1st Line Metastatic Breast Cancer Research Articles

Abstract P4-13-05: Evolving treatment patterns in hormone receptor-positive, HER2-negative metastatic breast cancer

Abstract Background: The last several years have seen the approval of multiple targeted agents for use alone or combined with standard endocrine therapies (ET) in the 1st, 2nd, and 3rd line hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) settings. Due to these new approvals, standards of care for treatment are evolving. Methods: Prescribing preferences (PPrefs) of 592 U.S.-based medical oncologists were studied using a validated, proprietary, case-based market research tool (Challenging Cases®). Data were acquired using blinded, audience-response iPad technology at 8 live and virtual events during 2016-2018. Two core hypothetical cases were presented: 1st line MBC and recurrent (REC) MBC. For each core case the following variables were introduced: time from completion of adjuvant (adj) therapy (Tx) to REC disease, site of metastases [visceral (VIS) vs non-visceral (N-VIS)], and age for the 1st line case, and type of metastases and line of Tx for the recurrent case. Rx choices for which there are published phase 3 data were offered, as well as a category for “other.” Results: Table 1.Preferred Rx for recurrent disease during or after 5 yrs of adjuvant non-steroidal aromatase inhibitor (NSAI)*ScenarioExemestane (EXE) + Everolimus (EVE)NSAI + CDK inhibitor (CDKi)Fulvestrant (FUL) + CDKiChemotherapy (CT)Endocrine therapy (ET)OtherREC 18 months (mos) into adj AI Tx, VIS) and N-VIS mets, Age 635%25%63%3%4%0%REC post 5 yrs adj AI and 2 yr treatment free interval (TFI), N-VIS mets, Age 674%49%34%1%12%1%REC post 5 yrs adj AI and 2 yr TFI, N-VIS mets, Age 853%34%19%0%42%1%* May not equal 100% due to rounding. Table 2.Preferred Rx for 2nd or 3rd recurrence*ScenarioEXE + EVENSAI + CDKiFUL + CDKiCTETAbemaciclibOtherREC post 5 yrs adj AI and 2 yr TFI, N-VIS mets, age 67 --> 12 mos 1st line Tx --> N-VIS mets31%12%38%6%12%1%1%REC post 5 yrs adj AI and 2 yr TFI, N-VIS mets, age 67 --> 12 mos 1st line NSAI + palbociclib Tx --> N-VIS mets38%1%33%9%15%0%3%REC 12 mos into adj AI, age 61,N-VIS mets -->12 mos Tx 1st line -->N-VIS mets21%9%53%9%6%0%1%REC post 5 yrs adj AI and 2 yr TFI, N-VIS mets, age 67 -->12 mos 1st line Tx, N-VIS mets --> 6 mos 2nd line Tx --> VIS and N-VIS mets23%1%9%59%5%2%1%* May not equal 100% due to rounding. In the setting of a patient (pt), age 63 with early REC on an adj AI, the most preferred strategy was FUL + a CDKi. In a pt, age 67, who completed 5 years of an adj AI with a TFI of 2 years, the most common preference was NSAI + a CDKi. In an older pt (age 85) who completed 5 years of an adj AI and TFI of 2 years, the most common choice of TX was single agent ET. For a pt with N-VIS mets treated in the 2nd line setting, FUL + a CDKi was the most preferred strategy. In a 2nd line pt with REC at 12 mos on adj Tx and after 12 mos of 1st line Tx, FUL + a CDKi and EXE + EVE were the most preferred therapies. In a 3rd line pt, with VIS mets CT was the preferred choice. Conclusion: Treatment patterns in HR+ HER2- MBC are evolving with the approval of several new agents and emerging data. Age, time to relapse, line of Tx, and type of mets may be some of the key factors that determine PPrefs in HR+, HER2- MBC. Citation Format: Lankford ML, Britton SL, Buettner AD, Scharf M, Tiscione B, Willey JP, Mahtani RL. Evolving treatment patterns in hormone receptor-positive, HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-05.

