Dr Bardia on the Limitations of HER2 Testing Assays in HER2-Low and -Ultralow Breast Cancer

Aditya Bardia, MD, MPH, FASCO, professor, Department of Medicine, Division of Hematology/Oncology, Director of Translational Research Integration, the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center, UCLA Health, discusses the need for expanded HER2 testing assays for patients with HER2-low and -ultralow metastatic breast cancer.

Current HER2 immunochemistry (IHC) assays were initially designed to identify high levels of HER2 expression and were not intended to detect low HER2 expression in patients with breast cancer, Bardia begins. Despite this limitation, studies involving fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) have shown efficacy even in tumors with low HER2 expression per IHC testing, Bardia reports. For instance, 

the phase 3 DESTINY-Breast06 trial (NCT04494425)

 included patients with hormone receptor–positive breast cancer that was either HER2-low or -ultralow, he explains.

, results from the primary analysis of the randomized, multicenter, open-label showed that treatment with T-DXd led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with chemotherapy alone in pretreated patients with hormone receptor–positive, HER2-low and -ultralow metastatic breast cancer. Notably, patients with HER2-low disease (n = 359) experienced a median PFS of 13.2 months when treated with the investigational agent compared with 8.1 months for those given investigator’s choice of chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; 

 < .0001). In the intention-to-treat (ITT) population comprised of patients with HER2-low and -ultralow disease, the median PFS was 13.2 months for T-DXd (n = 436) vs 8.1 months for chemotherapy (n = 430; HR, 0.63; 95% CI, 0.53-0.75; 

 <.0001). An exploratory analysis showed that in patients with HER2-ultralow disease, T-DXd (n = 76) generated a median PFS of 13.2 months vs 8.3 months for chemotherapy (n = 76; HR, 0.78; 95% CI, 0.50-1.21).

Although the HER2 IHC assay has been effective in identifying high HER2 expression, the limitations in detecting low HER2 expression highlight the need for improved diagnostic tools, Bardia emphasizes. This raises the question of whether oncologists need better assays, as the current HER2 IHC assay is inadequate for identifying low-expressing tumors, he concludes.

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Aditya Bardia, MD, MPH, FASCO, discusses HER2 IHC testing in patients with HER2-low and -ultralow metastatic breast cancer.

Aditya Bardia, MD, MPH, FASCO, discusses standard first-, second-, and third-line HER2-positive metastatic breast cancer management approaches.  

Dr Bardia on Current Approaches to HER2+ Breast Cancer Management

Aditya Bardia, MD, MPH, FASCO, professor, Department of Medicine, Division of Hematology/Oncology, Director of Translational Research Integration, the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center, UCLA Health, discusses current approaches to the management of HER2-positive breast cancer in the first- or second-line metastatic setting, as well as emerging treatment options in the third line and beyond.

Current first-line treatment approaches for patients with HER2-positive metastatic breast cancer typically involve a taxane along with trastuzumab (Herceptin) and pertuzumab (Perjeta), Bardia begins. After completing approximately 6 to 8 cycles of treatment with the taxane, patients may be able to continue receiving trastuzumab plus pertuzumab alone, he states.

In the second-line setting, the standard of care (SOC) is fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), Bardia continues. This was established in the phase 3 DESTINY-Breast03 trial (NCT03529110), in which T-DXd improved both progression-free survival and overall survival vs the prior second-line SOC, ado-trastuzumab emtansine (Kadcyla; T-DM1). Results from additional studies evaluating T-DXd vs taxane-based regimens are highly anticipated, according to Bardia. In particular, the ongoing phase 3 DESTINY-Breast09 trial (NCT04784715) is assessing the efficacy and safety of T-DXd alone or in combination with pertuzumab vs a taxane plus pertuzumab and trastuzumab in the first-line metastatic setting. This study has the potential to shift the treatment paradigm and establish T-DXd as a preferred first-line therapy for this patient population, Bardia says.

In the third-line setting and beyond, treatment options are less standardized and vary according to physician preference, Bardia notes. Many oncologists will opt for a combination of tucatinib (Tukysa), capecitabine (Xeloda), and trastuzumab, although others may prefer T-DM1 or trastuzumab in combination with other chemotherapy agents, Bardia says. This phase of treatment is also of interest for evaluating novel HER2-directed therapies, including TKIs and antibody-drug conjugates, which are continually being tested and integrated into treatment regimens based on emerging evidence, Bardia concludes.

Aditya Bardia, MD, MPH, FASCO, discusses standard first-, second-, and third-line HER2-positive metastatic breast cancer management approaches.


Dr Curigliano on the Efficacy of T-DXd in HER2-Low and HER2-Ultralow Breast Cancer

Giuseppe Curigliano, MD, PhD, director, Early Drug Development Division, co-chair, Experimental Therapeutics Program, the European Institute of Oncology, discusses key findings from the phase 3 DESTINY-Breast06 trial (NCT04494425) investigating fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in patients with hormone receptor–positive, HER2-low or HER2-ultralow metastatic breast cancer who have received prior endocrine therapy.

