Table 2.
Summary of clinical trials, outcomes and adverse events associated with novel BRAF inhibitors and ERK inhibitors in patients with metastatic melanoma.
| Treatment | Status | Sponsor | Phase and NCT | Clinical Outcomes | Adverse Events |
|---|---|---|---|---|---|
| BRAF inhibitors | |||||
| LGX818 in patients with advanced or metastatic BRAF mutant melanoma [222] |
Active, not recruiting | Array BioPharma | I, NCT01436656 | 25 BRAF-naïve and 29 BRAF inhibitor pretreated patients were enrolled in the study. The treatment was tolerable up to the MTD of 450 mg once daily, however the RP2D was declared as 300 mg once daily due to the increased risk of adverse events at 450 mg. BRAFi-naïve patients treated with 300–450 mg once daily saw an RR of 60% and PFS of 12.4 months (95% CI: 7.4-Not Reached), while for BRAFi-pretreated patients the RR was 22% and the PFS was 1.9 months (95% CI: 0.9–3.7 months). | Nausea, myalgia, PPED |
| LGX818 in combination with MEK162 in patients with advanced solid tumors [223] |
Active, not recruiting | Array BioPharma | Ib/II, NCT01543698 | The combination was safe with no substantial adverse evets observed. Nine BRAF naïve and 14 BRAF inhibitor pretreated patients were enrolled. The MTD was unable to be determined and the RP2D was 450–600 mg LGX818 + 45 mg MEK162 orally once daily. CR and PR for BRAF-naïve patients were 11% and 78% respectively. The PR for BRAF inhibitor pretreated patient groups was 21%. | Nausea, abdominal pain, headache, diarrhea, fatigue, visual impairment. |
| Encorafenib in combination with Binimetinib or Vemurafenib in patients with BRAF-mutant melanoma (COLUMBUS) [224] |
Active, not recruiting | Array BioPharma | III, NCT01909453 | The combination was efficacious, safe and tolerable. The median follow up and followup for overall survival was 32.1 months (95% CI: 29.5–32.3 months) and 36.8 months (95% CI: 35.9–37.5 months) respectively. Encorafenib + Binimetinib (n= 192): The median overall survival was 33.6 months (95% CI: 24.4–39.2 months. One and two year OS was 75.5% (95% CI: 68.8–81%) and 57.6% (95%CI: 50.3–64.3%) respectively. The median PFS was 14.9 months (95% CI: 0.2–2 months). PFS was longer in this group as compared to vemurafenib only group (HR:0.51, 95% CI: 0.39–0.67, p < 0.0001) and encorafenib only group (HR: 0.77, 95% CI: 0.59–1, p = 0.05). Overall response rates by masked independent central reiew was 64%. Vemurafenib only (n = 191): The median overall survival was 16.9 months (95% CI:14–24.5 months). Hazard ratio compared to combination group was 0.61 (95% CI: 0.47–0.79, p < 0.0001). The overall survival did not differ significantly. One and two year OS was 63.1% (95% CI: 55.7–69.6%) and 43.2% (95% CI: 35.9–50.2%) respectively. The median PFS was 7.3 months (95% CI: 5.6–7.9 months). Overall response rates by masked independent central reiew was 41%. Encorafenib only (n= 194): Overall survival was longer in this group compared to Vemurafenib only group (HR: 0.81, 95% CI: 0.58–0.98, p = 0.033). One and two year OS was 74.6% (95% CI: 67.6–80.3%) and 49.1% (95% CI:41.5–56.2%) respectively. The median PFS was 9.6 months (95% CI: 7.4–14.8 months). Overall response rates by masked independent central review was 52%. | Palmar-plantar erythrodysaesthesia, nausea, diarrhea, vomiting, fatigue, myalgia, arthralgia, increased γ-glutamyltransferase, increased blood creatine phosphokinase, hypertension |
| ERK inhibitor | |||||
| Ulixertinib in patients with advanced solid tumors [211] |
Completed | BioMed Valley Discoveries, Inc. | I, NCT01781429 | 135 patients were enrolled in the study. The treatment was well tolerated and had an acceptable safety profile at doses of 600 mg twice daily and this dose was established as MTD and RP2D. This dose demonstrated anti-tumor activity in patients with treatment naïve or those progressed on MAPK pathway inhibitors. The PR was 12%. | Diarrhea, fatigue, dehydration, nausea, rash, dermatitis acneiform, increased blood creatinine. |