Table 3.
Clinical experience with ribociclib combinations.
| Study name/ID | Combination drug | Phase | Population | MTD/RP2D/dose | Reported Grade 3/4 AEs | Clinical activity |
|---|---|---|---|---|---|---|
| HR+, HER2− breast cancer | ||||||
| CLEE011X2106/NCT01857193 (44) | Exemestane | Ib | Postmenopausal women with ER+, HER2− ABC previously treated with letrozole or anastrozole (N=14 treated with ribociclib + exemestane) |
Evaluated dose Ribociclib: 600 mg/day (3-weeks-on/1-week-off) Exemestane: 25 mg/day |
Neutropenia (71%), leukopenia (36%), lymphopenia (14%), ALT elevation (14%), AST elevation (14%), and anemia (14%) | 2 unconfirmed PR, 4 SD |
| CLEE011X2107/NCT01872260 (45, 47) | Letrozole | Ib | Pretreated and treatment-naïve postmenopausal women with ER+, HER2− ABC (N=47 treated with ribociclib + letrozole) |
RP2D: Ribociclib: 600 mg/day (3-weeks-on/1-week-off) Letrozole: 2.5 mg/day |
All patients: Neutropenia and neutrophil count reduced (60%), ALT elevation (4%), AST elevation (4%), asthenia (2%), constipation (2%), nausea (2%), UTI (2%), fatigue (1%) First line (n=28): Neutropenia and neutrophil count reduced (64%), ALT elevation (4%), AST elevation (4%), asthenia (4%), nausea (4%) Previously treated (n=19): Neutropenia and neutrophil count reduced (53%), ALT elevation (5%), AST elevation (5%), constipation (5%), fatigue (5%), UTI (5%) |
First line (n=28): 2 CR, 11 PR, 3 unconfirmed PR, 5 SD, 4 NCRNPD, ORR 46%, DCR 89%, CBR 79%, Median PFS 25.3 months Previously treated (n=19): Median PFS 5.5 months |
| CLEE011X2108/NCT02088684 (42) | Fulvestrant | Ib | Postmenopausal women with HR+, HER2− ABC (N=28). |
Ribociclib: 600 mg/day (3-weeks-on/1-week-off) or 400 mg/day (continuous) Fulvestrant: 500 mg on Days 1 and 15 of Cycle 1 and Day 1 of subsequent cycles |
Ribociclib 600 mg/day (3-weeks-on/1-week-off;n=13): Neutropenia (62%), fatigue (15%), leukocyte count reduced (15%), ALT elevation (8%), AST elevation (8%) Ribociclib 400 mg/day (continuous;n=15): Neutropenia (33%), leukocyte count reduced (7%), ALT elevation (7%), AST elevation (7%) |
Ribociclib 600 mg/day (3-weeks-on/1-week-off;n=13): 3 PR, 9 SD, 1 NCRNPD Ribociclib 400 mg/day (continuous;n=15): 2 PR, 7 SD, 5 NCRNPD |
| CLEE011X2106/NCT01857193 (52) | Everolimus + exemestane | Ib | Postmenopausal women with ER+, HER2− ABC previously treated with letrozole or anastrozole (N=77 treated with ribociclib + everolimus + exemestane) |
RP2D: Ribociclib: 300 mg/day (3-weeks-on/1-week-off) Everolimus: 2.5 mg/day Exemestane: 25 mg/day |
Neutropenia (31%), neutrophil count reduced (18%), leukocyte count reduced (12%), anemia (7%), thrombocytopenia (7%), lymphopenia (7%), ALT elevation (5%), AST elevation (4%), and lymphocyte reduced (4%) | ORR 9%, DCR 73%, CBR 26% |
| CLEE011X2107/NCT01872260 (51) | Alpelisib + letrozole | Ib | Pretreated and treatment-naïve postmenopausal women with ER+, HER2− ABC (N=46 treated with ribociclib + alpelisib + letrozole) |
RP2D: Ribociclib: 300 mg/day (3-weeks-on/1-week-off) Alpelisib: 200 mg/day Letrozole: 2.5 mg/day |
Increased ALT (30%), increased AST (26%), hyperglycemia (17%), neutropenia (17%), fatigue (13%), reduced neutrophil count (4%), anemia (4%), thrombocytopenia (2%), vomiting (2%), and nausea (2%) | ORR 16%, DCR 70%, CBR 26% |
| CLEE011A2201/NCT01919229 (43) | Letrozole | II | Postmenopausal women with HR+, HER2− Grade II/III, invasive, early breast cancer who have received no prior breast cancer treatment (N=14) |
Ribociclib: 600 mg/day or 400mg/day Letrozole: 2.5 mg/day |
All AEs were mild/moderate with no Grade 3/4 AEs |
Ribociclib 400 mg/day + letrozole: 96% decrease in Ki67 Ribociclib 600 mg/day + letrozole: 92% decrease in Ki67 Letrozole only: 69% decrease in Ki67 |
| MONALEESA-2/NCT01958021 (46) | Letrozole | III | Postmenopausal women with HR+, HER2− ABC who have received no prior treatment for advanced disease (N=668) |
Ribociclib: 600 mg/day (3-weeks-on/1-week-off) Letrozole: 2.5 mg/day |
Ribociclib + letrozole arm vs placebo + letrozole arm: Neutropenia (59% vs 1%), leukopenia (21% vs 1%), hypertension (10% vs 11%), increased ALT (9% vs 1%), lymphopenia (7% vs 1%), and increased AST (6% and 1%) |
Ribociclib + letrozole arm vs placebo + letrozole arm: Median PFS NR (95% CI, 19.3–NR) vs 14.7 months (95% CI, 13.0–16.5); HR=0.56; P=3.29×10−6 ORR 41% vs 28% (P<0.001) CBR 80% vs 72% (P=0.02) |
| NRAS- or BRAF-mutant melanoma | ||||||
| CMEK162X2114/NCT01781572) (62) | Binimetinib | Ib/II | Patients with advanced NRAS- mutant melanoma (N=22 received ribociclib + binimetinib) |
MTD: Ribociclib: 200 mg/day (3-weeks-on/1-week-off) Binimetinib: 45 mg BID RP2D: ongoing |
CPK elevation (18%), neutropenia (9%), acneiform (4%), dermatitis (4%), and rash (4%) | 7 PR, 11 SD, 33% had 20–30% tumor shrinkage, CBR 86% |
| CLEE011X2105/NCT01777776 (61) | Encorafenib | Ib/II | Patients with advanced BRAFV600-mutant melanoma (N=28 received ribociclib + encorafenib) |
MTD: ongoing RP2D: ongoing |
Hand–foot syndrome (11%), rash (4%), and myalgia (4%) | 2 confirmed PRs, 3 unconfirmed PRs, 10 SD, 1 SD >9 cycles |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBR, clinical benefit rate; CR, complete response; DCR, disease control rate; NCRNPD, not complete response nor progressive disease; NR, not reached; ORR, overall response rate; UTI, urinary tract infection.