Drug-related Interstitial Lung Disease Research Articles

Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial

Trastuzumab deruxtecan has shown encouraging activity in patients with treatment-refractory HER2-positive, RAS wild-type and BRAF wild-type metastatic colorectal cancer. Dose optimisation and further antitumour assessments in patients with RAS mutations and those with previous anti-HER2 therapy are warranted. We aimed to evaluate two doses of trastuzumab deruxtecan (5·4 mg/kg and 6·4 mg/kg) to establish the recommended dose in patients with pretreated HER2-positive, RAS wild-type or mutant metastatic colorectal cancer. DESTINY-CRC02 was a multicentre, randomised, two-stage, two-arm, phase 2 study done in 53 research hospitals and medical centres in Australia, Belgium, France, Italy, Japan, South Korea, Spain, Taiwan, the UK, and the USA. Eligible patients were aged 18 years and older or 20 years and older (depending on region) with pretreated pathologically documented, unresectable, recurrent, or metastatic HER2-positive, and RAS wild-type or mutant colorectal cancer. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and have received previous chemotherapy, and anti-EGFR, anti-VEGF, or anti-PD-L1 therapy, if clinically indicated. In stage 1, patients were randomly assigned (1:1), via a secure interactive response technology system, to receive 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan administered intravenously every 21 days. Stratification factors were ECOG performance status, HER2 status, and RAS status. In stage 2, patients were assigned into the 5·4 mg/kg treatment group only. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04744831, and is ongoing (not recruiting). Between March 5, 2021, and March 29, 2022, 135 patients were centrally screened, 122 of whom were enrolled. In stage 1, 40 patients each were randomly assigned to receive trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg. In stage 2, an additional 42 patients were enrolled in the 5·4 mg/kg group. 64 (52%) participants were male and 58 (48%) were female. The median duration of follow-up was 8·9 months (IQR 6·7-10·5) in the 5·4 mg/kg group and 10·3 months (5·9-12·7) in the 6·4 mg/kg group. The confirmed objective response rate by blinded independent central review was 37·8% (31/82 [95% CI 27·3-49·2]) in the 5·4 mg/kg group and 27·5% (11/40 [14·6-43·9]) in the 6·4 mg/kg group. 34 (41%) of 83 patients in the 5·4 mg/kg group and 19 (49%) of 39 in the 6·4 mg/kg group had grade 3 or worse drug-related treatment-emergent adverse events. The most common grade 3 or worse drug-related treatment-emergent adverse events were neutrophil count decreased (13 [16%] of 83 patients), anaemia (six [7%]), nausea (six [7%]), and white blood cell count decreased (five [6%]) in the 5·4 mg/kg group; and were neutrophil count decreased (10 [26%] of 39 patients), anaemia (eight [21%]), platelet count decreased (four [10%]), and white blood cell count decreased (four [10%]) in the 6·4 mg/kg group. Drug-related serious adverse events occurred in 11 (13%) of 83 patients in the 5·4 mg/kg group and six (15%) of 39 patients in the 6·4 mg/kg group; the most common in the 5·4 mg/kg group was nausea (three [4%] patients) and the most common in the 6·4 mg/kg group were fatigue (two [5%] patients), neutropenia (two [5%]), and thrombocytopenia (two [5%]). A drug-related treatment-emergent adverse event related to death occurred in one (1%) patient in the 5·4 mg/kg group (due to hepatic failure). Adjudicated drug-related interstitial lung disease or pneumonitis events were observed in seven (8%) patients in the 5·4 mg/kg group (all grade 1 or 2) and in five (13%) patients in the 6·4 mg/kg group (four grade 1 or 2; one grade 5). The promising antitumour activity and favourable safety profile support trastuzumab deruxtecan 5·4 mg/kg as the optimal single-agent dose for patients with pretreated HER2-positive metastatic colorectal cancer, including those with RAS mutations, previous anti-HER2 therapy, or both. Daiichi Sankyo and AstraZeneca.

Trastuzumab deruxtecan versus trastuzumab emtansine in Asian patients with HER2-positive metastatic breast cancer.

The global phase 3 DESTINY-Breast03 study (ClinicalTrials.gov; NCT03529110) showed statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) with trastuzumab deruxtecan (T-DXd) over trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. Here, we report a subgroup analysis of Asian patients enrolled in DESTINY-Breast03. In total, 309 patients (149 in the T-DXd arm and 160 in the T-DM1 arm) from Asian countries and regions were randomized. At data cutoff (July 25, 2022), the median duration of follow-up in the Asian subpopulation was 29.0 months with T-DXd and 26.0 months with T-DM1. The PFS (determined by blinded independent central review) hazard ratio was 0.30 (95% confidence interval 0.22-0.41) favoring T-DXd over T-DM1 (median PFS 25.1 vs. 5.4 months). Median OS was not reached in the T-DXd arm and was 37.7 months in the T-DM1 arm. The median treatment duration was 15.4 months with T-DXd and 5.5 months with T-DM1. The incidence of grade ≥3 drug-related treatment-emergent adverse events was similar between both treatment arms (49.0% vs. 46.5%) and was consistent with the overall DESTINY-Breast03 population. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.9% of patients treated with T-DXd and 2.5% treated with T-DM1, with a higher incidence in Japanese patients; none of these were grade ≥4 events. These efficacy and safety data reinforce the favorable benefit-risk profile of T-DXd in HER2-positive mBC, including in the Asian subgroup.

