Meghna Samant

Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA

BACKGROUND We characterized the incidence of central nervous system (CNS) metastases after treatment with trastuzumab emtansine (T-DM1) versus capecitabine-lapatinib (XL), and treatment efficacy among patients with pre-existing CNS metastases in the phase III EMILIA study. PATIENTS AND METHODS In EMILIA, patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer previously treated with trastuzumab and a taxane were randomized to T-DM1 or XL until disease progression. Patients with treated, asymptomatic CNS metastases at baseline and patients developing postbaseline CNS metastases were identified retrospectively by independent review; exploratory analyses were carried out. RESULTS Among 991 randomized patients (T-DM1 = 495; XL = 496), 95 (T-DM1 = 45; XL = 50) had CNS metastases at baseline. CNS progression occurred in 9 of 450 (2.0%) and 3 of 446 (0.7%) patients without CNS metastases at baseline in the T-DM1 and XL arms, respectively, and in 10 of 45 (22.2%) and 8 of 50 (16.0%) patients with CNS metastases at baseline. Among patients with CNS metastases at baseline, a significant improvement in overall survival (OS) was observed in the T-DM1 arm compared with the XL arm [hazard ratio (HR) = 0.38; P = 0.008; median, 26.8 versus 12.9 months]. Progression-free survival by independent review was similar in the two treatment arms (HR = 1.00; P = 1.000; median, 5.9 versus 5.7 months). Multivariate analyses demonstrated similar results. Grade ≥3 adverse events were reported in 48.8% and 63.3% of patients with CNS metastases at baseline administered T-DM1 and XL, respectively; no new safety signals were observed. CONCLUSION In this retrospective, exploratory analysis, the rate of CNS progression in patients with HER2-positive advanced breast cancer was similar for T-DM1 and for XL, and higher overall in patients with CNS metastases at baseline compared with those without CNS metastases at baseline. In patients with treated, asymptomatic CNS metastases at baseline, T-DM1 was associated with significantly improved OS compared with XL.In a retrospective analysis of the EMILIA study, the rate of central nervous system (CNS) progression in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer was similar for trastuzumab emtansine (T-DM1) and for capecitabine–lapatinib. In patients with treated, asymptomatic CNS metastases at baseline, T-DM1 was associated with significantly improved overall survival versus capecitabine–lapatinib.

Corticosteroid Use in Patients with Glioblastoma at First or Second Relapse Treated with Bevacizumab in the BRAIN Study

BACKGROUND Vascular endothelial growth factor inhibitors have corticosteroid-sparing effects in patients with high-grade gliomas. We assessed corticosteroid use in patients with recurrent glioblastoma treated with bevacizumab (BEV) in the BRAIN study (J Clin Oncol 2009;27:4733-4740). METHODS BRAIN was a phase II, multicenter, randomized, noncomparative trial of BEV alone (n = 85) or in combination with irinotecan (CPT-11) (n = 82) in adults with recurrent glioblastoma. Median corticosteroid dose for patients who used corticosteroids at baseline was summarized by treatment arm; the percentage of patients who had sustained (≥50% corticosteroid dose reduction for ≥50% of time on study drug) or complete (discontinuation of corticosteroid for ≥25% of time on study drug) reduction in corticosteroid dose overall and by objective response and progression-free survival was calculated. The incidence of corticosteroid-related adverse events was summarized. RESULTS In each treatment group, 50% of patients were using systemic corticosteroids at baseline. The majority of those experienced a reduction in dose while receiving BEV-based therapy. Thirteen (30.2%) BEV and 20 (46.5%) BEV + CPT-11 patients had a sustained reduction of corticosteroid dose; 7 (16.3%) BEV and 9 (20.9%) BEV + CPT-11 patients had a complete reduction of corticosteroid dose. The majority of patients who had an objective response or progression-free survival >6 months experienced corticosteroid dose reduction. Approximately 64% of patients who used corticosteroids while receiving BEV-based therapy experienced infection. CONCLUSION BEV may have corticosteroid-sparing effects in patients with recurrent glioblastoma. Corticosteroid reduction may positively affect patient health-related quality of life. Given the exploratory nature of the analyses in a noncomparative study, these results should be interpreted cautiously.

Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab

Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.

Relationship Between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer

Purpose: HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody–drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study. Experimental Design: Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations. Results: Longer progression-free survival (PFS) and overall survival (OS) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib–treated patients, but not in T-DM1–treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations. Conclusions: Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755–63. ©2016 AACR.

SABRE-B: an evaluation of paclitaxel and bevacizumab with or without sunitinib as first-line treatment of metastatic breast cancer

BACKGROUND The vascular endothelial growth factor (VEGF) pathway can be targeted through VEGF neutralization or VEGF receptor (VEGFR) blockade using tyrosine kinase inhibition. Because laboratory models suggest that combining these approaches might be synergistic, we sought to evaluate the feasibility and efficacy of combining sunitinib with paclitaxel + bevacizumab (PB). METHODS Patients with human epidermal growth factor receptor 2 (HER2)-negative, metastatic breast cancer receiving first-line chemotherapy were randomized to PB or PB with sunitinib (PBS), with planned escalation of the sunitinib dose. RESULTS Forty-six patients were randomized to PB or PBS with sunitinib dosed at 25 mg p.o. daily. Patients receiving PBS encountered substantial toxicity that precluded adequate treatment. The percentage of patients with grade ≥3 adverse events was greater in the PBS arm than the PB arm (83% versus 57%), and sunitinib dosing was modified in 78% of patients, most often due to neutropenia, febrile neutropenia, and fatigue. In addition, 44% of patients had sunitinib dose reduction to 12.5 mg, and 39% required discontinuation. Patients receiving PBS had more bevacizumab treatment interruptions and discontinuations because of toxicity. Median treatment duration was longer in the PB arm compared with the PBS arm (14.1 versus 11.1 weeks), reflecting early treatment discontinuation of PBS. Because of poor tolerability of the addition of sunitinib to PB, the planned sunitinib dose escalation was halted and the study accrual was terminated. CONCLUSION Adding sunitinib to standard doses of bevacizumab plus paclitaxel for metastatic breast cancer is not feasible. Different strategies will be required to evaluate whether there is additional clinical benefit to combining VEGF/VEGFR-targeted agents.

Safety and Efficacy of Combining Sunitinib with Bevacizumab + Paclitaxel/Carboplatin in Non-small Cell Lung Cancer

Introduction: Bevacizumab (B) improves survival of patients with metastatic, nonsquamous non-small cell lung cancer. Based on encouraging results from preclinical studies combining B with sunitinib (S), a phase II, randomized, open-label study (Study Assessing the Blockade of both VEGF Receptor and ligand to enhance Efficacy in Lung) was initiated to assess clinical outcomes of adding S to paclitaxel (P)/carboplatin (C) + B (PCB) for first-line treatment of locally advanced, metastatic, or recurrent nonsquamous non-small cell lung cancer. Methods: Study enrollment was to occur in three phases. In the first phase, patients received PC + B (15 mg/kg every 3 weeks), ±S (25 mg daily, 2 weeks on, 1 week off). If tolerated, the second phase would include a third cohort receiving 37.5 mg S. The third phase would consist of PCB ± highest tolerable dose S. Results: Between March 2007 and January 2008, 26 patients were randomized to receive PCB and 30 to PCB + S 25 mg. Because of poor tolerability, none of the patients were escalated to 37.5 mg S. Median treatment duration was 10.3 weeks for PCB and 6.0 weeks for PCB + S. Thirty-five percent of patients on PCB + S required S dose reduction, 52% required S treatment interruption, and 59% discontinued S because of adverse events, most frequently hematologic events (neutropenia, thrombocytopenia, and leukopenia) and fatigue. Patients receiving PCB + S required more B interruptions (38% versus 19% for PCB) and discontinuation (52% versus 35%) because of adverse events. Survival data were limited by small sample sizes and limited treatment duration. Overall survival was not mature at time of analysis: median 6.6 months for PCB + S and not reached for PCB. Two out of 25 efficacy-evaluable patients randomized to the PCB + S cohort had confirmed partial responses, compared with 5 of 19 randomized to the PCB cohort. Conclusions: The addition of S to PCB was not well tolerated because of toxicities. This combination should not be studied further at these doses and schedules.

