Background
Introduction to neoadjuvant therapy
Using pathologic complete response (pCR) and residual cancer burden (RCB) as endpoints in neoadjuvant studies
Chemotherapy in the neoadjuvant setting
Role of neoadjuvant paclitaxel in breast cancer
Development of nab-paclitaxel
Methods
Results
Author and year of study | Regimen | Phase | ER/PR status | HER2 status | Stage | ITT | pCR rate in populations of interest | Definition of pCR | |||
---|---|---|---|---|---|---|---|---|---|---|---|
Sequence |
nab-P | Concurrent agents |
n
| pCR (%) | |||||||
Veerapaneni 2008 [27] |
nab-P + cape | 260 mg/m2 q3w (21-day cycle) | Cape 825 mg/m2 BID days 1–14 (21-day cycle) | II | Unselected | Unselected | II–IIIB | 14 | 7 | NR | No residual invasive carcinoma |
Yardley 2010 [28] |
nab-P + gem + E + peg | 175 mg/m2 q2w × 6 cycles | Gem 2000 mg/m2 q2w + E 50 mg/m2 q2w + peg 6 mg q2w × 6 cycles | II | Unselected | Unselected | I–IIIC | 123 | 20 | TNBC (n = 44), 27 % | ypT0 ypN0 |
Robidoux 2010 [29] |
nab-P → 4 cycles FEC (+ trastuzumab for HER2+) | 100 mg/m2 qw × 12 cycles | None | II | Unselected | Unselected | IIB-IIIB | 66 | In-breast: 29; breast-plus-node: 26 | pCR in breast only: TNBC (n = 18), 28 % HR+/HER2+ (n = 9), 44 % HR-/HER2+ (n = 10), 70 % | In-breast ypT0 and breast-plus-node ypT0 ypN0 assessed |
Yardley 2011 [52] |
nab-P + carbo + trastuzumab + bevacizumab | 100 mg/m2 qw 3/4 (28-day cycles) × 6 cycles | Carbo AUC = 6 q3w + trastuzumab 2 mg/kg qw after 4 mg/kg in first week + bev 5 mg/kg qw (28-day cycles) × 6 cycles | II | Unselected | HER2+ | IIA–IIIC | 30 | 54 | ER+, 43 %; ER−, 66 % | ypT0 ypN0 |
Khong 2011 [68] |
nab-P + AC + peg | 100 mg/m2 qw 2/3 × 6 cycles | A 50 mg/m2 q3w + C 500 mg/m2 q3w + peg q3w × 6 cycles | I | Unselected | HER2− | II–III | 16 | NR | TNBC (n = 4), 100 % | ND |
Li 2012 [69] | Docetaxel + AC | NA | NA | II | Unselected | Unselected | II–III | 18 | 17 | Treatment arms combined: Basal-like (n = 12), 25 % Luminal (n = 26), 8 % HER2+ (n = 15), 53 % | RCB 0 |
AC → nab-P + carbo | 100 mg/m2 qw 3/4 × 3 cycles | Carbo AUC = 2 qw 3/4 × 3 cycles | 26 | 8 | |||||||
AC + trastuzumab → nab-P + carbo + trastuzumab | 100 mg/m2 qw 3/4 × 3 cycles | Carbo AUC = 2 qw 3/4 × 3 cycles | 28 | 46 | |||||||
Kaklamani 2012 [31] |
nab-P + lapatinib | 260 mg/m2 q3w (28-day cycles) × 4 cycles | Lapatinib 1000 mg qd × 12 weeks | Pilot | Unselected | HER2+ | I–III | 30 | ypT0 ypN0: 18; RCB 0: 21.7 | NR | ypT0 ypN0 and RCB 0 |
