(UPDATE) Fam-Trastuzumab Deruxtecan-nxki

Commentary by Breast Cancer Site Editor for JNCCN 360

William J. Gradishar, MD, FACP, FASCO

Betty Bramsen Professor of Breast Oncology and Chief, Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago

T-DXd (fam-trastuzumab deruxtecan-nxki), a unique antibody-drug conjugate, has proven to be a remarkably effective therapy for an expanding number of clinical situations in patients with HER2-positive breast cancer and the newly defined HER2-low subset of patients. The data from an accumulating array of randomized trials have shown the superiority of T-DXd compared with other HER2-directed therapies as well as chemotherapy for those with HER2-low disease. Ongoing trials are exploring whether it will become a preferred first-line choice for treatment of HER2-positive metastatic disease, a partner with other agents, and a possible choice in early-stage disease.

DISCLOSURES

Dr. Gradishar has received clinical research support/data safety monitoring board from Daiichi Sankyo, Genentech, Novartis, and Seattle Genetics and has served on a scientific advisory board or as a consultant or expert witness for ambrx, AstraZeneca, Merck & Co, and Pfizer.

The use of the antibody-drug conjugate T-DXd for the treatment of breast cancer has increased since its accelerated approval in 2019 for adults with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2–based regimens in the metastatic setting.¹ The U.S. Food and Drug Administration (FDA) has now granted regular approval of T-DXd in the HER2-positive setting² as well as for adults with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.³

T-DXd in HER2-Positive Breast Cancer

T-DXd is a HER2-targeted agent, so it was thus primarily evaluated in patients with HER2-positive breast cancer. Updated results from the DESTINY-Breast01 trial, as well as the findings from the DESTINY-Breast02 and DESTINY-Breast03 trials, continue to build upon the evidence supporting T-DXd in this setting.

DESTINY-Breast01

Longer follow-up of DESTINY-Breast01—the trial that led to the accelerated approval of T-DXd in 2019—has yielded new data. The original data cutoff was August 2019, and the updated data cutoff was June 2020. In the multicenter phase II trial, patients with HER2-positive metastatic breast cancer whose disease progressed during or after treatment with ado-trastuzumab emtansine (T-DM1) were administered 5.4 mg/kg of T-DXd.

A confirmed objective response rate of 61.4% was observed, with a median duration of response of 20.8 months; at the earlier data cutoff, the confirmed objective response rate was 60.9%, and the median duration of response was 14.8 months.⁴ The safety profile appeared to be congruent with previous reports.

Interstitial lung disease remains an identified risk with T-DXd, and thus an analysis was conducted to further investigate its occurrence. In a population comprising patients from the DESTINY-Breast01 trial, as well as those from two phase I studies (DS8201-A-J101 and DS8201-A-A104), 15.5% experienced an adjudicated T-DXd–related interstitial lung disease event during treatment.⁵ The majority of these events occurred within the first 12 months (97.0%) and were of grade 1 or 2 (79.0%).

DESTINY-Breast02

The phase III DESTINY-Breast02 trial acted as a confirmatory study for the single-arm DESTINY-Breast01 trial. Based on the primary results, the median durations of progression-free (17.8 vs. 6.9 months) and overall (39.2 vs. 26.5 months) survival were longer with T-DXd than with conventional capecitabine-based regimens (ie, capecitabine/lapatinib or capecitabine/trastuzumab).⁶

Adjudicated drug-related interstitial lung disease occurred in 10.4% of patients treated with T-DXd and in 0.5% of those who received a capecitabine-based regimen. In the population treated with T-DXd, 88.1% of cases were of grade 1 or 2; grade 5 interstitial lung disease was reported in 0.5% of patients.

DESTINY-Breast03

The first reported findings from the multicenter phase III DESTINY-Breast03 trial favored T-DXd over standard-of-care T-DM1 in patients with HER2-positive metastatic breast cancer who were previously treated with trastuzumab and a taxane.⁷ The median duration of progression-free survival with T-DXd was not reached compared with 6.8 months with T-DM1, respectively. The confirmed objective response rate was 79.1% with T-DXd and 34.2% with T-DM1; of note, the phase II DAISY trial reported a similar rate with T-DXd in this setting (70.6%).⁸

No new safety signals were observed⁷; the rates of treatment-emergent adverse events did not seem to differ between the arms. Compared with previous trials of T-DXd in more heavily pretreated patients, these data showed a significantly better interstitial lung disease profile.

An updated safety analysis “reinforced the consistent safety profile of T-DXd [and supported] the clinical benefit of T-DXd over T-DM1 in [this setting],” according to the investigators.⁹ T-DXd demonstrated a tolerable safety profile consistent with prior studies. The rates of interstitial lung disease or pneumonitis with T-DXd were found to be similar to those reported at the previous data cutoff.

