Targeted delivery for breast cancer therapy: the history of nanoparticle-albumin-bound paclitaxel

Figures & data

Box 1. Drug summary.

Drug name	Paclitaxel protein-bound particles for injectable suspension (nab-P)
Phase	Phase III
Indication	nab-P is indicated in Europe for the treatment of breast cancer after failure of first-line treatment for metastatic disease. Previous therapy should have included an anthracycline unless clinically contraindicated
Pharmacology description/mechanism of action	nab-P is an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nm. The active agent in nab-P is paclitaxel, a natural product with anti-tumor activity. Paclitaxel is obtained from Taxus media. The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine. nab-P is an anti-microtubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerisation
Route of administration	nab-P is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 ml of 0.9% sodium chloride injection, ultra stable promoter before i.v. infusion. Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin. Each millilitre of reconstituted suspension contains 5 mg paclitaxel. nab-P is free of solvents. After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for nab-P for injectable suspension (paclitaxel protein-bound particles for injectable suspension) is 260 mg/m^2 administered intravenously over 30 min every 3 weeks
Chemical structure
Pivotal trial(s)	[58]

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Figure 1. Patient survival over time (A) and patient survival over time in patients who received second-line or greater therapy (B).

Table 1. Studies with nab-P in the neoadjuvant setting.

Ref.	Schedule	Phase	Neoplasm	No. of patients	Response	PFS/OS	Toxicity
Berstein et al. [23]	AC → HER2+: nab-P + CBDCA + herecptin HER2−: nab-P + CBDCA + bevacizumab	III	Breast cancer RP < 50% after 2 AC	30	HER2+ pCR 62.5% HER2− pCR 30%	PFS at 6 mths 100%	Arthralgia G3 (6.6%) Ischemic attack (3.3%)
Inhorn et al. [38]	Neoadjuvant: gemcitabine 2000 mg/m^2 + epirubicin 50 mg/m^2 + nab-P 175 mg/m^2 q 14 × 6 cycles Adjuvant: gemcitabine 2000 mg/m^2 + nab-P 220 mg/m^2 q 14 × 4 cycles	II	Breast cancer	123 (112 evaluable)	pCR 18% PR 68% SD 5%	Not reported	Not reported
Paz et al. [39]	Arm A: docetaxel 75 mg/m^2 + doxorubicin 50 mg/m^2 + cyclophosphamide 500 mg/m^2 (TAC) × 6 cycles Arm B: AC q 14 × 4 → CBDCA (AUC 2) weekly × 3 + nab-P 100 mg/m^2 q 28 × 3 cycles Arm C (for HER2 + pts): AC q 14 × 4 → CBDCA (AUC 2) weekly × 3 + nab-P 100 mg/m^2 q 28 × 3 cycles + herceptin × 12 weeks	III	Breast cancer Stage II – III	52 (39 undergone surgery)	pCR: arm A 7%; arm B 7%; arm 40%	Not reported	Not reported
Yardley et al. [40]	nab-P 100 mg/m^2 weekly days 1, 8, 15 q 28 + CBDCA (AUC 6) day 1 q 28 × 6 cycles, bevacizumab 5 mg/kg weekly × 23 wks with trastuzumab conventional dose × 22 wks	II	Breast cancer cT1 – 4, N0 – 3, M0 FISH HER2 pos	29 (pathologic response available in 20 pts)	pCR 65% PR 35%	Not reported	Neutropoenia G3 – 4 (38%) Febrile neutropoenia (0%) Hematological toxicity G3 – 4 (0%) Hyperglycemia (10%) Proteinuria (7%) Hypertension (7%)
Robidoux et al. [41]	nab-P 100 mg/m^2 weekly × 12 wks → A (HER2−): FEC100 q 21 (F: 500 mg/m^2 + E: 100 mg/m^2 + C: 500 mg/m^2) × 3 cycles B (HER2+): FEC75 q 21 (F: 500 mg/m^2 + E: 75 mg/m^2 + C: 500 mg/m^2) × 4 cycles + herceptin	II	Breast cancer locally advanced	66	pC: 28% HER2 + 56% HER2− 17% RE pos 16% RE neg 35%	Not reported	Diarrhoea G2 – G3 (16 – 7%) Fatigue G2 – G3 (30 – 5%) Sensory neuropathy G2 – G3 (9 – 5%) Neutropoenia G3 (1.5%)
Veerapaneni et al. [42]	Capecitabine 825 mg/m^2 twice daily for 14 days + nab-P 260 mg/m^2 on day 1 q 21 × 4 cycles	II	Breast cancer infiltrating stage II – IIIB	14 (interruption for toxicities and low pCR)	pCR 7% PR 71% SD 21% PD 7%	Not reported	Hand-foot syndrome G3 – 4 (14.2%) Neutropoenia, neutropoenic fever (14.2%) Syncope (14.2%) Hypertension (7.1%)

