**6. Combination therapy with B-Raf and MEK 1/2 inhibitors**

Compared to the treatment modalities that were available prior to the development of targeted therapies, treatment with B-Raf inhibitors resulted in exceptional response rates and increases in overall survival. Investigation into inhibition at another downstream protein of the Ras-Raf-MEK-ERK MAPK pathway with MEK 1/2 inhibitors in the METRIC trials resulted in an overall response rate of approximately 30% and improved PFS of the oral selective MEK inhibitor trametinib when given orally (dose 2 mg) compared to treatment with dacarbazine in B-Raf-mutated melanoma [9, 36, 37]. Toxicities seen in the trial attributed to both drugs included rash, hypertension, diarrhea, edema, cardiac dysfunction, serum creatinine elevation, and ocular toxicities [10]. However, extrapolation from these studies and those of B-Raf inhibitors suggested that B-Raf inhibition was a more efficacious targeted therapy than MEK inhibition alone [38]. Relapse rates and side effect profiles with B-Raf inhibitor monotherapy were much higher than expected and were thought to be associated with reactivation of the MAPK pathway. For this reason, basic scientists and clinical investigators began combining B-Raf inhibitors with MEK inhibitors to block at two levels of this signaling pathway, intending to block any paradoxical activation after B-Raf inhibition [6]. Trametinib, cobimetinib, and bimimetinib are MEK inhibitors currently approved to be used in combination with B-Raf inhibitors in the treatment of advanced melanoma. Case reports also suggest that MEK inhibitors may be an effective therapy choice in patients with alternative mechanisms of MAPK activation, such as mutations in codons adjacent to that containing V600 [9].

The COMBI-DT, an initial phase II trial by Flaherty et al. evaluating dabrafenib and trametinib treatment in 247 patients with untreated B-Raf V600E- or V600Kmutated melanoma, found that dual targeted therapy (150 mg dabrafenib twice daily and 1 or 2 mg trametinib daily) resulted in a median PFS of 9.4 months versus 5.8 months for dabrafenib monotherapy. Median overall survival was 27.4 months for the combination therapy versus 20.2 months for the monotherapy. The hazard ratio for progression or death was 0.39 (95% CI 0.25–0.62, p < 0.001). Overall response was 76% in the dual therapy group compared to 54% with dabrafenib monotherapy (p < 0.03). Cutaneous side effects were significantly decreased with the addition of the MEK inhibitor [36, 37]. Following these results, phase III trials were performed showing similar outcomes. The COMBI-D phase III trial by Long et al. evaluated 423 patients with mutated B-Raf V600E or V600K advanced melanoma, who were treated with the combination of dabrafenib (150 mg twice daily) plus trametinib (2 mg daily) or dabrafenib alone. Median overall survival was 25.1 months in the combination group (95% CI 19.2–not reached) versus 18.7 months in the dabrafenib treatment group (95% CI 15.2–23.7, p = 0.017). Overall survival was 74% at 1 year and 51% at 2 years in the combination therapy group versus 68 and 42% in the monotherapy group. Median PFS was 11 months in the combination therapy group (95% CI 8–13.9) versus 8.8 months (95% CI 5.9–9.3, p = 0.0004). Rates of grade 3–4 adverse events were similar between both (32 versus 31%), pyrexia was the most common side effect with dabrafenib and trametinib combination therapy, while hyperkeratosis was the most common side effect in the dabrafenib alone group [39]. The COMBI-V study was a phase III trial

**9**

*B-Raf-Mutated Melanoma*

*DOI: http://dx.doi.org/10.5772/intechopen.86615*

by Robert et al. evaluating combination dabrafenib and trametinib therapy against vemurafenib monotherapy. A total of 704 patients with untreated mutant B-Raf V600E or V600K were randomized to receive dabrafenib (150 mg twice daily) with trametinib (2 mg once daily) versus vemurafenib (960 mg twice daily). Overall survival at 1 year was 72% in the combination therapy group (95% CI 67–77) versus 65% in the vemurafenib alone group (95% CI 59–70). Hazard ratio for death with combination therapy was 0.69 (95% CI 0.53–0.89, p = 0.005). Median PFS was 11.4 months in the combination therapy group and 7.3 months in the vemurafenib monotherapy group (HR 0.56, 95% CI 046–0.69, p = 0.001). Objective response rates were 64% in the combination therapy group and 51% in the monotherapy group (p < 0.001). Similar to the COMBI-D trial, rates of severe adverse events were comparable but rates of squamous cell carcinoma and other skin complications were significantly higher with vemurafenib monotherapy [40]. Based on these results, combination therapy with dabrafenib and trametinib was approved by the FDA for

