Table 1.
Outcomes and toxicities of treatment regimens for BRAF-mutant melanoma
| Agent | Trial | N | Overall response rate | Median PFS (months) | Median OS (months) | OS notes | Common grade 3+ toxicities | Serious AEs (%) |
|---|---|---|---|---|---|---|---|---|
| Vemurafenib | BRIM-3 [5–7] | 337 | 57%* | 6.9 [6.1–7.0] | 13.6 [12.0–15.2] | Median f/u of 13.4 months 4-year OS of 17.0% |
Rash Arthralgia Photosensitivity Keratoacanthoma Cutaneous SCC |
49 |
| Dabrafenib | BREAK-3 [8, 9] | 187 | 50%* [42.4–57.1] | 6.9 | 18.2 [16.6–NR] | Median f/u of 15.2 months | Pyrexia Arthralgia Hyperkeratosis Cutaneous SCC |
-- |
| Trametinib | METRIC [10, 11] | 214 | 29%* [22.6–35.1] | 4.9 | 15.6 | Median f/u of 14.7 months 5-year OS of 13.3% |
Hypertension Rash |
12 |
| Dabrafenib + trametinib | COMBI-d + COMBI-v [12–14] | 563 | 68%** | 11.1 [9.5 – 12.8] | 25.9 [22.6–31.5] | Median f/u of 22 months 5-year OS of 34% |
Pyrexia Hypertension Decreased ejection fraction |
48 |
| Vemurafenib + cobimetinib | CoBRIM [15, 16] | 247 | 70%** [63.5–75.3] | 12.3 [9.5 – 13.4] | 22.3 [20.3–NR] | Median f/u of 18.5 months 2-year OS 48.3% |
Increased liver function tests Increased creatine kinase Rash Diarrhea |
37 |
| Encorafenib + binimetinib | COLUMBUS [17••, 18••] | 192 | 64%* | 14.9 [11.0 – 20.2] | 33.6 [24.4–39.2] | Median f/u of 36.8 months 2-year OS 57.6% |
Increased liver function tests Increased creatine kinase Hypertension |
34 |
| Ipilimumab | MDX010-20× [19] | 137 | 10.9%** | 2.86 [2.76 – 3.02] | 10.1 [8.0–13.8] | Median f/u 27.8 months 2-year OS of 23.5% |
Diarrhea/colitis Fatigue Dyspnea |
– |
| Nivolumab | CHECKMATE-066× [20, 21] | 210 | 42.9%** | 5.1 [3.5 – 10.8] | 37.5 [25.5–NR] | Minimum f/u 38.4 months 3-year OS of 51.2% |
Diarrhea Pruritis Vomiting Rash |
15 |
| Pembrolizumab | KEYNOTE-006× [22, 23] | 556 | 42%* [38.1–46.5] | 8.4 [6.6–11.3] | 32.7 [24.5–41.6] | Median f/u 57.7 months for surviving patients 5-year OS 38.7% |
Diarrhea/colitis Fatigue Auto-immune Hepatitis Pneumonitis |
14 |
| Ipililumab + nivolumab | CHECKMATE-067× [24, 25] | 314 | 57.6%** [52.0–63.2] | 11.5 [8.7–19.3] | NR [38.2–NR] | Median f/u 46.9 months 4-year OS 53% |
Diarrhea/colitis Increased lipase Increased liver function tests Fatigue |
– |
Independent Review Committee reported
Investigator reported
BRAF mutation status was unknown in the ipilimumab trial and the CHECKMATE-066 trial was limited to BRAF wild-type melanoma. Subsequent retrospective studies have not found a correlation between BRAF mutant status and response to nivolumab or ipilimumab monotherapy [26, 27]. The KEYNOTE-006 and CHECKMATE-067 trials enrolled patients with both BRAF-mutant and BRAF wild-type melanomas. Response to pembrolizumab was similar in both groups in the KEYNOTE-006 trial while patients with BRAF mutations seemed to benefit more from anti-PD1/anti-CTLA4 combination therapy (in terms of OS) than those who were BRAF wt when compared with anti-PD1 monotherapy in the CHECKMATE-067 trial