Drug-related Interstitial Lung Disease Research Articles

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.

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]

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]

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.

TROPION-Lung02: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) in advanced non-small cell lung cancer (aNSCLC).

9004 Background: Despite advances in first-line (1L) immunotherapy ± CT, most patients (pts) with aNSCLC experience disease progression, necessitating novel strategies. Dato-DXd is an antibody drug conjugate (ADC) composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a topoisomerase I inhibitor payload via a plasma-stable tetrapeptide-based cleavable linker. Dato-DXd had encouraging efficacy and manageable safety in heavily pretreated aNSCLC. Dato-DXd + immunotherapy yielded greater preclinical activity than either agent alone. Methods: TROPION-Lung02 (NCT04526691) is a phase 1b, global, dose-escalation and -expansion study evaluating Dato-DXd (4 or 6 mg/kg) + pembro 200 mg ± Pt-CT (cisplatin 75 mg/m2 or carboplatin AUC 5) every 21 days across 6 cohorts. Pts in escalation may have received ≤2 prior lines of therapy for aNSCLC. Pts in expansion were primarily treatment (tx) naive (pts receiving Dato-DXd + pembro may have ≤1 prior Pt-based tx). The primary objective is to assess safety and tolerability, including dose-limiting toxicities (DLTs). Secondary objectives include evaluation of efficacy, pharmacokinetics, and immunogenicity. Results: As of the Oct 31, 2022, data cutoff (DCO), 120 pts were treated. All cohorts met DLT criteria to move to escalation. Median age was 65 years. PD-L1 expression was <1%, 1%-49%, and ≥50% in 40%, 33%, and 26% of pts, respectively. Median tx duration was 4.6 mo, with 55% receiving tx at DCO. The most frequent any-grade (gr) tx-emergent adverse events (TEAEs) were nausea (45%) and stomatitis (45%). Gr ≥3 TEAEs occurred in 61% of pts; most frequent were neutrophil count decreased (8%) and amylase increased (8%). TEAEs that were serious, associated with discontinuation, or associated with death occurred in 31%, 24% (16% associated with Dato-DXd), and 6% of pts, respectively. Dose reductions due to TEAEs associated with Dato-DXd occurred in 17%. Drug-related interstitial lung disease occurred in 12 pts (10%; 9 gr 1/2; 3 gr 3). The objective response rate (ORR) with 1L Dato-DXd + pembro doublet and Dato-DXd + pembro + Pt-CT triplet tx was 60% (95% CI, 36%-81%; 12 [2 unconfirmed]/20) and 55% (95% CI, 39%-70%; 23 [5 unconfirmed]/42), respectively. The ORR for any line of therapy was 38% (95% CI, 25%-54%; 18 [2 unconfirmed]/47) with doublet and 47% (95% CI, 34%-60%; 28 [5 unconfirmed]/60) with triplet tx. In both subsets, the disease control rate was 85% and median duration of response was not reached. Responses were observed in all 3 PD-L1 expression level subgroups. Although immature, median progression-free survival (95% CI) was 10.8 (8.3-15.2) and 7.8 mo (5.5-NE) with doublet and triplet tx, respectively. Conclusions: Dato-DXd + pembro ± Pt-CT demonstrated tolerable safety with notable 1L activity in this first and largest dataset with an ADC + immunotherapy ± Pt-CT in aNSCLC pts. Clinical trial information: NCT04526691 .

Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study.