Abstract P5-19-14: A phase 1b study of trebananib plus paclitaxel and trastuzumab or capecitabine and lapatinib in patients with HER2+ locally recurrent or metastatic breast cancer

Abstract Background: The angiopoietin axis is distinct and critical for angiogenesis. Trebananib suppresses tumor angiogenesis by binding to angiopoietin-1 and -2 (Ang1/2), thereby inhibiting their interaction with the Tie2 receptor. This interim analysis evaluated the tolerability and efficacy of trebananib plus paclitaxel and trastuzumab or capecitabine and lapatinib in HER2+ locally recurrent or metastatic breast cancer (MBC). Methods: Patients (pts) in cohorts A1 and A3 (no prior 1st-line trastuzumab, lapatinib, or chemotherapy for MBC) received trebananib (A1, 10 mg/kg; A3, 30 mg/kg) IV QW plus paclitaxel 80 mg/m2 IV QW and trastuzumab 8 mg/kg loading dose, then 6 mg/kg Q3W. Pts in cohorts B1 and B3 (history of failed 1st-line MBC treatment, no prior lapatinib or capecitabine) received trebananib (B1, 10 mg/kg; B3, 30 mg/kg) IV QW plus capecitabine 1000 mg/m2 PO Q12 h, days 1-14 Q21D and lapatinib 1250 mg PO QD. Cohorts were expanded to n = 20 if ≤1 of 6 or ≤2 of 9 pts had dose-limiting toxicities (DLTs). Cohort B3 was closed early due to poor enrollment. Endpoints were treatment-emergent adverse events (AEs) and DLTs (primary); and efficacy, pharmacokinetics (PK), and incidence of anti-trebananib antibodies (secondary). Results: All pts received ≥1 dose of trebananib. Across all cohorts, two DLTs occurred (A1: grade 3 transient ischemic attack, n = 1; A3: grade 3 increased gamma-glutamyltransferase, n = 1). Across A1 and A3, AEs >50% were peripheral edema, diarrhea, alopecia, fatigue, nausea, nail disorder, and rash; AEs grade ≥3 in >10% of pts were peripheral/sensory neuropathy and dyspnea. No pt in A1 or A3 died during treatment. Across B1 and B3, AEs >50% were diarrhea, nausea, palmar-plantar erythrodysesthesia syndrome (PPES), and peripheral edema; AEs grade ≥3 in >10% of pts were diarrhea, PPES, and neutropenia. One pt in B1 died from sepsis considered to be possibly related to administration of trebananib and capecitabine. Peripheral edema was a frequently reported AE for cohorts A1, A3, B1, and B3 (n = 13, 15, 10, 3); most were grade 1 and 2 and appeared to be manageable. No AEs of gastrointestinal perforation, ascites, or proteinuria were reported. Efficacy endpoints are summarized in Table 1. No apparent PK drug-drug interaction was observed. No pt developed neutralizing binding antibodies during treatment. Table 1 1ST LINE-TREATMENT≥2ND-LINE TREATMENT† A1 (n = 20)A3 (n = 20)B1 (n = 20)TUMOR RESPONSE* Evaluable pts, n201714Best response, n Complete response030Partial response16127Stable disease325Progressive disease001Not assessed101Objective response rate, %808850PROGRESSION-FREE SURVIVAL Median, months14.518.58.695% CI6.9–20.610.4–21.93.7–14.4DURATION OF RESPONSE* Evaluable pts, n16157Median, months12.616.68.395% CI4.3–20.28.2–not estimable4.1–16.8*Tumor response was assessed only in pts with measurable disease at baseline †>Efficacy results for B3 are not reported due to the small sample size (n = 5) Conclusion: Interim results from this phase 1b study of pts with HER2+ locally recurrent or MBC suggest that adding trebananib to paclitaxel and trastuzumab or capecitabine and lapatinib is tolerable and may improve antitumor activity. Citation Format: Peter A Kaufman, Gilles Freyer, Margaret Kemeny, Anthony Goncalves, Guy Jerusalem, Alison Stopeck, Nandagopal Vrindavanam, Florence Dalenc, Nuwan Nanayakkara, Benjamin Wu, Cheryl A Pickett-Gies, Hans Wildiers. A phase 1b study of trebananib plus paclitaxel and trastuzumab or capecitabine and lapatinib in patients with HER2+ locally recurrent or metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-14.