treatment of B-Raf-mutated V600E and -V600K advanced melanoma.

patients, the most significant of which were pyrexia and dehydration [42]. Second generation B-Raf inhibitors such as encorafenib were also tested in clinical trials in combination with MEK inhibitors. These drugs are associated with a 10× longer half-life than vemurafenib or dabrafenib [43]. Phase I/II trials have shown that combination therapy with encorafenib and the MEK inhibitor, binimetinib in B-Raf-mutated melanoma resulted in a median PFS of 11.3 months (95% CI 7.4–14.6) [44]. The COLUMBUS trial by Dummer et al. evaluated 577 patients with unresectable stage III or IV B-Raf V600E- or V600K-mutated melanoma that were treatment naïve or had progressed on prior immunotherapy treated with encorafenib (450 mg daily) plus binimetinib (45 mg twice daily) or with encorafenib (300 mg daily) or vemurafenib (960 mg twice daily) monotherapy. Median PFS was 14.9 months (95% CI 11–18.5) in the combination encorafenib and binimetinib group versus 9.6 months in the encorafenib group (95% CI 7.5–14.8) and 7.3 months in the vemurafenib group (95% CI 5.6–8.2) (95% CI 0.41–0.71, HR 0.54, p < 0.0001). Overall responses were detected in 63% of patients in the combination therapy group versus 51% of patients with the encorafenib group and 40% of patients in the vemurafenib group [45]. Overall survival was 33.6 months (95% CI 24.4–39.2) in the combination therapy group versus 23.5 months (95%

Another MEK inhibitor, cobimetinib, has also shown efficacy in combination with the B-Raf inhibitor vemurafenib in advanced melanoma. The coBRIM trial, a phase III trial by Larkin et al., studied 495 patients with untreated B-Raf-mutated V600E and -V600K advanced melanoma treated with vemurafenib (960 mg twice daily, continuously) and cobimetinib (60 mg daily for 21 days followed by 7 days off) versus vemurafenib alone. Median PFS was 9.9 months in the combination therapy group versus 6.2 months in the control group. The hazard ratio for death or progression was 0.51 (95% CI 0.39–0.68, p < 0.001). Overall response rates were 68% in the combination group versus 45% in the monotherapy treatment group (p < 0.001) with 10% of patients in the combination group achieving complete response (versus 4% in the vemurafenib alone group). Rates of adverse events trended toward higher occurrence in the combination therapy group; however, the difference was not significant (65% versus 59%) and rates of secondary skin cancers were lower in the combination therapy group [41]. A follow up study of the same patient population found a median PFS of 12.3 months (95% CI 9.5–13.4) in the combination therapy group versus 7.2 months in the vemurafenib group (95% CI 5.6-7.5, p < 0.0001). Median overall survival was 22.3 months for cobimetinib and vemurafenib treatment (95% CI 20.3–not estimable) versus 17.4 months for the vemurafenib group (95% CI 15-19.8, p = 0.005). Serious adverse events were seen in 37% of the combination treatment patients versus 28% of the monotherapy

#### *B-Raf-Mutated Melanoma DOI: http://dx.doi.org/10.5772/intechopen.86615*

*Cutaneous Melanoma*

containing V600 [9].