AC: Doxorubicin + ciclophosphamide; AUC: Area under the curve; CBDCA: Carboplatin; FEC: Fluorouracil + epirubicyn + cyclophosphamide; FISH: Fluorescence in situ hybridisation; HER2: Human epidermal growth factor 2; nab-P: Nab-paclitaxel; OS: Overall survival; pCR: Pathologic complete response; PD: Progression of disease; PFS: Progression free survival; PR: Partial response; pts: Patients; RE: Estrogen receptor; SD: Stable disease.

Table 2. Studies with nab-P in the adjuvant setting.

Reference	Schedule	Phase	Neoplasm	No. of patients	Response	PFS/OS	Toxicity
Pippen et al. [45,47]	AC × 4 cycles → nab-P q 14 × 4 cycles with pegfilgrastim on day 2 + bevacizumab for 1 year	II	Breast cancer HER2 negative	80	Not applicable	Not reported	Neutropoenia G4 (6.8%) Diarrhoea G3 (2.3%) Hypertension G3 (2.3%) Neuropathy G3 (2.3%) Fatigue G3 (2.3%) Mucositis G3 (2.3%)
Dickler et al. [43]	AC → dose dense nab-P (q 14 days)	Pilot study	Breast cancer high-risk	59	Not applicable	Not reported	Peripheral neuropathy G3 – 4 (14%) Neutropoenia G3 – 4 (20%)
McArthur et al. [44]	AC → dose dense standard paclitaxel or nab-P (q 14 days) + bevacizumab	Safety study	Operable breast cancer	182	Not applicable	Not reported	Peripheral neuropathy G3 – 4 (4 vs 7%) Fatigue G3 – 4 (13 vs 4%)
Raefsky et al. [49]	Nab-P weekly + cyclophosphamide (q 21 days) × 4 cycles	II	Not reported	63	Not applicable	Not reported	Neutropoenia G3 – 4 (30%) Non-hematological (< 5%)

nab-P: nab-paclitaxel; OS: overall survival; PFS: progression free survival; pts: patients.

Table 3. Studies with nab-P in monochemotherapy for metastatic disease.

