Abstract
Background: CLEOPATRA is a phase III study of placebo (Pla)+T+D and P+T+D in HER2-positive first-line MBC. The combination of both HER2-targeted antibodies, P+T, with D resulted in significantly improved progression-free survival (PFS) and overall survival (OS). The incidence of febrile neutropenia (FN) was higher with P+T+D versus Pla+T+D. We present analyses of adverse events (AEs) and treatment patterns for pts from Asia.
Methods: Pts were from Asia, Europe, North and South America. Study drugs were given intravenously, q3w: P/Pla, 840 mg initial dose, then 420 mg; T, 8 mg/kg initial dose, then 6 mg/kg; D, 75 mg/m2 with escalation to 100 mg/m2 if tolerated. Treatment was given until disease progression or unacceptable toxicity; 6 cycles of D were recommended, >6 cycles were at investigator's discretion. Dose modifications of P or T were not permitted. Two D dose reductions by 25% to 75 mg/m2 and 55 mg/m2 were allowed in order to manage toxicities; re-escalation was not permitted.
Results: The safety population comprised 253 pts from Asia (Pla+T+D: 128; P+T+D: 125) and 551 pts from other regions (Pla+T+D: 269; P+T+D: 282). The incidences of neutropenia, FN, diarrhea, mucosal inflammation, grade ≥3 AEs overall, and serious AEs were higher with P+T+D versus Pla+T+D. In the P arm, the largest increase in AEs in pts from Asia versus other regions was observed for FN and mucosal inflammation. D dose was more frequently reduced in pts from Asia; however, the incidence of AEs leading to discontinuation of all study treatment was balanced between pts from Asia and other regions. PFS and OS were improved with P+T+D in pts from all regions. In the whole study population, the hazard ratios (HR) for PFS and OS were 0.63 (95% CI 0.52-0.76) and 0.66 (0.52-0.84), respectively. In pts from Asia, the HR was 0.68 (0.48-0.95) for PFS and 0.64 (0.41-1.00) for OS. These efficacy analyses were unstratified.
| Pts with event, n (%) | Other regions | Asia | ||
| Pla+T+D | P+T+D | Pla+T+D | P+T+D | |
| n = 269 | n = 282 | n = 128 | n = 125 | |
| Neutropenia | 123 (46) | 141 (50) | 74 (58) | 74 (59) |
| FN | 15 (6) | 24 (9) | 15 (12) | 32 (26) |
| Diarrhea | 118 (44) | 179 (63) | 66 (52) | 93 (74) |
| Mucosal inflammation | 56 (21) | 67 (24) | 23 (18) | 46 (37) |
| Grade ≥3 AEs | 194 (72) | 199 (71) | 95 (74) | 103 (82) |
| Serious AEs | 69 (26) | 82 (29) | 35 (27) | 58 (46) |
| AEs leading to discontinuation of all study treatment | 15 (6) | 21 (7) | 6 (5) | 4 (3) |
| D dose escalation to 100 mg/m2 | 56 (21) | 47 (17) | 5 (4) | 1 (1) |
| D dose reduction to <75 mg/m2 | 32 (12) | 42 (15) | 57 (45) | 62 (50) |
| Use of granulocyte colony-stimulating factor (G-CSF) to treat FN | 8 (3) | 11 (4) | 12 (9) | 30 (24) |
| Subsequent G-CSF prophylaxis in pts with FN | 6 (2) | 3 (1) | 1 (1) | 11 (9) |
| Study treatment cycles, median | 15 | 18 | 15 | 20 |
| D cycles, median | 8 | 7 | 9 | 9 |
| Pts with event, n (%) | Other regions | Asia | ||
| Pla+T+D | P+T+D | Pla+T+D | P+T+D | |
| n = 269 | n = 282 | n = 128 | n = 125 | |
| Neutropenia | 123 (46) | 141 (50) | 74 (58) | 74 (59) |
| FN | 15 (6) | 24 (9) | 15 (12) | 32 (26) |
| Diarrhea | 118 (44) | 179 (63) | 66 (52) | 93 (74) |
| Mucosal inflammation | 56 (21) | 67 (24) | 23 (18) | 46 (37) |
| Grade ≥3 AEs | 194 (72) | 199 (71) | 95 (74) | 103 (82) |
| Serious AEs | 69 (26) | 82 (29) | 35 (27) | 58 (46) |
| AEs leading to discontinuation of all study treatment | 15 (6) | 21 (7) | 6 (5) | 4 (3) |
| D dose escalation to 100 mg/m2 | 56 (21) | 47 (17) | 5 (4) | 1 (1) |
| D dose reduction to <75 mg/m2 | 32 (12) | 42 (15) | 57 (45) | 62 (50) |
| Use of granulocyte colony-stimulating factor (G-CSF) to treat FN | 8 (3) | 11 (4) | 12 (9) | 30 (24) |
| Subsequent G-CSF prophylaxis in pts with FN | 6 (2) | 3 (1) | 1 (1) | 11 (9) |
| Study treatment cycles, median | 15 | 18 | 15 | 20 |
| D cycles, median | 8 | 7 | 9 | 9 |
Conclusions: AEs did not result in reduction of the median number of cycles administered in pts from Asia compared with other regions. However, given that 47% of pts from Asia had D dose reductions <75 mg/m2 with comparable survival benefits to pts from other regions, a reduction in the D starting dose should be considered in these pts. Based on the efficacy and safety profile of P+T+D, this regimen is the preferred treatment option for pts with HER2-positive first-line MBC from all geographic regions.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-10.
