Perez, Edith A.

36 Background: Black race is associated with worse outcomes in localized breast cancer. We evaluated the characteristics of patients enrolled in the Trial Assigning Individualized Options for Treatment (TAILORx) by race and ethnicity. Methods: The analysis included 10,071 evaluable patients with Recurrence Score (RS) data. Eligibility criteria included: (1) T1-2, N0 disease, (2) estrogen receptor (ER) and/or progesterone receptor (PR) positive disease that was also HER2/neu negative, (3) age 75 years or younger and medically appropriate for adjuvant systemic chemotherapy. Results: The study population included 8,501 whites (84%), 722 blacks (7%), 423 Asians (4%), and the remainder other/unknown race. With regard to ethnicity, 7,916 were nonHispanic (79%), 919 were Hispanic (9%), and 1,236 were of unreported ethnicity (12%). There was no significant difference in RS distribution (p = 0.14), median RS (17 vs. 17), and mean RS (19.6 vs. 18.4) in blacks compared with nonblacks. There was likewise no difference in Hispanic vs. nonHispanic ethnicity for RS distribution (p = 0.53), median RS (17 vs. 17), and mean RS (18.6 vs. 18.4). Blacks were significantly more likely to be younger (39% vs. 30% < 50 years), have larger tumors (37% vs. 31% > 2 cm), poor histologic grade (25% vs. 17%), and PR-negative disease (14% vs. 10%) (Chi square test p < 0.05). Hispanic women were also significantly younger (39% vs. 30% < 50 years), and demonstrated marginal but statistically significant differences in tumor size (65% vs. 69% > 2 cm), histologic grade (20% vs. 18% poor), and PR expression (12% vs. 10% negative) (Chi square test < 0.05). In 974 patients with information on body mass index (BMI), there was no correlation between BMI and RS (r = -0.04). BMI was higher for blacks than whites (medians 31.6 vs. 28.9, p = 0.02, Wilcoxon test), but not in Hispanics. Conclusions: In patients selected for participation in TAILORx there were no significant differences in RS by race, ethnicity, and BMI. Black and Hispanic patients were significantly younger, and blacks had tumors that were larger and more likely to be associated with poor grade. Clinical trial information: NCT00310180.

100 Background: Combining BEV with CT significantly improved progression-free survival (primary endpoint) in the E2100, AVADO, and RIBBON-1 trials in the 1st-line setting and the RIBBON-2 trial in the 2nd-line setting. Primary efficacy and safety results from RIBBON-2 have been published; here we present final OS results. Methods: Eligible patients (pts) had MBC that had progressed on 1st-line CT without BEV. 2nd-line CT (taxane, gemcitabine, capecitabine, or vinorelbine) was chosen before 2:1 randomization to CT with either BEV (10 mg/kg q2w or 15 mg/kg q3w) or PL continued until progression. Stratification factors were 2nd-line CT, hormone receptor status, and time from MBC diagnosis to 1st progression. All pts could receive BEV at progression. The primary endpoint was PFS. Final analysis of OS, a secondary endpoint, in the intent-to-treat population was planned after 557 events and provided 80% power to detect a hazard ratio (HR) of 0.77 (median OS increased from 14.0 to 18.2 months) at α=0.04. Results: At the time of data cutoff (Oct. 31, 2011), 184 (82%) of 225 pts in the CT/PL arm and 376 (82%) of 459 pts in the CT/BEV arm had died. BEV was administered in subsequent treatment lines in 12% vs 6% of pts, respectively. There was no difference in OS between treatment arms: HR 1.013 (95% CI 0.845–1.215), log-rank p=0.8843. Median OS was 17.8 months with CT/PL vs 18.6 months with CT/BEV. The 1-year OS rates were 69% vs 71%, respectively. Subgroup analyses by CT cohort showed HRs ranging from 0.86 (95% CI 0.58–1.29) in the capecitabine cohort (n=144) to 1.44 (95% CI 0.82–2.53) in the vinorelbine cohort (n=76). HRs were close to 1 for the two largest CT cohorts (taxane and gemcitabine). Exploratory analysis in the subgroup of patients with triple-negative MBC showed a HR of 0.85 (95% CI 0.58–1.26). Updated safety results were similar to those previously reported from the primary analysis. There were fewer fatal adverse events in the CT/BEV arm (1.5%) than in the CT/PL arm (3.2%). Conclusions: Final OS results from RIBBON-2 reveal no difference between treatment arms. No new safety signals were observed.