Safety and Efficacy of Trastuzumab Deruxtecan for Metastatic HER2+ and HER2-low Breast Cancer: An Updated Systematic Review and Meta-Analysis of Clinical Trials.

Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate (ADC) promising in treating metastatic HER2+ and HER2-low breast cancer. This updated systematic review and meta-analysis, integrating data from the latest clinical trials, aimed to evaluate the safety and efficacy of T-DXd in this patient population. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A comprehensive search was conducted across PubMed, Scopus, and Web of Science up to January 2024, focusing on clinical trials that assessed T-DXd's efficacy and safety. Eligibility criteria were based on the PICOS framework, and selected studies underwent rigorous quality assessment and data extraction. The primary outcomes were progression-free survival (PFS), overall survival (OS), and the incidence of adverse events. A random-effects meta-analysis was performed to synthesize the data. Seven studies involving 2,201 patients met the inclusion criteria. The pooled analysis revealed that T-DXd significantly improved PFS (OR=0.37, 95% CI: 0.27-0.52), indicating a robust efficacy in slowing disease progression. However, treatment was associated with an increased risk of anemia (OR=2.10, 95% CI: 1.36-3.25), fatigue (OR=1.56, 95% CI: 1.21-2.02), nausea (OR=6.42, 95% CI: 4.37-9.42), vomiting (OR=6.21, 95% CI: 3.14-12.25), constipation (OR=2.26, 95% CI: 1.53-3.34), and notably, drug-related interstitial lung disease (OR=10.89, 95% CI: 3.81-31.12). The efficacy outcomes demonstrated significant heterogeneity, which was addressed through sensitivity analysis. T-DXd shows significant efficacy in treating metastatic HER2+ and HER2-low breast cancer, offering a valuable therapeutic option for patients with advanced disease. However, the treatment is associated with notable adverse events, including a heightened risk of ILD. These findings underscore the need for careful patient selection, monitoring, and management strategies to mitigate risks. Future research should focus on optimizing treatment protocols and exploring methods to enhance safety profiles.

Trastuzumab deruxtecan versus treatment of physician’s choice in previously treated Asian patients with HER2-low unresectable/metastatic breast cancer: subgroup analysis of the DESTINY-Breast04 study

BackgroundIn the global phase 3 DESTINY-Breast04 study (NCT03734029), the anti-human epidermal growth factor 2 (HER2) antibody–drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated a statistically significant improvement in progression-free survival (PFS) and overall survival (OS), with manageable safety compared with treatment of physician’s choice (TPC) in patients with HER2-low metastatic breast cancer (mBC) who had received 1–2 prior lines of chemotherapy.MethodsThis subgroup analysis examined the efficacy and safety of T-DXd versus TPC in 213 patients from Asian countries and regions who were enrolled in the DESTINY-Breast04 trial and randomized to T-DXd (n = 147) or TPC (n = 66).ResultsMedian PFS with T-DXd and TPC was 10.9 and 5.3 months, respectively, in Asian patients with hormone receptor-positive mBC, and 10.9 and 4.6 months, respectively, in the overall Asian population. In both populations, median OS was not reached with T-DXd and was 19.9 months with TPC. The objective response rate was higher with T-DXd versus TPC in all Asian patients. Median treatment duration was 8.4 months with T-DXd and 3.5 months with TPC. The most common grade ≥ 3 drug-related treatment-emergent adverse events in Asian patients treated with T-DXd were neutropenia (16.3%), anemia (12.9%), and leukopenia (11.6%); the incidences of neutropenia and leukopenia were higher with TPC versus T-DXd. Adjudicated drug-related interstitial lung disease or pneumonitis with T-DXd was 14.3%; the majority of events were grade 1–2.ConclusionsT-DXd demonstrated clinically meaningful survival benefits versus TPC in Asian HER2-low mBC patients, regardless of hormone receptor status, with no new safety signals.Clinical trial registration numberClinicalTrials.gov, NCT03734029.

Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing biliary tract cancer (BTC) and pancreatic cancer (PC): Outcomes from DESTINY-PanTumor02 (DP-02).

4090 Background: Existing late-line treatment (Tx) options for BTC and PC offer limited long-term benefit. In DP-02, T-DXd showed tumor-agnostic potential, with an objective response rate (ORR) of 37.1% (95% CI 31.3, 43.2) and clinically meaningful survival outcomes in 267 pts with HER2-expressing tumors. Here we report subgroup analyses in the BTC and PC cohorts and characterize pts with an objective response (OR). Methods: This open-label Phase 2 study (NCT04482309) evaluated T-DXd (5.4 mg/kg Q3W) in pts with HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced/metastatic disease after ≥1 systemic Tx, or without Tx options. The primary endpoint was confirmed ORR by investigator (INV). Secondary endpoints included progression-free survival (PFS) and safety. Exploratory endpoints included efficacy outcomes by HER2 expression. Results: At data cutoff (June 2023), 41 pts with BTC and 25 pts with PC had received T-DXd (median [m] follow up [range]: 6.01 [0.7–29.1] and 4.99 [1.1–27.2] months [mo], respectively); 27 (65.9%) and 18 (72.0%) pts had ≥2 prior Tx regimens, 7 (17.1%) and 2 (8.0%) pts had prior anti-HER2 Tx, and 8 (19.5%) and 18 (72.0%) pts had prior topoisomerase 1 inhibitor Tx, respectively. In pts with BTC and IHC 3+ expression, 9 pts (56.3%; 95% CI 29.9, 80.2; primary tumor locations: n=2 ampulla of Vater; n=2 extrahepatic; n=4 gallbladder; n=1 intrahepatic) had confirmed OR by INV; of these pts, 6 had received ≥2 prior Tx regimens and 4 had PD-L1 immune cell status ≥1%. The Table shows efficacy outcomes in all pts and by central HER2 expression. In pts with BTC and PC, Grade (G) ≥3 drug-related adverse events occurred in 16/41 (39.0%) and 7/25 (28.0%) pts, respectively; adjudicated drug-related interstitial lung disease / pneumonitis occurred in 7/41 (17.1%; n=5 G2; n=1 G3; n=1 G5) and 1/25 (4.0%; n=1 G1) pts, respectively. Conclusions: T-DXd showed clinically meaningful benefit in pts with BTC across primary tumor locations. Low pt numbers limit interpretation of the PC cohort; however, data support further exploration of T-DXd in this population. Safety was consistent with the known profile. These data support T-DXd as a potential Tx for pts with HER2-expressing BTC. Clinical trial information: NCT04482309 . [Table: see text]

