Trastuzumab emtansine (T-DM1) in previously treated HER2-positive metastatic breast cancer (MBC): Results from an expanded access study.

2013 ◽  
Vol 31 (26_suppl) ◽  
pp. 166-166 ◽  
Author(s):  
Denise Aysel Yardley ◽  
Ian E. Krop ◽  
Patricia LoRusso ◽  
Nicholas J. Robert ◽  
Musa Mayer ◽  
...  
Keyword(s):  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Significant Activity ◽  
Bleeding Events ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Expanded Access ◽  
Previously Treated ◽  
Grade 3

166 Background: T-DM1 is an antibody-drug conjugate composed of trastuzumab, a stable linker, and the cytotoxic agent DM1. Few T-DM1 data are available in settings approximating clinical practice. We present safety and efficacy data from T-PAS, an expanded access study of T-DM1 in patients (pts) with previously treated HER2-positive MBC. Methods: T-PAS is a US multicenter study of T-DM1 (3.6 mg/kg q3w) in HER2-positive (IHC 3+ or FISH/CISH+) locally advanced or MBC. Key eligibility criteria: prior anthracycline and taxane; prior capecitabine or 5-FU and ≥2 HER2-directed agents (including trastuzumab and lapatinib) for MBC; LVEF ≥50%. Primary endpoint: safety; secondary endpoint: investigator-assessed objective response rate (ORR) in pts with measurable disease. Safety was assessed on day 1 of each cycle; ECHO/MUGA scans were every 12 weeks. Results: This analysis includes 215 pts enrolled in May 2010–Sep 2011 (data cutoff 7/31/2012). Pts received a median of 7 prior systemic MBC therapies (range 1–23) with a median cumulative anthracycline dose of 240 mg/m2(range 6–2645). At baseline, median LVEF was 60% and 50% of pts had investigator-reported cardiovascular disease. Median follow-up was 5.9 months (range 0.1–25.3); median T-DM1 duration was 5.0 months (range 0–23) with 15.8% receiving >18 cycles. ORR was 25.6% (42/164). Rate of grade ≥3 AEs was 43.7% and of SAEs of any grade was 18.1%. Most common all-grade AEs were fatigue (50.7%), nausea (36.3%), and headache (24.2%). Most common grade ≥3 AEs were thrombocytopenia (7.9%), fatigue (4.7%), and increased aspartate aminotransferase and anemia (each 3.7%). There were no grade ≥3 bleeding events. Cardiac dysfunction (primarily asymptomatic decreases in LVEF) was reported in 8 pts (3.7%); 4 were grade ≥3, 3 resulting in T-DM1 discontinuation. Conclusions: In this study that more closely reflects the real-world setting, the safety profile of T-DM1 was similar to that previously reported in conventional clinical trials, with no new safety signals. In this pretreated population (median of 7 prior therapies for HER2-positive MBC), significant activity was observed. Clinical trial information: NCT01120561.

Efficacy, safety, and biomarker results of trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8509-8509 ◽  
Author(s):  
Tom Stinchcombe ◽  
Rolf A. Stahel ◽  
Lukas Bubendorf ◽  
Philip Bonomi ◽  
Augusto E. Villegas ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Clinical Activity ◽  
Her2 Amplification ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Previously Treated

