Trastuzumab deruxtecan for HER2-low breast cancer: A treatment for a new population

Trastuzumab deruxtecan led to greater survival outcomes than chemotherapy treatment of physician’s choice (TPC)* in patients with HER2-low** advanced breast cancer, according to results of a phase III trial presented at ASCO 2022.

“In the DESTINY-Breast04 trial, we demonstrate, for the first time, that a HER2-targeted therapy, trastuzumab deruxtecan, produces statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) for patients with HER2-low metastatic breast cancer (MBC),” presented lead author Associate Professor Shanu Modi from the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, US.

Participants in this multinational, open-label trial were 557 patients (median age 56–58 years) with HER2-low unresectable and/or MBC with exposure to one or two prior lines of chemotherapy and ECOG performance status 0 or 1. They were randomized 2:1 to receive trastuzumab deruxtecan (5.4 mg/kg Q3W) or TPC.

A majority of the patients (88.7 percent; n=494) had hormone receptor-positive (HR+) disease. The patients were followed up for a median 18.4 months, with 58 and three patients in the trastuzumab deruxtecan and TPC group, respectively, still on treatment at data cut-off. The most utilized chemotherapy agent in the TPC group was eribulin (51.1 percent). About 70 percent of patients had prior exposure to CDK4/6 inhibitors.  

Among HR+ patients, the risk of progression or death was almost halved among patients in the trastuzumab deruxtecan compared with the TPC group (median PFS 10.1 vs 5.4 months; hazard ratio [HR], 0.51, 95 percent confidence interval [CI], 0.40–0.64; p<0.0001). [ASCO 2022, abstract LBA3; N Engl J Med 2022;doi:10.1056/NEJMoa2203690]

Similar results were observed in the overall population (median PFS 9.9 vs 5.1 months; HR, 0.50, 95 percent CI, 0.40–0.63; p<0.0001).

The PFS benefits in the HR+ population were generally consistent across all subgroups analysed including age, ECOG performance status, presence of visceral disease at baseline, prior exposure to CDK4/6 inhibitors, number of prior lines of chemotherapy, and IHC status.

Overall survival (OS) was also significantly improved with trastuzumab deruxtecan vs TPC, both in the HR+ population (median 23.9 vs 17.5 months; HR, 0.64, 95 percent CI, 0.48–0.86; p=0.0028) and in the overall population (median 23.4 vs 16.8 months; HR, 0.64, 95 percent CI, 0.49–0.84; p=0.0010).

Exploratory analysis showed that the benefits of trastuzumab deruxtecan over TPC were consistent in the HR-negative population (PFS: median 8.5 vs 2.9 months; HR, 0.46; OS: median 18.2 vs 8.3 months; HR, 0.48).

Objective response rate was greater with trastuzumab deruxtecan than TPC in both the HR+ (52.6 percent vs 16.3 percent) and HR-negative (50.0 percent vs 16.7 percent) populations. In the HR+ group, complete response (CR) was achieved in 3.6 percent [trastuzumab deruxtecan] vs 0.6 percent [TPC] and partial response (PR) in 49.2 percent vs 15.7 percent. In the HR-negative group, CR and PR were achieved in 2.5 percent vs 5.6 percent and 47.5 percent vs 11.1 percent, respectively.

Fewer patients in the trastuzumab deruxtecan than TPC group experienced progressive disease, be it in the HR+ (7.8 percent vs 21.1 percent) or HR-negative (12.5 percent vs 33.3 percent) populations. Duration of response was also longer in the trastuzumab deruxtecan than TPC group in the HR+ (10.7 vs 6.8 months) and HR-negative (8.6 vs 4.9 months) populations.

 

Consistent safety

Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 53 and 67 percent of trastuzumab deruxtecan and TPC recipients, respectively, with a comparable rate of serious TEAEs (28 percent vs 25 percent). TEAEs were associated with dose discontinuations in 16 percent vs 8 percent, dose interruptions in 39 percent vs 42 percent, dose reductions in 23 percent vs 38 percent, and deaths in 4 percent vs 3 percent.

