Table 4 Efficacy and safety data from Eve prospective studies published after the BOLERO-2 trial in HR+, HER2− aBC/mBC
Everolimus | |||||||||||
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Study | Study design | Population | N° of pts. | Previous CT allowed | Median TD (mos)/(R)DIa (mg/d) | ORR | mPFS (mos) | mOS (mos) | Any grade AEs (%) (Eve combination)b | G3/4 AEs (%) (Eve combination) b | Discontinuation ratec |
4EVER [38], phase IIIb, open label, single arm | Eve + Exe (10 + 25 mg/d) | Postmenopausal HR+, HER2− LABC/mBC progressing on or after an NSAI (either adjuvant or for advanced disease) | 299b | Yes, any number of lines for LABC/mBC, prior Exe allowed | TD/RDI, 4.4/0.98 | 8.9% (at 24 weeks) | 5.6 | mOS NR, OS at 48w 66.9% | Overall 98.7% Stomatitis 49.2% Fatigue 36.1% Diarrhea 26.4% Nausea 26.1% | Overall 58.9% Stomatitis 8.4% GPHD 6.7% Dyspnea 4.7% Anemia 4.3% | 24.7% |
BRAWO [39], phase IV, non-interventional | Eve + Exe (5–10 + 25 mg/d) | HR+, HER2− LABC/mBC progressed after a NSAI Eve + Exe as per clinical practice | 2074 | Yes, previous Exe allowed | TD 10 mg/d, 5.1 TD 5 mg/d, 4.6 | 8.2% | 6.6 | NA | Stomatitis 42.6% Fatigue 19.8% | Stomatitis 3.9% Fatigue 1.5% | 26% |
STEPAUT [40], phase IV, non-interventional | Eve + Exe (5–10 + 25 mg/d) | Postmenopausal HR+, HER2− LABC/mBC progressing on/after prior NSAIs in routine clinical practice | 225 | NS | TD/DI, NA/NA | NA | 9.5 | NA | Stomatitis/mucositis 48% Rash/exanthema 22.2% Dyspnea/cough 22.2% | Stomatitis/mucositis 4.4% GPHD/weight loss 2.7% Inappetence /nausea 2.2% | NA |
BALLET [41], phase IIIb, open label, single arm, expanded access trial | Eve + Exe (5–10 + 25 mg/d) | Postmenopausal HR+, HER2− LABC/mBC progressing on/after prior NSAIs | 2133 | Yes, any number of lines for LABC/mBC | TD/RDI, 3.7/0.98 | NA | NA | NA | Overall 94.7% Stomatitis 52.8% Asthenia 22.8% Diarrhea 16.8% Rash 16.5% Inappetence 16% | Overall 42.7% Stomatitis 9.4% Asthenia 3.6% Hyperglycemia 2.9% Dyspnea 2% NIP 1.9% | 17.1% |
EVEREXES [42], phase IIIb, open label, single arm, Asia and Africa | Eve + Exe (10 + 25 mg/d) | Postmenopausal HR+, HER2− LABC/mBC progressing on/after prior NSAI (adjuvant or for LABC/mBC) | 232 | Yes, no more than 1 prior CT line for LABC/mBC | TD/DI, NA/9.2 | 15.8% | 9.5 | NA | Stomatitis 60.4% Skin toxicity 27.8% Hyperglycemia 24.7% Fatigue 17.2% Weight loss 15.4% | Stomatitis 10.6% Hyperglycemia 7% Fatigue 2.2% NIP 1.3% Weight loss 0.9% | NA |
BOLERO-4 [43], phase II, multicenter, open-label, single-arm | First line: Eve + Let (10 + 2.5 mg/d); at PD second line: Eve + Exe (10 + 25 mg/d) | Postmenopausal HR+ HER2− LABC/mBC | 202, 50 | No | TD/DI, 14.8/8.5 and 2.9/8.3 | 45%, 6% | 22, 3.7 | mOS NR, OS at 24 m 78.7% | Eve + Let Overall 100% Stomatitis 68.8% Loss of weight 44% Diarrhea 41% Nausea 37% | Eve + Let Overall 58% Anemia 10% Hypertension 8% Stomatitis 6% Hypertriglyceridemia 6% | Eve + Let 15.8% |