DESTINY-Breast06 enrolled 866 patients who were randomly assigned to receive either T-DXd (n = 436) or investigator’s choice of chemotherapy (n = 430). At a median follow-up of 18 months, patients with HER2-low disease who received T-DXd (n = 359) achieved a statistically significant and clinically meaningful progression-free survival (PFS) benefit compared with those who received standard chemotherapy (n = 354), Curigliano says. The median PFS in the HER2-low population was 8.1 months per blinded independent central review with chemotherapy vs 13.2 months with T-DXd (HR, 0.62; 95% CI, 0.51-0.74; 

 < .0001). Furthermore, the median PFS in the intention-to-treat (ITT) population—comprising patients with both HER2-low or -ultralow disease—was 8.1 months with chemotherapy vs 13.2 months with T-DXd (HR, 0.63; 95% CI, 0.53-0.75; 

A trend toward improved overall survival (OS) in the ITT population was observed with T-DXd vs chemotherapy in the landmark 1-year analysis, Curigliano notes. The 12-month OS rates were 81.1% with chemotherapy vs 87.0% with T-DXd (HR, 0.81; 95% CI, 0.65-1.00).

Efficacy outcomes with T-DXd in patients with HER2-ultralow disease were consistent with those seen with the agent in patients with HER2-low disease, Curigliano emphasizes. In the HER2-ultralow population, the median PFS was 8.3 months with chemotherapy (n = 76) vs 13.2 months with T-DXd (n = 76; HR, 0.78; 95% CI, 0.50-1.21). The 1-year OS rates were 78.7% in the chemotherapy arm vs 84.0% in the T-DXd arm (HR, 0.75; 95% CI, 0.43-1.29).

Clinical benefit with T-DXd vs chemotherapy was observed across prespecified subgroups of patients with HER2-low disease, according to Curigliano. The confirmed overall response rate with T-DXd was 57.3% in the ITT population and 61.8% in the HER2-ultralow population. In these respective populations, the clinical benefit rates with T-DXd were 76.6% and 76.3%.

No new safety signals with T-DXd have been observed, Curigliano explains. Notably, any-grade interstitial lung disease was reported in 11.3% of patients who received T-DXd, Curigliano concludes.

Giuseppe Curigliano, MD, PhD, discusses findings from the phase 3 DESTINY-Breast06 trial of T-DXd in HER2-low or HER2-ultralow metastatic breast cancer.

As the role of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) expands for patients with metastatic HER2-positive breast cancer and novel antibody-drug conjugates (ADCs) enter the scene, increasing familiarity with these agents can optimize treatment outcomes and minimize toxicities, according to Aditya Bardia, MD, MPH, FASCO.

“It’s an exciting paradigm in terms of newer therapies that are coming in that are improving survival,” Bardia said in an interview with 

. “Hopefully, we can continue to build on the progress with combinations with ADCs, as well as newer ADCs, so we continuously improve survival and quality of life for patients with metastatic breast cancer.”

In the interview, Bardia discussed the evolving role of T-DXd for patients with HER2-positive advanced breast cancer, considerations for sequencing ADCs, and how the novel designation of HER2-ultralow disease emphasizes the need for more sensitive HER2 tests.

 in 2022 for select adult patients with unresectable or metastatic HER2-positive breast cancer who had previously received HER2-directed therapy, has solidified its role as a standard second-line treatment for this patient population.1 He also commented on findings from the phase 3 DESTINY-Breast06 trial (NCT04494425), which showed that T-DXd elicited a median progression-free survival of 13.2 months (95% CI, 9.8-17.3) and a 12-month overall survival rate of 84.0% in patients with HER2-ultralow metastatic breast cancer (n = 76).

Bardia is a professor in the Department of Medicine in the Division of Hematology/Oncology and the director of Translational Research Integration at the University of California, Los Angeles Jonsson Comprehensive Cancer Center.

: How has the clinical use of T-DXd shifted the treatment paradigm for patients with HER2-positive advanced breast cancer?

: T-DXd has been a transformative medication. It’s a HER2-directed ADC with deruxtecan as the payload and is approved for [patients with] HER2-positive metastatic breast cancer [and those with] HER2-low metastatic breast cancer, both hormone receptor (HR)–positive and HR-negative disease. [The agent] has impressive efficacy in both these groups; the major adverse effects are nausea, pneumonitis, and hair loss. [Using this agent] requires early recognition and management of pneumonitis.

The DESTINY-Breast 06 trial focused on patients with HER2-low and HER2-ultralow metastatic breast cancer. Now that there are many different classifications of HER2 expression, is there a need for improved HER2 testing to better classify these patients beyond simply HER2-positive and HER2-negative?