Sinclair 2012 [34] | Cohort 1:
nab-P → nab-P + bevacizumab + carbo | 100 mg/m2 qw × 2 weeks → 100 mg/m2 qw × 12 weeks | Bevacizumab 15 mg/m2 q3w × 3 cycles + carbo AUC = 6 q3w × 4 cycles | II | Unselected | HER2− | IIA–IIIC | 31 | ypT0 ypN0/is: 11; RCB 0 + 1: 37 | TNBC (n = 11): ypT0 ypN0/is, 27 %; RCB 0 + 1, 55 % | ypT0 ypN0/is and RCB 0 + 1 |
Cohort 2: bevacizumab → nab-P + bevacizumab + carbo → AC + bevacizumab | 100 mg/m2 qw × 12 weeks | Bevacizumab 15 mg/m2 q3w × 4 cycles + carbo AUC = 6 q3w × 4 cycles | 29 | ypT0 ypN0/is: 54; RCB 0 + 1: 64 | TNBC (n = 16): ypT0 ypN0/is, 81 %; RCB 0 + 1, 100 % | ||||||
Snider 2013 [70] |
nab-P + carbo + bevacizumab → AC + bevacizumab | 100 mg/m2 qw 3/4 (28-day cycle) × 4 cycles | Carbo AUC = 6 q4w + bevacizumab 10 mg/kg q2w (28-day cycle) × 4 cycles | NR | ER− PR− | HER2− | I–III | 41 | ypT0, 61; ypT0 ypN0, 53 | NA | ypT0 and ypT0 ypN0 assessed |
Masumoto 2014 [71] |
nab-P q3w + carbo → FEC | NR | NR | II | Unselected | Unselected | Operable; stage not reported | 55 | 36.5 | HER2+ ,59 %; TNBC, 57 %; ER+ HER2−, 4 % | ypT0 ypN0 |
Martin 2014 [37] |
nab-P qw 3/4 | 150 mg/m2 qw 3/4 × 4 cycles | NA | II | ER+ PR unselected | HER2− | I–III | 83 | 24.1 % | RCB 0 + 1 24.7 % of treated population (20/81) | RCB 0 + 1 |
Nahleh (S0800) 2014 [35] | Bevacizumab + nab-P → AC + peg-G | 100 mg/m2 qw × 12 weeks | Bevacizumab 10 mg/kg q2w × 12 weeks | II | Unselected | HER2− | IIB–IIIC | 215 | No bevacizumab, 21; bevacizumab, 36 (P = 0.021) | HR−: no bevacizumab, 28 % versus bevacizumab, 59 % (P = 0.014) HR+: no bevacizumab, 18 % versus bevacizumab, 25 % (P = 0.41) | ypT0 ypN0 |
nab-P → AC + peg-G | |||||||||||
AC + peg-G → nab-P | |||||||||||
Untch 2016 [39] |
nab-P → EC | 125 mg/m2 qwa
| – | III | Unselected | Unselected | Operable or inoperable; cT2-cT4a-d; cT1c and cN+ or pNSLN+ | 606 | ypT0 ypN0, 38; ypT0/is ypN0, 43; ypT0/is ypN0/+, 49 | HER2+: nab-P, 62 %; P, 54 % (P = 0.13) TNBC: nab-P, 48 %; P, 26 % (P < 0.001) | Primary: ypT0 ypN0; secondary endpoints included ypT0/is ypN0 and ypT0/is ypN0/+, and ypN0 |
Paclitaxel → EC | NA | 600 | ypT0 ypN0, 29; ypT0/is ypN0, 35; ypT0/is ypN0/+, 40 | ||||||||
Mrozek 2010 [36] |
nab-P + carbo + bevacizumab | 100 mg/m2 qw 3/4 × 6 cycles | Carbo AUC = 2 qw 3/4 + bevacizumab 10 mg/kg q2w × 6 cycles (no bevacizumab in 6th cycle) | II | Unselected | HER2− | II–III | 33 | 21 | TNBC, 55 % | ypT0 ypN0 |
Zelnak 2012 [32] |