LBA1000 Background: The primary aims were to determine whether adjuvant DD AC→PG will be superior to DD AC→P as well as to TAC in DFS and to compare the relative DFS of TAC and DD AC→P. Secondary endpoints include survival and toxicity. Methods: From Nov 3, 2004 to May 3, 2007, 4894 women were randomized; 1630 to TAC (docetaxel [T] 75 mg/m2, doxorubicin [A] 50 mg/m2, cyclophosphamide [C] 500 mg/m2 q3 wks x 6), 1634 to DD AC→P (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 followed by P 175 mg/m2 q2 wks x 4), and 1630 to DD AC→PG (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 → P 175 mg/m2 + G 2000 mg/m2q2 wks x 4). Primary G-CSF support was required and erythropoiesis-stimulating agents (ESA) were used at investigator discretion. 52% were postmenopausal, 65% had 1 - 3 positive nodes, and 80% had HR+ breast cancer. Log-rank tests were used for pair-wise comparisons of the primary (DFS) and secondary (OS) endpoints among the three treatment arms. Results: With 64 months median follow-up, 5-year DFS in DD AC→PG group was 80.6% compared with 82.2% in DD AC→P group (HR=1.1; p=0.27) and 80.1 % (HR=0.97; p=0.71) in TAC group. 5-year OS was 90.8% in DD AC→PG group as compared with 89.1% (HR=.89; p=0.25) in DD AC→P group and 89.6 % (HR=0.90; p=0.32) in TAC group. HR for DFS and OS of DD AC→P vs. TAC were 0.89 (p=0.14) and 1.01 (p=0.92) respectively. Toxicities for TAC, DD AC→P, DD AC→PG, respectively: febrile neutropenia (Gr 3/4: 9%, 4%, 4% [p<0.001]), sensory neuropathy (Gr 3/4: <1%, 7%, 6% [p<0.001]), diarrhea (Gr 3/4: 8 %, 2%, 2% [p<0.001]). Hgb was <10 in 12%, 26%, 33% with ESA use in 35.2%, 47%, 51.6% and transfusions in 3.7%, 6.3%, 9.4%. Deaths on treatment: N=13, 5, 7 (p=0.2). AML/MDS: N=5, 8, 11. All cycles completed in 91% for TAC and 88% for DD regimens. Conclusions: Addition of G to DD AC→P did not improve outcomes. No significant differences in efficacy endpoints were identified between DD AC→P and TAC, though toxicity profiles differed. Funding: NCI PHS U10-CA-37377, -69974, -12027, -69651 and NCCTG U10-CA25224, with additional funding from Eli Lilly & Company, and Amgen, Inc.