The HER2 immunohistochemistry [IHC] assay was designed to identify high expressers. It was never designed to identify low expression of HER2 in breast cancer. We’ve seen in different studies that T-DXd works even in low HER2-expressing tumors. DESTINY-Breast06 included patients with HER2-low and HER2-ultralow disease. It begs the question: Do we need better assays? Because the HER2 IHC assay was never designed to identify low-expressing tumors.

Since approximately 85% of patients with metastatic breast cancer could have HER2-ultralow disease, how much of an impact could T-DXd have on the overall breast cancer population?

Possibly even a larger proportion [of patients with metastatic disease could benefit from T-DXd] because there is decent variability among pathologists regarding the HER2-ultralow definition, and it’s a bit subjective. It’s possible we’ll see more reports of HER2-ultralow [disease]. T-DXd could be a medication that’s used regardless of [patients’] biomarker [status], similar to sacituzumab govitecan-hziy [Trodelvy], which is used regardless of patients’ TROP2 expression.

What patient characteristics and disease factors do you consider when choosing a treatment option for patients with HER2-positive disease in the first- or second-line metastatic setting?

At this time, the management for a patient with HER2-positive metastatic breast cancer in the first-line setting includes a taxane plus trastuzumab [Herceptin] and pertuzumab [Perjeta]. Then, after a few cycles of taxanes, usually 6 to 8 cycles, you can stop the taxanes and continue trastuzumab plus pertuzumab. In the second-line setting, [patients receive] T-DXd. That’s the uniform standard for most patients. However, we’re looking forward to additional studies, which are looking at T-DXd in the first-line setting vs taxanes plus trastuzumab and pertuzumab, which could change this workflow.

What treatment options exist in the third line and beyond for patients with HER2-positive disease who have progressed on an ADC?

The third line and beyond is pretty open at this time. Many oncologists use tucatinib [Tukysa] in combination with capecitabine [Xeloda] and trastuzumab. Some oncologists use ado-trastuzumab emtansine [T-DM1; Kadcyla]; some would consider trastuzumab plus other chemotherapy agents. It’s also a setting where newer HER2-directed therapies, such as TKIs and ADCs, are being evaluated.

What ADCs are under investigation in HER2-positive breast cancer that may change the treatment paradigm in the future?

There is a lot of interest in a drug called BB-1701, which is a HER2-directed ADC that has eribulin as the payload. Disitamab vedotin [RC48] is another HER2-directed ADC with a vedotin payload. There is interest in newer ADCs that might target HER2 but with a different payload. We know that works. T-DXd had activity even in patients who had received prior T-DM1, so there’s not complete cross-resistance based on the antibody. If you use a different payload that might show efficacy or activity.

As more ADCs become available, will ADC sequencing become an option?

Absolutely. We do that all the time with chemotherapy. We use 1 chemotherapy after the next. These ADCs allow more delivery of payloads, including chemotherapies, to cancer cells. I do see sequencing of ADCs being an option in the future.

What unmet needs remain for patients with HER2-positive breast cancer that could be addressed with future trials?

Unmet needs for patients with HER2-positive metastatic breast cancer [can be classified into] 3 broad themes. The first is brain metastases. Many patients continue to have morbidity and mortality from brain metastases. We need better agents to control brain metastases.

The second theme relates to understanding the biomarkers governing response and resistance to these agents, so we can more effectively sequence the different agents. Additionally, as the newer HER2-directed ADCs are coming in, [we need to] understand resistance and sequencing.

The third theme, which is a lofty goal but could be achieved, is: Can we combine different drugs to cure metastatic HER2-positive breast cancer? We generally don’t use the term cure for patients with metastatic disease, but I think it’s reasonable, at least to test this in a clinical trial setting, once we identify biomarkers and good combinations, to see if we can [achieve cures] at least for a subset of patients with metastatic HER2-positive breast cancer.

FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Accessed June 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer

Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). 

. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000

Articles

The expanding role of fam-trastuzumab deruxtecan-nxki (T-DXd) in treating metastatic HER2-positive breast cancer, along with the introduction of new antibody-drug conjugates (ADCs), is enhancing survival and quality of life for patients. T-DXd has become a standard second-line treatment, showing significant efficacy even in HER2-ultralow disease. Improved HER2 testing is needed to better classify patients. Future research aims to address brain metastases, understand biomarkers for response and resistance, and explore the potential for curing metastatic HER2-positive breast cancer through combination therapies.

Aditya Bardia, MD, MPH, FASCO, discusses the evolving role of T-DXd for patients with HER2-positive advanced breast cancer.