With further follow-up, patients treated with T-DXd demonstrated statistically significant overall (12 months: 94.1% vs. 86.0%; 24 months: 77.4% vs. 69.9%) and continued progression-free (median, 28.8 vs. 6.8 months) survival benefits versus those who received T-DM1.¹⁰ Drug-related interstitial lung disease or pneumonitis, as evaluated by an independent adjudication committee, occurred at a higher rate with T-DXd than with T-DM1 (15.2% vs. 3.1%); however, adjudicated drug-related events of grade 4 or 5 were not reported with T-DXd. The investigators noted that, although the duration of therapy was longer, T-DXd continued to demonstrate a manageable safety profile.

Based on these data, on May 4, 2022, the FDA granted regular approval of T-DXd in the treatment of 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.²

T-DXd in HER2-Low and HER2-Undetectable Breast Cancer

Breast cancers with low HER2 expression are often considered to be HER2-negative; thus, they are ineligible for anti-HER2 therapies. The practice-changing findings of the DESTINY-Breast04 trial identified a new subset of breast cancer—called HER2-low—and redefined the treatment paradigm in a large proportion of patients with metastatic breast cancer.¹¹ Other trials, such as DAISY, have investigated T-DXd in a similar clinical context.

DESTINY-Breast04

Based on the primary results of the multicenter phase III DESTINY-Breast04 trial, regardless of hormone receptor status, treatment with T-DXd prolonged the median durations of progression-free (9.9 vs. 5.1 months) and overall (23.4 vs. 16.8 months) survival compared with standard-of-care treatment plus conventional chemotherapy in patients with HER2-low metastatic breast cancer who were treated with one to two prior lines of chemotherapy in the metastatic setting.¹¹ Treatment-emergent adverse events of grade 3 or higher were observed less frequently with T-DXd than with standard chemotherapy (52.6% vs. 67.4%).

On August 5, 2022, the FDA approved T-DXd for adults with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.³ Approval was based on the aforementioned data.

DAISY

The investigators of the phase II DAISY trial sought to examine the safety and efficacy of T-DXd in heavily pretreated patients with metastatic breast cancer of various levels of HER2 expression. The response rate was 38.0% in those with HER2-low tumors; this finding was consistent with those noted in previous trials of patients with HER2-low expression.⁸ In patients with triple-negative disease, the response rate was 42.0%. A total of 2.8% of the overall population experienced an interstitial lung disease event, all of which were of grade 1 or 2.

T-DXd in Patients With Brain Metastases

Brain metastases are a frequent consequence of HER2-positive breast cancer; however, until recently, data were limited regarding T-DXd in this setting. The DESTINY-Breast01, DEBBRAH, and TUXEDO-1 trials have provided evidence of the clinical activity of this novel agent against brain metastases. Moreover, data from the DESTINY-Breast03 trial seemed to support T-DXd as a reasonable option for the second-line treatment of HER2-positive breast cancer with brain metastases.¹²

DESTINY-Breast01

The DESTINY-Breast01 subgroup analysis of patients with a history of brain metastases highlighted the “durable” clinical activity of T-DXd in this clinical context.¹³ The objective response rate, median duration of progression-free survival, and median duration of response were 58.3%, 18.1 months, and 16.9 months, respectively, in the subgroup of patients with brain metastases. Similarly, in the overall population, they were 60.9%, 16.4 months, and 14.8 months, respectively. The rates of disease progression seemed to be comparable between patients with and without brain metastases (33.0% vs. 25.0%); this finding suggested durable systemic disease control.

DESTINY-Breast03

Treatment with T-DXd was found to prolong the duration of progression-free survival (15 vs. 3 months) and improve the confirmed objective response rate (67.4% vs. 20.5%) compared with T-DM1 in patients with HER2-positive metastatic breast cancer who had stable brain metastases at baseline and underwent prior trastuzumab and taxane therapy, according to a subgroup analysis of the DESTINY-Breast03 trial.¹² Drug-related interstitial lung disease was reported in 10.5% of patients treated with T-DXd and in 1.9% of those who received T-DM1.

DEBBRAH

Based on the preliminary results of the phase II DEBBRAH trial, T-DXd demonstrated clinical activity in patients with HER2-positive or HER2-low advanced breast cancer and active brain metastases.¹⁴ The primary analysis of T-DXd in HER2-positive patients revealed a 16-week progression-free survival rate of 87.5% in those with nonprogressing brain metastases after local therapy.¹⁵ The intracranial objective response rate was 50.0% in patients with asymptomatic untreated brain metastases and 44.4% in those with brain metastases progressing after local therapy.

Fatigue, nausea, neutropenia, and constipation were among the most commonly reported adverse events. A total of 9.5% of patients experienced grade 1 interstitial lung disease or pneumonitis.