359PD - Final Efficacy and Safety Analysis of the Carin Phase III Trial: Capecitabine (Cap) and Bevacizumab (Bev) with or Without Vinorelbine (Vin) in 1St Line Metastatic Breast Cancer (Mbc)

ABSTRACT Aim: Recent 1st line phase III trials in MBC demonstrated improved progression-free survival (PFS) for the combination of Cap/Bev as compared to Cap alone, but inferior efficacy when compared to paclitaxel plus Bev. Frequently used to treat MBC, Vin has few overlapping toxicities with Cap. The CARIN trial aims at further improving efficacy by adding Vin to Cap/Bev for a less toxic alternative to taxane-based 1st line therapy. Methods: CARIN was a prospective, open-label, multicenter, randomized phase III trial. Key eligibility criteria included confirmed measurable or non-measurable HER2 negative, locally advanced or MBC, ECOG ≤2, and no prior palliative chemotherapy. The 600 patients (pts) randomized (1:1) received oral Cap 1000 mg/m2 BID days 1-14 plus Bev 15 mg/kg q3w IV (Arm A) or Cap/Bev regimen combined with Vin 25 mg/m2 IV days 1 + 8 (Arm B) until progression or unacceptable toxicity. Randomization was stratified by prior adjuvant anthracycline and/or taxane therapy (yes/no) and hormone receptor status (ER/PR + /-). The primary endpoint was defined as PFS; secondary endpoints included objective response rate, overall survival (OS) and safety. Results: 297 pts in Arm A and 295 in Arm B with a median age of 62 were included in the efficacy analysis. Median follow-up was 2.4 years. 38% of pts in Arm A and 32% in Arm B were taxane pretreated; 20.8% were triple negative. The median treatment exposure was 28 weeks for both arms. Median PFS was 8.7 and 9.6 months (ms) (p = 0.03). The effect was most pronounced in pts Grade 3 were 60.6% and 76.3% in Arm A vs B, respectively, with neutropenia and leucopenia being more common in Arm B. No unexpected side effects were observed. Results of a multivariate cox regression will be presented. Conclusions: The addition of Vin to Cap/Bev is at least as effective as the combination of taxanes/Bev as reported in the RIBBON-1 trial and seems an option for taxane pretreated and TNBC pts. Disclosure: A. Welt: Advisory boards: Roche, TEVA, Eisai, Novartis Professional fee for oral presentations: P. Fabre N. Marschner: 1. Share holdings and executive employee iOMEDICO AG 2. Advisory board Roche T. Decker: Advisory Board Roche; C. Salat: Professional fee for oral presentations: Roche; S. Busies: Employee iOMEDICO AG; S. Hegewisch-Becker: Advisory Boards: Roche, Lilly, Merck. All other authors have declared no conflicts of interest.

Real-world symptom burden and early treatment discontinuation in first-line metastatic breast cancer (MBC).

9619 Background: Treatment options in 1st line metastatic breast cancer (MBC) vary and may include chemotherapy, targeted, and hormone therapy. Some patients (pts) do not complete therapy as planned, perhaps due to treatment related toxicities. The current study examined the association of symptom burden with early treatment discontinuation (ETD) of 1st line therapy of MBC in real-world settings. Methods: Data were abstracted from medical records of pts at 9 community oncology practices. Eligible pts had stage IV breast cancer with start of 1st line therapy on 1/2004 to 6/2012, were ≥ 18 years, and had ≥ 1 Patient Care Monitor (PCM) survey during 1st line. The PCM is an 86-item survey of cancer-related symptoms collected as part of routine clinical care. Age, race, HER2 status, hormone status, oral and infused agents, dates of diagnosis, treatment, progression, and death were recorded. ETD was defined by direct indication of early stopping in the medical record, or by treatment duration ≤ 6 weeks without evidence of disease progression. Cox regression of ETD with time varying covariates was used to examine the impact of 23 separate symptoms as well as an overall composite symptom burden score based on pt responses on each symptom. Results: 797 pts were included, with mean age of 58.4 years, 62.1% White; with 340 on Chemotherapy (CT), 349 on CT + Targeted therapy (T) and 108 on Hormone therapy only (H). Overall, ETD occurred in 95 (11.9%) pts, with rates highest among CT (15.3%), followed by T (10.0%) and H (7.4%). Cox regression showed that 21 of 23 symptoms each increased the risk of ETD. In the composite symptom burden score (median 7.1; range 0 - 21) analysis, overall symptom burden was found to be significant (HR = 1.124, p < 0.0001), indicating a 12.4% increased risk of ETD with each additional symptom. Pts with 10+ symptom score had a significantly increased risk of ETD (HR = 3.09, p < 0.0001) compared to pts with < 5 symptom score. Pts with 15+ symptom score had the highest risk of ETD (HR = 5.75, p < 0.0001). Conclusions: Pts treated with CT for 1st line MBC had the highest rate of ETD. The likelihood of ETD increased as the number of symptoms increased. Future research is needed to evaluate ETD on pt outcomes, including overall survival.

