD/pneumonitis that was driving that.

Finally, if we looked at the time it took to either get to a point where someone needed to be dose reduced, or the drug was needed to be held, both of those parameters were longer with trastuzumab deruxtecan than they were with T-DM1.

Focusing on DESTINY-Breast03, what were the methods used and design of the study?

The methods of the original study were treating patients randomized in a 1:1 fashion to either receive trastuzumab deruxtecan intravenously every 3 weeks or T-DM1 intravenously every 3 weeks. With this updated safety, we were looking at specific parameters that we were interested about [including] nausea, vomiting, alopecia or hair loss, hematologic or blood count parameters. What we saw was nausea and vomiting, as well as alopecia/hair loss, was more common with trastuzumab deruxtecan. It seemed to peak early in initial cycles and then stay about the same throughout the study, not get worse, etc.

Fatigue was very similar between trastuzumab deruxtecan and T-DM1. An important caveat was during DESTINY-Breast03 enrollment, there were no mandatory antiemetics for nausea medicines as part of the protocol. It wasn't until during the study that trastuzumab deruxtecan was recognized as a moderately emetogenic drug. Now a multi-drug nausea regimen is recommended from the very beginning and is included in the trastuzumab deruxtecan label. We hope that now we are doing an even better job of controlling nausea for the patients that are receiving trastuzumab deruxtecan.

Who was the ideal patient being examined in this trial?

As opposed to the plenary [session], where DESTINY-Breast04 [NCT03734029] looked at patients who had HER2-low expression [and unresectable and/or metastatic breast cancer], this was a study of that 15% to 20% of patients with breast cancer who we know have too high [expression]. That's 3+ by immunohistochemistry, or fluorescence in situ hybridization–positive.

This study, opposed to DESTINY-Breast01 that was with very heavily pretreated patients, looked at patients in the so-called second-line setting. They had seen trastuzumab and a taxane in the metastatic setting or relapsed within 6 months of receiving HER2 directed therapy in the neoadjuvant or adjuvant setting.

What safety and efficacy findings were demonstrated in the trial?

The main efficacy finding with DESTINY-Breast03 was reported previously and showed a 72% reduction in the risk of progression, so really outstanding results compared with T-DM1 which previously was our standard in the second-line setting. Again, what we saw was although things like nausea, vomiting, and hair loss were more common with trastuzumab deruxtecan, overall serious events, or grade 3 or greater events, were very similar between the arms.

When we use these exposure adjusted incidence rates to compare how many AEs were happening compared with how long patients could remain on the therapy and continue to get benefit, we saw that, almost across the board, those were lower with trastuzumab deruxtecan than T-DM1.

What are the key takeaways of your research on DESTINY-Breast03?

The big takeaway from the safety update of DESTINY-Breast03 is that we were really quite reassured with the safety parameters. With additional follow-up of these patients that had been on trastuzumab deruxtecan for a median of 16 months, which is really quite a long time, we didn't identify any new safety signals; our pneumonitis rates remained quite low, less than 1% grade 3 and no grade 4 or grade 5 events.

The AEs that are common—like mild nausea, vomiting, etc, with increased recommendations around multi-drug antiemetic regimens—hopefully we're controlling better for the patients in our clinic.

What unmet needs still exist in this space?

There are unfortunately still multiple unmet needs. We are going to continue to bring trastuzumab deruxtecan up into earlier settings, meaning there are ongoing trials in the first-line with trastuzumab deruxtecan as well as both neoadjuvant and adjuvant studies, so studies where patients are in the curative setting. We're excited to see, with how fantastic the results have looked in DESTINY-Breast03, what we might see in earlier lines.

One big remaining question is how do we sequence the drugs we have? If we're conceivably using trastuzumab deruxtecan in the second-line, we have drugs like capecitabine [Xeloda], tucatinib [Tukysa], and trastuzumab that we can use on the third-line. We have T-DM1 that was not previously used in the first- or second-line now. So how do we sequence these and what are the activities of our existing 2 drugs going to be after patients have already seen trastuzumab deruxtecan? We don't have a lot of data on that.

What does this study mean for the future of this space? What do you think we can expect to see down the line?

I think that trastuzumab deruxtecan was a massive win and we're seeing that in HER2-positive breast cancer. We are also seeing it in areas like gastrointestinal cancers, or the ASCO plenary, even patients that have HER2-low breast cancers. I think this provides more excitement for antibody-drug conjugates as a way to get powerful payload or chemotherapy into the cancer cells while trying to spare a lot of the normal body through the antibody-drug conjugate platform.

We know that there are some similar antibody-drug conjugates in terms of platform and structure coming, some HER3 antibody-drug conjugates, a new TROP2 antibody-drug conjugate, as well in some other cancers, such as a CDH6 antibody-drug conjugate that is being looked at in renal cell and ovarian cancer.

References:

1. Hamilton EP, Bragaia VPH, Yeo W, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) unresectable and/or metastatic breast cancer (mBC): Safety follow-up of the randomized, phase 3 study DESTINY-Breast03. J Clin Oncol. 2022;40(suppl 16):1000. doi:10.1200/JCO.2022.40.16_suppl.1000

2. Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022