Trastuzumab Emtansine in Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: An Integrated Safety Analysis

PURPOSE The antibody-drug conjugate trastuzumab emtansine (T-DM1) combines the cytotoxic activity of DM1 with the human epidermal growth factor receptor 2 (HER2) -targeted, antitumor properties of trastuzumab. T-DM1 has shown activity in phase I and II single-arm studies in patients with pretreated HER2-positive metastatic breast cancer (MBC) and has demonstrated superior efficacy and improved tolerability versus standard MBC treatments in randomized phase II and III studies. This analysis, combining available data from all single-agent T-DM1 studies to date, was conducted to better define the T-DM1 safety profile. PATIENTS AND METHODS Six studies in patients with HER2-positive MBC who received T-DM1 3.6 mg/kg every 3 weeks and follow-up data from patients in an extension study were analyzed. Analyses included adverse events (AEs) by grade; AEs leading to death, drug discontinuation, or dose reduction; and select AEs. RESULTS Among 884 T-DM1-exposed patients, the most commonly reported all-grade AEs were fatigue (46.4%), nausea (43.0%), thrombocytopenia (32.2%), headache (29.4%), and constipation (26.5%). The most common grade 3 to 4 AEs were the laboratory abnormalities of thrombocytopenia (11.9%) and increased AST serum concentration (4.3%). These were manageable and not generally associated with clinical symptoms. There were 12 AE-related deaths. AEs resulted in dose reductions in 17.2% of patients and drug discontinuations in 7.0%. CONCLUSION In this analysis of 884 T-DM1-exposed patients, grade 3 or greater AEs were infrequent and typically asymptomatic and manageable. This favorable safety profile makes T-DM1 treatment suitable for exploration in other breast cancer settings.

SABRE-B: a randomized phase II trial evaluating the safety and efficacy of combining sunitinib (S) with paclitaxel (P) + bevacizumab (B) as first-line treatment for HER2-negative metastatic breast cancer (MBC): final results.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #3126 Background: B, a humanized monoclonal antibody that neutralizes VEGF, improves progression-free survival (PFS) when combined with taxanes in 1st-line MBC. S, an oral inhibitor of receptor tyrosine kinases, including PDGFRs and VEGFRs, has shown activity in MBC. Preclinical models suggest that the addition of S to B may increase the inhibition of the VEGF signaling pathway. SABRE-B was a Phase II randomized open-label study comparing the safety and efficacy of S in combination with P/B to P/B alone. Methods: Patients (pts) with HER2-negative MBC receiving 1st-line chemotherapy were eligible. P (90 mg/m2 qwk x 3 every 4 weeks), B (10 mg/kg q2wk) and S (25 mg qd x 21d) were administered in 28-day cycles. S dose was to be adjusted for myelosuppression, fatigue, or other treatment-related toxicities. Planned enrollment had 3 phases: an initial 2-arm phase with P/B vs. P/B/S (25 mg) to assess tolerability of S plus P/B. If P/B/S (25 mg) was tolerable, a second phase comparing P/B to P/B/S (25 mg) to P/B/S (37.5 mg) would begin. A final phase with the selected S dose would compare the clinical efficacy (PFS) of P/B/S to P/B. Results: From 3/2007-1/2008, 46 pts were randomized, 23 to P/B and 23 to P/B/S (25 mg). At the time of this analysis, the estimated mean treatment duration was longer in the P/B arm (14.7 weeks) compared with the P/B/S arm (10.9 weeks), reflecting a higher number of pts who discontinued early in the P/B/S arm. The percentage of pts with a Grade ≥3 AE was greater in the P/B/S arm compared with P/B (73.9% vs. 39.1%) and SAEs were greater in the P/B/S arm compared with P/B (43.5% vs. 30.4%). Neutropenia, febrile neutropenia, and fatigue were the most frequently reported AEs resulting in modifications to S dosing. Seventy percent of pts had an AE resulting in S dose interruption or modification. In addition to S doses being held, 17% required S dose reduction to 12.5 mg and 30% required discontinuation of S. Pts receiving P/B/S required more interruptions in B administration compared with P/B (52% vs. 44%), and more pts receiving P/B/S discontinued B compared with P/B (22% vs. 0%) because of AEs. There was one on-treatment death with P/B/S due to disease progression. Because of poor tolerability of the addition of S (25 mg) to P/B, the second phase of enrollment (S 37.5 mg) was never initiated. Conclusion : Given the high rate of S dose modifications and/or treatment discontinuations in the first phase of SABRE-B, it was determined that in 1st line MBC, adding S at these doses and schedules to the approved P/B regimen was not feasible and the study was closed. Targeted VEGF inhibition with B in combination with VEGFR tyrosine kinase inhibitors is of clinical interest, but will require additional clinical studies to define how to safely combine these agents. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3126.