3501 Background: T-DXd (6.4 mg/kg, every 3 weeks [Q3W]) demonstrated antitumor activity in pts with HER2+ mCRC in DESTINY-CRC01 (Siena et al. Lancet Oncol. 2021). We present primary results of DESTINY-CRC02 (NCT04744831), which assessed the efficacy and safety of T-DXd (5.4 and 6.4 mg/kg) in pts with HER2+ mCRC. Methods: This was a multicenter phase 2 study. Eligible pts had centrally confirmed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) mCRC. Pts with RAS wild-type (wt) or mutant (m) mCRC were eligible. Pts had received prior standard therapy, unless contraindicated; prior anti-HER2 therapy was allowed. In stage 1, 80 pts were randomized 1:1 to 5.4 (n = 40) or 6.4 (n = 40) mg/kg T-DXd Q3W. In stage 2, an additional 42 pts received 5.4 mg/kg T-DXd. Primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: At data cutoff (Nov 1, 2022), most pts in the 5.4 and 6.4 mg/kg T-DXd arms had HER2 IHC 3+ (78.0% and 85.0%), RAS wt tumors (82.9% and 85.0%), and a median of 3 and 4 prior lines of therapy, respectively. cORR was 37.8% (95% CI, 27.3-49.2%) in the 5.4 mg/kg arm and 27.5% (95% CI, 14.6-43.9%) in the 6.4 mg/kg arm (all partial responses in both arms). Key efficacy data are shown in the Table: Grade ≥3 treatment-emergent adverse events (AEs) were observed in 41/83 pts (49.4%) and 23/39 pts (59.0%) in the 5.4 and 6.4 mg/kg T-DXd arms, respectively. Serious AEs were observed in 20/83 pts (24.1%) and 12/39 pts (30.8%) in the 5.4 and 6.4 mg/kg arms, respectively. Independently adjudicated drug-related interstitial lung disease occurred in 7/83 pts (8.4%) with 5.4 mg/kg T-DXd and 5/39 pts (12.8%) with 6.4 mg/kg T-DXd, and most events were grade 1/2 (1 grade 5 in the 6.4 mg/kg arm). Conclusions: T-DXd showed promising antitumor activity in pts with HER2+ mCRC at both 5.4 and 6.4 mg/kg doses. Antitumor efficacy was observed irrespective of RAS mutation status at 5.4 mg/kg T-DXd, and in those with prior anti-HER2 therapy. Overall, safety was consistent with the known safety profile of T-DXd and favored the 5.4 mg/kg dose. Clinical trial information: NCT04744831 . [Table: see text]

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial

In the single-arm, phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan showed robust activity in patients with HER2-positive metastatic breast cancer who were refractory or resistant to trastuzumab emtansine; a population with scarce effective treatments. In DESTINY-Breast02, we aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in this patient population. This randomised, open-label, multicentre, phase 3 trial was conducted at 227 sites (hospitals, university hospitals, clinics, community centres, and private oncology centres) in North America, Europe, Asia, Australia, Brazil, Israel, and Türkiye. Eligible patients were aged 18 years or older, had unresectable or HER2-positive metastatic breast cancer, previously received trastuzumab emtansine, disease progression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate renal and hepatic function. Patients were randomly assigned (2:1) to receive trastuzumab deruxtecan (intravenously at 5·4 mg/kg once every 3 weeks) or treatment of physician's choice using block randomisation. Treatment of physician's choice was either capecitabine (1250 mg/m2; orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint was progression-free survival based on blinded independent central review in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03523585. Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). 608 (100%) patients were included in the full analysis set. The median age was 54·2 years (IQR 45·5-63·4) in the trastuzumab deruxtecan group and 54·7 years (48·0-63·0) in the treatment of physician's choice group. 384 (63%) patients were White, 603 (99%) were female, and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (8·8-26·0) in the treatment of physician's choice group. Median progression-free survival by blinded independent central review was 17·8 months (95% CI 14·3-20·8) in the trastuzumab deruxtecan group versus 6·9 months (5·5-8·4) in the treatment of physician's choice group (HR 0·36 [0·28-0·45]; p<0·0001). The most common treatment-emergent adverse events were nausea (293 [73%] of 404 with trastuzumab deruxtecan vs 73 [37%] of 195 with treatment of physician's choice), vomiting (152 [38%] vs 25 [13%]), alopecia (150 [37%] vs eight [4%]), fatigue (147 [36%] vs 52 [27%]), diarrhoea (109 [27%] vs 105 [54%]), and palmar-plantar erythrodysaesthesia (seven [2%] vs 100 [51%]). Grade 3 or higher treatment-emergent adverse events occurred in 213 (53%) patients receiving trastuzumab deruxtecan versus 86 (44%) receiving treatment of physician's choice; whereas drug-related interstitial lung disease occurred in 42 (10%; including two grade 5 death events) versus one (<1%). DESTINY-Breast02 shows the favourable benefit-risk profile of trastuzumab deruxtecan in patients with HER2 positive metastatic breast cancer, as previously reported in DESTINY-Breast01, and is the first randomised study to show that one antibody-drug conjugate can overcome resistance to a previous one. Daiichi Sankyo and AstraZeneca.