Advancements in HER2-Directed Therapies Abound for HER2+ Metastatic Breast Cancer 

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) demonstrated sustained improvement in response rates as well as progression-free survival (PFS) and overall survival (OS) vs ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive metastatic breast cancer following prior exposure to trastuzumab (Herceptin) and taxane chemotherapy, according to updated findings from an exploratory analysis of the phase 3 DESTINY-Breast03 trial (NCT03529110) that were presented at the 

The median PFS per investigator assessment was 29.0 months (95% CI, 23.7-40.0) with T-DXd (n = 261) vs 7.2 months (95% CI, 6.8-8.3) with T-DM1 (n = 263; HR, 0.30; 95% CI, 0.24-0.38). The 36-month PFS rates with T-DXd and T-DM1 were 45.7% (95% CI, 38.9%-52.2%) and 12.4% (95% CI, 8.1%-17.7%), respectively. The median investigator-assessed OS was 52.6 months (95% CI, 48.7-not evaluable [NE]) and 42.7 months (95% CI, 35.4-NE) with T-DXd and T-DM1, respectively (HR, 0.73; 95% CI, 0.56-0.94). The 36- and 42-month OS rates with T-DXd were 67.6% (95% CI, 61.3%-73.0%) and 62.5% (95% CI, 56.2%-68.3%), respectively; the respective rates with T-DM1 were 55.7% (95% CI, 49.2%-61.7%) and 50.1% (95% CI, 43.6%-56.2%).

“These data continue to support the use of T-DXd as standard of care in patients with HER2-positive metastatic breast cancer whose disease progressed after trastuzumab and taxane and show the longest OS in this setting,” Erika Hamilton, MD, lead study author and director of breast cancer and gynecologic cancer research at Sarah Cannon Research Institute in Nashville, Tennessee, and coauthors, wrote in the poster presentation.

DESTINY-Breast03 is an open-label, multicenter, phase 3 trial studying the activity and safety of second-line treatment with T-DXd vs T-DM1 in patients with unresectable or metastatic HER2-positive breast cancer. To be eligible for enrollment, patients had to have been previously treated with trastuzumab and taxane chemotherapy in the advanced or metastatic setting. Prior exposure to T-DM1 was not allowed.

Patients were randomized 1:1 to 5.4 mg/kg of T-DXd every 3 weeks or 3.6 mg/kg of T-DM1 every 3 weeks. PFS by blinded independent central review (BICR) served as the primary end point, with secondary end points of OS, objective response rate (ORR) and duration of response (DOR) by BICR as well as ORR, DOR, PFS, and PFS2 per investigator assessment, and safety. Stratification factors included hormone receptor status, prior exposure to pertuzumab (Perjeta), and history of visceral disease.

In prior findings from the first interim analysis of the trial, the median PFS per BICR with T-DXd was not reached vs 6.8 months with T-DM1 (HR, 0.28; 

 <.001), meeting the primary end point of the trial. At the time of the second interim analysis, the median PFS per BICR was 28.8 months with T-DXd vs 6.8 months with T-DM1 (HR, 0.33; nominal 

 <.0001). Moreover, T-DXd led to a statistically significant improvement in OS vs T-DM1 (HR, 0.64; 

Data from the trial served as the basis for the agent’s 

 for patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti–HER2-based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy.

The present analysis was conducted to better understand median OS, the only end point that had not been reached in either treatment arm at the first or second interim OS analysis.

As of the data cutoff date of November 30, 2023, 19.5% of patients in the T-DXd arm and 3.8% of patients in the T-DM1 arm remained on study therapy. The most common reasons for treatment cessation were progressive disease (T-DXd, 41.6%; T-DM1, 70.1%) and adverse effects ([AEs] 23.7%; 9.2%).

“Patient baseline demographics and characteristics were similar in both treatment groups,” the study authors said. “The median age was 54.3 years [range, 27.9-83.1) in the T-DXd group and 54.2 years [range, 20.2-83.0] in the T-DM1 group, and most patients in both groups had a HER2 immunohistochemistry score of 3+ [T-DXd, 89.7%; T-DM1, 88.2%]. Patients had also received a median of 2 prior lines of therapy in the metastatic setting in both treatment groups.”

The median follow-up was 43.0 months (range, 0.0-62.9) in the T-DXd arm and 35.4 months (range, 0.0-60.9) in the T-DM1 arm. The median treatment duration was 18.2 months (range, 0.7-56.6) in the T-DXd arm vs 6.9 months (range, 0.7-55.2) in the T-DM1 arm.

Additional findings indicated that the confirmed investigator-assessed ORR was 78.9% (95% CI, 73.5%-83.7%) with T-DXd vs 36.9% (95% CI, 31.0%-43.0%) with T-DM1. Most patients in both the T-DXd and T-DM1 arms experienced partial responses (T-DXd, 66.3%; T-DM1, 32.7%), although complete responses (12.6%; 4.2%) were also seen. Stable disease occurred in 18.4% and 45.2% of patients in the T-DXd and T-DM1 arms, respectively; progressive disease occurred in 0.8% and 12.9% of patients, respectively, and 1.9% and 4.9% were not evaluable.

