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.

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.

Results from a phase Ib study of trastuzumab emtansine (T-DM1), paclitaxel (T), and pertuzumab (P) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 528-528
Author(s):  
Shanu Modi ◽  
Anthony D. Elias ◽  
Patricia LoRusso ◽  
Meghna Samant ◽  
Ellie Guardino ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Single Agent ◽  
Metastatic Breast ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Phase Ii Studies ◽  
Previously Treated

528 Background: The antibody–drug conjugate T-DM1 has shown single-agent activity in phase II studies in patients (pts) with HER2–positive MBC. Preclinical data suggest synergy for T-DM1 combined with taxanes and with P. Methods: TDM4652g is a phase Ib, open-label, dose-escalation study evaluating the safety and tolerability of T-DM1 (qw and q3w) + T (qw) ± P (q3w) in pts with HER2-positive MBC previously treated with trastuzumab. A 3+3 dose-escalation scheme is used for T-DM1 + T to determine the maximum tolerated dose (MTD); P is added at this MTD. Initial restrictive dose-limiting toxicity (DLT) criteria were modified to establish a more clinically relevant MTD. Results: We report interim results with T-DM1 (qw and q3w) + T (+ P) using modified DLT criteria. 24 pts have been enrolled in these cohorts; median age was 53 yrs (range, 23–69)*; median number of prior systemic therapies in MBC was 7 (range, 2–15)*. See table below. Conclusions: Data support combining T-DM1 + T ± P at the MTD for future clinical trials. The MTD for weekly T-DM1 + T is 2.4 mg/kg + 80 mg/m2 qw; MTD for weekly T-DM1 + T + P is 2.4 mg/kg + 80 mg/m2 qw + 840 mg LD, 420 mg q3w. Updated results will be presented, including the MTD for T-DM1 q3w + T qw ± P q3w, outcomes from pts with prolonged follow-up, and duration of response from an extension trial. [Table: see text]

Rucaparib for recurrent, locally advanced, or metastatic urothelial carcinoma (mUC): Results from ATLAS, a phase II open-label trial.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 440-440 ◽  
Author(s):  
Petros Grivas ◽  
Yohann Loriot ◽  
Susan Feyerabend ◽  
Rafael Morales-Barrera ◽  
Min Yuen Teo ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

440 Background: ATLAS (NCT03397394) evaluated the efficacy/safety of the PARP inhibitor (PARPi) rucaparib in patients (pts) with previously treated locally advanced/unresectable UC or mUC. Methods: Pts with measurable disease who had progressed after 1–2 prior regimens (ie, platinum-based chemotherapy [PBC] and/or immune checkpoint inhibitors [ICI]) were enrolled regardless of tumor homologous recombination deficiency (HRD) status. Prior PARPi was not allowed. Pts received rucaparib 600 mg PO BID. Baseline tumor tissue or archival tissue ≤6 mo without intervening therapy was required; serial circulating tumor DNA samples were collected. Primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Key secondary endpoints: progression-free survival (PFS) and safety. Clinical benefit rate (CBR) was defined as complete or partial response or stable disease (SD) lasting ≥16 weeks. Results: As of Oct 7, 2019, 97 pts were enrolled (median age 66 y [range, 39–87]); most were men (n=76, 78.4%) and had ECOG PS 1 (n=65, 67.0%). Sixty-six pts (68.0%) had both prior PBC and ICI. Twenty pts (20.6%) were HRD-positive, 30 (30.9%) were HRD-negative and 47 (48.5%) had unknown HRD status; 4 pts had a deleterious BRCA1/2 alteration. Median time on treatment was 54 d (range, 2–224). There were no confirmed responses. Of 96 evaluable pts, 27 (28.1%) had a best response of SD; CBR was 12.5% and median PFS was 1.8 mo. No relationship was observed between HRD status and clinical activity. Treatment was discontinued by 93 pts (95.9%), mainly due to radiologic or clinical progression (73.1%). Most frequent any grade treatment-emergent (any cause) adverse events were asthenia/fatigue (n=56, 57.7%), nausea (n=40, 41.2%), and anemia (n=34, 35.1%). Conclusions: Single agent rucaparib did not show activity in pts with previously treated advanced UC and enrollment was suspended at the first interim analysis. The safety profile was consistent with that observed in pts with ovarian cancer. Next generation sequencing–based characterization of the genomic landscape of mUC will be presented. Clinical trial information: NCT03397394.

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]

A phase II trial of capecitabine (C) in combination with the farnesyltransferase (FT) inhibitor (FTI), tipifarnib (T), in patients (pt) with metastatic breast cancer (MBC): ECOG trial 1103

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1036-1036
Author(s):  
M. Wang ◽  
W. J. Gradishar ◽  
J. A. Sparano ◽  
E. A. Perez ◽  
G. Sledge
Keyword(s):  
Mononuclear Cells ◽  
Performance Status ◽  
Single Agent ◽  
Objective Response ◽  
Human Tumor ◽  
Metastatic Breast ◽  
Type I ◽  
Post Translational Modification ◽  
Ras Genes ◽  
Previously Treated

1036 Background: Approximately 30% of human cancers have mutated Ras genes that produce proteins that remain in an active state causing uncontrolled proliferative signals. Post-translational modification of Ras include farneyslation catalyzed by FT. Tipifarnib (R115777) is an oral FTI active against human tumor cell lines and exhibiting modest single agent activity in pts with previously treated MBC. A previous phase I trial reported that CT inhibited farneyslation in peripheral blood mononuclear cells without affecting the pharmacokinetics of either agent. Objective: To evaluate objective response rate (ORR) of CT in taxane refractory MBC and to secondarily evaluate associated toxicity and progression-free survival (PFS). Methods: Pt with measurable MBC, previously treated (rx) with an anthracycline and relapse on a taxane or within 30 days (d). Study rx: T- 300 mg, po BID × 14 d plus C- 1,000 mg/m2, po BID × 14 d, followed by 7 d rest. Tumor reassessment was repeated q 3 cycles. The study was designed to detect improvement in ORR from 25% with C alone to 40% for the CT combination (90.5% power; type I error rate of 9.9%; 21 responses in 64 eligible pt needed to be promising. Results: 66/71 pt are available for primary analysis. Median age 50 yrs. Performance status: 0–1, 100%. ORR: PR-4.8% (3/62) [95% CI 0.01, 0.13], SD - 21% (13/62) [ 95% CI 0.12, 0.33]. Median survival - 10.6 months. Toxicity (%): anemia - 8(G3/4), neutropenia - 30 (G3/4), thrombocytopenia - 8 (G3/4), HFS-8 (G3), nausea/vomiting - 11(G3), diarrhea - 8 (G3), sensory neuropathy - 5 (G3). Conclusion: CT in taxane -refractory MBC has low antitumor activity without excessive toxicity. More mature data, including PFS, will be presented. No significant financial relationships to disclose.

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