Abstract PD13-08: PD13-08 Phase 1 TROPION-PanTumor01 Study Evaluating Datopotamab Deruxtecan (Dato-DXd) in Unresectable or Metastatic Hormone Receptor–Positive/HER2–Negative Breast Cancer (BC)

Abstract Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd demonstrated compelling single-agent antitumor activity in heavily pretreated patients (pts) with metastatic triple-negative BC (Krop, SABCS 2021). This is the first report of results from the TROPION-PanTumor01 study in pts with unresectable or metastatic hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−; including HER2-low and HER2-zero) BC. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multicenter, open-label, 2-part dose-escalation/expansion study evaluating Dato-DXd in previously treated pts with solid tumors. Based on previous clinical findings and exposure-response results from pts with NSCLC, Dato-DXd 6 mg/kg IV Q3W is being evaluated in pts with unresectable or metastatic HR+/HER2− BC that progressed on standard therapies. The primary objectives were safety and tolerability. Tumor responses, including ORR (complete response [CR] + partial response [PR]) and DCR (CR + PR + stable disease [SD]), were assessed per RECIST version 1.1 by blinded independent central review. Results: As of the April 29, 2022, data cutoff, 41 pts had received Dato-DXd (median follow-up, 10.9 mo [range, 7-13]); 9 pts were ongoing. The primary cause of treatment discontinuation was disease progression (63%; progressive disease [PD] or clinical progression). Median age was 57 y (range, 33-75); 54% had de novo metastatic disease. Pts were heavily pretreated (Table) with a median of 5 (range, 3-10) prior regimens in the advanced setting; 95% had prior CDK4/6i (adjuvant/metastatic). Median time from initial treatment for metastatic disease to the first dose of Dato-DXd was 42.7 mo (range, 10.2-131.1). Treatment-emergent adverse events (TEAEs; all cause) were observed in 98% (any grade) and 41% (grade ≥3) of pts. Most common TEAEs (any grade, grade ≥3) were stomatitis (80%, 10%), nausea (56%, 0%), fatigue (46%, 2%), and alopecia (37%, 0%). Serious TEAEs were observed in 6 pts (15%); 1 pt died due to dyspnea, which was not considered to be treatment related. Dose reductions occurred in 5 pts due to stomatitis (n=3), fatigue (n=2), keratitis (n=1), and decreased appetite (n=1) (&amp;gt;1 AE per pt); 14 pts had treatment delayed due to stomatitis (n=8), retinopathy (n=1), dysphagia (n=1), fatigue (n=1), malaise (n=1), COVID-19 (n=1), cellulitis (n=1), urinary tract infection (n=1), decreased lymphocyte count (n=1), and nasal congestion (n=1; &amp;gt;1 AE per pt). Three pts discontinued treatment due to keratitis (n=1) and pneumonitis (n=2); 1 case of pneumonitis was adjudicated as grade 2 drug-related interstitial lung disease. The ORR was 29% (11 confirmed PRs; 1 pending confirmation), the DCR was 85% (35/41), and the clinical benefit rate (CR + PR + SD ≥6 mo) was 41% (17/41). Conclusions: Dato-DXd demonstrated a manageable safety profile and encouraging antitumor activity, with high disease control in heavily pretreated pts, the majority having received prior CDK4/6i. Based on these findings, the TROPION-Breast01 (NCT05104866) randomized phase 3 study comparing 2L+ Dato-DXd vs investigator’s choice chemotherapy is currently enrolling pts with HR+/HER2− BC. Prior Therapies in the Adjuvant or Metastatic Setting Citation Format: Funda Meric-Bernstam, Ian Krop, Dejan Juric, Takahiro Kogawa, Erika Hamilton, Alexander I. Spira, Toru Mukohara, Takuya Tsunoda, Senthil Damodaran, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Hong Zebger-Gong, Yui Kawasaki, Rie Wong, Aditya Bardia. PD13-08 Phase 1 TROPION-PanTumor01 Study Evaluating Datopotamab Deruxtecan (Dato-DXd) in Unresectable or Metastatic Hormone Receptor–Positive/HER2–Negative Breast Cancer (BC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-08.