Even after clinical evidence of progression during treatment with vemurafenib or dabrafenib, studies suggest that continued treatment with B-Raf inhibitors may prolong survival through impedance of disease growth while preventing a disease

Compared to the treatment modalities that were available prior to the development of targeted therapies, treatment with B-Raf inhibitors resulted in exceptional response rates and increases in overall survival. Investigation into inhibition at another downstream protein of the Ras-Raf-MEK-ERK MAPK pathway with MEK 1/2 inhibitors in the METRIC trials resulted in an overall response rate of approximately 30% and improved PFS of the oral selective MEK inhibitor trametinib when given orally (dose 2 mg) compared to treatment with dacarbazine in B-Raf-mutated melanoma [9, 36, 37]. Toxicities seen in the trial attributed to both drugs included rash, hypertension, diarrhea, edema, cardiac dysfunction, serum creatinine elevation, and ocular toxicities [10]. However, extrapolation from these studies and those of B-Raf inhibitors suggested that B-Raf inhibition was a more efficacious targeted therapy than MEK inhibition alone [38]. Relapse rates and side effect profiles with B-Raf inhibitor monotherapy were much higher than expected and were thought to be associated with reactivation of the MAPK pathway. For this reason, basic scientists and clinical investigators began combining B-Raf inhibitors with MEK inhibitors to block at two levels of this signaling pathway, intending to block any paradoxical activation after B-Raf inhibition [6]. Trametinib, cobimetinib, and bimimetinib are MEK inhibitors currently approved to be used in combination with B-Raf inhibitors in the treatment of advanced melanoma. Case reports also suggest that MEK inhibitors may be an effective therapy choice in patients with alternative mechanisms of MAPK activation, such as mutations in codons adjacent to that

The COMBI-DT, an initial phase II trial by Flaherty et al. evaluating dabrafenib and trametinib treatment in 247 patients with untreated B-Raf V600E- or V600Kmutated melanoma, found that dual targeted therapy (150 mg dabrafenib twice daily and 1 or 2 mg trametinib daily) resulted in a median PFS of 9.4 months versus 5.8 months for dabrafenib monotherapy. Median overall survival was 27.4 months for the combination therapy versus 20.2 months for the monotherapy. The hazard ratio for progression or death was 0.39 (95% CI 0.25–0.62, p < 0.001). Overall response was 76% in the dual therapy group compared to 54% with dabrafenib monotherapy (p < 0.03). Cutaneous side effects were significantly decreased with the addition of the MEK inhibitor [36, 37]. Following these results, phase III trials were performed showing similar outcomes. The COMBI-D phase III trial by Long et al. evaluated 423 patients with mutated B-Raf V600E or V600K advanced melanoma, who were treated with the combination of dabrafenib (150 mg twice daily) plus trametinib (2 mg daily) or dabrafenib alone. Median overall survival was 25.1 months in the combination group (95% CI 19.2–not reached) versus 18.7 months in the dabrafenib treatment group (95% CI 15.2–23.7, p = 0.017). Overall survival was 74% at 1 year and 51% at 2 years in the combination therapy group versus 68 and 42% in the monotherapy group. Median PFS was 11 months in the combination therapy group (95% CI 8–13.9) versus 8.8 months (95% CI 5.9–9.3, p = 0.0004). Rates of grade 3–4 adverse events were similar between both (32 versus 31%), pyrexia was the most common side effect with dabrafenib and trametinib combination therapy, while hyperkeratosis was the most common side effect in the dabrafenib alone group [39]. The COMBI-V study was a phase III trial

flare that can be seen with cessation of treatment [10, 34, 35].

**6. Combination therapy with B-Raf and MEK 1/2 inhibitors**

**8**

by Robert et al. evaluating combination dabrafenib and trametinib therapy against vemurafenib monotherapy. A total of 704 patients with untreated mutant B-Raf V600E or V600K were randomized to receive dabrafenib (150 mg twice daily) with trametinib (2 mg once daily) versus vemurafenib (960 mg twice daily). Overall survival at 1 year was 72% in the combination therapy group (95% CI 67–77) versus 65% in the vemurafenib alone group (95% CI 59–70). Hazard ratio for death with combination therapy was 0.69 (95% CI 0.53–0.89, p = 0.005). Median PFS was 11.4 months in the combination therapy group and 7.3 months in the vemurafenib monotherapy group (HR 0.56, 95% CI 046–0.69, p = 0.001). Objective response rates were 64% in the combination therapy group and 51% in the monotherapy group (p < 0.001). Similar to the COMBI-D trial, rates of severe adverse events were comparable but rates of squamous cell carcinoma and other skin complications were significantly higher with vemurafenib monotherapy [40]. Based on these results, combination therapy with dabrafenib and trametinib was approved by the FDA for treatment of B-Raf-mutated V600E and -V600K advanced melanoma.