CRA1002 Background: Weekly P is superior to q 3 week (wk) dosing, and adding B improves progression free survival (PFS) (E2100). Ix is a potent epothilone that can be effective after microtubule inhibitor resistance. NP is a novel albumin-bound formulation of P with promising activity in the first-line MBC setting. In this phase III trial, the efficacy of weekly Ix or NP is compared to P, in combination with B in patients (pts) with chemotherapy (CTX) naïve MBC. Toxicity including >Grade 2 sensory neuropathy (SN) is compared to P. Methods: Pts were randomized 1:1:1 to receive P (90 mg/m2), Ix (16 mg/m2) or NP (150 mg/m2) on a 3 wk on, 1 wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all pts, but became optional in 3/2011 and was added to stratification. The primary end point of PFS is defined as time from randomization to progression or all-cause death. With a target N=900 pts, the study was powered to detect a hazard ratio (HR) of 1.36 (median PFS 10 vs 13.6 mos). Eligibility included no prior CTX for MBC, >12 mos from adjuvant P and measurable disease. Results: 799 pts were enrolled between 11/08-11/11 (283 to P, 271 to NP, 245 to Ix); 98% received B. 72% had ER+ disease, 44% received adjuvant P. At the 1st interim analysis (165 events) the comparison of Ix to P crossed the futility boundary (FB) and accrual to Ix was closed. At the 2nd interim analysis (236 events), NP to P crossed the FB and the study was closed on 11/30/11. Median PFS was 10.4, 9.6 and 7.6 mos for P, NP and Ix, with HRs (95% CIs) of 0.94 (0.73-1.22) and 0.66 (0.51-0.84) for P to NP and Ix respectively. Grade 2+ SN was 48% for NP, 44% for Ix and 37% for P; Grade 3+ hematologic toxicity was 49% for NP, 20% for Ix, and 12% for P. Conclusions: In pts with CTX naive MBC, both NP and Ix are highly unlikely to be superior to P for PFS (when all are combined with B), and in combination with B, weekly P is the better tolerated drug. Toxicity including SN was greater in each experimental arm compared to P. Updated data will be presented, and correlative studies will be reported at a future date.

LBA4 Background: Lapatinib (L) is a HER1-HER2 tyrosine kinase inhibitor. The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial is a randomised, phase III trial comparing 3 oral L-containing regimens with T, each given for 1 year. Methods: From June 2007 to July 2011, 8381 patients (pts) were randomised from 946 sites in 44 countries to receive either L+T, T→L, L, or T. Anti-HER2 therapy was initiated after completing all chemotherapy (N=4613), concurrently with a taxane following anthracycline (N=3337), or concurrently with a non-anthracycline, platinum-containing regimen (N=431). The L arm was closed in Aug 2011 for futility and is not presented. The primary endpoint is invasive disease-free survival (DFS). L+T vs. T is tested for superiority and T→L vs. T is tested for non-inferiority at 1.11 margin. P≤0.025 is required for statistical significance. 850 DFS events in the L+T vs. T comparison would provide 80% power to detect a true hazard ratio (HR) of 0.80 with experiment-wide alpha=0.05. The current analysis was planned to occur either after observing these 850 events or at 4.5 yrs median follow up (MFU). Results: Pt and disease characteristics were well balanced. 40% were node-negative and 57% were hormone receptor positive. Only 555 DFS events for the L+T vs. T comparison were observed at 4.5 years MFU. HR for DFS was 0.84 (97.5% CI, 0.70-1.02; P=0.048; 4-yr DFS%=88% vs. 86%) for L+T vs. T and 0.93 (97.5% CI, 0.76-1.13; non-inferiority P=0.044; 4-yr DFS%=87% vs. 86%) for T→L vs. T. Diarrhoea (75% vs. 20%), rash (55% vs. 20%) and hepatobiliary (23% vs. 16%) adverse events were more frequent in L+T vs. T. Primary cardiac endpoints were infrequent (<1%) in all arms. Conclusions: L+T has lower risk of a DFS event compared with T, and T→L appeared non-inferior to T, but neither finding was statistically significant. The first DFS results of dual HER2 blockade in the adjuvant ALTTO at 4.5 years MFU are unexpected considering the effect shown by doubling the pCR rate with L+T vs. T in the NeoALLTO trial. Follow up continues. Clinical trial information: NCT00490139.

