T-DXd Yields Enduring Intracranial Activity in HER2+ Breast Cancer

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Findings from DESTINY-Breast12 support the use of T-DXd for patients with HER2-positive metastatic breast cancer.

“Overall, we believe that results from DESTINY-Breast12 support the use of T-DXd for patients with HER2-positive metastatic breast cancer, irrespective of the presence or absence of stable or active brain metastases,” according to Nancy U. Lin, MD.

“Overall, we believe that results from DESTINY-Breast12 support the use of T-DXd for patients with HER2-positive metastatic breast cancer, irrespective of the presence or absence of stable or active brain metastases,” according to Nancy U. Lin, MD.

Sustained overall and intracranial activity was observed in patients with HER2-positive metastatic breast cancer and stable or active brain metastases following treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), according to findings from the phase 3b/4 DESTINY-Breast12 trial (NCT04739761) presented at the 2024 European Society for Medical Oncology Congress (ESMO).1

In the cohort of patients with baseline brain metastases (n = 263), the primary end point was progression-free survival (PFS). The 12-month progression-free survival (PFS) rate was 61.6% (95% CI, 54.9%-67.6%) and the median PFS was 17.3 months (95% CI, 13.7-22.1). The 12-month PFS rates with the agent were consistent in those with stable (n = 157) and active (n = 106) brain metastases, at 62.9% (95% CI, 54.0%-70.5%) and 59.6% (95% CI, 49.0%-68.7%). Within the group of patients with active brain metastases, a slightly lower 12-month PFS rate was observed in those with previously untreated disease (n = 39), with a rate of 47.0% (95% CI, 29.6%-62.7%); those with previously treated disease (n = 67) had a 12-month PFS rate of 66.7% (95% CI, 53.4%-76.9%).

The primary end point was overall response rate (ORR) in the cohort of patients without brain metastases at baseline. In this group (n = 241), the confirmed ORR was 62.7% (95% CI, 56.5%-68.8%) and this was comprised of a complete response (CR) rate of 9.5% and a partial response (PR) rate of 53.1%. In those with measurable disease at baseline (n = 215), the ORR with the agent was 68.4% (95% CI, 62.2%-74.6%), which included CR and PR rates of 9.3% and 59.1%, respectively. Nancy U. Lin, MD, of the Department of Medical Oncology at Dana-Farber Cancer Institute, noted in an oral presentation that the ORR was in line with previous trials that have examined T-DXd in this setting.

“Overall, we believe that results from DESTINY-Breast12 support the use of T-DXd for patients with HER2-positive metastatic breast cancer, irrespective of the presence or absence of stable or active brain metastases,” Lin said. “The safety profile of T-DXd was consistent with previous reports, and no new safety signals were identified. Interstitial lung disease [ILD]/pneumonitis remains an important identified safety risk of T-DXd, and in particular, in patients with brain metastases on concomitant steroids. Careful attention to PCP prophylaxis and workup for opportunistic infections is warranted.”

Inspiration for the Research

About half of patients with HER2-positive metastatic brain cancer go on to develop brain metastases, Lin said. Although tucatinib (Tukysa)-based regimens have shown efficacy, the median PFS with this regimen in those with brain metastases who were enrolled to the HER2CLIMB trial (NCT02614794) was under 8 months, she added. As such, there is a need for additional effective therapeutic options for this population.

The FDA has approved T-DXd for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within 6 months of therapy completion.2 The full approval was based on findings from the phase 3 DESTINY-Breast03 trial (NCT03529110).

“Promising preliminary evidence of T-DXd’s intracranial activity in HER2-positive metastatic breast cancer has been observed in small, prospective patient cohorts, retrospective studies, and exploratory analyses, with intracranial response rates ranging from 44% to 73%,” Lin reported.1 “However, these data were not available at the time DESTINY-Breast12 was designed. In addition, there’s need for additional prospective data, particularly in patients with active brain metastases with respect to T-DXd.”

About DESTINY-Breast12

The multicenter, single-arm, two-cohort, open-label, phase 3b/4 DESTINY-Breast12 study enrolled patients with pathologically documented HER2-positive advanced or metastatic breast cancer with or without brain metastases at baseline. These patients had received up to 2 prior lines of treatment in the metastatic setting, not including tucatinib, and experienced progressive disease on previous HER2-directed regimens. To be included, they were required to be at least 18 years of age and have an ECOG performance status of 0 or 1. They could not have known or suspected leptomeningeal metastases.

Patients were divided into 2 cohorts: those with baseline brain metastases and those without. Those with brain metastases at baseline were divided further in those with stable brain metastases that were previously treated and those with active brain metastases which were untreated or previously treated and progressing but not requiring immediate local therapy. Those in both cohorts received T-DXd at 5.4 mg/kg intravenously every 3 weeks.

For those with baseline brain metastases, in addition to PFS serving as the primary end point, other end points included central nervous system (CNS) PFS, overall survival (OS), ORR, CNS ORR, safety, and tolerability. For those without brain metastases at baseline, in addition to ORR serving as the primary end point, other end points included OS, safety, and tolerability.

“There was no plan to formally compare the cohorts,” Lin said. “Measurable brain metastases could be included as target lesions for both CNS and overall response. Patient-reported outcomes and neurocognitive assessments were also collected, but not included as part of today’s presentation.”

Taking a Closer Look at the Patient Populations

Of the 263 patients who comprised the baseline brain metastases group, 157 had stable metastases and 106 had active metastases. Of those with active metastases, 39 were untreated and 67 were previously treated and progressing. Of this full group with baseline brain metastases, 55.1% discontinued treatment with T-DXd, the most common reason being progressive disease (30.8%). The median follow-up duration was 15.4 months (range, 0.1-30.0) and 44.9% of patients were still on treatment at data cutoff.