Another MEK inhibitor, cobimetinib, has also shown efficacy in combination with the B-Raf inhibitor vemurafenib in advanced melanoma. The coBRIM trial, a phase III trial by Larkin et al., studied 495 patients with untreated B-Raf-mutated V600E and -V600K advanced melanoma treated with vemurafenib (960 mg twice daily, continuously) and cobimetinib (60 mg daily for 21 days followed by 7 days off) versus vemurafenib alone. Median PFS was 9.9 months in the combination therapy group versus 6.2 months in the control group. The hazard ratio for death or progression was 0.51 (95% CI 0.39–0.68, p < 0.001). Overall response rates were 68% in the combination group versus 45% in the monotherapy treatment group (p < 0.001) with 10% of patients in the combination group achieving complete response (versus 4% in the vemurafenib alone group). Rates of adverse events trended toward higher occurrence in the combination therapy group; however, the difference was not significant (65% versus 59%) and rates of secondary skin cancers were lower in the combination therapy group [41]. A follow up study of the same patient population found a median PFS of 12.3 months (95% CI 9.5–13.4) in the combination therapy group versus 7.2 months in the vemurafenib group (95% CI 5.6-7.5, p < 0.0001). Median overall survival was 22.3 months for cobimetinib and vemurafenib treatment (95% CI 20.3–not estimable) versus 17.4 months for the vemurafenib group (95% CI 15-19.8, p = 0.005). Serious adverse events were seen in 37% of the combination treatment patients versus 28% of the monotherapy patients, the most significant of which were pyrexia and dehydration [42].

Second generation B-Raf inhibitors such as encorafenib were also tested in clinical trials in combination with MEK inhibitors. These drugs are associated with a 10× longer half-life than vemurafenib or dabrafenib [43]. Phase I/II trials have shown that combination therapy with encorafenib and the MEK inhibitor, binimetinib in B-Raf-mutated melanoma resulted in a median PFS of 11.3 months (95% CI 7.4–14.6) [44]. The COLUMBUS trial by Dummer et al. evaluated 577 patients with unresectable stage III or IV B-Raf V600E- or V600K-mutated melanoma that were treatment naïve or had progressed on prior immunotherapy treated with encorafenib (450 mg daily) plus binimetinib (45 mg twice daily) or with encorafenib (300 mg daily) or vemurafenib (960 mg twice daily) monotherapy. Median PFS was 14.9 months (95% CI 11–18.5) in the combination encorafenib and binimetinib group versus 9.6 months in the encorafenib group (95% CI 7.5–14.8) and 7.3 months in the vemurafenib group (95% CI 5.6–8.2) (95% CI 0.41–0.71, HR 0.54, p < 0.0001). Overall responses were detected in 63% of patients in the combination therapy group versus 51% of patients with the encorafenib group and 40% of patients in the vemurafenib group [45]. Overall survival was 33.6 months (95% CI 24.4–39.2) in the combination therapy group versus 23.5 months (95%