TUXEDO-1

The primary results of the phase II TUXEDO-1 trial, which evaluated T-DXd in patients with HER2-positive breast cancer and active brain metastases, expanded upon the evidence obtained from the preliminary analysis of DEBBRAH. The intracranial response rate was 73.3% in the intention-to-treat population.¹⁶ At a median follow-up of 11 months, the median duration of progression-free survival was 14 months.

In this study population, grade 1 or 2 fatigue, nausea, and diarrhea were the most frequently occurring nonhematologic toxicities. One patient experienced grade 2 interstitial lung disease.

T-DXd in Combination

Since the fall of 2020, when the T-DXd Spotlight was originally posted, much of the recent research has shifted focus to the evaluation of this agent in combination regimens. The BEGONIA, DS8201-A-U105, and TRIO-US B-12 TALENT trials, in particular, have yielded valuable insight.

BEGONIA

The ongoing, multicenter phase Ib/II BEGONIA trial, which evaluated first-line T-DXd in combination with durvalumab, yielded “promising” early safety and efficacy outcomes in patients with HER2-low locally advanced or metastatic triple-negative breast cancer.¹⁷ The confirmed objective response rate was 100%, and the median duration of response was not reached. Serious adverse events and adverse events of grade 3 or 4 were reported in 9% and 36% of patients, respectively.

DS8201-A-U105

Based on the primary analysis from part II of the multicenter phase Ib DS8201-A-U105 trial, in previously treated patients with immunotherapy-naive HER2-positive metastatic breast cancer, the addition of the PD-1 inhibitor nivolumab to T-DXd did not appear to improve outcomes compared with previously reported data for T-DXd monotherapy.¹⁸ Moreover, according to the investigators, data from the small HER2-low cohort are insufficient to determine the effects of this combination therapy. The confirmed objective response rates were 65.6% and 50.0% in the HER2-positive and HER2-low cohorts, respectively.

The combination safety profile was found to be similar to that of each drug as monotherapy. In parts I and II of the trial, treatment-emergent adverse events of grade 3 or higher occurred in 50.0% of patients. Nausea was the most frequently reported any-grade treatment-emergent adverse event (56.3%). A total of 14.6% of patients with HER2-positive tumors had adjudicated drug-related interstitial lung disease.

TRIO-US B-12 TALENT

The phase II TRIO-US B-12 TALENT trial was conducted to assess the safety and efficacy of neoadjuvant T-DXd, either alone or in combination with endocrine therapy, in patients with localized, hormone receptor–positive, HER2-low breast cancer. Based on the results of an interim analysis, the objective response rate was higher with T-DXd alone.¹⁹ Hypokalemia, diarrhea, neutropenia, fatigue, headache, vomiting, dehydration, and nausea were the most frequently reported treatment-related adverse events of grade 3 or higher with T-DXd.

Additional Clinical Trials Underway for T-DXd in Breast Cancer

The multicenter phase III DESTINY-Breast05 trial (ClinicalTrials.gov identifier NCT04622319) is being conducted to compare postneoadjuvant therapy (additional adjuvant treatment for patients who do not achieve pathologic complete response after neoadjuvant therapy) with T-DXd versus T-DM1 in high-risk patients with HER2-positive residual invasive breast cancer. Another phase III study, DESTINY-Breast09 (NCT04784715), is evaluating T-DXd with or without pertuzumab versus a taxane, trastuzumab, and pertuzumab in the first-line treatment of patients with HER2-positive metastatic breast cancer.

The global DESTINY-Breast11 trial (NCT05113251) is investigating several T-DXd regimens in the neoadjuvant setting. Patients with high-risk disease will be treated with T-DXd monotherapy or T-DXd followed by paclitaxel plus trastuzumab and pertuzumab (THP) versus dose-dense doxorubicin plus cyclophosphamide followed by THP.

Although the DESTINY-Breast01, DESTINY-Breast03, DEBBRAH, and TUXEDO-1 trials have answered many questions regarding the activity of T-DXd in patients with HER2-positive breast cancer and brain metastases, the phase IIIb/IV DESTINY-Breast12 trial (NCT04739761) is being conducted to further expand upon these findings. The phase II HER3CLIMB-04 trial (NCT04539938), which is evaluating tucatinib plus T-DXd in patients with HER2-positive locally advanced or metastatic breast cancer with and without brain metastases, should also shed light on the safety and efficacy of the agent in this setting.

References

1. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-her2-positive-breast-cancer-who-have-progressed-available. Accessed January 25, 2023.
2. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer. Accessed January 25, 2023.
3. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves first targeted therapy for HER2-low breast cancer. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-her2-low-breast-cancer. Accessed January 25, 2023.
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16. Bartsch R, Berghoff AS, Furtner, J, et al. Trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients with active brain metastases: Primary outcome analysis from the TUXEDO-1 trial. Ann Oncol 2022;33(suppl):Abstract 165MO.
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19. Bardia A, Hurvitz S, Press MF, et al. TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer. 2022 San Antonio Breast Cancer Symposium. Abstract GS2-03.