8509 Background: T-DM1 is an antibody-drug conjugate approved for HER2-positive metastatic breast cancer. We report primary results from a fully enrolled, ongoing phase 2 study (NCT02289833) of pts with previously treated HER2-overexpressing mNSCLC who received single-agent T-DM1. Methods: Eligible pts had HER2-overexpressing mNSCLC and were previously treated with platinum-based therapy. Pts received T-DM1 3.6 mg/kg every 3 weeks and were analyzed in 2 cohorts based on centrally determined HER2 status (immunohistochemistry [IHC]2+ vs IHC3+ [≥10% cells stained with 2+ or 3+ intensity, respectively]). HER2 amplification was assessed via ISH (HER2 gene ratio ≥2.0). The primary endpoint is objective response rate (ORR; proportion of pts with confirmed [≥4 weeks] complete or partial response per RECIST v1.1). Results: The clinical cutoff date for this analysis was Oct 26, 2016.Of 393 screened pts, 102 (27%) were IHC2+ and 29 (7%) were IHC3+. In total, 49 pts (IHC2+, n = 29; IHC3+, n = 20) received T-DM1. At cutoff, median follow-up was 16.3 (range 0.9*–22.4; * = censored observation) months. No IHC2+ pt had a response (0%, 95% CI 0–11.9); 4 IHC3+ pts had partial responses (20%, 95% CI 5.7–43.7) with a median duration of response of 7.3 (range 2.9–8.3) months. Median progression-free survival (PFS) in IHC2+ and IHC3+ pts was 2.6 (95% CI 1.4–2.8) and 2.7 (95% CI 1.4–8.3) months, respectively. At 6 months after start of study treatment, 9 pts (IHC2+, n = 4; IHC3+, n = 5) were still at risk for a PFS event. Median overall survival was 12.2 (95% CI 3.8–not estimable [NE]) months in IHC2+ pts and 12.1 (95% CI 9.3–NE) months in IHC3+ pts. Of 16 pts with HER2 amplification (IHC2+, n = 5; IHC3+, n = 11), 3 responded, all in the IHC3+ cohort (27.3%, 95% CI 6.0–61.0). Eleven pts (22%) experienced a grade 3–4 adverse event, with fatigue and dyspnea being the only events reported in > 1 pt (n = 2 each). Conclusions: This is the first study to report on the clinical activity of T-DM1 in HER2-overexpressing mNSCLC. Objective responses were observed in IHC3+ pts. Additional molecular analyses are underway to refine markers for optimal pt selection. Clinical trial information: NCT02289833.

Exposure–safety relationship of trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer (MBC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 646-646 ◽  
Author(s):  
Jin Jin ◽  
Bei Wang ◽  
Yuying Gao ◽  
Meghna Samant ◽  
Chunze Li ◽  
...  
Keyword(s):  
Single Agent ◽  
Locally Advanced ◽  
Safety Data ◽  
Multivariate Logistic Regression Analysis ◽  
Metastatic Breast ◽  
Trastuzumab Emtansine ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Data Set ◽  
Grade 3

646 Background: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate composed of trastuzumab, the cytotoxic agent DM1, and a stable thioether linker. The effects of T-DM1 exposure on safety in patients with HER2-positive locally advanced or MBC are reported. Methods: The exposure–safety analysis included 618 patients with pharmacokinetic (PK) data who received single-agent T-DM1 3.6 mg/kg q3w from five phase 2 or 3 studies: TDM4258g, TDM4374g, TDM4450g/BO21976, TDM4688g, and EMILIA. Exposure parameters observed in cycle 1 were T-DM1 conjugate AUC, T-DM1 conjugate Cmax, and DM1 Cmax, (no PK accumulation). Safety endpoints were worst grade of thrombocytopenia (TCP) or hepatotoxicity (HPT) by protocol definitions. A multivariate logistic regression analysis was conducted to evaluate the association of exposure and clinically relevant covariates with the probability of experiencing TCP or HPT. Platelet counts (PLT), alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (TBL) versus time profiles were also evaluated by exposure quartiles to further test exposure effect on lab values. A secondary analysis for patients in the EMILIA study alone (n=307) was also conducted. Results: Grade ≥3 TCP and grade≥ 3 HPT were observed in 72 patients and 45 patients in the exposure–safety data set, respectively. Data from the pooled studies showed no statistically significant association between exposure and the incidence of grade ≥3 TCP (T-DM1 AUC P=0.99, T-DM1 Cmax P=0.97, DM1 Cmax P=0.72), or grade ≥3 HPT (T-DM1 AUC P=0.25, T-DM1 Cmax P=0.93, DM1 Cmax P=0.95). Additionally, no obvious difference was observed for longitudinal PLT, ALT, AST, or TBL profiles across exposure quartiles, with no exposure–safety relationship for the probability that PLT, ALT, AST, or TBL exceeded grade 3 thresholds. Similar results were observed for the EMILIA analysis. Conclusions: For patients with HER2-positive locally advanced or MBC treated with T-DM1 3.6 mg/kg q3w, no exposure–safety relationship was observed for TCP, HPT, PLT, or liver function based on T-DM1 or DM1 exposure.