Pooled analysis by best confirmed response to trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ metastatic breast cancer (mBC) from DESTINY-Breast-01, -02, and -03.

1023 Background: DESTINY-Breast (DB)-01, -02, and -03 evaluated T-DXd in pts with HER2+ mBC who received ≥1 prior line of therapy. These studies showed confirmed objective response rates by independent central review (ICR; blinded for DB-02 and -03) of 62%, 70%, and 79% and complete response (CR) rates of 7%, 14%, and 21%, respectively, with T-DXd. We report a pooled analysis according to pts’ best confirmed response in DB-01, -02, or -03. Methods: Endpoints included best confirmed response per (blinded) ICR ([B]ICR) based on RECIST v1.1, duration of response (DoR), progression-free survival (PFS) by (B)ICR, overall survival (OS), and safety. Results: The median (range) duration of T-DXd treatment for pts with a CR, partial response (PR), or stable disease (SD)/progressive disease (PD) was 27.4 (4.5-45.1) mo, 14.0 (2.1-39.3) mo, or 6.2 (0.7-40.1) mo, respectively. Of 834 evaluable pts assigned to T-DXd in DB-01, -02, or -03, 125 (15.0%) had a CR, 477 (57.2%) had a PR, and 232 (27.8%) had SD/PD. Pts with CR had a median of 2 prior regimens (range, 1-11) in the metastatic setting, whereas pts with PR or SD/PD had a median of 3 prior regimens. As shown in the Table, pts with CR had more favorable PFS and OS outcomes vs pts with PR or SD/PD. The proportion of pts with drug-related, serious treatment-emergent adverse events (TEAEs) was numerically lower in pts with CR (8.0%) than those with PR (12.4%) or SD/PD (15.5%). Pts with CR also had numerically lower rates of drug-related TEAEs associated with T-DXd discontinuation (14.4% vs 17.8% or 16.8%) and adjudicated drug-related interstitial lung disease (ILD)/pneumonitis (8.8% [0 fatal] vs 15.1% [2 fatal] or 11.6% [5 fatal]) and longer median time to first ILD onset (461 days vs 211 or 125 days) vs pts with PR or SD/PD. Conclusions: Pts treated with T-DXd benefited from durable responses resulting in prolonged PFS and OS, especially those with a CR. Despite longer treatment duration in responders, safety remained generally manageable and did not result in a higher percentage of pts with TEAEs over time. These results further support the use of T-DXd across broad pt groups with HER2+ mBC. Clinical trial information: NCT03248492 , NCT03523585 , NCT03529110 . [Table: see text]

Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing head and neck tumors: Outcomes from DESTINY-PanTumor02 (DP-02).

6037 Background: In DP-02, T-DXd demonstrated an objective response rate (ORR) by investigator (INV) of 37.1% (95% CI 31.3, 43.2) and clinically meaningful survival outcomes in 267 pretreated pts with HER2-expressing tumors. In this post-hoc analysis, we report outcomes and characterize those with an objective response (OR) in a subset of pts with head and neck cancers (previously included in the ‘other tumor’ cohort), most of which were salivary gland tumors. Methods: This open-label, Phase 2 study (NCT04482309) evaluated T-DXd (5.4 mg/kg Q3W) in pts with HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced/metastatic disease after ≥1 systemic treatment or without treatment options. The primary endpoint was confirmed ORR by INV. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), and safety. Exploratory endpoints included efficacy outcomes by HER2 expression. Results: At data cutoff (June 2023), 24 pts with head and neck tumors (n=19 salivary gland, n=3 squamous cell carcinoma [SCC], n=1 adenoid cystic carcinoma, n=1 lacrimal gland) had received treatment (median [m] follow up: 20.8 months [range: 4.7–31.6]). Of these pts, 15 (62.5%) had received ≥2 prior treatment regimens. 10/24 pts (41.7%; 95% CI 22.1, 63.4; n=8 salivary gland, n=1 SCC, n=1 lacrimal gland) had a confirmed OR by INV; 9 responders had received prior radiation therapy, and 4 had known PD-L1 immune cell status ≥1%. The Table shows efficacy outcomes in all pts and by HER2 expression (central testing). Grade (G) ≥3 drug-related adverse events occurred in 10/24 (41.7%) pts. Adjudicated drug-related interstitial lung disease / pneumonitis occurred in 3/24 (12.5%) pts (n=1 G1; n=1 G2; n=1 G5). Conclusions: T-DXd showed clinically meaningful benefit in pretreated pts with head and neck tumors. Responses were observed across HER2 expression levels. Safety was consistent with the known profile. These data support T-DXd as a potential treatment for pretreated pts with HER2-expressing head and neck tumors. Clinical trial information: NCT04482309 . [Table: see text]

DESTINY-Breast07: Dose-expansion interim analysis of T-DXd monotherapy and T-DXd + pertuzumab in patients with previously untreated HER2+ mBC.