Reference	Schedule	Phase	Neoplasm	No. of patients	Response	TTP/PFS/OS	Toxicity
Ibrahim et al. [29]	nab-P 300 mg/mq q 21	II	Breast cancer	63	ORR 48% RR 64% (1st-line CT) RR 21% (from 2nd line)	TTP 26.6 wks OS 63.6 wks	Neutropoenia G4 (24%) Sensory neuropathy G3 (11%) Febrile neutropoenia G4 (5%)
Blum et al. [30]	Arm A: nab-P 100 mg/m^2 Arm B: nab-P 125 mg/m^2 days 1, 8, 15 q 28	II	Breast cancer, taxane-refractory	Arm A: 106 Arm B: 75	Arm A: RR 14%; SD ≥ 16 wks: 12% Arm B: RR 16%; SD ≥ 16 wks: 21%	Arm A: PFS 3 mth OS 9.2 mth Arm B: PFS 3.5 mth OS 9.1 mth	Pts who developed treatment-limiting peripheral neuropathy typically could be restarted on a reduced dose after a 1 – 2-wk delay. G4 neutropoenia occurred in < 5% of pts
Mirtsching et al. [49]	nab-P 125 mg/m^2 days 1, 8, 15 q 28 (HER2 + pts allowed to receive herceptin)	II	Breast cancer, locally advanced or metastatic		ORR 42.6% ORR HER2 + 64.7% ORR HER2− 31%	TTP 12.4 mth OS 25 mth	The most common toxicities (G3 – 4) were neutropoenia (11.1%), infection (9.7%), neuropathy (8.3%), fatigue (4.2%) and nail disorder (4.2%)
Gradishar et al. [24]	Arm A: nab-P 260 mg/m^2 q 21 Arm B: paclitaxel 175 mg/m2 q 21	III	Breast cancer	454	Arm A: RR 33% Arm B: RR 19%	Arm A: TTP 23 wks OS 65 wks Arm B: TTP 16.9 wks OS 55.7 wks	Neutropoenia: arm A < arm B (p < 0.001) Time to improvement G3 neuropathy: arm A < arm B (22 vs 79 days)
Guan et al. [27]	Arm A: palcitaxel 175 mg/m^2 q 21 Arm B: nab-P 260 mg/m^2 q 21	III	Breast cancer, metastatic	210	Arm A: RR 27% Arm B: RR 52%	Arm A: TTP 5.7 m Arm B: TTP 7.8 m	G3 – 4 toxicities similar between groups
Gradishar et al. [28]	Arm A: nab-P 300 mg/m^2 q 21 Arm B: nab-P 100 mg/m^2 weekly Arm C: nab-P 150 mg/m^2 weekly Arm D: docetaxel 100 mg/m^2 q 21	III	Breast cancer, metastatic	302	Arm A vs B vs C vs D: 37 vs 45 vs 49 vs 35% (p = 0.224)	PFS: Arm A: 12.9 mth Arm B: 7.5 mth Arm C: 14.6 m Arm D: 7.5 mth ORR: Arms B & C: 47% Arm D: 35%	Neutropoenia G3 – 4: arms A – C < arm D Fatigue: arms A – C < arm D Peripheral neuropathy: arms A – C = arm D

HER2: Human epidermal growth factor 2; m: Months; nab-P: Nab-paclitaxel; OS: Overall survival; PFS: Progression free survival; pts: Patients; TTP: Time to progression; w: Weeks.

Table 4. Studies with nab-P in combination with other agents for metastatic disease.

