Considerable and durable overall and intracranial activity occurred with Enhertu (T-DXd; fam-trastuzumab deruxtecan-nxki) in patients with HER2-positive metastatic breast cancer with stable and active brain metastases (cancer that spreads from the primary location to the brain), as demonstrated in findings from the phase 3b/4 DESTINY-Breast12 study presented at the 2024 ESMO Congress.
In the cohort of patients with baseline brain metastases (263 patients), the primary end point was progression-free survival (PFS; the time during and after treatment when a patient with cancer lives with the disease without worsening). The 12-month PFS rate was 61.6% and the median PFS was 17.3 months. The 12-month PFS rates with the agent were consistent in those with stable (remaining the same size; 157 patients) and active (increasing in size; 106 patients) brain metastases, at 62.9% and 59.6%. Within the group of patients with active brain metastases, a slightly lower 12-month PFS rate was observed in those with previously untreated disease (39 patients), with a rate of 47%; those with previously treated disease (67 patients) had a 12-month PFS rate of 66.7%.
The primary end point was overall response rate (ORR; the percentage of patients with a partial or complete response to treatment) in the cohort of patients without brain metastases at baseline. In this group (241 patients), the confirmed ORR was 62.7% and this was comprised of a complete response (disappearance of all signs of cancer from treatment; CR) rate of 9.5% and a partial response (PR; decrease in tumor size) rate of 53.1%. In those with measurable disease at baseline (215 patients), the ORR with the agent was 68.4%, which included CR and PR rates of 9.3% and 59.1%, respectively. Dr. Nancy U. Lin, 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 Enhertu in this setting.
“Overall, we believe that results from DESTINY-Breast12 support the use of [Enhertu] 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 [Enhertu] was consistent with previous reports, and no new safety signals were identified. Interstitial lung disease [thickening or scarring of the tissue within lungs; ILD]/pneumonitis (inflammation of the lungs) remains an important identified safety risk of [Enhertu], and in particular, in patients with brain metastases on concomitant steroids. Careful attention to PCP prophylaxis (preventive treatment to prevent a type of lung infection) 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 Tukysa (tucatinib)-based regimens have shown efficacy, the median PFS with this regimen in those with brain metastases who were enrolled to the HER2CLIMB trial was under eight months, she added. As such, there is a need for additional effective therapeutic options for this population.
The FDA has approved Enhertu 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 six months of therapy completion. The full approval was based on findings from the phase 3 DESTINY-Breast03 trial.
About DESTINY-Breast12
The phase 3b/4 DESTINY-Breast12 study enrolled patients with HER2-positive advanced or metastatic breast cancer with or without brain metastases at the start of the study. These patients had received up to two prior lines of treatment in the metastatic setting, not including Tukysa, 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 (fully active or limited in strenuous activity). They could not have known or suspected leptomeningeal metastases (when cancer cells spread from the original location to the meninges, thin layers of tissue that protect the brain and spinal cord).
Patients were divided into two 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 Enhertu every three 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 (the time when a patient with cancer is still alive; 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.
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 Enhertu, the most common reason being progressive disease (30.8%). The median follow-up duration was 15.4 months, 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, and 39.4% of patients were still on the agent at data cutoff.
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% 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% and 60.1%, respectively. The confirmed ORR in the full population of patients with baseline brain metastases was 51.7%; in those with stable and active metastases, these rates were 49.7% and 54.7%, respectively. When restricted to patients with measurable disease at baseline, the ORR in the full group of baseline brain metastases (198 patients) was 64.1%; in those with stable (109 patients) and active (89 patients) brain metastases, these rates were 67.0% and 60.7%, respectively.
A total of 138 patients were enrolled with measurable CNS disease at baseline. In this group, the confirmed CNS ORR was 71.7%. In those with stable metastases (77 patients), the confirmed CNS ORR was 79.2%; in those with active metastases (61 patients), this rate was 62.3%. Within those with active brain metastases, the confirmed CNS ORRs in the subgroups of patients with untreated (23 patients) or previously treated and progressing (38 patients) metastases were 82.6% and 50%, respectively.
The 12-month OS rates in those with or without brain metastases at baseline were 90.3% and 90.6%, respectively, at data maturity of 16.3% and 17%, respectively. “The median OS was not reached,” Lin noted. When OS is not reached in a trial, this means that at the time of analysis, more than half of patients in the study were still alive.
A Spotlight on Safety Data
Regarding safety, in the baseline brain metastases group (263 patients), 98.5% of patients experienced any-grade side effects; these effects were grade 3 (severe) or higher for 51% of patients. Serious side effects occurred in 23.6% of patients. Any-grade, grade 3 or higher, and serious side effects determined to potentially be related to the ADC occurred in 92%, 38%, and 9.5% of patients, respectively. Side effects required dose reductions and interruptions in 22.8% and 55.5% of patients, respectively; side effects led to discontinuation for 15.2% of patients. Eight patients experienced side effects that led to death, with six determined to possibly be related to Enhertu.
In the group of patients without brain metastases at baseline (241 patients), 98.3% of patients experienced any-grade side effects, 49.0% experienced grade 3 or higher side effects, and 19.1% experienced serious side effects; these effects were possibly related to the ADC in 95.4%, 40.7%, and 10.4% of patients, respectively. Side effects led to dose reduction or interruption for 27% and 51.5% of patients, and discontinuation for 9.5% of patients. Six patients experienced side effects that proved fatal and five were possibly related to Enhertu.
“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 side effects of special interest with Enhertu. In patients with baseline brain metastases, investigator-reported ILD or pneumonitis occurred in 16% of patients; this effect was grade 1 (mild) for 9.9% of patients, grade 2 (moderate) for 3% of patients, grade 3 for 0.4% of patients and grade 4 (life threatening) 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 (when the heart’s left ventricle pumping less blood than it should) 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%).
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