The median DOR was 30.5 months (95% CI, 23.0-NE) and 17.0 months (95% CI, 14.1-23.7) with T-DXd and T-DM1, respectively; the 36-month DOR rates were 48.9% (95% CI, 41.3%-56.1%) and 28.7% (95% CI, 18.9%-39.2%), respectively.

In terms of safety, any-grade drug-related treatment-emergent adverse effects (TEAEs) occurred in 98.1% and 87.4% of patients in the T-DXd and T-DM1 arms, respectively. The most frequent events in the T-DXd arm were nausea (77.0%), fatigue (53.3%), and vomiting (52.9%), compared with thrombocytopenia (55.9%), increased transaminases (47.5%), and fatigue (35.2%).

Additionally, exposure-adjusted incidence rates (EAIRs) taking into account differences between treatment durations were consistently lower with T-DXd for any-grade TEAEs (T-DXd, 0.53; T-DM1, 1.10), grade 3 or greater TEAEs (0.31; 0.60), and serious TEAEs (0.15; 0.26).

“Despite longer treatment duration, the safety profile of T-DXd remained manageable, with no cumulative toxicities observed with longer follow-up, and was consistent with the previous analysis,” study authors explained.

Updated safety findings also showed 4 new cases of grade 2 adjudicated drug-related interstitial lung disease (ILD) and pneumonitis with T-DXd and 1 case of grade 1 ILD with T-DM1. One event had not recovered or resolved, 2 had recovered or resolved with sequelae, and 1 recovered or resolved completely. The EAIRs for ILD and pneumonitis were 0.09 with T-DXd and 0.04 with T-DM1. Regarding the time to first ILD and pneumonitis event in the T-DXd arm, 5.4%, 4.6%, 4.2%, and 2.3% of cases occurred within 6 months, between 6 and 12 months, between 12 and 24 months, and after 24 months of the time of diagnosis, respectively.

Regarding subsequent therapy post-trial, of the 80.5% and 96.2% of patients in the T-DXd and T-DM1 arms, respectively, who discontinued study treatment, 69.6% and 78.9% received additional systemic therapy. The remaining 2.9% and 12.6% of patients in the T-DXd arm underwent surgery and radiation, respectively. In the T-DXd arm, subsequent systemic treatments included trastuzumab (39.6%), T-DXd (8.3%), T-DM1 (52.1%), pertuzumab (11.8%), taxane (15.3%), taxane plus trastuzumab (8.3%), other HER2-directed therapy (39.6%: HER2-directed TKI, 36.1%; other HER2-directed antibody or antibody-drug conjugate, 9.0%), hormone therapy (20.1%), or other systemic therapy (69.4%).

The median PFS from the time of randomization to progression on next line of therapy or death per investigator assessment was 45.2 months (95% CI, 39.3-NE) with T-DXd and 23.1 months (95% CI, 17.8-29.7) months with T-DM1 (HR, 0.53; 95% CI, 0.41-0.68).

A sensitivity analysis for OS adjusted for post-trial treatment with T-DXd was also conducted in the T-DM1 arm, revealing a median OS of 39.8 months (95% CI, 32.4-NE) and a hazard ratio of 0.66 (95% CI, 0.51-0.87).

“Results of this long-term follow-up further support previously demonstrated superiority of T-DXd over T-DM1 for the treatment of patients with HER2-positive metastatic breast cancer whose disease progressed after trastuzumab and taxane,” study authors concluded.

Hamilton EP, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated survival results of DESTINY-Breast03. 

. 2024;42(suppl 16):1025. doi:10.1200/JCO.2024.42.16_suppl.1025

FDA D.I.S.C.O. Burst Edition: FDA approval of Enhertu (fam-trastuzumab deruxtecan-nxki) for adult patients with unresectable or metastatic HER2-positive breast cancer. FDA. May 24, 2022. Accessed June 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-enhertu-fam-trastuzumab-deruxtecan-nxki-adult-patients

Trastuzumab deruxtecan. Prescribing information. Daiichi Sankyo; 2024. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761139s028lbl.pdf

Updated findings from the phase 3 DESTINY-Breast03 trial presented at the 2024 ASCO Annual Meeting show that fam-trastuzumab deruxtecan-nxki (T-DXd) significantly improves progression-free survival (PFS) and overall survival (OS) compared to ado-trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxane chemotherapy. T-DXd demonstrated a median PFS of 29.0 months versus 7.2 months with T-DM1, and a median OS of 52.6 months versus 42.7 months with T-DM1. Safety profiles were manageable, with no cumulative toxicities observed.

Trastuzumab deruxtecan improved responses and survival vs T-DM1 in HER2+ metastatic breast cancer after prior exposure to trastuzumab and a taxane.

