Table 2.
Frequencies of AE of combination therapy arms, as observed in the safety population of pivotal clinical trials comparing BRAFi +MEKi combinations versus vemurafenib6 9 24
| Combination regimen of interest | Dabrafenib+Trametinib (D+T) |
Vemurafenib+Cobimetinib (V+C) |
Encorafenib+Binimetinib (E+B) |
| Data cut-off dates (safety analysis) | 13 Mar 2015 | 30 Sep 2015 | 19 May 2016 |
| Median follow-up time | 19.8 months | 18.5 months | 16.6 months |
| Study | COMBI-V | coBRIM | COLUMBUS Part 1 |
| N° pts rand. (intention to treat) (safety population) | 352 (350) | 247 (247) | 192 (192) |
| Daily dose (mg) | 300/2 | 1920/60 | 450/90 |
| CTC AE grade | Any | 3–4 | Any | 3–4 | Any | 3–4 |
| Dermatological events, including new skin neoplasms | ||||||
| Rash* | 84 (24.0) | 3 (0.9) | 101 (40.9) | 13 (5.3) | 27 (14.1) | 2 (1.0) |
| Rash maculopapular | 13 (3.7) | 2 (0.6) | 38 (15.4) | 18 (7.3) | 3 (1.6) | 0 |
| Dry skin | 33 (9.4) | 0 | 38 (15.4) | 2 (0.8) | 27 (14.1) | 0 |
| Pruritus | 36 (10.3) | 0 | 49 (19.8) | 3 (1.2) | 21 (10.9) | 1 (0.5) |
| Erythema | 35 (10.0) | 0 | 26 (10.5) | 0 | 13 (6.8) | 0 |
| Dermatitis acneiform* | 23 (6.6) | 0 | 34 (13.8) | 6 (2.4) | 6 (3.1) | 0 |
| Alopecia | 23 (6.6) | 0 | 41 (16.6) | 1 (0.4) | 26 (13.5) | 0 |
| Hyperkeratosis | 18 (5.1) | 0 | 25 (10.1) | 1 (0.4) | 27 (14.1) | 1 (0.5) |
| Palmoplantar keratoderma | – | – | 5 (2.0) | 0 | 17 (8.9) | 0 |
| Palmo–plantar erythrodysesthesia*† | 14 (4.0) | 0 | 17 (6.9) | 0 | 13 (6.8) | (0) |
| Actinic keratosis | 5 (1.4) | 0 | 13 (5.3) | 8 (3.2) | – | – |
| Keratosis pilaris* | 4 (1.1) | 0 | 9 (3.6) | 0 | 9 (4.7) | 0 |
| Photosensitivity reaction* | 15 (4.3) | 0 | 84 (34.0) | 1 (0.4) | 8 (4.2) | 1 (0.5) |
| Sunburn | 3 (0.9) | 0 | 37 (15.0) | 2 (0.8) | 0 | 0 |
| (Cutaneous) squamous cell carcinoma* | 5 (1.4) | 5 (1.4) | 10 (4.0) | 9 (3.6) | 5 (2.6) | 0 |
| Keratocanthoma* | 2 (0.6) | 2 (0.6) | 4 (1.6) | 3 (1.2) | 4 (2.1) | 0 |
| Skin papilloma* | 8 (2.3) | 0 | 17 (6.9) | 0 | 12 (6.3) | 0 |
| Basal cell carcinoma* | 3 (0.9) | 2 (0.6) | 15 (6.1) | 14 (5.7) | 3 (1.6) | 0 |
| Gastrointestinal events | ||||||
| Diarrhoea* | 120 (34.3) | 4 (1.1) | 150 (60.7) | 16 (6.5) | 70 (36.4) | 5 (2.6) |
| Nausea | 126 (36.0) | 1 (0.3) | 105 (42.5) | 3 (1.2) | 79 (41.1) | 3 (1.6) |
| Vomiting | 107 (30.6) | 4 (1.1) | 63 (25.5) | 4 (1.6) | 57 (29.7) | 3 (1.6) |
| Abdominal pain | 39 (11.1) | 1 (0.3) | 27 (10.9) | 1 (0.4) | 32 (16.7) | 5 (2.6) |
| Abdominal pain upper | 33 (9.4) | – | 12 (4.9) | 0 | 23 (12.0) | 2 (1.0) |
| Constipation | 54 (15.4) | 0 | 27 (10.9) | 0 | 42 (21.9) | 0 |
| General disorders (and symptoms/disorders of central nervous system) | ||||||
| Fatigue | 110 (31.4) | 4 (1.1) | 91 (36.8) | 11 (4.5) | 55 (28.6) | 4 (2.1) |
| Asthenia | 61 (17.4) | 5 (1.4) | 47 (19.0) | 5 (2.0) | 35 (18.2) | 3 (1.6) |
| Fever* | 193 (55.1) | 16 (4.6) | 71 (28.7) | 3 (1.2) | 35 (18.2) | 7 (3.6) |
| Peripheral oedema/swelling*‡ | 48 (13.7) | 1 (0.3) | 34 (13.8) | 0 | 3 (1.6%) | 0 |
| Headache* | 112 (32.0) | 4 (1.1) | 44 (17.8) | 1 (0.4) | 42 (21.8) | 3 (1.6) |
| Dizziness* | 34 (9.7) | 1 (0.3) | 15 (6.1) | 0 | 24 (12.5) | 3 (1.6) |
| Investigations/laboratory examinations | ||||||