LBA1 Background: Adjuvant endocrine therapy with AI vs T improves outcomes in postmenopausal HR+ BC. TEXT and SOFT were designed to test whether adjuvant AI improves outcomes in premenopausal women with HR+ BC treated with OFS (AI question) and to determine the value of OFS in women who remain premenopausal and are suitable for adjuvant T (OFS question). Methods: TEXT and SOFT, randomized phase 3 trials, enrolled 5,738 premenopausal women with HR+ early BC from Nov03 to Apr11 (2672 TEXT; 3066 SOFT). TEXT randomized women within 12wk of surgery to 5y E+OFS vs T+OFS; chemotherapy (CT) was optional and concurrent with OFS. SOFT randomized women to 5y E+OFS vs T+OFS vs T alone, either within 12wk of surgery if no CT planned, or within 8mo of completing (neo)adjuvant CT. OFS was by choice of 5y triptorelin, oophorectomy, or ovarian irradiation. The primary endpoint is disease-free survival (DFS: randomization until invasive local, regional, distant recurrence, or contralateral breast; 2nd malignancy; death). Due to low event rates, protocol amendments in 2011 changed the analysis plans to answer the AI question (E+OFS vs T+OFS) by joint analysis of TEXT and SOFT. By Q3’2013 with >5y median follow-up, 436 DFS events were projected, providing 84% power for HR=0.75 with E+OFS vs T+OFS (stratified logrank 2-sided α=0.05). Results: At 5.7y median follow-up, 514 (11%) DFS events were reported in the ITT population comparing E+OFS (n=2346) vs T+OFS (n=2344). Patients assigned E+OFS had significantly reduced DFS hazard (HR=0.72; 95% CI, 0.60-0.86; P=0.0002) vs T+OFS; 5y DFS was 91.1% vs 87.3%. Reductions were similar for secondary endpoints of BC-free interval (HR=0.66 (0.55-0.80) 5y BCFI 92.8% vs 88.8%) and distant recurrence-free interval (HR=0.78 (0.62-0.97)), though not overall survival (HR=1.14 (0.86-1.51)) at this early follow-up (194 (4%) deaths). Grade 3-4 targeted AEs were reported in 31% E+OFS vs 29% T+OFS patients. Conclusion: In premenopausal women with HR+ BC, adjuvant treatment with E+OFS significantly reduced the risk of recurrence compared to T+OFS. Clinical trial information: NCT00066703 / NCT00066690 .

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.

653 Background: Next-generation sequencing often reveals potentially actionable molecular alterations; however, data on approved targeted therapies in non-indicated tumors are limited. MyPathway (NCT02091141) evaluates agents targeting the HER2, EGFR, BRAF, or Hedgehog (Hh) pathways in tumors for which these therapies are not currently indicated. Here, we present early response data for patients with GI tumors. Methods: Eligible patients had metastatic tumors with potentially actionable genomic alterations, identified by a CLIA-certified lab, and progression on standard therapy. Based on the identified alteration, patients received standard doses of trastuzumab + pertuzumab (HER2), erlotinib (EGFR), vemurafenib (BRAF), or vismodegib (Hh). Response was evaluated by the investigator using RECIST v1.1. Results: As of Aug 21, 2015, 96 patients had enrolled, 36 of whom (38%) had GI tumors with the following alterations: HER2 (n=28 [22 amplifications, 5 activating mutations, 1 both]), BRAF (n=4), Hh (n=2 [2 PTCH-1 mutations]), and EGFR (n=2). Patients had a median of 4 (range, 1–8) prior lines of therapy. Tumor types and interim best response data are shown below. Among all evaluable patients with GI tumors (n=26), 5 have had a PR to targeted therapy (duration 3–10+ months). Conclusions: Targetable molecular alterations were found in a variety of GI tumors, resulting in clinical benefit from targeted treatments that would not have otherwise been realized. These early results support this molecular testing strategy. Accrual to the trial continues; based on activity observed, the HER2-positive colorectal cancer cohort will be expanded to ≥30 patients. Additional data will be presented at the meeting. Clinical trial information: NCT02091141. [Table: see text]