Huebner, L

Abstract Background: CALGB 40502/NCCTG N063H (Alliance) compared weekly NP or Ix to P; most patients received bevacizumab. Ix was inferior to P, and NP was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms compared to P (Rugo et al, JCO 2015). We report long-term follow-up (FU) of this trial with an unplanned subset analysis in hormone receptor positive (HR+) and triple negative (TNBC) breast cancer. Methods: Patients were randomized 1:1:1 to receive P (90 mg/m2), Ix (16 mg/m2) or NP (150 mg/m2) on a 3 week (wk) on, 1 wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all patients, but became optional in 3/2011 and was added to stratification. The primary endpoint was progression-free survival (PFS); secondary endpoints included safety and overall survival (OS). With a target N=900 patients, the study was powered to detect a hazard ratio of 1.36 (median PFS 10 vs 13.6 months). Eligibility included no prior chemotherapy for MBC, >12 mo from adjuvant P and measurable disease. Results: 799 patients were randomized between 11/08 and11/11 (283 to P, 271 to NP, 245 to Ix); 98% received bevacizumab. 68% (546) had HR+ disease, 25% (201) had TNBC. Median FU is 5 years. Median PFS is unchanged at 10.8, 9.2 and 7.4 mo for P, NP and Ix with hazard ratios (95% CIs) of 1.13 (0.94-1.34) and 1.44 (1.2-1.72) for NP and Ix to P, respectively. Median OS was 27.1, 24.2 and 23.6 months for P, NP and Ix with hazard ratios of 1.10 (0.91-1.34) and 1.3 (1.07-1.57) for NP and Ix to P, respectively. The effects of NP vs P on PFS and OS were significantly modified by subtype (interaction p=0.0018 and 0.0073), whereas Ix vs P was unchanged (interaction p's > 0.9, Table). More patients discontinued treatment due to adverse events in the experimental arms (14 vs 27 vs 23% for P, NP and Ix). Table P (mo)NP (mo)NP to P; HR (95% CI)Ix (mo)Ix to P, HR (95% CI)TNBC, PFS6.47.40.79 (0.55-1.12)15.61.39 (0.99-1.96)3HR+, PFS12.29.61.29 (1.04-1.59)181.5 (1.21-1.86)3TNBC, OS15.3210.74 (0.51-1.07)215.11.28(0.9-1.82)4HR+, OS33.226.61.25 (0.99-1.58)225.41.35(1.07-1.714Interaction tests: 1. p=0.0018; 2. p=0.0073; 3. p=0.96; 4. p=0.92 mo: months; HR: hazard ratio·· Conclusion: In patients with chemotherapy-naive MBC, Ix was inferior to P for PFS, and P was better tolerated than either NP or Ix. In this retrospective subset analysis, Ix and NP were inferior to P in HR+ disease, with a suggestion of improved PFS and OS with NP in patients with TNBC. Further investigation is required to explain and validate the subtype specificity seen in this exploratory analysis. Support: U10CA180820, U10CA180821, U10CA180882, U10CA180888. ClinicalTrials.gov Identifier: NCT00785291 Citation Format: Rugo HS, Barry WT, Moreno-Aspitia A, Lyss A, Huebner L, Mayer EL, Naughton M, Layman RM, Carey LA, Somer RA, Toppmeyer D, Velasco M, Perez EA, Hudis CA, Winer E. Long-term follow-up of CALGB 40502/NCCTG N063H (Alliance): A randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-Paclitaxel (NP) or ixabepilone (Ix) +/- bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-06.

Abstract Purpose Dual HER2 targeting increases pathologic complete response (pCR) rate to neoadjuvant therapy and improves outcomes in both early and metastatic HER2-positive disease. CALGB 40601 is a randomized phase III trial examining the impact of dual HER2 blockade consisting of trastuzumab (H) and lapatinib (L) added to paclitaxel (T) on pCR, considering tumor and microenvironment molecular features. We previously found that pCR was numerically but not significantly increased with dual therapy, and that tumor molecular subtype and evidence of immune activation significantly and independently affected pCR (Carey et al, JCO 2016). In this secondary analysis, we sought to evaluate the effects of treatment arm and gene expression-defined subgroups on invasive disease free survival (IDFS). Patients and Methods Patients (Pts) with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment with equal probabilityto paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. A paclitaxel plus lapatinib (TL) arm was closed early based on reports of futility from other trials. A secondary endpoint was IDFS, defined as the time from surgery until local or distant recurrence, new primary, or death from any cause, whichever was first. Gene expression signatures were identified by RNA sequencing. Results Between 12/2008 and 2/2012, 305 pts were enrolled. 261 pts had IDFS and gene expression information available (THL, n = 103; TH, n =101; TL, n = 57); there were no significant differences in clinical characteristics between this subset and the entire population. The median IDFS follow-up was 4.6 years with 40 IDFS events having occurred (THL, n=7; TH, n=19; TL, n=14). IDFS was significantly longer in the THL arm compared to standard TH (HR=0.34; 95% CI: 0.14-0.82; p=0.02). IDFS was also significantly longer among pCR than non-pCR pts (HR=0.40; 95% CI: 0.19-0.81; p=0.01), and did not differ by hormone receptor (HR) status, clinical stage, tumor size, race, menopausal status or age. Among gene expression signatures, only immune activation measured by an IgG signature was associated with longer IDFS (HR=0.71; 95% CI: 0.51-0.98; p=0.04); this signature was previously also associated with pCR. Multivariate analysis showed dual therapy (HR=0.35; p=0.02), pCR (HR=0.36; p=0.01), IgG (HR=0.69; p=0.05), and molecular subtype (LumA vs HER2E, HR=0.24, p=0.005) were associated with longer IDFS. A subgroup analysis by hormone receptor status revealed that among pts with HR+ disease, pts with luminal A experienced longer IDFS (HR=0.23; p=0.02) compared to those with luminal B or HER2-enriched molecular subtypes. Conclusion Dual HER2-targeting with lapatinib added to 16 weeks of TH produced significantly longer IDFS than TH alone, despite modest effects on pCR. Similar to pts with HER2-negative disease, pts with luminal A had better IDFS than those with other molecular subtypes. Immune activation as measured by RNA-based signature independently predicted both pCR and IDFS. Support: U10CA180882, U10CA180821, U24CA196171, P50-CA58823, Susan G Komen, BCRF Citation Format: Krop IE, Hillman D, Polley M-Y, Tanioka M, Parker J, Huebner L, Henry NL, Tolaney SM, Dang C, Harris L, Berry DA, Perou CM, Partridge A, Winer EP, Carey LA. Invasive disease-free survival and gene expression signatures in CALGB (Alliance) 40601, a randomized phase III neoadjuvant trial of dual HER2-targeting with lapatinib added to chemotherapy plus trastuzumab [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-02.