Second-Line T-DXd Data Remain Strong in HER2+ Metastatic Breast Cancer

Treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with chemotherapy in pretreated patients with hormone receptor–positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]–) metastatic breast cancer, and a consistent PFS benefit was observed in patients with HER2-ultralow disease (IHC 0 with membrane staining), according to data from the primary analysis of the phase 3 DESTINY-Breast06 trial (NCT04494425).

 showed that patients with HER2-low disease treated with the antibody-drug conjugate (ADC; n = 359) experienced a median PFS of 13.2 months per blinded independent central review (BICR) assessment compared with 8.1 months for those given investigator’s choice of chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; 

In the intention-to-treat (ITT) population comprising patients with HER2-low and -ultralow disease, the median PFS was 13.2 months for T-DXd (n = 436) vs 8.1 months for chemotherapy (n = 430; HR, 0.63; 95% CI, 0.53-0.75; 

 <.0001). Patients with HER2-ultralow disease treated with T-DXd (n = 76) achieved a median PFS of 13.2 months compared with 8.3 months for those given chemotherapy (n = 76; HR, 0.78; 95% CI, 0.50-1.21).

“Including HER2-ultralow [disease], the proportion of patients who could benefit from T-DXd will be close to 85% in hormone receptor–positive, HER2-negative breast cancer,” lead study author Giuseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology, said in a presentation of the data.

 for the treatment of patients with unresectable or metastatic HER2-low breast cancer, based on data from the phase 3 DESTINY-Breast04 trial (NCT03734029).

 Notably, that study enrolled patients irrespective of hormone receptor status, and T-DXd was evaluated in an earlier line of treatment in DESTINY-Breast06.

In the multicenter, open-label, randomized DESTINY-Breast06 study, investigators enrolled patients with hormone receptor–positive metastatic breast cancer that was either HER2-low or -ultralow, and patients needed to be naive to chemotherapy in the metastatic setting. Prior treatment requirements included at least 2 lines of endocrine therapy with or without targeted therapy for metastatic breast cancer; or 1 line of treatment in the metastatic setting with either progression within 6 months of beginning first-line treatment with endocrine therapy plus a CDK4/6 inhibitor or recurrence within 24 months of beginning adjuvant endocrine therapy.

Patients were randomly assigned 1:1 to receive 5.4 mg/kg of T-DXd once every 3 weeks or investigator’s choice of chemotherapy consisting of capecitabine (Xeloda; 59.8%), nab-paclitaxel (Abraxane; 24.4%), or paclitaxel (15.8%). Stratification factors included prior CDK4/6 inhibitor use (yes vs no), HER2 expression (low vs ultralow), and prior taxane use in the non-metastatic setting (yes vs no).

BICR-assessed PFS in the HER2-low population served as the trial’s primary end point. Secondary end points included PFS in the ITT population; overall survival (OS) in the HER2-low and ITT populations; investigator-assessed PFS in the HER2-low population; overall response rate (ORR) in the HER2-low and ITT populations; safety; and patient-reported outcomes (PROs). Notably, PFS and OS in the HER2-ultralow population were exploratory end points.

In the ITT population, the median age was 58.0 years (range, 28-87) in the T-DXd arm and 57.0 years (range, 32-83) in the chemotherapy arm. Most patients in the T-DXd arm (57.8%) and chemotherapy arm (59.8%) had an ECOG performance status of 0. HER2 status included IHC 0 with membrane staining (T-DXd, 17.4%; chemotherapy, 17.7%), IHC 1+ (54.8%; 54.4%), and IHC 2+/ISH– (26.8%; 27.4%). Additionally, patients had either estrogen receptor (ER)–positive/progesterone receptor (PR)–positive disease (58.0%; 55.1%), ER-positive/PR-negative disease (38.3%; 42.1%), or ER-negative/PR-positive disease (0.7%; 0.5%).

Primary endocrine resistance at baseline was seen in 29.4% of patients in the T-DXd arm and 32.6% of patients in the chemotherapy arm. In the T-DXd arm, 30.5% of patients had de novo disease at diagnosis, 3.0% had bone-only disease at baseline, 86.2% had visceral disease at baseline, and 67.9% had liver metastases at baseline. Those respective rates were 30.7%, 3.0%, 84.7%, and 65.8% in the chemotherapy arm.

In the ITT population, the median number of lines of endocrine therapy in the metastatic setting was 2.0 (range, 1-4) for the T-DXd group vs 2.0 (range, 1-5) for the chemotherapy group. Specifically, patients received either 1 prior line of endocrine therapy in the metastatic setting (T-DXd, 14.9%; chemotherapy, 19.2%), 2 prior lines of endocrine therapy (67.8%; 67.3%), or at least 3 prior lines of endocrine therapy (17.2%; 13.6%). Notably, 8.5% and 9.3% of patients received first-line endocrine therapy plus a CDK4/6 inhibitor within 6 months of enrollment in the T-DXd and chemotherapy arms, respectively. Prior therapies in the metastatic setting included endocrine therapy alone (52.8%; 51.9%), endocrine therapy plus a CDK4/6 inhibitor (89.0%; 89.5%), and endocrine therapy plus other targeted therapy (32.8%; 29.5%).