1009 Background: Trastuzumab deruxtecan (T-DXd) is approved for adult patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) who received a prior anti-HER2–based regimen. DESTINY-Breast07 is a Phase 1b/2 multicenter, open-label, modular study exploring the safety, tolerability, and antitumor activity of T-DXd alone or in combination with other anticancer agents (NCT04538742). These results are from an interim analysis of the dose-expansion phase assessing T-DXd ± pertuzumab (P) as first-line (1L) treatment in HER2+ mBC. Methods: Pts had locally assessed HER2+ mBC with measurable disease and no or stable brain metastases. A disease-free interval of ≥12 months from (neo)adjuvant therapy was required; no prior therapy for mBC was allowed. Pts were stratified by hormone receptor and disease status (recurrent vs de novo), and PD-L1 expression. Pts received T-DXd 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W) as monotherapy or in combination with P 420 mg IV Q3W, with an 840 mg loading dose. Primary endpoints were safety and tolerability; key secondary endpoints included objective response rate (ORR) and progression-free survival (PFS), per RECIST 1.1 by investigator. Results: Seventy-five pts were treated in the T-DXd module and 50 pts in the T-DXd + P module; median follow up was 19.2 months (range 8.7–29.2) and 20.6 months (range 13.3–26.7), respectively. Median age was 57 years in both modules. As of August 1, 2023, the most common adverse event (AE) was nausea (T-DXd, 70.7% [4.0% Grade 3]; T-DXd + P, 68.0% [0% Grade 3]). Diarrhea was reported in 34.7% (2.7% Grade 3) and 60.0% (6.0% Grade 3) of pts in the T-DXd and T-DXd + P modules, respectively. There were no Grade ≥4 nausea or diarrhea events. Adjudicated drug-related interstitial lung disease (ILD) / pneumonitis was reported in six (8.0%) and five (10.0%) pts in the T-DXd and T-DXd + P modules, respectively (all Grade ≤2). One non-treatment-related AE with outcome of death was reported in the T-DXd module (post-acute COVID-19 syndrome); none with T-DXd + P. The confirmed ORR was 77.3% (80% confidence interval [CI] 70.0, 83.6) with T-DXd and 82.0% (80% CI 73.1, 88.8) with T-DXd + P. PFS rate at 12 months was 77.3% (80% CI 69.0, 83.7) with T-DXd and 89.4% (80% CI 81.9, 93.9) with T-DXd + P. Conclusions: Safety profiles were consistent with the known profiles for T-DXd and P, with no Grade ≥3 ILD events. Early data showed promising efficacy in both modules. The DESTINY-Breast07 study is ongoing; analyses from the Phase 3 DESTINY-Breast09 clinical trial will provide definitive data on TDXd ± P in 1L HER2+ mBC. Clinical trial information: NCT04538742 . [Table: see text]

Analysis of drug-related interstitial lung disease (ILD) inpatients (pts) treated with datopotamab deruxtecan (Dato-DXd).

Analysis of drug-related interstitial lung disease (ILD) inpatients (pts) treated with datopotamab deruxtecan (Dato-DXd).

Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: Results from the bladder cohort of the DESTINY-PanTumor02 (DP-02) study.

4565 Background: In DP-02, T-DXd showed robust responses and clinically meaningful survival outcomes in 267 pretreated pts with HER2-expressing solid tumors; the objective response rate (ORR) by investigator (INV) was 37.1% (95% CI 31.3, 43.2). Here we report subgroup analyses in the bladder cohort (urothelial carcinoma including transitional cell carcinoma of the renal pelvis, ureter, urinary bladder, or urethra), and characterize pts with an objective response (OR). Methods: This open-label, Phase 2 study (NCT04482309) evaluated T-DXd (5.4 mg/kg Q3W) in pts with HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced/metastatic disease after ≥1 systemic treatment (Tx), or without Tx options. The primary endpoint was confirmed ORR by INV. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), and safety. Exploratory endpoints included efficacy outcomes according to HER2 expression. Results: At data cutoff (June 2023), 41 pts with urothelial cancers had received T-DXd (median [m] follow up [range]: 12.65 [0.4–26.8] months); 27 (65.9%) had received ≥2 prior Tx regimens. 16/41 pts (39.0%; 95% CI 24.2, 55.5) had a confirmed OR by INV; 12 responders had received ≥2 prior Tx regimens, 14 had received prior immunotherapy Tx, and 14 had known PD-L1 immune cell status ≥1%. The Table shows efficacy outcomes in all pts and by HER2 expression (central testing). Grade (G) ≥3 drug-related adverse events occurred in 17/41 (41.5%) pts. Adjudicated drug-related interstitial lung disease / pneumonitis occurred in 4/41 (9.8%) pts (n=1 G1; n=3 G2). Conclusions: T-DXd showed clinically meaningful responses in pretreated pts with urothelial cancers, including across HER2 expression levels (IHC 3+ and 2+). Safety was consistent with the known profile. These data support further evaluation of T-DXd as a potential Tx for pretreated pts with HER2-expressing urothelial cancers. Clinical trial information: NCT04482309 . [Table: see text]

Datopotamab deruxtecan (Dato-DXd) in Chinese patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Results from the phase 1/2 TROPION-PanTumor02 study.

