Dataset Information

Mechanism of action and resistance to Trastuzumab Deruxtecan in patients with metastatic breast cancer: the DAISY trial

ABSTRACT: Trastuzumab deruxtecan (T-DXd) is an anti-HER2 (human epidermal growth factor receptor 2) antibody-drug conjugate which has previously shown a meaningful high efficacy in HER2-positive and HER2-low metastatic breast cancer (mBC). However, the mechanism of action of this drug remains partially unknown. DAISY (NCT04132960) is a phase II, open-label study that included patients with mBC whose disease progressed after at least one line of chemotherapy in the metastatic setting. Patients were enrolled in three cohorts according to HER2 expression determined by immunohistochemistry: HER2-overexpressing (n=68), HER2-low (n=72), and HER2-non expressing mBC (n=37). Patients were treated with T-DXd 5.4 mg/kg every 3 weeks until progression disease or unacceptable toxicity. In the per cohort analysis, the objective response rate was of 70.6% (95% CI: 58.3-81) in cohort 1, 37.5% (95% CI: 26.4-49.7) in cohort 2, and 29.7% (95% CI: 16-47) in cohort 3 (p <0.0001). The median progression-free survival was 11.1 months (95% CI: 8.5-14.4; HR: 0.53, 95% IC: 0.34-0.84, p=0.007) in cohort 1, 6.7 months (95% CI: 4.4-8.3; HR: 1) in cohort 2, and 4.2 months (95% CI: 2-5.7; HR: 1.96, 95% IC: 1.21-3.15, p=0.006) in cohort 3. Exploratory analyses showed a lower T-DXd distribution in HER2-non expressing BC. A deep-learning histologic approach identified an association between a cluster of IHC0 cells and non-response to T-DXd. No quantitative modulation of tumor microenvironment was observed after 6 to 8 weeks of cycle 1. Finally, recurrent mutations on SLX4 were identified in 20% of samples at resistance (n=4/20) as compared to 2% in baseline samples (2/88). In conclusion, HER2 expression is a key determinant of T-DXd antitumor activity but several other biomarkers are still unknown.

ORGANISM(S): Homo sapiens (human)

SUBMITTER:

PROVIDER: S-BSST974 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:Trastuzumab deruxtecan (T-DXd) is an anti-HER2 (human epidermal growth factor receptor 2) antibody-drug conjugate which has previously shown efficacy in patients with HER2-overexpressing and HER2-low metastatic breast cancer (mBC). However, the mechanisms of action and resistance of this drug remain partially unclear. DAISY (NCT04132960) is a phase II, open-label study that included patients with mBC whose disease progressed after at least one line of chemotherapy in the metastatic setting. Patients were enrolled in three cohorts according to HER2 expression determined by immunohistochemistry (IHC); cohort 1: HER2-overexpressing (HER2 IHC 3+ or HER2 IHC 2+/ISH+, n=72), cohort 2: HER2-low (HER2 IHC2+/ISH- or HER2 IHC 1+, n=74), and cohort 3: HER2 IHC 0 mBC (n=40). Patients were treated with T-DXd 5.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. In the full analysis set population (n=177), the confirmed objective response rate (ORR) was of 70.6% (95% CI: 58.3-81) in cohort 1, 37.5% (95% CI: 26.4-49.7) in cohort 2, and 29.7% (95% CI: 15.9-47) in cohort 3 (p <0.0001). The median progression-free survival (PFS) was 11.1 months (95% CI: 8.5-14.4) in cohort 1, 6.7 months (95% CI: 4.4-8.3) in cohort 2, and 4.2 months (95% CI: 2-5.7); in cohort 3. Cohort 1 was significantly associated with longer PFS (adjusted HR: 0.53, 95% IC: 0.34-0.84, p=0.007), and cohort 3 with shorter PFS (adjusted HR: 1.96, 95% IC: 1.21-3.15, p=0.006) as compared to cohort 2. Exploratory analyses showed that HER2 spatial distribution predicted T-DXd response in patients with HER2-overexpressing mBC and that the transcriptomic response to T-DXd was different according to HER2 expression. No quantitative modulation of tumor microenvironment was observed after 6 to 8 weeks of treatment. Finally, recurrent mutations of the DNA repair gene SLX4 were identified in 20% of samples at resistance (4/20) as compared to 2% in baseline samples (2/88), suggesting that SLX4 mutations could mediate secondary resistance to T-DXd. These data suggest that HER2 is a key determinant of T-DXd efficacy. However, an antitumor activity is also observed in a subgroup of patients without detectable HER2 expression and resistance could be partially mediated by payload sensitivity.