Exposure–efficacy relationship of trastuzumab emtansine (T-DM1) in EMILIA, a phase III study of T-DM1 versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 644-644 ◽  
Author(s):  
Bei Wang ◽  
Jin Jin ◽  
Russell Wada ◽  
Liang Fang ◽  
Dan Lu ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Cox Proportional Hazards Models ◽  
Phase Iii Study

644 Background: T-DM1 is an antibody–drug conjugate composed of trastuzumab (T), a stable thioether linker, and the potent cytotoxic agent DM1. In the phase III study EMILIA, median PFS and OS were significantly prolonged with T-DM1 vs XL in patients (pts) with HER2-positive locally advanced or MBC previously treated with T and a taxane; (PFS hazard ratio [HR]=0.65, p<0.001; OS HR=0.68, p<0.001). We report the effects of T-DM1 exposure on efficacy outcomes in EMILIA. Methods: In EMILIA, pts were randomized 1:1 to receive T-DM1 3.6 mg/kg q3w (n=495) or XL (n=496) in 21-day cycles. Pharmacokinetic (PK) samples were from cycle 1 (n=350, T-DM1 arm only). Exposure variables were T-DM1 AUC, T-DM1 Cmin, total T AUC, and DM1 Cmaxcalculated by noncompartmental analysis. A logistic regression model was used to evaluate the relationship between T-DM1 exposure and objective response rates (ORR) in the T-DM1 arm. Multivariate Cox proportional hazards models were used to calculate HRs of OS and PFS for each T-DM1 exposure quartile vs all randomized pts in the XL arm, adjusting for baseline covariates. Results: For ORR, mean T-DM1 AUC was 536 day*ug/mL for responders and 502 day*ug/mL for non-responders (P=0.09); mean DM1 Cmax was 4.55 ng/mL and 4.64 ng/mL, respectively (P=0.64). OS and PFS HRs (and 95% CIs) of T-DM1 vs XL stratified by T-DM1 exposure quartiles are shown (Table). Conclusions: In EMILIA, no clear trends were observed between T-DM1 exposure and PFS, OS, or ORR, following administration of T-DM1 3.6 mg/kg q3w. However, there was a suggestion of improved OS HR by stratified T-DM1 Cmin quartiles, albeit with mostly overlapping 95% CIs. Ongoing T-DM1 clinical trials will further evaluate this potential relationship. [Table: see text]

Safety of trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive locally advanced or metastatic breast cancer (mBC): Final results from KAMILLA Cohorts 1 (global) and 2 (Asia).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1039-1039
Author(s):  
Rachel Wuerstlein ◽  
Paul Ellis ◽  
Filippo Montemurro ◽  
Antonio Antón Torres ◽  
Suzette Delaloge ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Her2 Positive ◽  
Open Label ◽  
Primary Endpoints ◽  
Safety Population ◽  
Hemorrhagic Events ◽  
Previously Treated ◽  
Grade 3

1039 Background: KAMILLA is an open-label, single-arm, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC (NCT01702571). The treated (safety) population of KAMILLA comprises 2 cohorts: a larger global Cohort 1 (n=2002) and a smaller Asia Cohort 2 (n=181 [China, n=154; Thailand, n=15; Indonesia, n=12]). Here we report results from Cohort 2 in the context of those previously reported for Cohort 1. Methods: Pts had HER2-positive, locally advanced or mBC with progression after chemotherapy and anti-HER2 therapy or ≤6 months (mo) of completing adjuvant therapy. T-DM1 3.6 mg/kg was given intravenously every 3 weeks until disease progression, consent withdrawal, or unacceptable toxicity. Primary endpoints were grade ≥3 (G≥3) adverse events of primary interest (AEPIs), specifically hepatic events, allergic reactions, thrombocytopenia (TCP), and hemorrhage events; all other G≥3 treatment-related AEs (TRAEs); and all-grade pneumonitis. Results: As of 31 July 2019,KAMILLA enrolled 2185 pts (Cohort 1, n=2003; Cohort 2, n=182), of which 2002 and 181 in each cohort, respectively, received ≥1 study dose and were included in the safety population. Baseline characteristics were generally similar between cohorts. Median (range) T-DM1 exposure was 5.6 mo (0–46) for Cohort 1 and 5.0 mo (0–31) for Cohort 2. The overall G≥3 AEPI rate was higher in Cohort 2 vs Cohort 1 (Table), mostly driven by a higher G≥3 TCP rate in Cohort 2. In Cohort 2, G≥3 TCP (the most frequently reported G≥3 AEPI) did not appear to be associated with G≥3 hemorrhagic events — the majority of G≥3 TCP events (128/138) fully resolved, with a duration of ≤15 days for 98/138 of these events. G≥3 TRAE rates were 18.4% in Cohort 1 and 48.6% in Cohort 2, the latter mainly due to TCP and platelet count decreased; any-grade pneumonitis rates were 1.0% and 2.2%, respectively. No other safety signals were identified. Median progression-free survival and overall survival were similar for both cohorts (Table). Conclusions: These data confirm prior observations in an Asian subgroup of the phase 3 EMILIA trial of T-DM1 in pts with previously treated mBC. Although the G≥3 TCP rate was higher in the Asia cohort, the majority of these events resolved fully. OS and PFS were similar in both cohorts. These data reinforce the favorable T-DM1 benefit-risk profile in mBC. Clinical trial information: NCT01702571 .[Table: see text]