CI 19.6–33.6) in the encorafenib group and 16.9 months in the vemurafenib group (95% CI 14–24.5) (HR 0.62, 95% CI 0.47–0.79, p < 0.0001) [46]. Adverse events in the combination therapy group included increased γ-glutamyltransferase, creatinine phosphokinase and hypertension. Encorafenib monotherapy was associated with palmoplantar erythrodysaesthesia syndrome, myalgia and arthralgia; while vemurafenib monotherapy was associated with arthralgia. Interestingly, combination therapy with encorafenib and binimetinib allowed a higher maximum tolerated dose of encorafenib, suggesting as with the other combinations of B-Raf and MEK inhibitors dual blockade of the MAPK pathway abrogates side effects associated with B-Raf inhibition alone. Fewer adverse events ultimately resulted in treatment discontinuation in the combination therapy group [45, 46]. Although it is difficult to compare end points between clinical trials, median PFS for encorafenib and binimetinib in the COLUMBUS trial was longer (14.9 months) than for either dabrafenib-trametinib in the COMBI-D (11 months) and COMBI-V (11.4 months) trials or for vemurafenib-cobimetinib in the coBRIM trial (12.3 months) [39, 40, 42, 45, 46]. This difference may be due to the longer half-life of encorafenib or it may also be the result of B-Raf treatment in a population of patients that did not all have access to immunotherapy due to local approved indications and regulations. This may have resulted in a group of patients on the COLUMBUS trial that was dissimilar to those studied in the other B-Raf inhibitor trials [45].

Overall, the above studies suggest that dual therapy with B-Raf and MEK inhibitors provides a longer PFS and increased overall response rates compared to B-Raf inhibition alone [38, 42, 47–50]. Most importantly, combination therapy is also associated with a modified side effect profile, particularly in those caused by reactivation of Ras and the MAPK pathway such as cutaneous squamous cell carcinomas [27]. Although the data suggest that encorafenib-binimetinib treatment may result in a slightly longer PFS, there is little direct evidence available to help clinicians pick between B-Raf/MEK inhibitor therapies [45, 46]. Therefore, the potential side effect profile may be helpful in guiding the decision. Approximately 50% of patients treated with dabrafenib and trametinib develop pyrexia, while 47% of patients treated with vemurafenib and cobimetinib develop significant photosensitivity [36, 40–42, 47]. Encorafenib and binimetinib dual therapy resulted in elevated γ-glutamyltransferase, creatinine phosphokinase, and hypertension [45, 46]. All combinations are associated with similar rates of MEK inhibitorrelated toxicities such as serous retinopathy and left ventricular dysfunction [45, 46]. Other potential differences that may aid in picking therapy include the need to refrigerate trametinib and to take dabrafenib and trametinib on an empty stomach.

Monotherapy with a MEK inhibitor in B-Raf wild type tumors has been of great interest. Binimetinib treatment in melanomas with N-Ras mutations resulted in a PFS of 2.8 months (versus 1.5 months with dacarbazine), however overall survival was not improved [51, 52]. In vivo studies have also seen clinical activity from MEK inhibitor treatment in combination with CDK4/6 inhibitors, MDM2 antagonists, and PI3K/AKT inhibitors in melanoma [9]. Unfortunately, monotherapy with a MEK inhibitor such as trametinib after failure or B-Raf treatment showed no response [6, 10].

## **7. Adjuvant therapy with B-Raf inhibition**

The above studies evaluated combined targeted therapy in advanced melanoma, where the patients were either not surgical candidates or had metastatic disease. However, investigators have also evaluated whether adjuvant targeted therapy after surgical resection may result in increased progression-free or overall survival.

**11**

*B-Raf-Mutated Melanoma*

*DOI: http://dx.doi.org/10.5772/intechopen.86615*

**8. B-Raf targeted therapy in brain metastases**

The COMBI-AD trial by Long et al. was a phase III trial, where 870 patients with resected stage IIIA, IIB and IIIC B-Raf V600E- or V600K-mutated melanoma were randomly assigned to placebo or treatment with dabrafenib (150 mg twice daily) and trametinib (2 mg daily). Estimated relapse free survival rates at 3 years were 58% in the treatment group versus 39% in the placebo group (HR for death 0.47, 95% CI 0.39–0.58, p < 0.001). Overall survival at 3 years was 86% in the treatment group versus 77% in the placebo group (HR for death 0.57, 95% CI 0.42–0.79, p = 0.0006). Combination treatment with dabrafenib and trametinib also resulted in increased metastasis-free survival and lower rates of relapse. Despite the 53% improvement in relapse free survival and 43% improvement in overall survival, these improvements must be weighed against the 26% discontinuation rate due to adverse events (most frequently pyrexia and fatigue) [53]. Hauschild et al. confirmed these results in an extended follow up, evaluating relapse free survival rates at 3 and 4 years for dabrafenib and trametinib co-therapy versus placebo. At 3 years, relapse free survival rates were 59% for combination therapy (95% CI 55–64%) versus 40% in the placebo arm (95% CI 35–45%). At 4 years, relapse free survival rates were 54% for combination therapy (95% CI 49–59%) versus 38% in the placebo arm (95% CI 34–44%) [54]. Single agent vemurafenib (960 mg twice daily) as adjuvant therapy was also studied after resection in patients with stage IIC, IIIA, IIIB, or IIIC melanoma. Treatment resulted in a substantial but not significant increase in disease-free survival [55]. These new data suggest that B-Raf and MEK inhibition not only play an important role in the treatment of metastatic melanoma, but they also may provide benefit to patients with stage III disease after surgical resection.