Project description:BackgroundTrastuzumab deruxtecan (T-DXd) is FDA-approved for treatment of patients with HER2 positive and HER2-low metastatic breast cancer. Currently, there is limited understanding of pre-treatment risk factors for pneumonitis associated with T-DXd.MethodsConsecutive breast cancer patients who received at least one dose of T-DXd at a single academic cancer study between January 1, 2019, and February 20, 2024, were identified for analysis. Pneumonitis was documented by the treating oncologist at the time of toxicity and retrospectively independently confirmed by a member of the study team through chart and radiologic review. Pre-treatment variables of interest were collected, including patient demographics, radiation dosimetry variables, and chest imaging abnormalities.ResultsOf 179 total patients, 23 (12.8%) had pneumonitis after T-DXd exposure. Patients with pneumonitis had lower baseline oxygen saturation (98% vs. 97%, p = 0.02) and were more likely to have received abemaciclib (26.1% vs. 9.6%, p = 0.03) before T-DXd. Multiple pre-treatment variables were not found to be associated with T-DXd pneumonitis, including chest imaging abnormalities (41.9% vs. 47.8%, p = 0.59), prior immune checkpoint inhibitor treatment (16.0% vs. 8.7%, p = 0.50) and prior chest or breast radiation (61.5% vs. 47.8%, p = 0.20). On multivariate analysis, prior treatment with abemaciclib remained significantly associated with T-DXd pneumonitis (OR 3.25 [1.07-9.11], p = 0.04), while neither pre-treatment chest imaging abnormalities nor prior chest or breast radiation were associated (OR 1.60 [0.62-4.20], p = 0.33); OR 0.51 [0.20-1.33], p = 0.17).ConclusionsIn this cohort, prior treatment with abemaciclib may be a risk factor for T-DXd pneumonitis. Conversely, pre-treatment chest imaging abnormalities, prior immune checkpoint inhibitor treatment, and prior chest or breast radiation did not increase the risk of T-DXd pneumonitis. Larger studies are warranted to validate these findings toward an improved understanding of risk factors for pneumonitis after T-DXd exposure.

Project description:ImportanceThe initial assessment of pertuzumab use for treatment of metastatic breast cancer by health technology assessment agencies suggested that pertuzumab was not cost-effective. In Ontario, Canada, pertuzumab became funded in November 2013 based on the substantial clinical benefit. To date, there is a paucity of analysis of pertuzumab using real-world data for cost-effectiveness.ObjectiveTo assess the cost-effectiveness of pertuzumab, trastuzumab, and chemotherapy vs trastuzumab and chemotherapy for patients with metastatic breast cancer.Design, setting, and participantsA population-based retrospective economic evaluation was conducted in Ontario, Canada. Patients who received first-line treatments for metastatic breast cancer from January 1, 2008, to March 31, 2018, were identified. Patients were followed up from the start of treatment up to 5 years, with maximum follow-up to March 31, 2019. Patients were identified from the Ontario Cancer Registry and linked to the New Drug Funding Program database to identify receipt of first-line treatment (N = 1158).InterventionsTreatment with pertuzumab, trastuzumab, and chemotherapy after public funding (November 25, 2013) compared with treatment with trastuzumab and chemotherapy before funding.Main outcomes and measuresCost-effectiveness, from a public payer perspective, was estimated from administrative data with a 5-year time horizon, adjusted for censoring, and discounted (1.5%). Incremental cost-effectiveness ratios for life-years gained and quality-adjusted life year (QALY) with bootstrapped 95% CIs were calculated. Sensitivity analysis with price reduction of pertuzumab alone or in combination with trastuzumab was conducted.ResultsA total of 579 pairs of matched patients receiving pertuzumab and controls were included. The mean (SD) age of the matched study cohort was 58 (12.97) years; 1151 were women (99.4%). Pertuzumab resulted in 0.61 life-years gained and 0.44 QALYs gained at an incremental cost of $192 139 (all costs measured in Canadian dollar values, CAD) with an incremental cost-effectiveness ratio of $316 203 per life-year gained and $436 679 per QALY. The main factors associated with cost included the cost of pertuzumab (60%), outpatient cancer treatment delivery (24%), and trastuzumab (15%). With 100% price reduction of pertuzumab, the incremental cost-effectiveness ratio was $174 027 per QALY. When the price of pertuzumab and trastuzumab were both reduced by more than 71%, the incremental cost-effectiveness ratio decreased below $100 000 per QALY.Conclusions and relevanceThe findings of this population-based study suggest that pertuzumab may increase survival for patients with metastatic breast cancer but would not be considered cost-effective, even after 100% price reduction, under conventional thresholds.

Dataset Information

Mechanism of action and resistance to Trastuzumab Deruxtecan in patients with metastatic breast cancer: the DAISY trial

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets