Silas Inman

Fam-trastuzumab deruxtecan-nxki (Enhertu) can be considered a new standard-of-care option for patients with HER2-low, hormone receptor–positive metastatic breast cancer (MBC) due to improved progression-free survival (PFS) outcomes reported from the phase 3 DESTINY-Breast04 study (NCT03734029), according to data presented at the 

2022 American Society of Clinical Oncology (ASCO) Annual Meeting

In those with hormone receptor–positive, HER2-low MBC, which was the population explored for the primary end point of the study, trastuzumab deruxtecan elicited a median PFS of 10.1 months (95% CI, 9.5-11.5) compared with 5.4 months (95% CI, 4.4-7.1) for chemotherapy (HR, 0.51; 95% CI, 0.40-0.64; 

 < .0001). The median overall survival (OS) was 23.9 months (95% CI, 20.8-24.8) with trastuzumab deruxtecan compared with 17.5 months (95% CI, 15.2-22.4) for chemotherapy (HR, 0.64; 95% CI, 0.40-0.86; 

 = .003). Fewer grade 3 or greater adverse events (AEs) were reported with the antibody-drug conjugate trastuzumab deruxtecan compared with chemotherapy 52.6% and 67.4% of patients, respectively.

“Trastuzumab deruxtecan is the first HER2-targeted therapy to demonstrate statistically significant and clinically meaningful improvement in PFS and OS compared [with] standard chemotherapy for patients with HER2-low metastatic breast cancer,” said lead author Shanu Modi, MD, who is a medical oncologist at Memorial Sloan Kettering Cancer Center. “The benefits of trastuzumab deruxtecan were seen across subgroups, including the hormone receptor–positive and –negative patients and [immunohistochemistry] IHC 1+ and 2+ breast cancers.”

In the DESTINY-Breast04 study, 557 patients were randomly assigned 2:1 to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 373) or physician’s choice of chemotherapy at locally approved dosing (n = 184). Chemotherapy consisted of capecitabine (Xeloda; 20.1%), eribulin (Halaven; 51.1%), gemcitabine (10.3%), paclitaxel (8.2%), or nab-paclitaxel (Abraxane; 10.3%).

Low expression of HER2 was defined as an IHC score of 1+ or 2+ with a negative in situ hybridization (ISH) test, which represents approximately 65% of breast cancer diagnoses, Modi noted. Overall, 88.7% of patients were hormone receptor–positive and 11.3% were negative.

“Our currently available HER2-targeted therapies have not been effective for patients in this subgroup. We currently treat [patients with] HER2-low breast cancer as HER2-negative breast cancer, where therapy is really guided by hormone receptor status,” Modi said. “Ultimately, once we’ve exhausted endocrine therapy and a few lines of targeted agents, we have limited late-line options available for these patients, most commonly offering palliative single-agent chemotherapy, which has modest activity. We have a big unmet need for more effective therapies.”

Patient characteristics were balanced between each arm and representative of the overall population of patients with HER2-negative breast cancer. In the trastuzumab deruxtecan arm, the median age of patients was 57.5 years (range, 31.5-80.2) and 99.5% were female. HER2-low was IHC 1+ for 57.6% of patients and IHC 2+ and ISH-negative for 42.4%. ECOG performance status was split between 0 (53.6%) and 1 (46.4%). The primary locations of metastases were the brain (6.4%), liver (71.3%), and lung (32.2%). Patients had received a median of 3 (range, 1-9) prior lines of therapy, which consisted of targeted or immunotherapy (74.8%), endocrine therapy (93.0%), and chemotherapy (100%).

Across all patients enrolled in the study, the median PFS was 9.9 months (95% CI, 9.0-11.3) with trastuzumab deruxtecan compared with 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63). The median OS in this group was 23.4 months (95% CI, 20.0-24.8) with trastuzumab deruxtecan compared with 16.8 months (95% CI, 14.5-20.0) for chemotherapy, representing a 6.6-month improvement in survival with the agent (HR, 0.64; 95% CI, 0.49-0.84; 

In those with hormone receptor–negative disease, the median PFS was 8.5 months (95% CI, 4.3-11.7) with trastuzumab deruxtecan and 2.9 months (95% CI, 1.4-5.1) for chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). The median OS in the hormone receptor–negative cohort was 18.2 months (95% CI, 13.6-not estimable) with trastuzumab deruxtecan vs 8.3 months (95% CI, 5.6-20.6) with chemotherapy (HR, 0.48; 95% CI, 0.24-0.95).

Across all patients, the overall response rate (ORR) was 52.3% (95% CI, 47.1%-57.4%) with trastuzumab deruxtecan compared with 16.3% (95% CI, 11.3%-22.5%) with chemotherapy. In the hormone receptor–negative arm, the ORRs were 50.0% (95% CI, 33.8%-66.2%) and 16.7% (95% CI, 3.6%-41.4%) for trastuzumab deruxtecan (n = 40) and chemotherapy (n = 18), respectively.

In those with hormone receptor–positive disease, the ORR was 52.6% (95% CI, 47.0%-58.0%) for trastuzumab deruxtecan (n = 333) vs 16.3% (95% CI, 11.0%-22.8%) for chemotherapy (n = 166). In this group, the median duration of response was 10.7 months with trastuzumab deruxtecan compared with 6.8 months for physician's choice.

Trastuzumab deruxtecan demonstrated a consistent improvement in PFS across subgroups. For patients with hormone receptor–positive disease, those with a HER2 IHC score of 1+ had a median PFS of 10.3 months (95% CI, 8.6-12.3) with trastuzumab deruxtecan compared with 5.3 months (95% CI, 4.1-7.8) with chemotherapy (HR, 0.48; 95% CI, 0.35-0.65). Among individuals with hormone receptor–positive HER2 IHC 2+ and ISH-negative disease, the median PFS was 10.1 months (95% CI, 8.2-12.2) for trastuzumab deruxtecan and 5.9 months (95% CI, 4.3-7.9) for chemotherapy (HR, 0.55; 95% CI, 0.38-0.80).

In patients with hormone receptor–positive disease who received prior treatment with a CDK4/6 inhibitor, the median PFS was 10.0 months (95% CI, 8.3-11.4) with trastuzumab deruxtecan compared with 5.4 months (95% CI, 4.0-7.8) for chemotherapy (HR, 0.55; 95% CI, 0.42-0.73). For those with hormone receptor–positive disease who did not receive a CDK4/6 inhibitor, the median PFS was 11.7 months (95% CI, 9.5-17.7) with trastuzumab deruxtecan compared with 5.9 months (95% CI, 4.3-8.2) for chemotherapy (HR, 0.42; 95% CI, 0.28-0.64).

“Overall, these results establish HER2-low metastatic breast cancer as a targetable population with trastuzumab deruxtecan as a new standard of care in this setting,” Modi said.

At the time of the cutoff, the median treatment duration was 8.2 months for trastuzumab deruxtecan and 3.5 months for chemotherapy. Adverse events led to treatment discontinuation for 16.2% of patients in the trastuzumab deruxtecan arm compared with 8.1% for chemotherapy. Dose reductions were required due to an AE for 22.6% of patients in the trastuzumab deruxtecan group vs 38.4% for chemotherapy.

Treatment-emergent adverse events (TEAE) were experienced by 99.5% of those in the trastuzumab deruxtecan arm compared with 98.3% of those treated with physician’s choice of therapy. Exposure adjusted AE rates were 1.30 per patient year for trastuzumab deruxtecan and 2.66 for physician’s choice of chemotherapy. Serious AEs occurred in 27.8% of patients treated with trastuzumab deruxtecan and for 25.0% with physician’s choice.

The most frequently observed treatment-related AEs for trastuzumab deruxtecan and chemotherapy, respectively, were nausea (73% vs 23.8%), fatigue (47.7% vs 42.4%), skin and subcutaneous tissue disorders, including alopecia (37.7% vs 32.6%), vomiting (34% vs 9.9%), neutropenia (33.2% vs 51.2%), and anemia (33.2% vs 22.7%).

There were 14 drug-related deaths with trastuzumab deruxtecan (3.8%) compared with 5 for physician’s choice of therapy (2.9%). Adjudicated interstitial lung disease (ILD)/pneumonitis occurred in 45 patients treated with trastuzumab deruxtecan (12.1%), with 5 patients having a grade 3 event and 3 having a grade 5 event.