As discussed previously, B-Raf inhibitor therapy is an effective treatment option for patients with inoperable or metastatic melanoma. Unfortunately, melanoma has one of the highest cerebral tropisms of any malignancy. Approximately 20% of stage IV patients have brain metastases at time of diagnosis and up to 40–50% of patients with stage IV melanoma will ultimately develop intracranial disease [56]. This development contributes significantly to mortality in 20–54% of metastatic melanoma patients; and once brain metastases are diagnosed, median survival decreases to 4–5 months [56–58]. Therefore, in evaluating the efficacy of targeted and immunotherapies in advanced melanoma, it is important to evaluate whether these agents are active in the central nervous system. The BREAK-MB trial showed that dabrafenib (150 mg twice a day) had an acceptable safety profile and induced a response in the metastatic brain lesions of 39% of B-Raf V600E mutant advanced melanoma if no prior local therapy had been used and in 31% of patients with prior local therapy. Median progression-free survival was 16 weeks and median overall survival was 31 weeks [59]. The COMBI-MB trial by Davies et al. was a phase II trial of dabrafenib (150 mg twice a day) and trametinib (2 mg daily) in 125 patients with V600 mutant melanoma. About 58% of patients with asymptomatic brain metastases and no prior therapy showed a response (95% CI 46–69) with a median progression-free survival of 5.6 months (95% CI 5.3–7.4) and a median overall survival of 10.8 months (95% CI 9.7–19.6). About 56% of patients who had received prior therapy showed a response with a median PFS of 7.2 month (95% CI 1.7–6.5), while 59% of patients with symptomatic brain metastases showed a response with a median PFS of 5.5 months (95% CI 2.8–7.3). About 44% of patients with V600D/K/R mutations responded to dabrafenib and trametinib with a median PFS of 4.2 months (95% CI 1.7–6.5) [60]. Vemurafenib has been studied in a phase 2 trial with similar results [57, 58]. Interestingly, these

*Cutaneous Melanoma*

CI 19.6–33.6) in the encorafenib group and 16.9 months in the vemurafenib group (95% CI 14–24.5) (HR 0.62, 95% CI 0.47–0.79, p < 0.0001) [46]. Adverse events in the combination therapy group included increased γ-glutamyltransferase, creatinine phosphokinase and hypertension. Encorafenib monotherapy was associated with palmoplantar erythrodysaesthesia syndrome, myalgia and arthralgia; while vemurafenib monotherapy was associated with arthralgia. Interestingly, combination therapy with encorafenib and binimetinib allowed a higher maximum tolerated dose of encorafenib, suggesting as with the other combinations of B-Raf and MEK inhibitors dual blockade of the MAPK pathway abrogates side effects associated with B-Raf inhibition alone. Fewer adverse events ultimately resulted in treatment discontinuation in the combination therapy group [45, 46]. Although it is difficult to compare end points between clinical trials, median PFS for encorafenib and binimetinib in the COLUMBUS trial was longer (14.9 months) than for either dabrafenib-trametinib in the COMBI-D (11 months) and COMBI-V (11.4 months) trials or for vemurafenib-cobimetinib in the coBRIM trial (12.3 months) [39, 40, 42, 45, 46]. This difference may be due to the longer half-life of encorafenib or it may also be the result of B-Raf treatment in a population of patients that did not all have access to immunotherapy due to local approved indications and regulations. This may have resulted in a group of patients on the COLUMBUS trial that was dissimilar