| ALT level increased | 49 (14.0) | 9 (2.6) | 65 (26.3) | 28 (11.3) | 21 (10.9) | 10 (5.2) |
| AST level increased | 42 (12.0) | 5 (1.4) | 60 (24.3) | 22 (8.9) | 16 (8.3) | 4 (2.1) |
| γ-GT level increased | 38 (10.9) | 19 (5.4) | 54 (21.9) | 36 (14.6) | 29 (15.1) | 18 (9.4) |
| Blood AP increased | 26 (7.4) | 7 (2.0) | 42 (17.0) | 12 (4.9) | 16 (8.3) | 1 (0.5) |
| Blood CPK level increased | 10 (2.9) | 6 (1.7) | 87 (35.2) | 30 (12.1) | 44 (22.9) | 13 (6.8) |
| Blood creatinine level increased | 15 (4.3) | 0 | 37 (15.0) | 3 (1.2) | 12 (6.3) | 2 (1.0) |
| Lipase level increased | – | – | 9 (3.6) | 8 (3.2) | 4 (2.1) | 3 (1.6) |
| Hyperglycaemia* | 17 (4.9) | 8 (2.3) | 8 (3.2) | 1 (0.4) | 9 (4.7) | 4 (2.1) |
| Hyponatremia* | 16 (4.6) | 15 (4.3) | 13 (5.3) | 7 (2.8) | 2 (1.0) | 1 (0.5) |
| Anaemia | 26 (7.4) | 7 (2.0) | 39 (15.8) | 4 (1.6) | 29 (15.1) | 8 (4.2) |
| Neutropenia* | 32 (9.1) | 17 (4.9) | 3 (1.2) | 0 | 5 (2.6) | 2 (1.0) |
| Musculoskeletal events | ||||||
| Arthralgia | 93 (26.6) | 3 (0.9) | 94 (38.1) | 6 (2.4) | 49 (25.5) | 1 (0.5) |
| Pain in extremity | 45 (12.9) | 4 (1.1) | 29 (11.7) | 3 (1.2) | 21 (10.9) | 2 (1.0) |
| Myalgia | 66 (18.8) | 0 | 37 (15.0) | 1 (0.4) | 26 (13.5) | 0 |
| Cardiovascular events | ||||||
| QT interval prolongation (ECG)* | 5 (1.4) | 2 (0.6) | 11 (4.5) | 3 (1.2) | 0 | 0 |
| Ejection fraction decreased* | 29 (8.3) | 13 (3.7) | 29 (11.7) | 5 (2.0) | 11 (5.7) | 2 (1.0) |
| Hypertension | 103 (29.4) | 54 (15.4) | 39 (15.8) | 15 (6.1) | 21 (10.9) | 11 (5.7) |
| Ocular events | ||||||
| Vision blurred | 17 (4.9) | 0 | 28 (11.3) | 0 | 30 (15.6) | 0 |
| Chorioretinopathy* | 2 (0.6) | 0 | 32 (13.0) | 2 (0.8) | 5 (2.6) | 2 (1.0) |
| Retinal detachment* | – | – | 22 (8.9) | 5 (2.0) | 15 (7.8) | 1 (0.5) |
| Pulmonary events | ||||||
| Cough | 77 (22.0) | 0 | 23 (9.3) | 0 | 16 (8.3) | 1 (0.5) |
| Pneumonia* | 2 (0.6) | 0 | 6 (2.4) | 3 (1.2) | 3 (1.6) | 3 (1.6) |
| Pulmonary embolism* | 7 (2.0) | 7 (2.0) | 2 (0.8) | 2 (0.8) | 6 (3.1) | 2 (1.0) |
| Renal events | ||||||
| Acute kidney injury* | 4 (1.1) | 4 (1.1) | 7 (2.8) | 3 (1.2) | 3 (1.6) | 2 (1.0) |
| Dehydration* | 15 (4.3) | 6 (1.7) | 11 (4.5) | 5 (2.0) | 11 (4.5) | 5 (2.0) |
Listed are AE with event frequencies (of any grade) ≥10%, and/or with event frequencies (≥2% for grade ≥3 AE) and frequency independent, clinically relevant ‘AE of specific interest’.
Values in bold indicates CTC grade 3 and grade 4 toxicity reported; values in italics indicates different data cut-off dates for safety analysis (D+T only).
*D+T: values and frequencies reported at initial safety analysis (14 April 2014) only,2 extended listings are published in the European Public Assessment Report (EMA/589140/2015, dated 2 Septmber 2015).
†D+T: term ‘hand–foot syndrome’ was reported, including the terms palmo–plantar erythrodysesthesia, planto–palmar hyperkeratosis and palmoplantar keratoderma.
‡E+B: frequencies for peripheral swelling were reported.
–, not reported; AE, adverse event; ALT, alanine aminotransferase;AP, alkaline phosphatase;AST, aspartate aminotransferase;CPK, creatine phosphokinase;CTC, common toxicity criteria;GT, γ-gamma-glutamyl transferase; pts rand., patients randomised.