Phase Ib study of open-label AMG 386 plus paclitaxel (P) and trastuzumab (T) or capecitabine (C) and lapatinib (L) in patients (pts) with HER2+ locally recurrent or metastatic breast cancer (MBC).

529 Background: AMG 386, an investigational peptibody, reduces tumor angiogenesis by blocking interaction of angiopoietins 1 and 2 with the Tie2 receptor. This interim analysis evaluates the tolerability and efficacy of AMG 386 + P/T or C/L in HER2+ MBC. Methods: In part 1, pts in cohorts A1 and A3 (no prior 1st-line MBC T or L ) received AMG 386 IV QW plus P 80 mg/m2 IV QW and T 8 mg/kg loading dose, then 6 mg/kg Q3W; pts in cohorts B1 and B3 (history of failed 1st-line MBC T treatment; no prior L or C) received AMG 386 IV QW plus C 1000 mg/m2 PO Q12 hrs, days 1-14 Q21D and L 1250 mg PO QD. A1 and B1 received AMG 386 at 10 mg/kg; A3 and B3 received AMG 386 at 30 mg/kg. In part 2, cohorts were expanded to n = 20 if ≤ 1 of 6 or ≤ 2 of 9 pts had dose-limiting toxicities (DLTs). Primary endpoints were adverse events (AEs) and DLTs; secondary endpoints included efficacy and pharmacokinetics (PK). Interim results from A1, A3, and B1 will be presented. Results: 46 pts were enrolled at interim analysis; all received ≥ 1 dose of study treatment (A1, A3, B1; n = 20, 6, 20). The median follow-up for A1, A3, and B1 was 39.6, 22.7, and 31.3 wks. Across cohorts, there was 1 DLT in A1. AEs > 50% were peripheral edema, diarrhea, fatigue and alopecia in A1 and A3 combined, and diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome (PPES), and peripheral edema in B1. AEs grade ≥3 occurring in > 2 pts were peripheral neuropathy, peripheral sensory neuropathy, dyspnea (n = 5, 4, 3, respectively, in A1 and A3 combined); PPES, diarrhea, and neutropenia (n = 6, 5, 3, respectively, in B1). Objective response rates were 80% in A1, 50% in A3, and 50% in B1. Median (95% CI) progression-free survival was 14.5 mo (6.8-20.5) in A1 and 10.1 mo (3.7-14.7) in B1. Median duration of response (DOR) was 12.6 mo (4.3-20.2) in A1 and 8.5 mo (4.1-not evaluable) in B1. PFS and DOR were not yet evaluable in A3. No changes were apparent in any PK parameters in these combinations relative to within study or historical monotherapy PK data. Conclusions: In this ongoing phase 1b study of pts with HER2+ MBC, interim results suggest that adding AMG 386 to P/T or C/L is tolerable and has antitumor activity. Updated data will be presented.

Tesetaxel: Activity of an oral taxane as first-line treatment in metastatic breast cancer.

1016 Background: Tesetaxel, unlike standard taxanes (docetaxel, paclitaxel), is not a substrate for Pgp, a major cause of taxane resistance in tumor models. In a DU4475 breast cancer xenograft that overexpresses Pgp, tesetaxel induced a 94% reduction in tumor size, markedly exceeding the activity of docetaxel (46%) and paclitaxel (26%). Tesetaxel is associated with substantially less neuropathy preclinically than equi-myelotoxic doses of docetaxel. In clinical studies to date, tesetaxel is not associated with hypersensitivity reactions (0% incidence in > 450 patients [pts]), thus eliminating the need for premedication and extended observation. In a prior study, tesetaxel (27-35 mg/m2 Q3 wks) achieved a 38% partial response (PR) rate as 2nd-line therapy in pts with metastatic breast cancer (MBC) who had progressed after multidrug anthracycline-containing regimens. To extend these data, we initiated a phase 2 study of tesetaxel as 1st-line therapy in women with MBC. Methods: Eligibility included MBC; HER2-; ECOG PS 0-1; and adequate organ function. Adjuvant chemotherapy (including taxanes) was allowed. Tesetaxel was administered orally without anti-allergic premedication at a starting dose of 27 mg/m2 once every 3 wks. Overall response rate (ORR; RECIST) was the primary endpoint. Results: All 45 pts have been accrued. Median age is 58 y (range 36-80); median time from diagnosis, 4.0 y (range 0-21); triple negative status, 8 pts at diagnosis, 14 at time of metastasis. Metastatic sites are lung (22 pts), lymph nodes (22), liver (24), and bone (21). Prior treatment includes anti-estrogen therapy (32 pts), adjuvant chemotherapy (31), prior taxane (25), and radiotherapy (28). ORR in 24 pts evaluable for response is 50% (1 CR [4%], 11 PR [46%]); 5 responding pts had prior taxane therapy. Neutropenia is the most common ≥ Grade 3 adverse event with 50% of cases observed after dose escalation to 35 mg/m2; febrile neutropenia and Grade 3 peripheral neuropathy occurred in 2 pts each. There were no hypersensitivity reactions. Conclusions: Tesetaxel is highly active in 1st-line MBC and overcomes multiple limitations of standard taxanes. Updated ORR and PFS for all pts will be presented. Weekly dosing will be evaluated in a new cohort of pts.