In the adjuvant/neoadjuvant setting, prior therapies included endocrine therapy (T-DXd, 63.1%; chemotherapy, 59.5%) and cytotoxic chemotherapy (52.3%; 54.4%), which included a taxane (41.1%; 41.2%) and anthracycline (45.2%; 47.9%).

Among the 436 patients randomly assigned to the T-DXd arm and the 430 assigned to the chemotherapy arm, 99.5% and 97.0% of patients were treated, respectively. At the March 18, 2024, data cutoff and a median follow-up of 18.2 months for the ITT population, 79.5% of patients in the T-DXd arm discontinued study treatment due to progressive disease (57.1%), adverse effects (AEs; 4.4%), patient decision (4.4%), other reasons (3.9%), and death (1.2%). In the chemotherapy arm, 92.8% of patients discontinued study treatment due to progressive disease (70.0%), AEs (9.4%), patient decision (8.2%), protocol noncompliance (0.2%), other reasons (5.0%), and death (1.0%).

At data cutoff, OS data were only 40% mature. Second interim and final OS analyses will be performed at approximately 56% and 74% maturity, respectively.

Data from the primary analysis showed OS trends favoring T-DXd in the HER2-low population (HR, 0.83; 95% CI, 0.66-1.05; 

 = .1181) and ITT population (HR, 0.81; 95% CI, 0.65-1.00). Patients in the HER2-low population treated with T-DXd experienced a 12-month OS rate of 87.6% compared with 81.7% for those given chemotherapy. The 12-month OS rates were 87.0% and 81.1% in the ITT population for T-DXd and chemotherapy, respectively. Notably, 20.1% of patients in the HER2-low population who received chemotherapy were given T-DXd following treatment discontinuation. This rate was 17.9% in the ITT population.

An OS trend favoring T-DXd was also observed in the HER2-ultralow population (HR, 0.75; 95% CI, 0.43-1.29). The 12-month OS rates were 84.0% and 78.7% for T-DXd and chemotherapy, respectively.

A subgroup analysis of the HER2-low population showed that the PFS benefit for T-DXd was observed across all prespecified subgroups.

Additional data showed patients in the HER2-low population treated with T-DXd experienced a confirmed ORR of 56.5%, including a complete response (CR) rate of 2.5%, a partial response (PR) rate of 54.0%, and a stable disease (SD) rate of 34.8%, compared with an ORR of 32.2% for those given chemotherapy. The respective CR, PR, and SD rates for chemotherapy were 0%, 32.2%, and 48.0%. The clinical benefit rate (CBR) was 76.6% for T-DXd and 53.7% for chemotherapy, and the median duration of response (DOR) was 14.1 months and 8.6 months, respectively.

In the ITT population, those administered T-DXd experienced a confirmed ORR of 57.3%, including a CR rate of 3.0%, a PR rate of 54.4%, and a SD rate of 33.9%, compared with an ORR of 31.2% for those given chemotherapy. The respective CR, PR, and SD rates for chemotherapy were 0%, 31.2%, and 49.3%. The CBR was 76.6% for T-DXd and 51.9% for chemotherapy, and the median DOR was 14.3 months and 8.6 months, respectively.

For patients with HER2-ultralow disease, the confirmed ORR was 61.8% for T-DXd and 26.3% for chemotherapy. The CR, PR, and SD rates were 5.3%, 56.6%, and 28.9% for T-DXd, respectively. Those respective rates were 0%, 26.3%, and 55.3% for chemotherapy. The CBR was 76.3% for T-DXd and 43.4% for chemotherapy, and the respective median DORs were 14.3 months and 14.1 months.

Regarding safety for all treated patients, any-grade treatment-emergent AEs (TEAEs) occurred in 98.8% of patients given T-DXd (n = 434) and 95.2% of patients given chemotherapy (n = 417). Treatment-related TEAEs (TR-TEAEs) were reported in 96.1% of patients administered T-DXd and 89.4% of those given chemotherapy. The rates of grade 3 or higher TR-TEAEs were 40.6% and 31.4%, respectively, and the respective rates of serious TEAEs were 20.3% and 16.1%.

In the T-DXd arm, the rates of TEAEs associated with treatment discontinuation, dose interruptions, and dose reductions were 14.3%, 48.4%, and 24.7%, respectively. Those respective rates were 9.4%, 38.4%, and 38.6% in the chemotherapy arm. TEAEs led to death in 2.5% of patients in the T-DXd arm vs 1.4% of patients in the chemotherapy arm. Notably. TR-TEAEs led to death in 1.2% of patients in the experimental arm and 0% of patients in the chemotherapy arm, per investigator assessment.