Of the 241 patients without brain metastases at baseline, 60.6% discontinued treatment with the antibody-drug conjugate (ADC); the most common reason for doing so was also progressive disease (35.7%). The median follow-up duration in this group was 16.1 months (range, 0.8-28.4) and 39.4% of patients were still on the agent at data cutoff.

“Approximately two-thirds of patients had hormone receptor–positive disease, and the majority of patients had measurable disease. A little over 7% of patients in both cohorts were treated in the first-line setting; 50% of patients had received 1 prior line in the metastatic setting, and approximately 40% of patients had received 2 prior lines,” Lin noted. “The vast majority of patients received both trastuzumab [Herceptin] and pertuzumab [Perjeta]. T-DM1 [ado-trastuzumab emtansine; Kadcyla] was received in approximately 40% of patients across both cohorts. Most patients with brain metastases had received previous radiotherapy. The median time from the last radiotherapy until treatment initiation was 164 days.”

Additional Efficacy Insights

Additional data from the cohort of patients with baseline brain metastases showed that the 12-month CNS PFS rate was 58.9% (95% CI, 51.9%-65.3%) at a data maturity rate of 38.4%. Broken down further, the CNS PFS rates in those with stable and active brain metastases were 57.8% (95% CI, 48.2%-66.1%) and 60.1% (95% CI, 49.2%-69.4%), respectively. The confirmed ORR in the full population of patients with baseline brain metastases was 51.7% (95% CI, 45.7%-57.8%); in those with stable and active metastases, these rates were 49.7% (95% CI, 41.9%-57.5%) and 54.7% (95% CI, 45.2%-64.2%), respectively. When restricted to patients with measurable disease at baseline, the ORR in the full group of baseline brain metastases (n = 198) was 64.1% (95% CI, 57.5%-70.8%); in those with stable (n = 109) and active (n = 89) brain metastases, these rates were 67.0% (95% CI, 58.1%-75.8%) and 60.7% (95% CI, 50.5%-70.8%), respectively.

A total of 138 patients were enrolled with measurable CNS disease at baseline. In this group, the confirmed CNS ORR was 71.7% (95% CI, 64.2%-79.3%). In those with stable metastases (n = 77), the confirmed CNS ORR was 79.2% (95% CI, 70.2%-88.3%); in those with active metastases (n = 61), this rate was 62.3% (95% CI, 50.1%-74.5%). Within those with active brain metastases, the confirmed CNS ORRs in the subgroups of patients with untreated (n = 23) or previously treated and progressing (n = 38) metastases were 82.6% (95% CI, 67.1%-98.1%) and 50.0% (95% CI, 34.1%-65.9%), respectively.

The 12-month OS rates in those with or without brain metastases at baseline were 90.3% (95% CI, 85.9%-93.4%) and 90.6% (95% CI, 86.0%-93.8%), respectively, at data maturity of 16.3% and 17.0%, respectively. “The median OS was not reached,” Lin noted.

A Spotlight on Safety Data

Regarding safety, in the baseline brain metastases group (n = 263), 98.5% of patients experienced any-grade adverse effects (AEs); these effects were grade 3 or higher for 51.0% of patients. Serious AEs occurred in 23.6% of patients. Any-grade, grade 3 or higher, and serious AEs determined to potentially be related to the ADC occurred in 92.0%, 38.0%, and 9.5% of patients, respectively. AEs required dose reductions and interruptions in 22.8% and 55.5% of patients, respectively; AEs led to discontinuation for 15.2% of patients. Eight patients experienced AEs that led to death, with 6 determined to possibly be related to T-DXd.

In the group of patients without brain metastases at baseline (n = 241), 98.3% of patients experienced any-grade AEs, 49.0% experienced grade 3 or higher AEs, and 19.1% experienced serious AEs; these effects were possibly related to the ADC in 95.4%, 40.7%, and 10.4% of patients, respectively. AEs led to dose reduction or interruption for 27.0% and 51.5% of patients, and discontinuation for 9.5% of patients. Six patients experienced AEs that proved fatal and 5 were possibly related to T-DXd.

“The toxicity profiles were qualitatively similar regardless of the presence or absence of brain metastases,” Lin said. “The most common all-grade toxicities were nausea, fatigue, and constipation. No new safety signals were identified.”

Lin also reported on AEs of special interest with T-DXd. In patients with baseline brain metastases, investigator-reported ILD or pneumonitis occurred in 16.0% of patients; this effect was grade 1 for 9.9% of patients, grade 2 for 3.0% of patients, grade 3 for 0.4% of patients, and grade 4 for 0.4% of patients. In those without baseline brain metastases, 12.9% experienced investigator-reported ILD or pneumonitis; patients experienced grade 1 (9.1%), 2 (2.5%), 5 (1.2%) cases. A decrease in left ventricular ejection fraction occurred in 11.8% of those with baseline brain metastases (grade 2, 11.0%; grade 3, 0.8%) and 10.8% without baseline brain metastases (grade 1, 1.7%; grade 2, 9.1%).

Disclosures: Lin serves as a consultant, advisor, or steering committee member for Artera, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Eisai, Janssen, Olema Pharmaceuticals, Seagen, and Stemline Therapeutics. She received travel support from Olema Pharmaceuticals and institutional research support from AstraZeneca, Genentech, Olema Pharmaceuticals, Pfizer, Seagen, and Zion Pharmaceuticals. She received royalties for book chapter(s) from UpToDate.

References

  1. Lin NU, Ciruelos E, Jerusalem G, et al. Trastuzumab deruxtecan in patients with HER2+ advanced/metastatic breast cancer with or without brain metastases: DESTINY-Breast12 primary results. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation LBA18.
  2. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Accessed September 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer


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