Abstract GS2-01: GS2-01 Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized, phase 3 study DESTINY-Breast02

Abstract In DESTINY-Breast01 (NCT03248492) and DESTINY-Breast03 (NCT03529110), trastuzumab deruxtecan (T-DXd) demonstrated unprecedented activity in patients (pts) with HER2+ (immunohistochemistry 3+; immunohistochemistry 2+/in situ hybridization+) advanced metastatic breast cancer (mBC), leading to regulatory approvals in several countries for HER2+ unresectable/mBC after a prior anti–HER2-based regimen. DESTINY-Breast02 (NCT03523585) is a phase 3 trial of T-DXd vs treatment of physician’s choice (TPC) in patients with centrally confirmed HER2+ mBC previously treated with trastuzumab emtansine (T-DM1). It acts as a confirmatory study for the pivotal phase 2 DESTINY-Breast01 trial. Here we report the primary results of DESTINY-Breast02. Methods: Pts with HER2+ mBC were randomized 2:1 to receive T-DXd or TPC (trastuzumab + capecitabine or lapatinib + capecitabine) and stratified by hormone receptor (HR) status (HR+/HR-), prior pertuzumab treatment, and history of visceral disease. The primary endpoint of this time-driven primary analysis was progression-free survival (PFS) as determined by blinded independent central review (BICR). The powered secondary endpoint was overall survival (OS). Other secondary endpoints included confirmed objective response rate (ORR) by BICR, duration of response (DoR) by BICR, PFS by investigator assessment, safety, and others. Results: 608 pts were randomized to receive T-DXd (n = 406) or TPC (n = 202). Pts receiving T-DXd and TPC had a median age of 54.2 years (range, 22.4-88.5 years) and 54.7 years (range, 24.7-86.5 years), respectively, with a median of 2 (range, 0-10 and range,1-8) prior lines of systemic therapy (excluding hormone therapy) in the metastatic setting. Median treatment duration was 11.3 mo in the T-DXd arm and ~4.5 mo in the TPC arm. Efficacy and safety results are shown in the table below. T-DXd significantly improved PFS (HR, 0.36; 95% CI, 0.28-0.45; P &amp;lt;0.000001) and OS (HR, 0.66; 95% CI, 0.50-0.86; P = 0.0021) compared with TPC. Confirmed ORR was 69.7% (14% complete response) with T-DXd and 29.2% (5.0% complete response) with TPC. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 52.7% and 44.1% of pts receiving T-DXd and TPC, respectively. Adjudicated drug-related interstitial lung disease (ILD) occurred in 10.4% of pts with T-DXd vs 0.5% of pts with TPC. In pts receiving T-DXd, most ILD cases (88.1%) were grade 1/2 and grade 5 ILD was reported in 2 (0.5%) pts. Conclusions: Results from DESTINY-Breast02 confirmed the clinical benefit and superiority of T-DXd over conventional chemotherapy-based regimens in pts with HER2+ mBC previously treated with T-DM1, as evidenced by significant and clinically meaningful improvements in PFS and OS. These data, together with earlier reported results from the DESTINY-Breast03 study of T-DXd vs T-DM1 solidify T-DXd as an optimal treatment option in pts with progressive HER2+ mBC across broad settings. Editorial Acknowledgment Under guidance of the authors, assistance in medical writing and editorial support was provided by Caylin Bosch, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table. Summary of Efficacy and Safety Results for T-DXd and TPC in Patients With HER2+ mBC Previously Treated With T-DM1 Citation Format: Ian Krop, Yeon H. Park, Sung-Bae Kim, Giuliano Borges, Sercan Aksoy, Joaquin Gavila Gregori, Rebecca Roylance, Elgene Lim, Rinat Yerushalmi, Flora Zagouri, Francois P. Duhoux, Tanja Fehm, Toshimi Takano, Anton Egorov, Iris Wu, Jillian Cathcart, Changan Chu, Fabrice Andre. GS2-01 Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized, phase 3 study DESTINY-Breast02 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-01.

Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial

An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110. Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group. Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration. Daiichi Sankyo and AstraZeneca.

976P Phase II trial of trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutated (HER2m) metastatic non-small cell lung cancer (NSCLC): Registrational data from DESTINY-Lung01

