Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives
T-DXd Shows Promise In Treating HER2+ Breast Cancer With Brain Mets
Nancy Lin, MD, discusses the efficacy of T-DXd for brain metastases as seen in DESTINYBreast-12 compared with other agents.
The phase 3b/4 DESTINYBreast-12 study (NCT04739761) assessed the efficacy and safety of trastuzumab deruxtecan (T-DXd; Enhertu) in patients with HER2+ metastatic breast cancer. Participants were divided into two groups: those with stable or active brain metastases (BM cohort) and those without BM.
The primary endpoints were progression-free survival (PFS) for the BM cohort and objective response rate (ORR) for the non-BM cohort. Secondary endpoints included CNS PFS, CNS ORR, and safety.
Results showed that T-DXd demonstrated significant and durable clinical activity in both groups, including intracranial activity. The BM cohort had a 12-month PFS of 61.6%, and the non-BM cohort had a 12-month ORR of 62.7%.
The most common adverse event was interstitial lung disease/pneumonitis, occurring in 16% of the BM cohort and 12.9% of the non-BM cohort.
Overall, T-DXd appears to be a promising treatment option for patients with HER2+ metastatic breast cancer, especially those with stable or active BM.
Here, Nancy Lin, MD, professor of medicine, Harvard Medical School, and medical oncologist, Harvard Cancer Institute, in Boston, Massachusetts, discusses the efficacy of T-DXd for brain metastases compared with other agents.
Transcription:
0:05The other agent that comes top of mind is tucatinib [Tukysa], either tucatinib with trastuzumab [Herceptin] or tucatinib with T-DM1 [trastuzumab emtansine; Kadcyla], as was shown in both HER2CLIMB [NCT02614794] and then HER2CLIMB-02 [NCT03975647]. The patient populations in HER2CLIMB are different from [DESTINYBreast-12 (DB-12)]. HER2CLIMB enrolled patients who had to have had trastuzumab, protuzumab, T-DM1, whereas in DB-12, only 40% of patients had had prior T-DM1. So we have to be a little careful with cross-talk comparisons. Having said that, the median PFS in HER2CLIMB among the brain met population is just over 7 months and intracranial response rate was around 50%.
AstraZeneca's Top-Selling Cancer Drug Tagrisso Receives FDA Green Light For Another Lung Cancer Indication
Thursday, the FDA approved AstraZeneca Plc's AZN Tagrisso (osimertinib) for adult patients with unresectable, Stage III epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy (CRT).
Tagrisso is indicated for patients with exon 19 deletions or exon 21 (L858R) mutations.
Also Read: Latest Trial Setback For AstraZeneca's Dato-DXd, The Drug Fails To Extend Lives Of Pretreated Breast Cancer Patients.
Tagrisso is AstraZeneca's top-selling cancer drug, and in the second quarter of 2024, it generated around $1.6 billion in sales.
The approval follows the FDA's Priority Review based on results from the LAURA Phase 3 trial.
Tagrisso reduced the risk of disease progression or death by 84% compared to placebo.
Median progression-free survival (PFS) was 39.1 months in patients treated with Tagrisso versus 5.6 months for placebo.
Overall survival (OS) results remain immature at this current analysis. The trial continues to assess OS as a secondary endpoint.
Each year in the US, there are more than 200,000 people diagnosed with lung cancer, and 80-85% of these patients are diagnosed with NSCLC, the most common form of lung cancer.
Approximately 15% of NSCLC patients in the US have EGFR mutations. Nearly one in five people diagnosed with NSCLC has an unresectable tumor.
The safety and tolerability of Tagrisso in the LAURA trial was consistent with its established profile and no new safety concerns were identified.
Tagrisso is approved for patients with EGFR mutations in the first-line metastatic setting as monotherapy, in combination with chemotherapy, and as an adjuvant treatment for early-stage disease.
Last week, the FDA approved AstraZeneca's Fasenra (bevacizumab) for eosinophilic granulomatosis with polyangiitis (EGPA), a rare, immune-mediated vasculitis (inflammation of the blood vessels) that can damage multiple organs.
Price Action: AZN stock is up 0.94% at $78.27 at the last check Thursday.
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T-DXd Sustained Substantial, Durable Clinical Activity In Patients With HER2+ Metastatic Breast Cancer
Trastuzumab deruxtecan (T-DXd) was effective in patients with HER2-positive (HER2+) metastatic breast cancer, with no new safety profiles observed.
According to research presented at the European Society for Medical Oncology Congress 2024 in Barcelona, Spain, by Nancy Lin, MD, trastuzumab deruxtecan (T-DXd) was found to be safe in treating patients with HER2–positive (HER2+) metastatic breast cancer (mBC). This included numerous patients who had stable or active brain metastases (BM).1
"Approximately half of patients with HER2+ [mBC] will develop brain metastases," explained Lin while presenting the preliminary abstract. "The median PFS [progression-free survival for] patients with brain metastases in the HER2CLIMB clinical trial [NCT02614794] was less than 8 months."