Bevacizumab in metastatic breast cancer: a meta-analysis of randomized controlled trials

Numerous studies have demonstrated that angiogenesis and in particular VEGF over-expression play an essential role in the progression and metastatic potential of breast cancer. Bevacizumab is a humanized recombinant monoclonal antibody that specifically blocks the binding of VEGF to high-affinity receptors and it has been recently used for the treatment of metastatic breast cancer. We conducted a meta-analysis to synthesize available evidence for use of bevacizumab in metastatic breast cancer patients. Systematic review and meta-analysis of available trials. Primary outcomes were overall survival, progression free survival (PFS) and objective response rate (ORR). Five trials were identified with 3,163 eligible patients. Combination of bevacizumab and chemotherapy resulted in a statistically significant improvement in PFS (HR = 0.70, 95% CI 0.60-0.82, P = 9.3 x 10(-6)) and ORR (RR = 1.26, 95% CI 1.17-1.37, P = 9.96 x 10(-9)) compared with chemotherapy alone. Differences in objective response rates were substantial independently by the type of chemotherapy used, while PFS advantages were observed only for taxanes. The pooled HR for overall survival did not show significant advantage for the use of bevacizumab compared to placebo arm (HR = 0.90, 95% CI 0.80-1.03, P = 0.119). This meta-analysis shows that the addition of bevacizumab to chemotherapy offers meaningful improvement in PFS and ORR in patients with metastatic breast cancer. Bevacizumab treatment might be suggested for treatment of 1st line metastatic breast cancer, but more data are needed until statistical overall survival differences will be documented and firm guideline recommendation could be given.

Randomized phase II study of weekly versus every-3-week ixabepilone plus bevacizumab (ixa/bev) versus paclitaxel plus bev (pac/bev) as first-line therapy for metastatic breast cancer (MBC)

1029 Background: Pac/bev is superior to pac alone as first-line therapy for MBC. Ixa/bev has greater preclinical activity than pac/bev in human tumor models. The primary objective of this trial was to evaluate objective response rates (ORR) of ixa/bev given weekly or every 3 weeks relative to pac/bev as 1st line therapy for women with advanced breast cancer. Methods: Women with measurable disease and no prior chemotherapy for advanced breast cancer (locally advanced or MBC) were randomized in a 3:3:2 ratio to Arm A (ixa 16 mg/m2 IV on days 1, 8 & 15 q28 days/ bev 10 mg/kg IV q 2 wks), Arm B (ixa 40 mg/m2 IV q3 wks / bev 15 mg/kg IV q 3 wks) or Arm C (pac 90 mg/m2 IV, schedule/bev as in Arm A). Treatment was continued until disease progression or unacceptable toxicity. Results: Key efficacy and safety results from a pre-planned analysis of all randomized subjects after at least 24 weeks of follow-up are presented. Baseline characteristics were balanced between arms except for liver metastasis. Conclusions: The combination of ixa/bev weekly or q 3 wks demonstrated encouraging clinical activity and safety comparable to 1st line pac/bev in E2100. Final PFS will be provided when data is mature. These results support ongoing clinical trials of ixa given weekly or q 3wk in 1st line MBC, and in combination with bev. [Table: see text] [Table: see text]

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.

Abstract 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.

Preliminary safety results from a multicenter phase II noncomparative two arm pilot of bevacizumab with anastrozole or fulvestrant as 1st line metastatic breast cancer therapy.

