Another Win for Antibody-Drug Conjugate in HER2+ Breast Cancer With Brain Mets

Trastuzumab deruxtecan (Enhertu, T-DXd) therapy produced “substantial and durable” overall and intracranial clinical activity in patients with HER2-positive advanced breast cancer, according to data from the DESTINY-Breast12 trial.

Patients had stable and active brain metastases at baseline in the phase IIIb/IV study. The estimated overall median progression-free survival (PFS) was 17.3 months in patients who received the antibody-drug conjugate, reported Nancy Lin, MD, of the Dana-Farber Cancer Institute in Boston.

The 12-month PFS came in at 61.6% overall, at 62.9% in those with stable brain metastases, and at 59.6% in those with active brain metastases. The 12-month central nervous system (CNS) PFS overall was 58.9%, with rates that were consistent with both patients with stable and active brain metastases (57.8% and 60.1% respectively), she said at the European Society for Medical Oncology (ESMO) annual congress in Barcelona. Trial results were simultaneously published in Nature Medicine.

“Overall, we believe that results … support the use of T-DXd for HER2-positive metastatic breast cancer, irrespective of the presence, or absence, of stable or active brain metastases,” Lin stated.

ESMO invited discussant Cristina Saura Manich, MD, PhD, of the Vall d’Hebron University Hospital in Barcelona, noted that the HER2Climb study of the combination of tucatinib (Tukysa), trastuzumab, and capecitabine “is the only randomized study with a significant number of patients with active brain metastases that reported a statistically positive and clinically meaningful results.” HER2Climb led to FDA approval of the triplet for the treatment of patients with HER2-positive advanced breast cancer patients with CNS involvement who have received one or more prior anti-HER2 based regimens.

So, “until today the preferred treatment options for patients in second line with active brain metastases was the tucatinib-trastuzumab-capecitabine combination,” Manich said. “After today’s presentation, I believe the preferred option for second-line treatment should now be trastuzumab deruxtecan, regardless of whether the patient has active brain metastases or not.”

Lin pointed out that about half of patients with HER2-positive metastatic breast cancer will develop brain metastases.

Preliminary evidence of T-DXd intracranial activity in HER2-positive metastatic breast cancer was observed in small prospective patient populations, retrospective studies, and exploratory analyses, with intracranial ORRs ranging from 44-73%, she added. “However, there is need for additional prospective data, particularly in patients with active brain metastases with respect to T-DXd.”

Patients in DESTINY-Breast12 included those with 0-2 previous lines of therapy in the metastatic setting, with an ECOG performance status of 0 or 1. Prior HER2 inhibitor agents included trastuzumab and pertuzumab (Perjeta). A little over 60% received intracranial radiotherapy. Median age was around 53 and most were white.

The brain metastases cohort included 157 patients with stable (previously treated) brain metastases and 106 with active brain metastases (untreated or previously treated but progressing at the time of study entry). A second cohort included 241 patients with no baseline brain metastases.

Regarding the study’s reported overall response rates (ORR), Lin reported:

• The ORR among patients with baseline brain metastases (inclusive of intracranial and extracranial response) was 51.7%.
• ORRs were 49.7% and 54.7%, respectively, among those with stable and active brain metastases.
• When restricted to patients with measurable disease at baseline (n=198) the ORR was 64.1%.
• CNS ORR was 71.7% among 138 patients with measurable CNS disease at baseline (79% among patients with stable brain metastases, and 62.3% in those with active brain metastases).

In patients with no baseline brain metastases, the ORR was 62.7% in the overall population of 241 patients, and 68.4% among 215 patients who had measurable disease at baseline.

Overall survival (OS) was “high,” Lin reported, with 12-month OS rates of 90.3% in the group with baseline brain metastases, and 90.6% in the group without.

As for T-DXd’s safety profile, Lin observed it was “consistent” with previous reports, with no new safety signals.

However, 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 [pneumocystis pneumonia prophylaxis] and work-up for opportunistic infection is warranted,” she said.

Lin noted that there were six cases of grade 5 ILD among patients with brain metastases, five of whom were on concomitant steroids and not on PCP prophylaxis, and four cases of ILD co-occurring with opportunistic infection.

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