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 
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 

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.