“The drug has been in use now for a couple years and I think we have all gotten a little more comfortable, first responding to pulmonary symptoms more quickly and also how to manage it,” said Julie R. Gralow, MD, FACP, FASCO, chief medical officer and executive vice president of ASCO, and previously director of Breast Medical Oncology at the Seattle Cancer Care Alliance. “I think it was much more of a concern a couple of years ago and now we have learned how to be more aware and to act quickly.”

In December 2019, the FDA granted an accelerated approval to trastuzumab deruxtecan for adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting. This accelerated approval was transitioned to a full regulatory approval on May 4, 2022. The prescribing information includes a box warning on the risk of ILD.

The efficacy of trastuzumab deruxtecan in HER2-low could be derived from the unique 8:1 ratio of antibody (trastuzumab) to toxic payload, which consists of a topoisomerase I inhibitor. “This is a new generation antibody-drug conjugate, and that is because it has some advanced pharmaceutical properties compared [with] other HER2 therapies,” Modi said. “The most unique thing is the high payload linked to each antibody. It is twice as much as T-DM1 [ado-trastuzumab emtansine; Kadcyla]. The payload itself is unique and novel, it is a topoisomerase I inhibitor, which is not a type of chemotherapy we usually use in breast cancer.”

“The linker technology is also very different from T-DM1, it is a cleavable linker,” she added. “When the linker is cleaved it releases the chemotherapy payload in a way that the chemotherapy retains memory permeability and now it can pass through the HER2-positive cell and into the microenvironment and has the ability to penetrate other cells in the neighboring area that may not express HER2. It offers a broader range of activity in heterogenous situations, and we know HER2 expression [in breast cancer] is very heterogenous. I think that is why, for the first time, we’re seeing activity for a HER-targeted agent.”

Several clinical trials are exploring trastuzumab deruxtecan for patients with breast cancer and other malignancies. The DESTINY-Breast05 study (NCT04622319) is comparing the agent with T-DM1 for those with residual invasive breast cancer following neoadjuvant therapy. Additionally, arm 6 of the BEGONIA study (NCT03742102) is exploring the treatment for patients with triple-negative breast cancer in combination with the PD-L1 inhibitor durvalumab (Imfinzi).

Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. 

. 2022;40 (suppl 17):abstr LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3

Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. 

. Published online June 5, 2022. doi:10.1056/NEJMoa2203690

This article originally appeared on Cancer Network®. 

Articles

The phase 3 DESTINY-Breast04 trial using fam-trastuzumab deruxtecan-nxki showed a reduction in the risk of disease recurrence or death for patients with HER2-low, hormone receptor–positive metastatic breast cancer.

Trastuzumab deruxtecan doubles PFS in HER2-low metastatic breast cancer

Results of the prospective LUMINA study (NCT01791829) revealed that patients older than 55 years with low-grade, T1N0, luminal A breast cancer and Ki67 expression at or below 13.25% can forgo radiotherapy after breast conserving surgery without risking higher rates of disease recurrence, according to a presentation at the 

In the single-arm, cohort study, radiotherapy was omitted from treatment for 500 women with low-risk luminal A breast cancer. After 5 years, there were only 10 local recurrences, for a cumulative local recurrence risk rate of 2.3% (90% CI, 1.3%-3.8%), which was below the cutoff for significance of 5%. The overall survival rate at 5 years was 97.2% (90% CI, 95.9%-98.4%), with just 1 death related to breast cancer, according to lead author Timothy J. Whelan, MD, FASCO.

“Women 55 years and older with a T1N0 grade 1 to 2 luminal A breast cancer following breast conserving surgery treated with endocrine therapy alone had a very low rate of local recurrence at 5 years,” Whelan, who is a professor in the Department of Oncology and Canada Research Chair in Breast Cancer Research at McMaster University, and a radiation oncologist at the Juravinski Cancer Centre in Hamilton, Ontario, Canada, said in a press briefing on the data. “The prospective and controlled nature of this multicenter study supports that such patients are candidates for omission of radiotherapy.”