In the primary analysis of DESTINY-Lung01 (NCT03505710; data cutoff May 3, 2021), T-DXd (a HER2-targeting antibody–drug conjugate) in pts with previously treated HER2m NSCLC had a confirmed objective response rate (ORR) of 55% (95% CI, 44-65) and a safety profile generally consistent with previous reports (Li N Engl J Med 2021). This update provides additional subgroup analyses and longer follow-up in all pts. Pts with HER2m NSCLC refractory to standard therapy received T-DXd 6.4 mg/kg IV Q3W. Primary endpoint was ORR per RECIST v1.1 by independent central review (ICR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. At data cutoff (December 3, 2021), 91 pts with HER2m NSCLC were assessed. At baseline, 36.3% had asymptomatic central nervous system metastasis (CNS met); 33.0% had >2 prior therapies; 94.5% had prior platinum-based chemotherapy (CT). Median follow-up and treatment duration were 16.7 and 6.9 mo, respectively. The table shows primary endpoint for the overall and subgroup populations, including pts with CNS met. In the overall population, median PFS was 8.2 mo (95% CI, 6.0-11.9); median OS was 18.6 mo (95% CI, 13.8-25.8); median DOR was 10.6 mo (5.8-17.7); DCR was 92.3% (95% CI, 84.8-96.9). Drug-related treatment-emergent adverse events (TEAEs) occurred in 88 (96.7%) pts. The most common TEAEs were nausea (76.9%), vomiting (47.3%), and alopecia (46.2%). Adjudicated drug-related interstitial lung disease occurred in 25 (27.5%) pts (3 grade [G] 1, 16 G 2, 4 G 3, 2 G 5).Table: 976PT-DXd efficacy in HER2m NSCLCOverall N = 91Prior therapyCT n = 86CT and anti–PD-(L)1 n = 57CNS metHER2 KD mut n = 85≤2 lines n = 61>2 lines n = 30Yes n = 33No n = 58ORR by ICR, n (%) 95% CI50 (54.9) 44.2-65.434 (55.7) 42.5-68.516 (53.3)34.3-71.746 (53.5) 42.4-64.337 (64.9) 51.1-77.118 (54.5) 36.4-71.932 (55.2) 41.5-68.349 (57.6) 46.5-68.3Complete response1 (1.1)NA1 (1.2)001 (1.7)NAPartial response49 (53.8)45 (52.3)37 (64.9)18 (54.5)31 (53.4)Stable disease34 (37.4)34 (39.5)16 (28.1)14 (42.4)20 (34.5)Progressive disease3 (3.3)2 (2.3)1 (1.8)03 (5.2)Nonevaluable4 (4.4)4 (4.7)3 (5.3)1 (3.0)3 (5.2)DOR, median, mo 95% CI10.6 5.8-17.712.0 5.7-18.310.6 5.6-18.3NANA, not available. Open table in a new tab NA, not available. T-DXd showed durable anticancer activity that was consistent across subgroups including pts with >2 prior therapies and pts with CNS met. The updated results show no new safety signals and provide further evidence supporting T-DXd as a new treatment standard in pts with previously treated HER2m NSCLC.

Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies

This pooled analysis of nine phase I and II trastuzumab deruxtecan (T-DXd) monotherapy studies described drug-related interstitial lung disease (ILD)/pneumonitis in patients treated with T-DXd. Patients who received T-DXd across nine studies were included. Investigator-assessed ILD/pneumonitis events were retrospectively reviewed by an independent adjudication committee; events adjudicated as drug-related ILD/pneumonitis are summarized. The analysis included 1150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%; other cancer, 3.0%). Median treatment duration was 5.8 (range, 0.7-56.3) months, with a median of 4 (range, 1-27) prior lines of therapy. The overall incidence of adjudicated drug-related ILD/pneumonitis was 15.4% (grade 5, 2.2%). Most patients with ILD/pneumonitis experienced low-grade events (grade 1 or 2, 77.4%); 87.0% had their first event within 12 months [median, 5.4 (range, <0.1-46.8) months] of their first dose of T-DXd. Based on data review, adjudicated ILD/pneumonitis onset occurred earlier than identified by investigators for 53.2% of events [median difference in onset date, 43 (range, 1-499) days]. Stepwise Cox regression identified several baseline factors potentially associated with increased risk of adjudicated drug-related ILD/pneumonitis: age <65 years, enrollment in Japan, T-DXd dose >6.4 mg/kg, oxygen saturation <95%, moderate/severe renal impairment, presence of lung comorbidities, and time since initial diagnosis >4 years. In this pooled analysis of heavily treated patients, the incidence of ILD/pneumonitis was 15.4%, with most being low grade and occurring in the first 12 months of treatment. The benefit-risk of T-DXd treatment is positive; however, some patients may be at increased risk of developing ILD/pneumonitis, and further investigation is needed to confirm ILD/pneumonitis risk factors. Close monitoring and proactive management of ILD/pneumonitis are warranted for all.