8548 Background: Dato-DXd consists of a humanized anti-TROP2 IgG1 mAb conjugated to a potent topoisomerase I inhibitor via a stable cleavable linker. In the Phase 3 TROPION-Lung01 study, Dato-DXd demonstrated a statistically significant improvement in progression-free survival (PFS) over docetaxel in pts with previously treated, locally advanced or metastatic NSCLC (Ahn et al, ESMO 2023). The Phase 1/2, multicenter, open-label, multiple cohort TROPION-PanTumor02 study (NCT05460273) was designed to assess Dato-DXd in Chinese pts with advanced or metastatic solid tumors. Here we present results from the NSCLC cohort. Methods: Chinese pts (aged ≥18 years) with locally advanced or metastatic NSCLC with or without actionable genomic alterations (AGAs), who had been previously treated with immunotherapy and platinum-based chemotherapy (pts without AGAs) or targeted therapy and platinum-based chemotherapy (pts with AGAs), were enrolled. Pts received Dato-DXd (6 mg/kg IV Q3W). The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR) per RECIST v1.1. Analyses presented are based on the primary analysis data cut-off (DCO; Oct 9, 2023) with 6 months (mos) follow-up post the last pt’s first dose. Results: In the NSCLC cohort, 40 pts from 11 sites in China were enrolled. Median age was 59 years (range 33–74); 29 pts (72.5%) were male, and 18 (45.0%) were current or former smokers. 23 (57.5%)/17 (42.5%) pts had tumors with non-squamous/squamous histology. 5 pts (12.5%) had NSCLC with AGAs; 4 of these pts had sensitizing EGFR mutations. At DCO, 8 pts were ongoing treatment; median study follow-up was 8.1 mos (range 1.1–11.9). Overall, confirmed ORR by ICR was 45.0% (all partial responses), disease control rate by ICR was 85.0%, median duration of confirmed response was 8.3 mos, and median time to onset of response from first dose was 1.4 mos. ORR by ICR was 56.5% (13/23) in the non-squamous subgroup, 29.4% (5/17) in the squamous subgroup, and 75.0% (3/4) in pts with EGFR mutations. Median PFS by ICR (95% CI) was 7.4 mos (5.7–not calculable [NC]) overall, 9.6 mos (7.1–NC) in the non-squamous subgroup, and 5.5 mos (1.4–NC) in the squamous subgroup. Median treatment duration was 5.6 mos (range 0.7–10.6). Treatment-emergent adverse events (TEAEs) occurred in 95.0% of pts; grade ≥3 TEAEs occurred in 57.5%, and there were no fatal TEAEs. The most common TEAEs were nausea (62.5%), stomatitis (57.5%) and anemia (57.5%). TEAEs led to dose reduction/discontinuation in 20.0%/10.0% of pts. No adjudicated drug-related interstitial lung disease was reported. Conclusions: Dato-DXd showed encouraging efficacy in Chinese pts with advanced or metastatic NSCLC; the non-squamous subgroup appeared to derive the most benefit. The efficacy/safety profile was consistent with previous studies, with no new safety signals observed. Clinical trial information: NCT05460273 .

Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study

Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations. In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting. Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis. Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting. AstraZeneca and Daiichi Sankyo.

Abstract PO3-17-07: Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan

Abstract Background: Trastuzumab deruxtecan (T-DXd) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate. T-DXd has shown great efficacy in HER2-positive breast cancer, hence receiving approval in Japan in March 2020. In Japan, all-patient postmarketing surveillance (PMS) is underway to evaluate the risk of interstitial lung disease/pneumonitis (ILD/p) in patients with breast cancer treated with T-DXd. Due to the limited generalizability of results from clinical trials, there is a need for more information about ILD/p in a real-world setting. Herein we present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT1080225197) with an observation period of 18 months that enrolled all patients treated with T-DXd for recurrent/advanced HER2-positive breast cancer. Patients who initiated T-DXd treatment between May 2020 (launch date of T-DXd) and May 2021 were included in the interim analysis to ensure the observation period of 6 months from the initial treatment of T-DXd. This interim analysis is based on safety data from the first 6 months of 1204 patients. Data collected includes baseline characteristics and information on ILD/p. All potential ILD/p (identified based on the AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee. The incidence of ILD/p was calculated from adjudicated drug-related ILD/p. Results: The interim analysis set included 1204 patients with median age of 60 years. Three of the 1204 patients (0.2%) received T-DXd as a first-line treatment, 30 (2.5%) as second-line, 1159 (96.3%) as third- line or later treatment. At baseline, 105 (8.7%) of patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, 8 (0.7%) had severe renal impairment (15≤ creatinine clearance (CLcr) < 30 mL/min), 4 (0.3%) had end-stage renal disease (CLcr < 15 mL/min), 5 (0.4%) had severe liver impairment (total bilirubin >4.5 mg/dL), and 32 (2.7%) had comorbid ILD/radiation pneumonitis. Those were defined as exclusion criteria in clinical trials of T-DXd. The median dose at the start of administration of T-DXd was 5.4 mg/kg (range:2.7-5.4). During the first 6 months from the initial treatment, T-DXd was discontinued in 403 (33.5%) of the 1204 patients. The most common reasons for discontinuation were disease progression in 232 (57.6%) of the discontinued 403 patients followed by ILD/p in 97 (24.1%) of the 403 patients. In the first 6 months, the incidence of all grade, grade ≥3, and grade 5 ILD/p were 8.2% (n=99), 1.7% (n=20) and 0.4% (n=5), respectively. The incidence of ILD/p stratified by baseline characteristics identified as potential risk factors of drug-related ILD/p is shown in Table. Conclusion: This is the first report demonstrating real-world experience with T-DXd in Japan. The interim analysis revealed useful information including patient and treatment profiles of T-DXd and the incidence of ILD/p during the first 6 months from the initial treatment in a real-world setting in Japan. The final analysis of the ongoing PMS is warranted for further evaluation. Incidence of interstitial lung disease/pneumonitis by patient baseline characteristics XX XX ILD/p: interstitial lung disease/pneumonitis, 95% CI: 95% confidence interval, CLCr: creatinine clearance using the Cockcroft-Gault equation * includes ILD/p, pulmonary fibrosis, radiation pneumonitis, chronic obstructive pulmonary disease, emphysema, and Asthma (Source: Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open 2022;7(4):100554) Citation Format: Junji Tsurutani, Hideki Mizutani, Ayumi Tanabe. Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-07.