Randomized Phase II Trial of First-Line Trastuzumab Plus Docetaxel and Capecitabine Compared With Trastuzumab Plus Docetaxel inHER2-Positive Metastatic Breast Cancer

2010 ◽  
Vol 28 (6) ◽  
pp. 976-983 ◽  
Author(s):  
Andrew M. Wardley ◽  
Xavier Pivot ◽  
Flavia Morales-Vasquez ◽  
Luis M. Zetina ◽  
Maria de Fátima Dias Gaui ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Response Rate ◽  
Performance Status ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
First Line ◽  
Her2 Positive ◽  
Grade 3

PurposeTo evaluate trastuzumab (H) and docetaxel (T) with or without capecitabine (X) as first-line combination therapy for human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer.Patients and MethodsPatients with HER2-positive locally advanced or metastatic breast cancer were randomly assigned to H (8 mg/kg loading; 6 mg/kg every 3 weeks) plus T (75 mg/m2in HTX arm, 100 mg/m2in HT arm, every 3 weeks) with or without X (950 mg/m2twice per day on days 1 to 14 every 3 weeks). The primary end point was overall response rate (ORR).ResultsIn 222 patients, median follow-up was approximately 24 months. ORR was high with both regimens (70.5% with HTX; 72.7% with HT; P = .717); complete response rate was 23.2% with HTX compared with 16.4% with HT. HTX demonstrated significantly longer progression-free survival: median 17.9 months compared with 12.8 months with HT (hazard ratio, 0.72; P = .045), which translates to a gain of around 5 months. Two-year survival probability was 75% with HTX compared with 66% with HT. Febrile neutropenia (27% v 15%) and grade 3/4 neutropenia (77% v 54%) incidences were higher with HT than HTX. Treatment-related grade 3 hand-foot syndrome (17% v < 1%) and grade 3/4 diarrhea (11% v 4%) occurred more commonly with HTX than HT. One case of congestive heart failure occurred in each arm.ConclusionHTX is an effective and feasible first-line therapy for HER2-positive locally advanced or metastatic breast cancer, although it should be reserved for patients with good performance status who are not receiving long-term steroids.

A phase II study of mitoxantrone, etoposide, and thiotepa with autologous marrow support for patients with relapsed breast cancer.

1990 ◽  
Vol 8 (11) ◽  
pp. 1782-1788 ◽  
Author(s):  
R Wallerstein ◽  
G Spitzer ◽  
F Dunphy ◽  
S Huan ◽  
G Hortobagyi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Poor Response ◽  
High Dose ◽  
Significant Activity ◽  
Heavily Pretreated ◽  
Grade 3

To further improve the effect of high-dose chemotherapy in the treatment of locally advanced and metastatic breast cancer, we sought to develop a second active high-dose noncross-resistant regimen to use in tandem with our customary high-dose regimen of cyclophosphamide, etoposide, and cisplatin (CVP). We performed a phase II trial of high-dose mitoxantrone 30 mg/m2, etoposide 200 mg/m2 every 12 hours x 6, and thiotepa 250 mg/m2 x 3 days (MVT) in 31 patients with heavily pretreated metastatic breast cancer and one with locally advanced chemotherapy-refractory breast cancer. These patients were ineligible for high-dose CVP chemotherapy because of the amount of prior treatment and poor-response status. Of the 32 patients, 14 responded to cycle 1, did not experience any grade 4 toxicity, and received a second cycle of MVT. Overall, seven of 31 patients achieved a complete response (CR; 23%). Four of the 14, who were partial responders to the first cycle, achieved a CR after the second cycle. The overall response rate was 19 of 31 (61%) with an overall median freedom from progression of 4 to 5 months and an overall median survival of 9 months. Toxicity consisted primarily of mucositis (grade 3 or 4 in 69%). The results indicate that high-dose MVT produces significant activity, even in heavily pretreated patients. Administration of a second cycle of high-dose therapy with MVT increased the CR rate, and the morbidity and mortality from the second cycle were not greater than that for the first cycle. Because of the high incidence of grade 3 or 4 mucositis with this regimen, we are currently completing a follow-up study of high-dose mitoxantrone and thiotepa alone.

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