1 Introduction
2 Chemotherapeutic Agents for Metastatic Breast Cancer
Drug class | Agents | Mechanism of action |
---|---|---|
Anthracyclines | Doxorubicin, epirubicin | DNA intercalation and induction of cell death |
Antimetabolites | Capecitabine, S-1, gemcitabine | Inhibits processes required for DNA synthesis |
Antimicrotubule agents | Paclitaxel | Stabilizes microtubules by inhibiting the shortening of microtubules |
Docetaxel | ||
Ixabepilone | ||
Eribulin | Inhibits microtubules by suppressing microtubule growth at the plus end | |
Vinorelbine | Inhibits microtubules by inhibiting the polymerization of tubulin dimers and depolymerization | |
Platinum analogues | Carboplatin, cisplatin | Induces DNA adduct formation and cell death |
Topoisomerase inhibitor | Irinotecan | Interferes with DNA coiling to inhibit transcription and replication |
3 Clinical and Pharmacological Evaluation of Eribulin
3.1 Pharmacological Properties
Eribulin dose | ||||
---|---|---|---|---|
0.7 mg/m2 (n = 3) | 1.0 mg/m2 (n = 3) | 1.4 mg/m2 (n = 6) | 2.0 mg/m2 (n = 3) | |
C
max, ng/mL | 288.5 ± 43.0 | 380.6 ± 52.9 | 519.4 ± 107.2 | 717.6 ± 104.3 |
AUC0–∞, ng·h/mL | 299.2 ± 124.5 | 379.6 ± 65.2 | 672.7 ± 113.7 | 1,370.1 ± 282.2 |
t
1/2, h | 36.4 ± 11.2 | 42.9 ± 10.9 | 39.4 ± 8.3 | 59.9 ± 13.4 |
DLTa, n (%) | 0 | 0 | 2 (33)b
| 3 (50)c
|
3.2 Clinical Properties
3.2.1 Phase II Studies
201 [27] | 211 [28] | 221 [29] | |
---|---|---|---|
n
| 103 | 291 | 80 |
Prior chemotherapy | Any prior regimen of chemotherapy with A and T (median 4) | 2–5 prior regimens of chemotherapy with A, T and CAP (median 4) | ≤3 prior regimens of chemotherapy including A and T (median 3) |
Dosing schedule | 1.4 mg/m2 IV inf d1 + 8 + 15 q4w 1.4 mg/m2 IV inf d1 + 8 q3w | 1.4 mg/m2 IV inf d1 + 8 q3w | 1.4 mg/m2 IV inf d1 + 8 q3w |
Tumour response | |||
PR (%) | 11.5 [total] 10.2 [q4w cohort] 14.3 [q3w cohort] | 9.3 | 21.3 |
SD, % | 11.5 [total] 10.2 [q4w cohort] 14.3 [q3w cohort] | 46.5 | 42.5 |
ORRa (%) | 11.5 [total] 10.2 [q4w cohort] 14.3 [q3w cohort] | 9.3 | 21.3 |
CBRb (%) | 17.2 [total] 11.9 [q4w cohort] 28.6 [q3w cohort] | 17.1 | 27.5 |
Median duration of response (months) | 5.6 | 4.1 | 3.9 |
Median PFS (months) | 2.6 | 2.6 | 3.7 |
Median OS (months) | 9.0 | 10.4 | 11.1 |
3.2.2 Phase III Studies
305 (EMBRACE) [30] | 301 [31] | |||||
---|---|---|---|---|---|---|
Eribulin | TPC | Eribulin | CAP | |||
n
| 508 | 254 | 554 | 548 | ||
Median OS, months | 13.1* | 10.6 | 15.9†
| 14.5 |
Independent review | Investigator review | Independent review | Investigator review | Independent review | Independent review | |
---|---|---|---|---|---|---|
Median PFS, months | 3.7 | 3.6‡
| 2.2 | 2.2 | 4.1 | 4.2 |
Tumour response (%) | ||||||
CR | 1 | <1 | 0 | 0 | NR | NR |
PR | 12 | 13 | 5 | 7 | NR | NR |
SD | 44 | 47 | 45 | 45 | NR | NR |
ORRa
| 12§
| 13¶
| 5 | 7 | 11 | 12 |
CBRb
| 23 | 28 | 17 | 20 | NR | NR |
305 (EMBRACE) [30] | ||||||
---|---|---|---|---|---|---|
OS (months) | HR (95 % CI) | OS (months) | HR (95 % CI) | |||
Eribulin | TPC | Eribulin | CAP | |||