Overall, the above studies suggest that dual therapy with B-Raf and MEK inhibitors provides a longer PFS and increased overall response rates compared to B-Raf inhibition alone [38, 42, 47–50]. Most importantly, combination therapy is also associated with a modified side effect profile, particularly in those caused by reactivation of Ras and the MAPK pathway such as cutaneous squamous cell carcinomas [27]. Although the data suggest that encorafenib-binimetinib treatment may result in a slightly longer PFS, there is little direct evidence available to help clinicians pick between B-Raf/MEK inhibitor therapies [45, 46]. Therefore, the potential side effect profile may be helpful in guiding the decision. Approximately 50% of patients treated with dabrafenib and trametinib develop pyrexia, while 47% of patients treated with vemurafenib and cobimetinib develop significant photosensitivity [36, 40–42, 47]. Encorafenib and binimetinib dual therapy resulted in elevated γ-glutamyltransferase, creatinine phosphokinase, and hypertension [45, 46]. All combinations are associated with similar rates of MEK inhibitorrelated toxicities such as serous retinopathy and left ventricular dysfunction [45, 46]. Other potential differences that may aid in picking therapy include the need to refrigerate trametinib and to take dabrafenib and trametinib on an empty stomach. Monotherapy with a MEK inhibitor in B-Raf wild type tumors has been of great interest. Binimetinib treatment in melanomas with N-Ras mutations resulted in a PFS of 2.8 months (versus 1.5 months with dacarbazine), however overall survival was not improved [51, 52]. In vivo studies have also seen clinical activity from MEK inhibitor treatment in combination with CDK4/6 inhibitors, MDM2 antagonists, and PI3K/AKT inhibitors in melanoma [9]. Unfortunately, monotherapy with a MEK inhibitor such as trametinib after failure or B-Raf treatment showed no

The above studies evaluated combined targeted therapy in advanced melanoma, where the patients were either not surgical candidates or had metastatic disease. However, investigators have also evaluated whether adjuvant targeted therapy after surgical resection may result in increased progression-free or overall survival.

to those studied in the other B-Raf inhibitor trials [45].

**10**

response [6, 10].

**7. Adjuvant therapy with B-Raf inhibition**

The COMBI-AD trial by Long et al. was a phase III trial, where 870 patients with resected stage IIIA, IIB and IIIC B-Raf V600E- or V600K-mutated melanoma were randomly assigned to placebo or treatment with dabrafenib (150 mg twice daily) and trametinib (2 mg daily). Estimated relapse free survival rates at 3 years were 58% in the treatment group versus 39% in the placebo group (HR for death 0.47, 95% CI 0.39–0.58, p < 0.001). Overall survival at 3 years was 86% in the treatment group versus 77% in the placebo group (HR for death 0.57, 95% CI 0.42–0.79, p = 0.0006). Combination treatment with dabrafenib and trametinib also resulted in increased metastasis-free survival and lower rates of relapse. Despite the 53% improvement in relapse free survival and 43% improvement in overall survival, these improvements must be weighed against the 26% discontinuation rate due to adverse events (most frequently pyrexia and fatigue) [53]. Hauschild et al. confirmed these results in an extended follow up, evaluating relapse free survival rates at 3 and 4 years for dabrafenib and trametinib co-therapy versus placebo. At 3 years, relapse free survival rates were 59% for combination therapy (95% CI 55–64%) versus 40% in the placebo arm (95% CI 35–45%). At 4 years, relapse free survival rates were 54% for combination therapy (95% CI 49–59%) versus 38% in the placebo arm (95% CI 34–44%) [54]. Single agent vemurafenib (960 mg twice daily) as adjuvant therapy was also studied after resection in patients with stage IIC, IIIA, IIIB, or IIIC melanoma. Treatment resulted in a substantial but not significant increase in disease-free survival [55]. These new data suggest that B-Raf and MEK inhibition not only play an important role in the treatment of metastatic melanoma, but they also may provide benefit to patients with stage III disease after surgical resection.