TAMRAD [44], phase II, open-label, randomized | Eve + TAM (10 + 20 mg/d) vs. TAM (20 mg/d) | Postmenopausal HR+, HER2−, LABC/mBC progressing on/after prior NSAI (adjuvant or for LABC/mBC) | 54, 57 | Yes, any number of lines for LABC/mBC | TD/DI, 6.2/NA and 4.8/NA | 14%, 13% | 8.6, 4.5 | NR, 32.9 | Pain 82% Fatigue 72% Anemia 69% Stomatitis 56% Leukopenia 54% | Stomatitis 11% Pain 9% Infections 7% Anorexia 7% Fatigue 6% | Eve + TAM 22% |
PrE0102 [45], phase II, randomized, double-blind, placebo-controlled | Eve + Fulve (10 mg/d)fvs. Fulve | Postmenopausal HR+ HER2− LABC/mBC progressing on/after prior NSAI (adjuvant or for LABC/mBC) | 66, 65 | Yes, no more than 1 prior CT line for LABC/mBC | TD/DI, 5.1/NA and 4.6/NA | 18.2%, 12.3% | 10.3, 5.1 | 28.3, 31.4 | Mucositis 53% Fatigue 42% Rash 38% Anemia 31% Diarrhea 23% | Mucositis 11% NIP 6% Fatigue 6% | Eve + Fulv 20% |
MANTA [46], phase II, open-label, randomized | Eve + Fulve (10 mg/d)f, cVIS + Fulve, (50 mg BID)g, iVIS + Fulve (2 days on, 5 days off; 125 mg BID)h, Fulve | Postmenopausal HR+, LABC/mBC progressing on/after prior NSAI (either adjuvant or for LABC/mBC) | 65, 103, 98, 67 | Yes, no more than 1 prior CT line for LABC/mBC | TD/DI, NA/NA for all arms | 41.2%, 30.4%, 28.6%, 25.0% | 12.3, 7.6, 8.0, 5.4 | NR, 27.1, 24.2, 24.4 | Stomatitis 60% Asthenia 53.3% Rash 50.0% Diarrhea 31.7% Decreased appetite 30.0% | Stomatitis 11.7% Rash 5.0% Asthenia 3.3% Diarrhea 1.7% Decreased appetite 1.7% | 18.8% |
Safra et al. [47], phase II, open-label, single-arm, multicenter trial | Eve + Let (10 + 2.5 mg/d) | Postmenopausal ER+, HER2− LABC/mBC progressing on/after prior ET (either adjuvant or for LABC/mBC) | 72 | No | TD/DI, NA/NA | 23.3% | 8.8 | 22.9 | Fatigue 61.1% Stomatitis 54.2% Rash 33.4% Cough 33.3% Decreased appetite 31.9% | Anemia 9.7% Stomatitis 8.3% Fatigue 5.6% Diarrhea 5.6% Hyperglycemia 4.2% | 12.5% |
BOLERO-6 [48], phase II, open-label, randomized | Eve + Exe (10 + 25 mg/d) vs. Eve (10 mg/d) vs. capecitabine (1250 mg/m2 BID) | Postmenopausal HR+ HER2− LABC/mBC progressing on/after prior NSAI | 104, 103, 102 | Yes, no more than 1 prior CT line for LABC/mBC, prior Exe not allowed | TD/RDI, 6.3/0.92, 4.6/0.98, and 6.1/0.78 | NA | 8.4, 6.8, 9.6 | 23.1, 29.3, 25.6 | Overall 100% Stomatitis 49% Fatigue 38% Diarrhea 35% Anemia 32% GGT elevation 15% AST elevation 15% | Overall 70% Anemia 13% Stomatitis 9% GGT elevation 9% Fatigue 8% AST elevation 7% Pneumonitis 7% | Eve + Exe 8% |
Yardley et al. [49], phase II, open label | Eve (10 mg/d) added to the most recent ET on which a patient progressed | Post/premenopausal HR+, HER2− LABC/mBC refractory to ET (either adjuvant or for LABC/mBC) | 47 | Yes no more than 1 prior CT line for LABC/mBC | TD/DI, 4.1/NA | 6% | 6.6 | 21.1 | Fatigue 38% Stomatitis 32% Mucosal inflammation 28% Rash 28% | Fatigue 4% Stomatitis 6% Mucosal inflammation 4% Rash 4% | 15% |