Across 26 centers in Canada, the study enrolled 500 patients with hormone receptor–positive breast cancer, with estrogen receptor positivity on greater than 1% of cells and the progesterone receptor expressed on more than 20% of cells. All patients had HER2-negative disease. At baseline, patients had undergone lumpectomy and had either started or were planning to start endocrine therapy.

Only those with a Ki67 of 13.25% of less were included in the study. Ki67 testing was completed centrally using a systematic approach of counting cells in 5 random fields at 3 different locations across Canada. “The reliability testing was greater than 0.90, and was up to 0.98, actually. We were very comfortable with the reliability testing in this study,” Whelan said. “Increasingly, Ki67 is being used in many hospital laboratories to look at proliferation in cancer and was recommended recently by the FDA for adjuvant therapy with abemaciclib [Verzenio]."

The mean age of patients in the study was 67 years, with 40% being between the age of 55 and 65, 48% between the age of 65 and 74, and 12% were age 75 and older. The mean tumor size at the time of resection was 1.1 cm, with a tumor of less than 0.5 cm present for 8% of patients, 0.51 to 1.0 cm for 43% of patients, and 1.1 to 2.0 cm for 49% of patients. The tumor grades were 1 (66%) and 2 (34%) and the main endocrine therapies administered were tamoxifen (41%) and an aromatase inhibitor (59%).

“Over the past 2 decades, we have realized the risk of local recurrence has been steadily decreasing. This has been attributed to the detection of smaller screened cancers, better surgical therapies, and more effective hormonal therapy,” Whelan explained. “We now know that breast cancer is composed of many different molecular subtypes, in particular 4. The first subtype, luminal A, is characterized by estrogen receptor positivity and low Ki67, which is a measure of proliferation. This has the lowest risk of recurrence.”

Other efficacy end points favored omitting radiotherapy for patients with luminal A breast cancer. At the 5-year analysis, there were only 8 cases of contralateral breast cancer, for a contralateral recurrence risk of 1.9% (90% CI, 1.1%-3.2%). A recurrence at any location was experienced by 12 patients, for an overall recurrence risk of 2.7% (90% CI, 1.6%-4.1%). The disease-free survival rate, which includes recurrence, second cancers, and death from other causes was 89.9% (90% CI, 87.5%-92.2%).

“Radiotherapy is an inconvenient treatment. It can last daily for up to 5 weeks and it is a costly therapy. It is associated with a number of [adverse] effects [AEs], including early [AEs], like skin irritation and fatigue, and late [AEs], such as breast pain and distortion that can affect how the breast looks and overall quality of life,” said Whelan. “It is also associated with very rare, serious AEs like cardiac disease and second cancers.”

In North America, there are over 300,000 diagnoses per year of invasive breast cancer, Whelan noted. With this rate and prevalence of the luminal A subtype, he predicted these results could lead to the omission of radiotherapy for 30,000 to 40,000 patients per year.

“These exciting data are very reassuring and could impact a large number of patients with cancer who have very low chances of their breast cancer returning even without radiation therapy,” ASCO Expert in radiation oncology Corey W. Speers, MD, PhD, from the University of Michigan Rogel Cancer Center, said. “These findings are the first of a number of recent trials in breast cancer looking at reducing treatments that are still commonly used but that may not be necessary for appropriately selected patients.”

Follow up in the study will continue for a total of 10 years for each patient, to better assess the impact of omitting radiotherapy on long-term recurrence rates, new primary cancers, and survival. The start date of the study was July 2013 (NCT01791829).

Whelan TJ, Smith S, Nielsen TO, et al. LUMINA: A prospective trial omitting radiotherapy (RT) following breast conserving surgery (BCS) in T1N0 luminal A breast cancer (BC). 

. 2022;40(suppl 17):LBA501. doi:10.1200/JCO.2022.40.17_suppl.LBA501

Radiotherapy can be avoided after surgery in certain patients with low-grade luminal A breast cancer who have low Ki67 expression and no positive lymph nodes, according to data from 2022 ASCO.

Silas Inman

Articles

Trastuzumab deruxtecan doubles PFS in HER2-low metastatic breast cancer

Certain luminal a breast cancers can forgo radiotherapy after breast conserving surgery