Abstract P5-18-06: Trastuzumab emtansine in HER2-positive metastatic breast cancer: pooled safety analysis from seven studies

Background: The antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1) combines the antitumor activities of trastuzumab with intracellular delivery of the cytotoxic agent DM1 and represents a new approach to therapy for HER2-positive MBC. Recently, the first phase 3 data have been reported with significant improvements in PFS (9.6 vs 6.4 months; HR=0.650; P Methods: Data were included from treated patients in 7 studies of single-agent T-DM1 3.6 mg/kg q3w: 1 phase 1 study in previously treated MBC (TDM3569g, Krop 2010, n=15 treated at 3.6 mg/kg q3w); 3 phase 2 single-arm studies in previously treated MBC (TDM4258g, Burris 2011, N=112; TDM4374g, Krop 2012, N=110; TDM4688g, Gupta 2011, n=51); 1 randomized phase 2 study in previously untreated MBC (Hurvitz 2011, TDM4450g/BO21976, n=69); 1 extension study (TDM4529/BO25430, n=43 from parent studies); and 1 phase 3 study in MBC previously treated with trastuzumab and a taxane (EMILIA, Blackwell 2012, n=490). Data were analyzed in 4 groups: (1) all T-DM1-treated pts (7 studies, N=882), (2) pts originally enrolled in single-arm studies (n = 288), (3) T-DM1 pts from TDM4450g (n = 69), and (4) T-DM1 pts from EMILIA (n = 490). Results: Among all pts (N = 882), median age was 53 years (range 25–85 years); 52.7% had ≥3 metastatic sites; 81.7% had received prior treatment for MBC; and the median number of prior non-endocrine agents for MBC was 3.0 (range 0–19). All-grade AEs occurring in ≥25% of patients were fatigue (45.4%), nausea (42.3%), headache (28.7%), thrombocytopenia (28.7%), and constipation (25.5%). Grade ≥3 AEs occurring in ≥2% were thrombocytopenia, increased AST, increased ALT, fatigue, hypokalemia, and anemia. Table 1 describes the grade ≥3 incidence of these AEs, as well as selected AEs with known association to T-DM1 or potential risk based on the components of T-DM1 or on preclinical data. Conclusions: The safety profile of T-DM1 3.6 mg/kg q3w was consistent across the studies and the different patient populations with HER2-positive MBC. Additional analyses on hepatic transaminase increases and those exploring potential associations between thrombocytopenia and hemorrhage will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-06.