nab-P → vin + trastuzumab | 260 mg/m2 q2w × 4 cycles | – | II | Unselected | HER2+ | I–III | 27 | 48.1 | ER+/PR+, 18.1 %; ER−/PR−, 68.8 % | ypT0 ypN0 |
Connolly 2015 [72] |
nab-P + carbo + placebo | 100 mg/m2 qw × 12 weeks | Carbo AUC = 2 qw + placebo 3 times per week × 12 weeks | II | Unselected | HER2− | Operable; T1cN1-3 or T2-4, any N, all M0 | 31 | 29 | TNBC: placebo, 58.3 % versus vorinostat, 41.7 % | ypT0 ypN0 |
nab-P + carbo + vorinostat | 100 mg/m2 qw × 12 weeks | Carbo AUC = 2 qw + vorinostat 400 mg 3 times per week × 12 weeks | 31 | 25.8 | |||||||
Huang 2015 [30] |
nab-P + carbo | 125 mg/m2 qw × 4 cycles | Carbo AUC = 2 qw × 4 cycles | II | Unselected | Unselected | II–III | 30 | 26.7 | HER2+, 43.6 % versus 39.6 % for nab-P versus P (P = 0.769) | ypT0/is ypN0 |
Paclitaxel + carbo | NA | Paclitaxel 80 mg/m2 qw + carbo AUC = 2 qw × 4 cycles | 90 | 25.6 | |||||||
Shimada 2015 [40] |
nab-P → EC | 260 mg/m2 q3w × 4 cycles | – | NA | Unselected | HER2− | II–III | 53 | 5.7 | NR | ypT0/is, ypNany |
Tanaka 2015 [33] | EC or FEC → nab-P + trastuzumab | 260 mg/m2 q3w | – | II | Unselected | HER2+ | I–IIIA | 46 | 49 | ER+, 36 %; ER−, 71 % | ypT0/is ypN0 |
Gluz 2015 [41] |
nab-P + gem | 125 mg/m2 qw 2/3 | gem 1000 mg/m2 qw 2/3 | II | ER- PR- | HER2− | I-IV | 182 | 28.7 | NA | ypT0/is ypN0 |
nab-P + carbo | 125 mg/m2 qw 2/3 | Carbo AUC 2 day 1, 8 q3w | 154 | 45.9 | NA |
Trial |
nab-P schedule and dose | Neutropenia (%) | Peripheral neuropathy (%) | Fatigue (%) |
---|---|---|---|---|
Veerapaneni [27] | q3w 260 mg/m2
| NR | NR | NR |
Kaklamani [31] | q3w 260 mg/m2
| NR | 0a
| 7a
|
Masumoto [71] | q3w | NR | NR | NR |
Shimada [40] | q3w 260 mg/m2
| 37.7 | 1.9 | NR |
Tanaka [33] | q3w 260 mg/m2
| 36 | 84b
| 64 |
Yardley [28] | q2w 175 mg/m2
| 11 | 2b
| 7 |
Zelnak [32] | q2w 260 mg/m2
| 38 | 88 | 73 |
Robidoux [29] | qw 100 mg/m2
| 3a
| 5a
| 6a
|
Sinclair [34] | qw 100 mg/m2
| 75 | 0c
| 13 |
Sinclair [73] | qw 100 mg/m2
| 71a
| 7a,c
| 7a
|
Nahleh [35] | qw 100 mg/m2
| NR | NR | NR |
Untch [39] | qw 125 mg/m2d
| 60.8a
| 10.4a
| 5a
|
Connolly [72] | qw 100 mg/m2
| NR | NR | NR |
Huang [30] | qw 125 mg/m2
| 100 | 43e
| NR |
Mrozek [36] | qw 3/4 100 mg/m2
| 58a
| NR | NR |
Yardley [52] | qw 3/4 100 mg/m2
| 39a
| 0a
| NR |
Khong [68] | qw 2/3 100 mg/m2
| NR | NR | NR |
Li [69] | NR | NR | NR | NR |
Snider [70] | qw 3/4 100 mg/m2
| 78a
| NR | 5 |
Martin [37] | qw 3/4 150 mg/m2
| 16a
| 2.5a
| 3.7a
|
Unselected disease
nab-Paclitaxel with HER2-targeted therapies
nab-Paclitaxel with bevacizumab
Recent trials
Toxicities
