Trastuzumab Deruxtecan Outperforms Standard of Care in Second-line HER2+ Breast Cancer

Heather McArthur, MD, MPH

The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu) continues to shake up the treatment landscape for patients with HER2positive metastatic breast cancer with the latest FDA approval solidifying its role as a second-line option.¹

Data from the DESTINY-Breast03 trial (NCT03529110) supported the approval. In DESTINY-Breast03, investigators evaluated trastuzumab deruxtecan in 261 patients vs standard-of-care ado-trastuzumab emtansine (T-DM1; Kadcyla) in 263 patients, all of whom were previously treated with trastuzumab (Herceptin) and taxane therapy. The median progression-free survival (PFS) was not reached (95% CI, 18.5not estimable) with trastuzumab deruxtecan vs 6.8 months (95% CI, 5.6-8.2) T-DM1 (HR, 0.28; 95% CI, 0.22-0.37; P < .0001).^1,2

Median overall survival (OS) was not estimable in either treatment arm, with 94.1% (95% CI, 90.3%-96.4%) of patients in the investigative arm alive at 1 year vs 85.9% (95% CI, 80.9%-89.7%) of patients in the control arm (HR, 0.55; 95% CI, 0.36-0.86; P < .007). Among patients with stable brain metastases who received trastuzumab deruxtecan (n = 62), the median PFS was 15.0 months (95% CI, 12.6-22.2) vs 5.7 months (95% CI, 2.9-7.1) with T-DM1 (n = 52; HR, 0.38; 95% CI, 0.23-0.64).³

“It’s an exciting time to be treating breast cancer with these novel agents,” Heather McArthur, MD, MPH, said in an interview with OncologyLive^®. “These are not small, incremental improvements and outcomes that we’re describing. We’re describing huge improvements in PFS and, in my [opinion], more importantly, OS. Life expectancy [for patients] with metastatic disease has completely evolved now from where we were even 5 years ago.”

In our discussion, McArthur, the Komen Distinguished Chair in Clinical Breast Cancer Research, an associate professor in the Department of Internal Medicine, and clinical director of the Breast Cancer Program at Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center in Dallas, Texas, described how the data from DESTINY-Breast03 reshapes the treatment landscape and offers added benefit to patients with brain metastases.

OncologyLive®: Please discuss the top takeaways from the DESTINY-Breast03 trial.

McArthur: [The data were a] game-changer in DESTINY-Breast03. Trastuzumab deruxtecan went head-to-head with T-DM1, which was an established standard of care based on the EMILIA [NCT00829166] data. Investigators have reported an improvement in PFS, which was the primary end point for [DESTINY-Breast03], with a hazard ratio of 0.28, which is an unprecedented improvement in PFS.

Specifically, the 12-month PFS [rate] was approximately 76% vs 34% with T-DM1. One of the secondary end points [investigators] looked at was OS, which had a hazard ratio approaching 0.5, indicating an approximately 50% reduction in risk of death in favor of trastuzumab deruxtecan. So you can see that [these data] were a total game changer—with the benefit being observed in all subgroups. [Trastuzumab deruxtecan] really became a new standard in the second line [and] very firmly sets it in the second-line setting. T-DM1 is an excellent drug and can be used later on.

We’ve had a number of drugs approved in this space, including the tucatinib [Tukysa] [plus trastuzumab and capecitabine] regimen, [and it] is really an exciting time to have all these tremendous options [available].

What stood out in the DESTINY-Breast03 data specifically for patients with brain metastases?

[The trial] allowed patients with clinically stable treated brain metastases to participate. Approximately a quarter of patients on study met that criterion. Patients were allowed to enroll if they had completed whole brain radiation at least 2 weeks prior to enrollment. [The trial] also at one point allowed for [patients with] stable untreated brain metastasis [to enroll] until an amendment was undertaken and changed some of the eligibility criteria.

The PFS benefits observed in the intention-to-treat population were maintained in the population who had brain metastasis. In a comparison of the Kaplan-Meier curves for those who had brain metastases vs those who did not, the hazard ratios were almost identical.

With regard to interstitial lung disease [ILD], how did investigators address and manage these adverse effects vs prior trials?

In DESTINY-Breast01 [NCT03248492], which was the initial single-arm study looking at trastuzumab deruxtecan, there were, unfortunately, some fatal cases of ILD. On that study scans were completed approximately every 9 weeks. In DESTINY-Breast03, [scans were completed at] a more conservative interval of [every] 6 weeks.

There was [also] heightened awareness [among] the community about the potential complication of ILD, and there was some clear guidance for [managing this adverse effect] in DESTINY-Breast03. For example, with grade 1 [incidence], which is asymptomatic radiographic ILD, [the direction] is to hold the drug until resolution. I think the more frequent scanning permitted greater detection of ILD in that grade 1 category and allowed for intervention earlier on. And so, fortunately, although approximately 10% of patients experienced ILD, none of the cases were grade 4 or 5; none were serious or fatal.

What are the next steps for trastuzumab deruxtecan? Could there be a role for this agent in the frontline setting?

There are some interesting data indicating that [agents such as trastuzumab deruxtecan] may be particularly effective in treatment-resistant disease, which is why [in] that second line and that residual disease setting this type of agent might be so impactful. [The] DESTINY-Breast05 trial [NCT04622319] is evaluating trastuzumab deruxtecan vs T-DM1 in patients with high-risk residual early-stage breast cancer after receiving neoadjuvant HER2-directed therapy.

Additionally, an anticipated trial [in the frontline setting] based on the head-to-head trial [in metastatic disease] will seek to demonstrate benefit in favor of trastuzumab deruxtecan. One could see that agent then moving on to the up-front setting for [early-stage disease], displacing some of the conventional cytotoxic therapy [regimens] we typically see that often use a taxane, a platinum agent, or sometimes an anthracycline. I think those would be studies to anticipate.

My hope is that... these novel antibody-drug conjugates will [continue to have] successful application to allow for better outcomes for our patients with less toxicity and that we might be able to, at [some] point, de-escalate [treatment] so that cytotoxic chemotherapy is no longer indicated.

References

1. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. Updated May 11, 2022. Accessed May 12, 2022. bit.ly/3M7mgnH
2. Enhertu. Prescribing information. Daiichi Sankyo Inc; 2022. Accessed May 12, 2022. bit.ly/37GA6OE
3. Cortés J, Kim SB, Chung WP, et al; DESTINY-Breast03 Trial Investigators. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;38(12):1143-1154. doi:10.1056/NEJMoa2115022