The median treatment duration was 11.0 months (range, 0.4-39.6) for T-DXd and 5.6 months (range, 0.1-35.9) for chemotherapy. The most common TEAE associated with treatment discontinuation was pneumonitis (5.3%) in the T-DXd arm and peripheral sensory neuropathy (1.4%) in the chemotherapy arm. The most common TEAE linked to dose reduction was nausea (4.4%) for T-DXd and palmar-plantar erythrodysesthesia (PPE; 16.5%) for chemotherapy.

Any-grade TR-TEAEs reported in at least 20% of patients in either arm included nausea (T-DXd, 65.9%; chemotherapy, 23.5%), fatigue (46.8%; 34.3%), alopecia (45.4%; 19.4%), neutropenia (37.6%; 27.6%), increased aminotransaminases (29.3%; 11.0%), anemia (28.1%; 19.4%), vomiting (27.2%; 9.4%), diarrhea (23.7%; 22.5%), decreased appetite (23.5%; 9.4%), leukopenia (23.3%; 14.6%), and PPE (0.5%; 32.4%).

Any-grade interstitial lung disease (ILD)/pneumonitis occurred in 11.3% of patients treated with T-DXd, including grade 1 (1.6%), grade 2 (8.3%), grade 3 (0.7%), and grade 5 (0.7%). Only 1 instance of ILD/pneumonitis (grade 2) was reported in the chemotherapy arm. Any-grade decreased left ventricular ejection fraction was reported in 8.1% of patients in the T-DXd arm and 2.9% of patients in the chemotherapy arm. For T-DXd, patients experienced grade 1 (0.2%), grade 2 (7.1%), and grade 3 (0.7%) decreased left ventricular ejection fraction. Those respective rates were 0% for grade 1, 2.6% for grade 2, and 0.2% for grade 3.

Cardiac failure was not reported in any patients in the T-DXd arm. For the chemotherapy arm, 0.7% of patients experienced any-grade cardiac failure, including 0.2% each for grades 2 through 4.

Curigliano noted that clinical validation of diagnostics and cutoffs for HER2-ultralow disease will be needed in the future. Investigators will also conduct additional subgroup analyses, biomarker and translational analyses, and a PRO analysis in the future.

In a discussion of the abstract, Ian Krop, MD, PhD, a professor of internal medicine (medical oncology), director of the Clinical Trials Office, chief clinical research officer, and associate director of Clinical Sciences at Yale Cancer Center in New Haven, Connecticut, explained the importance of improving the sensitivity of HER2 testing for patients with breast cancer.

“Current IHC testing is relatively poor at distinguishing HER2-low and -ultralow cancers from HER2 0 cancers,” Krop said. “There are probably multiple reasons for this, but an important one is that the original test was designed to distinguish high levels of HER2 [IHC 3+] from all the lower levels. It was not designed to distinguish the very low levels to the even lower or 0 cancers.”

: Dr Curigliano reported serving as leadership for ESMO, ESMO Open, and the European Society of Breast Cancer Specialists; receiving honoraria from Ellipses Pharma; serving in a consulting or advisory role for AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celcuity, Daiichi Sankyo, Exact Sciences, Foundation Medicine, Gilead Sciences, GlaxoSmithKline, Guardant Health, Hengrui Therapeutics, Lilly, Menarini, Merck, Novartis, Pfizer, Roche/Genentech, Samsung, Seagen, and Veracyte; being a member of the speakers’ bureau for AstraZeneca, Daiichi Sankyo, Exact Sciences, Foundation Medicine, Gilead Sciences, Lilly, Menarini, Novartis, Pfizer, Roche/Genentech, Samsung, and Seagen; receiving institutional research funding from Merck; and receiving travel expenses from AstraZeneca, Daichii Sankyo, Pfizer, and Roche/Genentech.

FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed June 2, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-low-breast-cancer

Treatment with fam-trastuzumab deruxtecan-nxki (T-DXd) significantly improved progression-free survival (PFS) compared to chemotherapy in pretreated patients with hormone receptor-positive, HER2-low, and HER2-ultralow metastatic breast cancer, as demonstrated in the phase 3 DESTINY-Breast06 trial. The study showed a median PFS of 13.2 months for T-DXd versus 8.1 months for chemotherapy. Secondary endpoints, including overall survival (OS) and overall response rate (ORR), also favored T-DXd. Safety profiles indicated higher rates of treatment-emergent adverse events (TEAEs) in the T-DXd arm.

Trastuzumab deruxtecan improved PFS vs chemotherapy in pretreated, HR-positive, HER2-low or -ultralow metastatic breast cancer.

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