Breast cancerImage credit: Pixel-Shot - stock.Adobe.Com
Lin is the associate chief of the Division of Breast Oncology at Susan F. Smith Center for Women's Cancers, director of the Metastatic Breast Cancer Program, and director of the Program for Patients with Breast Cancer Brain Metastases, Dana-Farber Cancer Institute in Boston, Massachusetts. She is also a professor of medicine, Harvard Medical School.
T-DXd, sold as Enhertu by Daiichi Sankyo, Inc/AstraZeneca Pharmaceuticals LP, has been used to treat patients with metastatic or unresectable HER2+ breast cancer if they have already received anti–HER2-based therapies. The DESTINY-Breast12 phase 3b/4 study (NCT0473976) is the largest prospective study of this population known to the investigators. This study aimed to assess the PFS and objective response rate (ORR) of patients with stable or active BM who received T-DXd after being treated with 1 or more anti–HER2-based regimens.1,2
The BM cohort and non-BM cohort were made up of adults with HER2+ mBC who had progressed on 2 or fewer prior lines of therapy (LOT). Patients in the BM cohort were further split into stable or active groups based on whether BM were untreated or treated but progressing. All patients received 5.4 mg/kg of T-DXd every 3 weeks intravenously. PFS and ORR were the primary end points of the study, but secondary end points included central nervous system (CNS) PFS, CNS ORR, and overall survival and safety in the BM cohort with safety.
Patients were included in the study if they were 18 years and older, had not received more than 2 prior therapy regimens in a metastatic setting, had disease progression on at least 1 anti–HER2-based regimen, and had a score of 1 or 2 on the Eastern Cooperative Oncology Group performance status.1,2
There were 504 patients treated, with 263 in the BM cohort and 241 in the non-BM cohort. A total of 157 patients had stable BM, and 106 had active BM, of whom 39 had previously untreated disease. The median (range) prior LOT was 1 (0-4) in both cohorts, and the median follow-up time was 15.4 (0.1-30.0) months in the BM cohort and 16.1 (0.8-28.4) months in the non-BM cohort.1,2
In the BM cohort, the PFS rate was 61.6% (95% CI, 54.9%-67.6%) and the CNS PFS rate was 58.9% (95% CI, 51.9%-65.3%) over 12 months. The stable and active BM subgroups had similar rates of CNS PFS, at 57.8% (95% CI, 48.2%-66.1%) and 60.1% (95% CI, 49.2%-69.4%), respectively. The CNS ORR was 79.2% (95% CI, 70.2%-88.3%) in stable BM subgroup and 62.3% (95% CI, 50.1%-74.5%) in the active BM subgroup.
Sixteen percent of the BM cohort and 12.9% of the non-BM cohort reported interstitial lung disease/pneumonitis, and 5 events co-occurred with opportunistic infection, affecting 1.9% of the BM cohort.2
Overall survival (OS), said Lin, was high; patients with BM had a 12-month OS rate of 90.3%, and patients without BM had an OS rate of 90.6%. The median OS was not reached.1,2
"In terms of safety, grades 3 or higher adverse events occurred in approximately half of patients in both cohorts," Lin said. "However, treatment discontinuation due to toxicity was uncommon, occurring in 15% of patients with brain metastases and 9.5% of patients without brain metastases."
The most common adverse event that led to discontinuation was interstitial lung disease, which was recorded in 16.0% of patients with BM at baseline.2 Lin noted that 11 treatment-related deaths occurred during the study and that only 1 case of radiation necrosis was recorded, although she speculated on whether there was incomplete recording for that adverse event.
Regarding study limitations, DESTINY-Breast12 was a single-arm, open-label trial and excluded patients with leptomeningeal metastases. Conclusions on the efficacy of the treatment were based on single-arm, time-to-event efficacy analyses. Additionally, cross-trial comparisons are difficult because the final data set is immature and there are no long-term follow-up data. Patients with no measurable disease at baseline were included in the ORR analysis in the non-BM cohort. Moreover, intracranial radiotherapy had been used previously in some patients with stable or active BM, which could have affected the results. Brain imaging was not performed in patients without BM at baseline, so only symptomatic CNS metastases could be evaluated. Lastly, Black and Asian patients were underrepresented.1,2
The study investigators concluded that T-DXd induced substantial and durable overall and intracranial clinical activity in patients with HER2+ mBC with no new safety signals. These new data indicate that T-DXd can be used in previously treated patients with HER2+ mBC, including in patients with active and stable BM.1,2
"Overall, we believe that results from DESTINY-Breast12 support the use of T-DXd for patients with HER2+ [mBC], irrespective of the presence or absence of stable or active brain metastases," Lin concluded.
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