Abstract PO3-04-02: Exposure-efficacy and safety analysis of trastuzumab deruxtecan (T-DXd) in patients with advanced/metastatic HER2+ breast cancer (BC): Analyses from Phase 3 Studies DESTINY-Breast02 (DB-02) and DESTINY-Breast03 (DB-03)

Abstract Exposure-efficacy and exposure-safety analyses of trastuzumab deruxtecan (T-DXd) in patients with advanced/metastatic HER2+ breast cancer (BC): Analyses from Phase 3 Studies DESTINY-Breast02 (DB-02) and DESTINY-Breast03 (DB-03) Authors: Claire Li1, Russ Wada2, Hanbin Li2, Helen Kastrissios2, Malaz Abutarif1, Tushar Garimella1 , Amit Khatri1 1Quantitative Clinical Pharmacology, Daiichi Sankyo, Basking Ridge, NJ, USA 2QuanTx Consulting Mountain View, CA, USA Background: T-DXd, an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload, is approved for adult patients with unresectable or metastatic HER2+ BC with a prior anti-HER2–based therapy either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. The analysis evaluated the relationship between T-DXd pharmacokinetic (PK) exposure and efficacy/safety endpoints following 5.4 mg/kg Q3W in HER2+ BC subjects. Methods: Exposure-efficacy (E-E) analyses were evaluated from BC subjects in two Phase 3 studies, DB-02 (N=404 for T-DXd; 3L+ BC) and DB-03 (N=257 for T-DXd; 2L+ BC). In studies DB-02 and DB-03, 202 and 263 subjects in control arm were treated with treatment of investigator’s/physician’s choice (TPC) and T-DM1, respectively. Exposure-safety (E-S) analyses were conducted using 12 clinical studies ranging from Phase 1 to 3 (N=2216, 68.7% BC), including DB-02 and DB-03. Population PK-predicted exposure metrics included T-DXd and DXd peak concentration, trough concentration, and AUC in Cycle 1 and at steady state. Key efficacy endpoints were progression-free survival (PFS) based on blinded independent central review (BICR) and overall survival (OS). Safety endpoints included any Grade and Grade ≥ 3 adjudicated drug-related interstitial lung disease (ILD). Exploratory analyses were conducted for other safety endpoints (i.e., Grade ≥ 3 TEAEs). Results: T-DXd exposure was a significant predictor (p< 0.01) of OS in DB-02. In study DB-03, T-DXd exposure was a marginally significant covariate (p< 0.05) for OS in univariate Cox regression but was dropped in the multivariate analysis. The relationship between T-DXd exposure and PFS in both studies were not statistically significant (p >0.01), suggesting a flat E-E relationship due to the narrow exposure range resulting from the single-dose level (5.4 mg/kg Q3W) in both studies. Clinically meaningful efficacy in the T-DXd arm relative to the control arm was observed in both studies (PFS: 17.8 months [T-DXd arm] vs. 6.9 months [TPC arm] in study DB-02 and 28.8 months [T-DXd arm] vs. 6.8 months [T-DM- arm] in study DB-03). Therefore, the E-E analyses supports clinically meaningful efficacy across the entire exposure range with the T-DXd 5.4 mg/kg dose in BC subjects. For E-S, a statistically significant relationship (p< 0.001) was observed between increasing T-DXd exposures across all the dose levels (0.8 to 8 mg/kg) and increasing hazard of any Grade and Grade ≥ 3 ILD. The predicted Day 360 incidence rate of any Grade and Grade ≥3 ILD at 5.4 mg/kg Q3W T-DXd in BC subjects was 14.8% and 3%, respectively. These findings are consistent with previous safety analyses. Observed rates of the exploratory safety endpoints were also generally consistent with previous model-predicted rates of adverse events in BC1. Conclusions: The E-E analyses support clinically meaningful efficacy (PFS and OS) relative to control with a flat exposure-response relationship in HER2+ BC subjects at the T-DXd 5.4 mg/kg dose. The E-S analyses showed any Grade and Grade ≥ 3 ILD event rates for this dose are comparable to prior studies1. Those event rates appeared to increase with increasing T-DXd exposures. Overall, these model-based analyses continue to support T-DXd 5.4 mg/kg Q3W dosing in previously treated HER2+ BC. Reference: Yin O, Iwata H, Lin, C, et al. Exposure-Response Relationships in Patients with HER2-Positive Metastatic Breast Cancer and Other Solid Tumors Treated with Trastuzumab Deruxtecan. J Clin Pharm Ther. 2021; 110(4):986-96 Citation Format: Claire Li, Russ Wada, Hanbin Li, Helen kastrissios, malaz Abutarif, Tushar Garimella, Amit Khatri. Exposure-efficacy and safety analysis of trastuzumab deruxtecan (T-DXd) in patients with advanced/metastatic HER2+ breast cancer (BC): Analyses from Phase 3 Studies DESTINY-Breast02 (DB-02) and DESTINY-Breast03 (DB-03) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-02.

Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial

DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. Daiichi Sankyo and AstraZeneca.

Datopotamab deruxtecan in locally advanced/metastatic urothelial cancer: Preliminary results from the phase 1 TROPION-PanTumor01 study.

603 Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd has shown encouraging antitumor activity and a manageable safety profile in patients (pts) with solid tumors. We report preliminary results in pts with advanced/metastatic (a/m) urothelial cancer from the ongoing phase 1 TROPION-PanTumor01 study (NCT03401385). Methods: Pts with unresectable a/m urothelial cancer treated with ≥1 prior line of therapy received intravenous Dato-DXd 6 mg/kg Q3W. Primary study objectives were safety and tolerability. Secondary endpoints were objective response rate (ORR; complete response [CR] + partial response [PR]), and disease control rate (DCR; CR + PR + stable disease) per RECIST 1.1 by BICR. This is the first data disclosure from this cohort in an ongoing expansion cohort study. Results: At data cutoff (May 18, 2023), 18 pts had received Dato-DXd. Median follow-up was 9.1 (range 5–17) months; 6 (33.3%) pts were receiving ongoing treatment. Median age was 63.5 (range 46–79) yrs. Pts were heavily pretreated, 15 (83.3%) had received ≥3 prior regimens. All pts received prior immunotherapy, 17 (94.4%) prior platinum-based chemotherapy, and 4 (22.2%) prior taxanes. Treatment-emergent adverse events (TEAEs) occurred in 100% (any grade [gr]) and 44.4% (gr ≥3) of pts, and drug-related TEAEs occurred in 94.4% (any gr) and 16.7% (gr ≥3) of pts. No drug-related serious AEs were reported, and no TEAEs associated with death were observed. Any gr TEAEs associated with reduction, interruption, and discontinuation of treatment were reported in 11.1%, 33.3%, and 5.6% of pts, respectively (Table). Adjudicated drug-related interstitial lung disease (gr 2) occurred in 1 (5.6%) pt. Confirmed ORR was 27.8% (95% CI 9.7–53.5); 1 pt achieved a CR and 4 achieved a PR. DCR was 77.8% (95% CI 52.4–93.6). Clinical evaluation of this cohort is ongoing and updated results will be presented. Conclusions: In heavily pretreated pts with a/m urothelial cancer, Dato-DXd demonstrated a tolerable and manageable safety profile with encouraging antitumor activity. Dato-DXd is being evaluated in pts with urothelial cancer as part of the phase 1/2 TROPION-PanTumor02 (NCT05460273) and the phase 2 TROPION-PanTumor03 (NCT05489211) studies. Clinical trial information: NCT03401385 . [Table: see text]

Real-world experience with trastuzumab deruxtecan among patients with gastric cancer: 4 month-interim analysis of an all-patient post-marketing surveillance study in Japan.

273 Background: Interstitial lung disease (ILD) is an important identified risk in the Japanese risk management plan of trastuzumab deruxtecan (T-DXd). In Japan, all-patient post-marketing surveillance (PMS) is underway to investigate the risk of ILD among patients with gastric cancer treated with T-DXd in a real-world setting. We present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT2001200001) with an observation period of 12 months that enrolled all patients treated with T-DXd for HER2-positive unresectable advanced or recurrent gastric cancer between Sep 2020 and Dec 2021. This interim analysis is based on safety data from the first 4 months of all enrolled patients. All potential ILD (identified based on the pre-specified list of AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee (ILD-AC). The incidence of ILD was calculated from adjudicated drug-related ILD. Results: The interim analysis set included 1074 patients with median age of 70 years (range: 23-100). Of the 1074 patients, 1051 (97.9%) received T-DXd as third-line or later treatment. One hundred and eight patients (10.1%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, and 32 (3.0%), 3 (0.3%), and 23 (2.1%) patients had severe renal impairment (15≤ creatinine clearance (CL) <30 mL/min), end-stage renal disease (CL <15 mL/min), and ILD/radiation pneumonitis at baseline, respectively (all of which were defined as exclusion criteria in clinical trials of T-DXd). Median initial dose of T-DXd was 6.4 mg/kg (range: 3.1-6.4). Median treatment duration of T-DXd was 4.0 months (range: 0.7-4.0). During the first 4 months from the initial treatment, T-DXd was discontinued in 50.9% (547/1074) of patients. The most common reasons for treatment discontinuation were disease progression (n=390, 71.3%), adverse events other than ILD (n=76, 13.9%), and ILD (n=56, 10.2%). All potential ILD that occurred during the first 4 months were adjudicated by ILD-AC, and the incidence of all grades, grade ≥3, and grade 5 adjudicated drug-related ILD were 5.2% (n=56), 1.5% (n=16) and 0.7% (n=7), respectively. Of the 56 patients with adjudicated drug-related ILD, 54 (96.4%) discontinued T-DXd. The incidence of adjudicated drug-related ILD by time from initial treatment of T-DXd were 0.7% (7/1074) at ≤ 1 month, 2.0% (19/949) at 1-2 months, 2.7% (22/829) at 2-3 months, and 1.2% (8/652) at 3-4 months. Conclusions: The interim analysis revealed patient experiences and treatment profiles of T-DXd and the incidence of ILD during the first 4 months since initial treatment in a real-world setting in Japan. The final analysis including a risk factor analysis for ILD of the ongoing PMS is planned.

Trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2-expressing salivary gland carcinoma: a pooled analysis of two phase I studies.

HER2-expressing salivary gland carcinoma (SGC) is associated with poor prognosis. Trastuzumab deruxtecan (T-DXd, DS-8201) has shown evidence of antitumor activity for several HER2-expressing solid tumors in multiple studies. This study aimed to present the efficacy and safety of T-DXd in patients with HER2-expressing SGC from a pooled analysis. Patients with HER2-expressing SGC were pooled from two phase I, open-label studies of T-DXd: a two-phase, multiple-dose, first-in-human study (NCT02564900) and a single-sequence crossover drug-drug interaction study (NCT03383692). Endpoints included efficacy (objective response rate [ORR], duration of response [DoR] and progression-free survival [PFS]) and safety. This pooled analysis included 17 patients with SGC (median age: 57 years; male: 88.2%); median (range) follow-up duration was 12.0 (2.3-‍34.8) months. Among these patients, 14 had received prior HER2-targeted agents and 13 had undergone prior radiotherapy. The investigator-assessed confirmed ORR was 58.8% (95% confidence interval [CI], 32.9-‍81.6). The median (95% CI) DoR and PFS were 17.6 months (4.0 to not evaluable [NE]) and 20.5 months (11.1-NE), respectively. All 17 patients reported treatment-emergent adverse events (TEAEs); 76.5% reported TEAEs of grade ≥3. The most common TEAEs were decreased appetite (94.1%), nausea (88.2%) and neutrophil count decreased (76.5%). Of the 17 patients, five (29.4%) reported adjudicated drug-related interstitial lung disease (grade 1, n = 3; grade 2, n =1; grade 3, n = 1). The results of this pooled analysis provide evidence that clinical benefit is achievable with T-DXd in patients with HER2-expressing SGC. FIH study, NCT02564900; DDI study, NCT03383692.

Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer: a plain language summary of the DESTINY-Breast03 study.

This is a summary of a publication about the DESTINY-Breast03 study, which was published in the New England Journal of Medicine in March 2022. The study included 524 adults with advanced breast cancer that is HER2-positive, which means it has high levels of a protein called HER2. All of the participants in this study had their cancer worsen after previously receiving treatment. The treatment that was previously given to participants was a combination of a drug called trastuzumab with a type of chemotherapy called a taxane. The researchers wanted to know whether a drug called trastuzumab deruxtecan (T-DXd) could improve participants' cancer more than the standard treatment. The standard treatment is a drug called trastuzumab emtansine (T-DM1). The researchers looked at the results of this study before it was finished. This is a summary of those results. Researchers in this study found that the risk of dying or the participants' cancer getting worse was reduced by 72% in the T-DXd group compared with the T-DM1 group. This is also called progression-free survival. 79.7% of participants in the T-DXd group had their tumors shrink significantly or disappear, compared to 34.2% of those in the T-DM1 group. During the study, 10.9% of participants who received T-DXd had serious drug-related medical problems, compared to 6.1% who received T-DM1. Of the participants who received T-DXd, 10.5% experienced drug-related interstitial lung disease (ILD) or pneumonitis, compared to 1.9% of those who received T-DM1. ILD and pneumonitis are potentially serious lung problems. When the researchers first looked at the results, they could not yet be certain that T-DXd helped participants survive longer overall than T-DM1. But, when they looked at the results later in the study, they found that T-DXd did help participants to survive longer overall than T-DM1. These newer results were published separately and are not part of this summary. A link to more information about the newer results can be found at the end of this summary. T-DXd gave participants a meaningful benefit overall compared to T-DM1. T-DXd could be a treatment option for people with advanced HER2-positive breast cancer that has been previously treated. Clinical Trial Registration: NCT03529110 (DESTINY-Breast03) (ClinicalTrials.gov).

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study

BackgroundTrastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate that consists of an anti-human epidermal growth factor receptor 2 (HER2) antibody bound by a cleavable tetrapeptide-based linker to a cytotoxic topoisomerase I inhibitor. Prior to marketing approval in Japan in September 2020, this expanded-access study was conducted to provide T-DXd to previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas.MethodsThis multicenter, open-label, expanded-access study was conducted between March 25 and September 25, 2020 at 17 Japanese sites. Previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas received T-DXd 6.4 mg/kg via intravenous infusions at 3-week intervals. Serious adverse events (SAEs), all potential cases of interstitial lung disease (ILD)/pneumonitis, all liver-related events potentially meeting Hy’s Law criteria, and all cases of overdose were reported on the case report forms.ResultsA total of 64 patients were treated with T-DXd. Among the 17 (26.6%) patients with reported SAEs, 10 (15.6%) had SAEs related to T-DXd treatment. Febrile neutropenia was the most common SAE (n = 6). SAEs led to death in six patients; drug-related SAEs (sepsis and febrile neutropenia) led to death in one patient. Drug-related ILD, as determined by the external Adjudication Committee, occurred in three patients (Grade 1, Grade 2, and Grade 3: all n = 1).ConclusionThis expanded-access study provided T-DXd to a broader population of Japanese patients prior to marketing approval in Japan, bridging the gap between clinical trials and drug approval. No new safety concerns were identified.