Reference	Schedule	Phase	Neoplasma	No. of patients	Response	TTP/PFS/OS	Toxicity
Roy et al. [31]	nab-P 125 mg/m^2 + gemcitabine 1000 mg/m^2 days 1 – 8 q 21	II	Breast cancer, metastatic, 1st line	50	PR 42% CR 8%	TTP 6.9 mth PFS 7.9 mth	Neutropoenia was commonest toxicity (42% and 12% G3 and 4 neutropoenia). Only one patient developed febrile neutropoenia.
Somer et al. [32]	nab-P 125 mg/m^2 days 1 – 8 q 21 Capecitabine 825 mg/m^2 p.o. b.i.d. days 1 → 14 q 21	II	Breast cancer, metastatic, 1st line	43 (38 evaluable for response)	ORR 47.5% PR 39.5% CR 8%	Not reported	HF syndrome G3 – 4 (6.9%) Fatigue G3 – 4 (9.3%) Gastrointestinal G3 – 4 (6.9%) Neutropoenia G3 – 4 (11.6%) Febrile neutropoenia G4 (4.6%) Neuropathy G1 – 2 (25%)
Danso et al. [33]	nab-P 125 mg/m^2 days 1 – 15 Bevacizumab 10 mg/kg days 1 – 15 q 28	II	Breast cancer HER2−, metastatic, 1st line	49 (27 evaluable for response)	ORR 30% (PR) SD > 16 wks: 22%	PFS 9.2 mth	G3 – 4 hematological adverse events were neutropoenia (30%, 16%) and anemia (8%, 3%). The most common non-hematologic G3 – 4 adverse event was sensory neuropathy (10%, 2%)
Gluck et al. [34]	Gemcitabine 1500 mg/m^2 days 1 – 15 nab-P 150 mg/m^2 days 1 – 15 Bevacizumab 10 mg/kg days 1 – 15 q 28	II	Breast cancer, HER2−, metastatic, 1st line	15	PR 91% PD 9%	Not reported	Alopecia (62%) Fatigue (38%) G3- – 4 toxicities (0%)
Conlin et al. [35]	Arm A: nab-P 260 mg/m^2 day 1 q 21 + bevacizumab 15 mg/kg day 1 q 21 Arm B: nab-P 260 mg/m^2 day 1 q 14 + GCSF + bevacizumab 10 mg/kg day 1 q 14 Arm C: nab-P 130 mg/m^2 wkly + bevacizumab 10 mg/kg day 1 q 14	II	Breast cancer HER2−, metastatic, 1st line	Arm B was closed early for unacceptable safety profile	Arm A: ORR 42% Arm B: ORR 42% Arm C: ORR 41%	Arm A: TTP 7.7 mth Arm B: TTP 6.4 mth Arm C: TTP 9.2 mth	Fatigue G ≥ 2 (arm A 39%, arm B 57%, arm C 39%) Bone pain (arm A 10%, arm B 19%, arm C 4%) Neurotoxicitiy G ≥ 2: 50% Febrile neutropoenia < 2%
Seidman et al. [36]	nab-P 100 mg/m^2 + CBDCA AUC 2 days 1 – 15 q 28 + herceptin (4 → 2 mg/kg) wkly	II	Breast cancer HER2+, metastatic	30 (26 evaluable for response)	CR 7.6% PR 38.4%	TTP 16 mth	G3 neutropoenia occurred in 50% of pts, and was the only G4 toxicity (7%). Febrile neutropoenia occurred in 1 pt (3%). G3 non-hematological toxicity was uncommon: fatigue (7%), nausea/emesis (7%). Neuropathy was mild and infrequent: G3 (3%) and G2 (7%)

nab-P: nab-paclitaxel; OS: overall survival; PFS: progression-free survival; pts: patients; TTP: time to progression.

Gradishar WJ, Tjulandin S, Davidson N, Superior efficacy of albumin-bound paclitaxel, ABI-007, compared with polyethylated castor oil-based paclitaxel in women with metastatic breast cancer: results of a Phase III trial. J Clin Oncol 2005;23(31):1-10

 Google Scholar

Berstein JA, Mehta R. In vivo response-adapted dose-dense (dd) doxorubicin and cyclophosphamide (AC) -> weekly carboplatin and albumin-bound paclitaxel (nab-TC)/trastuzumab (H)/bevacizumab (B) in large and inflammatory breast cancer (BC): a phase II study. ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25(Suppl 18S):11078

 Google Scholar

Inhorn RC, Daniel B, Daniel D, Correlation of SPARC, ER, PR, and HER2 tumor with progression-free survival from a phase II neoadjuvant trial of gemcitabine, epirubicin, and nab-paclitaxel. J Clin Oncol 2009;27(Suppl 15s): abstract 618

 Google Scholar

Paz IB, Lau S, Garberoglio C, Nab-paclitaxel and carboplatin with or without trastuzumab (trast) as part of neoadjuvant chemotherapy (NCT) in patients with stage II – III breast cancer (BC). J Clin Oncol 2008;26(Suppl): abstract 567

 Google Scholar

Yardley DA, Raefsky E, Castillo R, Results of a multicenter pilot study of weekly nab-paclitaxel, carboplatin with bevacizumab, and trastuzumab as neoadjuvant therapy in HER2+ locally advanced breast cancer with SPARC correlatives. J Clin Oncol 2009;27(Suppl 15s): abstract 527