Abstract Abstract #4113 Background: Estrogen modulates angiogenesis through effects on endothelial cells and by induction of vascular endothelial growth factor (VEGF) expression. Increased VEGF promotes tumor growth and is associated with a poor response to anti-estrogen therapy. This trial evaluates the impact of bevacizumab (B) combined with anastrozole (A) or fulvestrant (F) on progression free survival (PFS) as first line endocrine therapy in metastatic breast cancer (MBC).
 Methods: Study design: Two arm nonrandomized, noncomparative trial of A or F in combination with B. Eligibility: 0 prior hormonal or chemotherapy for MBC, measureable or evaluable disease, normal LVEF, postmenopausal, normal organ function. Treatment: Arm 1: Patients (pts) who either were endocrine therapy naïve, ≥ 12 months from adjuvant endocrine therapy, or who had intolerance to or progression on tamoxifen were treated with anastrozole 1 mg po daily. Arm 2: Patients who were ≤ 12 months from adjuvant aromatase inhibitors (AIs), intolerant of or progressed on adjuvant AIs, or at physician's discretion were treated with fulvestrant 500 mg IM loading dose, 250 mg D15 and every q28 days thereafter. B 10 mg/kg q2wks beginning day 1 was administered in both arms. Concurrent trastuzumab (T) was administered in HER2+ patients. Response assessments were performed q8 wks. Pts were treated until disease progression or toxicity.
 Results: 44 pts have been enrolled with data available for 29 pts. 18 pts (62%) were treated with anastrozole and 11 pts (38%) with fulvestrant. Median age: 64 yrs (range 44-88), ECOG PS 0-17 pts (59%) and PS 1 -12 pts (41%). 7 pts (24%) presented with de novo stage IV disease. 52% had 2 or more metastatic disease sites with bone metastases predominating 16 pts (55%), 7 pts (24%) with bone only disease. There were no G3/4 heme toxicities. G3/4 non-hematologic events consisted of G3 hypertension in 3 pts (10%), arthralgias 1 pt (3%), and CHF 1 pt (3%). This symptomatic LVEF of 40% occurred in arm 1 during cycle 3 and was noted to recover to 50-55% within 1 wk. This pt did not receive T. A median of 4.5 cycles have been administered. PRs were noted in 7 pts (24%) and 14 pts (48%) demonstrated SD. PD was noted in 3 pts and 5 pts were not yet evaluable. 73% of pts are progression free at 12 months. At a median follow up of 7.5 months, median PFS and overall survival has not been reached.
 Conclusions: The combination of bevacizumab with anastrozole or fulvestrant is feasible and well tolerated with adverse events as expected, reflecting standard bevacizumab related toxicities. Bevacizumab in combination with endocrine therapy is promising with early evidence of a high rate of clinical benefit at 72%. Further follow up is warranted. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4113.

Metastatic breast cancer (MBC): FDA approval overview

1013 Background: Improved survival in a randomized controlled trial is the gold standard for drug approval in 1st line MBC. Time to progression (TTP) and progression-free survival (PFS) have been used for drug approvals in 2nd-3rd-line MBC. Methods: Review of clinical trials leading to new drug approvals for MBC. Results: 1st-line MBC: trastuzumab + paclitaxel was approved based on superior TTP supported by a statistically significant improvement in 12-month survival rates in the trastuzumab group, since overall survival (OS) data were immature. An OS improvement was confirmed after approval in spite of 65% crossover to the trastuzumab group. Gemcitabine + paclitaxel was approved based on superior TTP supported by a strong trend toward improved survival in an interim analysis (18.6 vs. 15.8 mo, p=0.0489). 2nd-3rd-line MBC: Paclitaxel was approved based on superior TTP (4.2 vs. 3.0 mo, p=0.027). The docetaxel approval was based on a statistically significant survival advantage (11.4 vs. 8.7 mo, p=0.01) for docetaxel compared to mitomycin + vinblastine. Capecitabine was approved in combination with docetaxel for patients with failure of prior anthracycline chemotherapy. Approval was based on a statistically significant survival advantage (442 vs. 352 days, p=0.01) with the capecitabine + docetaxel combination compared to docetaxel monotherapy. Lapatinib was approved for patients with MBC whose tumors over-express HER2 and with failure of prior chemotherapy. Approval was based on a TTP improvement (median TTP 27.1 weeks vs. 18.6 weeks p=0.0001) with lapatinib + capecitabine compared to capecitabine alone. The ixabepilone approval for patients with MBC resistant to taxanes and anthracyclines was based on a statistically significant improvement in PFS (5.7 vs. 4.1 mo, p<0.0001) with the ixabepilone + capecitabine combination compared to capecitabine monotherapy. Conclusions: Survival was the basis for approval in the 1st-line setting and TTP and PFS have served as the basis for approval in the 2nd-3rd line setting. TTP and PFS have not been the basis for FDA approvals for 1st-line MBC. No significant financial relationships to disclose.