Total | 13.2 | 10.5 | 0.81 (0.66, 0.99) | 15.9 | 14.5 | 0.88 (0.77, 1.00) |
HER2+ | 11.3 | 9.1 | 0.76 (0.47, 1.24) | 14.3 | 17.1 | 0.97 (0.69, 1.36) |
HER2− | 13.2 | 10.5 | 0.81 (0.64, 1.02) | 15.9 | 13.5 | 0.84 (0.72, 0.98) |
ER+ | 13.8 | 11.4 | 0.81 (0.63, 1.04) | 18.2 | 16.8 | 0.90 (0.74, 1.09) |
ER− | 10.2 | 7.8 | 0.78 (0.54, 1.13) | 14.4 | 10.5 | 0.78 (0.64, 0.96) |
TN | 9.5 | 7.0 | 0.71 (0.46, 1.10) | 14.4 | 9.4 | 0.70 (0.55, 0.91) |
3.3 Tolerability
4 Ongoing Studies of Eribulin and Other Agents
Study design | Treatments | Study identifier | |||
---|---|---|---|---|---|
Regimen setting | Disease type | Trial details (estimated enrolment) | Primary endpoint | ||
Non-metastatic disease | |||||
Neo-adjuvant | HER2+ | Phase I/II, OL, SG (56) | pCR | Eribulin + carboplatin, trastuzumab | NCT01388647 [34] |
HER2− | Phase II, OL, SG (47) | pCR | Eribulin then dose-dense doxorubicin + cyclophosphamide | NCT01498588 [35] | |
HER2− | Phase II, R, PG, OL (152) | pCR | Eribulin then FAC vs paclitaxel then FEC | NCT01593020 [36] | |
HER2− | Phase II, R, PG, OL (76) | pCR | Eribulin + cyclophosphamide vs docetaxel + cyclophosphamide | NCT01527487 [37] | |
TN | Phase II, SG, OL (30) | pCR | Eribulin + carboplatin | NCT01372579 [38] | |
Adjuvant | TN, HER2+, HER2− | Phase II, PG, OL (148) | 2-year DFS | Eribulin or eribulin + trastuzumab in patients who do not achieve pCR following neo-adjuvant chemotherapy | NCT01401959 [39] |
ER+ | Phase II, SG, OL (67) | Feasibility | Eribulin + capecitabine | NCT01439282 [40] | |
NS | Phase II, SG, OL (80) | Feasibility | Dose-dense doxorubicin + cyclophosphamide then eribulin | NCT01328249 [41] | |
Metastatic disease | |||||
First-line | HER2+ | Phase II, SG, OL (52) | ORR | Eribulin + trastuzumab | NCT01269346 [42] |
First-line | HER2− | Phase II, SG, OL (52) | ORR | Eribulin | NCT01268150 [44] |
Second-line | HER2− | Phase II, R, PG, OL (141) | PFS | Eribulin +/− ramucirumab | NCT01427933 [45] |
Second-line | TN | Phase I/II SG, OL (80) | MTD, PFS | Eribulin + PLX 3397 | NCT01596751 [46] |
Fourth-line | NS | Phase I/II, R, OL (116) | Tolerability, response | Eribulin + capecitabine | NCT01323530 [47] |
NS | HER2+ | Phase II, R, PG, OL (80) | TTP, tolerability | Eribulin + lapatinib | NCT01534455 [43] |
NS | NS | Phase I/II, SG, OL (58) | MTD, CBR | Eribulin + cyclophosphamide | NCT01554371 [48] |
NS | NS | Phase I, SG, OL (54) | Tolerability, AUC, C
max, QT time | Eribulin + sorafenib | NCT01585870 [49] |
Drug class | Agents (current phase in the trial) |
---|---|
Anthracyclines | Liposomal doxorubicin (approved) |
Antimetabolites | Pemetrexed (phase III) |
Antimicrotubule agents (new formulation) | Nanoparticle albumin-bound (nab)–paclitaxel (approved) |
EndoTAG-1 (phase II) | |
Paclitaxel poliglumex (phase II) | |
Antimicrotubule agents (novel taxane) | Larotaxel (phase II) |
Tesetaxel (phase II) | |
Cabazitaxel (phase II) | |
Antimicrotubule agents (novel non-taxane) | Vinflunine (phase III) |
Indibulin (phase I/II) | |
Platinum analogues | Satraplatin (phase II) |
Topoisomerase inhibitor | NKTR-102 (phase III) |