Discussion
Predictive biomarkers of response
Ongoing trials
Trial #, PI, institution | Phase | Planned N
| Patient population | Stage | Regimen |
nab-P treatment |
---|---|---|---|---|---|---|
ETNA (NCT01822314), Luca Gianni, San Raffaele Hospital, Italy | III | 632 | High-risk HER2− | Operable T2N0-1, T3N0 and locally advanced T3N1, T4, any N2-3 |
nab-P or P → AC or EC or FEC | 125 mg/m2 qw 3/4 × 4 cycles |
NCT00397761, Anita Aggarwal, Washington Hospital Center | II/III | 33 | Unselected | II–IIIB |
nab-P + capecitabine | NA |
NCT01525966, George Somlo, City of Hope Medical Center | II | 49 | TNBC | II–IIIC |
nab-P + carbo | Dose not given; qw every 28 days for 4 courses |
NCT00944047, Qamar Khan, University of Kansas Medical Center Cancer Center | II | 30 | Low HER2 | II–III |
nab-P + trastuzumab → ddAC | 100 mg/m2 qw × 12 weeks |
NCT01036087, Naoto Ueno, MD Anderson Cancer Center | II | 40 | HER2− IBC | NR | Panitumumab → panitumumab + nab-P + carbo → FEC | 100 mg/m2 qw × 12 weeks |
NCT00856492, Zeina Nahleh, Barbara Ann Karmanos Cancer Institute | II | 200 | HER2− IBC or LABC | IIB–IIIC |
nab-P ± bevacizumab before or after AC + peg | Dose not given; qw × 12 weeks |
NCT00618657, Rita Mehta, Chao Family Comprehensive Cancer Center, UC Irvine | II | 120 | HER2+ or HER2− | IA-IIIC |
nab-P + carbo + trastuzumab (HER2+)
nab-P + carbo + bevacizumab (HER2−) | qw × 12 (HER2+) q2w × 5 (HER2−) |
NCT00617942, William Sikov, Brown University | II | 60 | HER2+ | IIA–IIIB |
nab-P + trastuzumab qw + carbo q3w | 100 mg/m2 qw |
NCT00777673, Jasgit Sachdev, University of Tennessee Cancer Institute | II | 60 | TNBC | NA |
nab-P + carbo + bevacizumab → AC + bevacizumab | Dose not given; qw 3/4 × 4 cycles |
NCT01830244, Mustafa Khasraw, Barwan Health, Australia | II | 60 | Unselected | T2-4, N0-2 |
nab-P + EC | 125 mg/m2 qw × 12 weeks |
NCT02530489, Jennifer Litton, MD Anderson Cancer Center | II | 37 | TNBC | NA |
nab-P + atezolizumab followed by surgery and then adjuvant atezolizumab | 100 mg/m2 qw × 12 weeks |
NCT02598310, Mitsuhiko Iwamoto, Osaka Medical College, Japan | II | 30 | ER−/HER2+ | Operable (tumor size ≤ 3 cm, N0) |
nab-P + trastuzumab | 260 mg/m2 q3w |
NCT01625429, Zhimin Shao, Fudan University, China | II | 30 | Unselected | II–III |
nab-P + carbo (+trastuzumab for HER2+) | 125 mg/m2 qw 3/4 |
NCT02489448, Lajos Pusztai, Yale University | I/II | 61 | TNBC | I–III |
nab-P + durvalumab followed by ddAC | 100 mg/m2 qw × 12 weeks |