Impact of taxanes in association with anthracyclines in 1st line chemotherapy for metastatic breast cancer (MBC): Comprehensive review of 2805 patients in 7 phase III trials

659 Background: The real advantage of taxanes in adjunction to antracycline-based chemotherapy in 1st line MBC is still unclear. We performed a comprehensive review (not a meta-analysis) (Simes, Stat Med 1987) including all phase III trials of 1st line chemotherapy for MBC, to look if the combination of antracyclines (doxo- or epi-rubicin) plus taxanes (paclitaxel or docetaxel) (AT) adds some benefit over standard antracicline-based regimen (AnonT) in activity and efficacy. Methods: We included phase III (prospective and randomized) published or presented at ASCO, ESMO/ECCO between 2000 and 2003; randomized phase II were excluded. Analysis was accomplished to look at significant differences in 1) time to progression (TTP); 2) overall response rate (ORR); 3) overall survival (OS) 4) complete response rate (CR) and 5) WHO G3–4 per patient toxicity (neutropenia, febrile neutropenia, FN, cardiotoxicity and neurotoxicity). For these analyses, ratios (HR and RR) and 95% confidence intervals (CI) were derived. Results: We gathered 7 trials (3 published and 4 presented) which account overall 2806 patients (pts). Pts characteristics were similar within each trial. When AT and AnonT were pooled and compared, significant differences were seen in ORR (HR 1,36, 95% CI 1,07–1,36; data on 2805 pts), CR (RR 2,04, 95% CI 1,13–3,68; data on 2100 pts), neutropenia (RR 1,19, 95% CI 1,09–1,31; data on 2805 pts), FN (RR 2,82, 95% CI 1,01–7,84; data on 2100 pts), neurotoxicity (RR 13,2, 95% CI 1,51–114,98; data on 1892 pts). A borderline significance in favor of AT were present in TTP (HR 1,10, 95% CI 1,00–1,21; data on 2805 pts). Not significant trend in favor of AT were seen in OS (HR 1,05, 95% CI 0,90–1,22; data on 2376 pts), and cardiotoxicity (RR 3,48, 95% CI 0,68–17,72; data on 1884 pts). Conclusions: The adjunction of taxanes to antracyclines in 1st line chemotherapy for MBC pts seems to add a significant benefit in activity (ORR, CR), and a slight advantage in TTP versus standard comparator arm. OS didn't seem significantly greater. Neutropenia, FN and neurotoxicity are significantly higher. No significant financial relationships to disclose.

First line hormonal treatment (HT) for metastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T) in postmenopausal patients (pts) - A randomized phase III trial of the EORTC Breast Group

515 Background: E is an aromatase inactivator, with demonstrated efficacy in MBC progressing under T, which remained standard 1st line HT over decades. The randomized EORTC phase II trial of E vs T, which showed promising activity in 1st line MBC (Ann. Oncol. 2003, 14: 1391–8) was extended in a phase III reported here, aiming at a true comparison of efficacy and tolerability of both drugs. Methods: Postmenopausal MBC pts with ECOG PS ≤2 and measurable, hormone responsive disease (ER &/or PgR + or unknown with disease free interval >2y) previously untreated with HT for MBC, were randomized to receive open label E 25mg or T 20mg daily. One prior chemotherapy (CT) for MBC was permitted. Prior adjuvant T was allowed if treatment free interval exceeded 6 mo. The trial was powered to detect an increase in median progression free survival (PFS, primary endpoint) of 3 mo in favor of E. Secondary endpoints were survival and tolerability. All analyses were intent to treat. Results: 382 pts accrued by 81 centers received E (190 pts) or T (192 pts). Both groups were balanced for median age (62.5), prior adjuvant CT (E 28%, T 29%) or CT for MBC (E 8%, T 7%), hormone receptor status, PS, prior adjuvant T (21% both) and dominant metastatic site (visceral E 48%, T 47%; bone E 35%, T 36%; soft tissue E 17%, T 17%). On 15/12/2003, 286 events (progression or death under treatment) and 136 deaths were reported. The median PFS is significantly longer under E than T (10.9 vs 6.7 months, p 0.04) with an HR of 0.79 (95% CI 0.62 - 0.99) in favor of E. Best response rates (%) under E were CR 7.4, PR 36.8, SD 27.4, PD 18.4, NE (not evaluable) 10.0; under T, CR 2.6, PR 26.6, SD 37.0, PD 27.6, NE 6.2). No pt withdrew due to toxicity. Grade 2–3 toxicities observed in ≥10% were bone pain (E 12%, T 18%), other pain (E 7%, T 14%) and hot flashes (E 5%, T 12%). Conclusions: E is a safe and highly active steroidal aromatase inactivator, superior to T in MBC. In view of its efficacy and excellent tolerance, E represents a good choice as first line therapy in hormone responsive MBC. Its safety profile makes E also attractive for use in the adjuvant and preventive settings. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Pfizer; Schering-Plough Pfizer