 Google Scholar

Robidoux A, Buzdar AU, Quinaux E, A phase II neoadjuvant trial of sequential weekly nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide in locally advanced breast cancer. Clin Breast Cancer 2010;10:81-6

 PubMed Web of Science ®Google Scholar

Veerapaneni A, Boisvert M, Choi A, Aggarwal A. Capecitabine and ABI-007 chemotherapy as neoadjuvant treatment of locally advanced breast cancer. J Clin Oncol 2008;26(Suppl): abstract 11535

 Google Scholar

Dickler MN, Traina T, Panageas K, Adjuvant (adj) bevacizumab (B) plus dose-dense (dd) doxorubicin/cyclophosphamide (AC) followed by nanoparticle albumin- bound paclitaxel (nab-p) in early stage breast cancer (BC) patients (pts): cardiac safety. ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25(Suppl 18S):567

 Google Scholar

McArthur HL, Rugo H, Nulsen B, Cardiac safety of adjuvant bevacizumab (B) plus dose-dense doxorubicin/cyclophosphamide (AC) followed by nanoparticle albumin-bound paclitaxel (nab-P) in patients with early stage breast cancer [abstract 4104]. San Antonio, TX. Breast Cancer Symposium 10 – 15 December; 2008

 Google Scholar

Raefsky E, Inhorn R, Lange M, Preliminary safety results from a multicentre phase II trial of nanoparticle-albumin bound paclitaxel/cyclophsphamide in early breast cancer plus trastuzumab in HER-+ patients (pts). J Clin Oncol 2009;27(Suppl 15s): abstract e11509

 Google Scholar

Ibrahim NK, Samuels B, Page R, Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol 2005;23:6019-26

 PubMed Web of Science ®Google Scholar

Blum JL, Savin MA, Edelman G, Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes. Clin Breast Cancer 2007;7:850-6

 PubMed Web of Science ®Google Scholar

Gradishar WJ, Tjulandin S, Davidson N, Superior efficacy of albumin-bound paclitaxel, ABI-007, compared with polyethylated castor oil-based paclitaxel in women with metastatic breast cancer: results of a Phase III trial. J Clin Oncol 2005;23:1-10

 PubMed Web of Science ®Google Scholar

Guan Z, Feng F, Li QL, Randomized study comparing nab-paclitaxel with solvent-based paclitaxel in Chinese patients (pts) with metastatic breast cancer (MBC). ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25(Suppl 18S):1038

 Google Scholar

Gradishar WJ, Krasnojon D, Cheporov S, Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 2009;27:3611-19

 PubMed Web of Science ®Google Scholar

Roy V, LaPlant BR, Gross GG, ; North Central Cancer Treatment Group. Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531). Ann Oncol 2009;20:449-53

 PubMed Web of Science ®Google Scholar

Somer BG, Schwartzberg LS, Arena F, Phase II trial of nab-paclitaxel (nanoparticle albumin-bound paclitaxel (ABX)) + capecitabine (XEL) in first-line treatment of metastatic breast cancer (MBC). ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25(Suppl 18S):1053

 Google Scholar

Danso MA, Blum JL, Robert NJ, Phase II trial of weekly nab-paclitaxel in combination with bevacizumab as first-line treatment in metastatic breast cancer. J Clin Oncol 2008;26(Suppl): abstract 1075

 Google Scholar

Gluck S, Lobo C, Reis I, Phase II study of nab-paclitaxel, bevacizumab, and gemcitabine for first-line therapy of patients with HER2-negative metastatic breast cancer (MBC). J Clin Oncol 2008;26(Suppl): abstract 1089

 Google Scholar

Conlin AK, Hudis CA, Bach A, Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC). J Clin Oncol 2009;27(Suppl 15s); abstract 1006

 Google Scholar

Seidman AD, Conlin AK, Bach A, Phase II study of weekly nanoparticle albumin bound (nab)paclitaxel with carboplatin and trastuzumab as 1st-line therapy for HER2-positive metastatic breast cancer (MBC). J Clin Oncol 2008;26(Suppl): abstract 1047

 Google Scholar