The most common grade ≥3 drug-related TEAEs in the trastuzumab deruxtecan group were neutropenia, anaemia, and fatigue (14, 8, and 8 percent, respectively), while the most common in the TPC group were neutropenia and leukopenia (41 and 19 percent, respectively). The most common TEAEs associated with treatment discontinuation were interstitial lung disease (ILD)/pneumonitis in the trastuzumab deruxtecan group (8.2 percent) and peripheral sensory neuropathy in the TPC group (2.3 percent), while the most common associated with dose reduction were nausea and fatigue for trastuzumab deruxtecan (4.6 percent) and neutropenia for TPC (14.0 percent).

“Lung toxicity is an important toxicity of trastuzumab deruxtecan and requires awareness, vigilance, and early intervention,” Modi pointed out.

In terms of grade ≥3 AEs of special interest, there were five grade 3 and three grade 5 events of drug-related ILD/pneumonitis with trastuzumab deruxtecan and one grade 1 event with TPC. There was one grade 3 event each of decreased ejection fraction and cardiac failure in the trastuzumab deruxtecan group.

Patients in the trastuzumab deruxtecan and TPC group were treated for a median 8.2 and 3.5 months, respectively.

“In general, there were no new safety signals for trastuzumab deruxtecan in this HER2-low population [and] the overall safety profile was consistent with other studies,” said Modi.

 

Filling a treatment gap, establishing a new patient population

“Approximately 60 percent of HER2-negative MBC express low levels of HER2,” said Modi and co-authors. As currently available treatments for HER2-positive breast cancer do not improve clinical outcomes in these patients, they are treated as HER2-negative patients.

“Ultimately, all patients with HER2-low MBC, both HR+ and negative, have limited options in the late-line setting and are typically treated with palliative single-agent chemotherapy. This offers only modest benefits. Hence, there is a substantial need for more effective therapies,” Modi said.

“With these results, we have expanded the benefits of HER2-targeted therapy to a new population of breast cancer patients and have established trastuzumab deruxtecan as the new standard of care (SoC) for patients with HER2-low MBC,” announced Modi.

“These findings have the potential to impact survival for approximately 50 percent of all patients diagnosed with MBC today,” she said.

“By effectively creating a new category of breast cancer, HER2-low, this trial will redefine how we classify breast cancer and will significantly expand the population of patients who can benefit from HER2-targeted therapy,” commented ASCO Expert in breast cancers, Associate Professor Jane Lowe Meisel from the Emory University School of Medicine, Atlanta, Georgia, US, who was unaffiliated with the study.

 

On the home front

In Asian populations (including Singapore), recent published data from the Asian Breast Cancer Cooperative Group (ABCCG) show a HER2-low breast cancer prevalence of approximately 43 percent which is consistent with international estimates of 45–55 percent. [BMC Med 2022;20:105; J Clin Oncol 2020;38:1951-1962]

“The results of DESTINY-Breast04 show that even in heavily pre-treated metastatic HER2-low patients who have seen an average of three lines of prior therapies, trastuzumab deruxtecan still gives significant and clinically meaningful benefits of approximately 10 months of PFS and almost 2 years of OS. There was an almost 7-month survival difference compared with the group who received current standard therapies,” said Clinical Assistant Professor Ryan Shea Tan Ying Cong, a consultant at the Division of Medical Oncology, National Cancer Centre Singapore, who was not affiliated with the current study.

“This is a new SoC and will have a significant impact affecting a large proportion of MBC patients with HER2-low breast cancer,” he noted.

“In addition, there are many ongoing clinical studies testing trastuzumab deruxtecan in other settings of early- to late-stage HER2-low breast cancer which could extend this benefit to more patients. This includes the DESTINY-Breast05 and DESTINY-Breast06 trials which are ongoing in Singapore,” Tan pointed out.