Impact of taxanes in association with anthracyclines in 1st line chemotherapy for metastatic breast cancer (MBC): Comprehensive review of 2805 patients in 7 phase III trials

659 Background: The real advantage of taxanes in adjunction to antracycline-based chemotherapy in 1st line MBC is still unclear. We performed a comprehensive review (not a meta-analysis) (Simes, Stat Med 1987) including all phase III trials of 1st line chemotherapy for MBC, to look if the combination of antracyclines (doxo- or epi-rubicin) plus taxanes (paclitaxel or docetaxel) (AT) adds some benefit over standard antracicline-based regimen (AnonT) in activity and efficacy. Methods: We included phase III (prospective and randomized) published or presented at ASCO, ESMO/ECCO between 2000 and 2003; randomized phase II were excluded. Analysis was accomplished to look at significant differences in 1) time to progression (TTP); 2) overall response rate (ORR); 3) overall survival (OS) 4) complete response rate (CR) and 5) WHO G3–4 per patient toxicity (neutropenia, febrile neutropenia, FN, cardiotoxicity and neurotoxicity). For these analyses, ratios (HR and RR) and 95% confidence intervals (CI) were derived. R...

First line hormonal treatment (HT) for metastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T) in postmenopausal patients (pts) - A randomized phase III trial of the EORTC Breast Group

515 Background: E is an aromatase inactivator, with demonstrated efficacy in MBC progressing under T, which remained standard 1st line HT over decades. The randomized EORTC phase II trial of E vs T, which showed promising activity in 1st line MBC (Ann. Oncol. 2003, 14: 1391–8) was extended in a phase III reported here, aiming at a true comparison of efficacy and tolerability of both drugs. Methods: Postmenopausal MBC pts with ECOG PS ≤2 and measurable, hormone responsive disease (ER &/or PgR + or unknown with disease free interval >2y) previously untreated with HT for MBC, were randomized to receive open label E 25mg or T 20mg daily. One prior chemotherapy (CT) for MBC was permitted. Prior adjuvant T was allowed if treatment free interval exceeded 6 mo. The trial was powered to detect an increase in median progression free survival (PFS, primary endpoint) of 3 mo in favor of E. Secondary endpoints were survival and tolerability. All analyses were intent to treat. Results: 382 pts accrued by 81 centers received E (190 pts) or T (192 pts). Both groups were balanced for median age (62.5), prior adjuvant CT (E 28%, T 29%) or CT for MBC (E 8%, T 7%), hormone receptor status, PS, prior adjuvant T (21% both) and dominant metastatic site (visceral E 48%, T 47%; bone E 35%, T 36%; soft tissue E 17%, T 17%). On 15/12/2003, 286 events (progression or death under treatment) and 136 deaths were reported. The median PFS is significantly longer under E than T (10.9 vs 6.7 months, p 0.04) with an HR of 0.79 (95% CI 0.62 - 0.99) in favor of E. Best response rates (%) under E were CR 7.4, PR 36.8, SD 27.4, PD 18.4, NE (not evaluable) 10.0; under T, CR 2.6, PR 26.6, SD 37.0, PD 27.6, NE 6.2). No pt withdrew due to toxicity. Grade 2–3 toxicities observed in ≥10% were bone pain (E 12%, T 18%), other pain (E 7%, T 14%) and hot flashes (E 5%, T 12%). Conclusions: E is a safe and highly active steroidal aromatase inactivator, superior to T in MBC. In view of its efficacy and excellent tolerance, E represents a good choice as first line therapy in hormone responsive MBC. Its safety profile makes E also attractive for use in the adjuvant and preventive settings. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Pfizer; Schering-Plough Pfizer