**10. Future directions**

In vivo data and studies involving patient tumor samples have found that soon after B-Raf inhibitor initiation, immune activation is enhanced in the tumor microenvironment through multiple mechanisms [6]. The microphthalmiaassociated transcription factor (MITF) is activated by MAPK signaling to suppress the expression of melanocyte-lineage antigens. Blockade of this pathway with B-Raf inhibitors upregulates expression of these melanoma-specific antigens, increasing the immune system's ability to recognize and target tumor cells. By the time tumor progression is noted on B-Raf inhibitors, these markers are usually downregulated and suppressed. B-Raf inhibition is also associated with an increase in tumor infiltrating lymphocytes early after treatment initiation. Finally, B-Raf inhibition often results in decreases in the immunosuppressive cytokines interleukin (IL)-6 and IL-8. Associated with a better tumor response to B-Raf inhibition, these findings suggest that adding immunotherapy or employing immunotherapy somewhere in the treatment course may be beneficial [38, 68]. Mouse studies have also demonstrated that treatment with dabrafenib, trametinib, and an anti-PD1 immunotherapy resulted in improved outcomes compared to either therapy alone [38, 69]. Attempts at combining vemurafenib and ipilimumab have been terminated due to poor tolerability including fulminant hepatitis [6]. However, clinical investigators have been evaluating responses to alternative combinations of B-Raf and MEK inhibitors with checkpoint inhibitors. Ribas et al. performed a phase I study combining dabrafenib, trametinib, and an anti-PD-L1 monoclonal antibody MEDI4736. Six patients with B-Raf-mutated advanced melanoma were treated with either MED14736 (3 or 10 mg/kg IV every 2 weeks), dabrafenib (150 mg twice daily) and trametinib (2 mg daily), or trametinib alone. Thrombocytopenia was the main dose limiting toxicity identified. About 100% of patients had a response to combination therapy [70]. Another phase I trial combining atezolizumab, an anti-PD-L1 antibody (800 mg every 2 weeks), cobimetinib (60 mg daily) and vemurafenib (960 mg twice a day for the first 21 days, then 720 mg daily) in 34 patients with B-Raf-mutated advanced melanoma found that this combination resulted in a manageable and reversible safety profile. Partial or complete responses were detected in 85.3% of patients [71, 72]. Combination therapy in a phase 1/2 trial with pembrolizumab (2 mg/kg every 3 weeks), dabrafenib (150 mg twice daily) and trametinib (2 mg daily) in 15 patients with advanced B-Raf mutant melanoma found manageable and reversible dose limiting toxicities and adverse events. About 60% of patients had a complete or partial response [73]. Finally, a phase I trial of pembrolizumab (2 mg/kg every 3 weeks), dabrafenib (150 mg twice a day), and trametinib (2 mg daily) was compared with dabrafenib/trametinib treatment in 60 patients with B-Raf-mutated metastatic melanoma found a median PFS in the triple therapy group of 16 months (95% CI 8.6–21.5) versus 10.3 months in the dual therapy group (95% CI 7–15.6, HR 0.66, p-0.04287). Rates of response were also more durable, 60% of patients on triple therapy had responses that lasted over 18 months compared to 26% dual therapy [74]. Many other clinical trials are ongoing evaluating the clinical benefit of treatment with combinations of B-Raf inhibitors and immunotherapy (NCT02130466, NCT02967692, NCT02908672, NCT02858921, NCT02224781, NCT01656642, NCT01673854, NCT01940809, NCT02631447, NCT03235245, and NCT02902042). Some tissue and mouse studies indicate that MEK inhibition impairs T cell proliferation and localization to the tumor tissue, suggesting combination therapies with MEK inhibitors and immunotherapy may not be synergistic. However, these findings have not been recapitulated in clinical trials (NCT01767454) [9].

Additionally, immunotherapy monotherapy trials have shown that treatment with nivolumab and pembrolizumab in B-Raf mutant and B-Raf inhibitor refractory disease is associated with promising results [9, 38]. A small study of 19 pts showed an improved overall survival with a transition of therapy from vemurafenib to ipilimumab within 4 months of starting [10].

In addition to combination therapies, clinicians and scientists have been evaluating alternative methods to avoid or overcome resistance mechanisms after B-Raf therapy. These include using Bcl inhibitors to prevent cell escape through the YAP pathway, autophagy inhibitors that act through Bcl-2m Bcl-XL and Bcl-w, mTor inhibitors, ERK inhibitors, additional MAPK inhibitors, or Jak inhibitors to bypass other mechanisms of survival [9, 10].

### **11. Conclusions**

Compared to other currently approved therapies for advanced melanoma, B-Raf inhibitors are associated with a rapid onset of tumor regression, often within 1–2 weeks of treatment [9]. The speed of response is particularly beneficial in patients with a rapidly progressive or high burden of disease, as well as those with a poor performance status. The ECOG 6134 trial (NCT02224781) is accruing in an

**15**

**Author details**

Sarah E. Fenton, Jeffrey A. Sosman and Sunandana Chandra\*

provided the original work is properly cited.

Division of Hematology and Oncology, Northwestern University, Chicago, IL, USA

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: sunandana.chandra@northwestern.edu

*B-Raf-Mutated Melanoma*

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

maintaining an acceptable safety and tolerability profile.

attempt to answer whether initial treatment with checkpoint inhibitors or targeted therapy is more beneficial. This is a crucial study for which an answer will provide vital evidence for the sequencing of immunotherapy and B-Raf targeted therapy. The introduction of B-Raf inhibitors has been an important component in the revolution of melanoma treatment that has occurred in the last decade. Vemurafenib, dabrafenib, and encorafenib in combination with MEK inhibitors such as cobimetinib, trametinib, and binimetinib, have resulted in unprecedented overall responses and increases in survival. Combination therapy has also improved patient outcomes and decreased the likelihood of significant side effects such as new cutaneous malignancies. Testing for B-Raf mutations and treatment with B-Raf inhibitors is now standard of care in oncology clinics throughout the world. However, there is still significant ongoing work in management of tumor resistance mechanisms and combination and/or sequential regimens are being studied with immuno-oncologic agents, as an example, to try to further boost the efficacy, while

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

*Cutaneous Melanoma*

in clinical trials (NCT01767454) [9].

other mechanisms of survival [9, 10].

**11. Conclusions**

to ipilimumab within 4 months of starting [10].

due to poor tolerability including fulminant hepatitis [6]. However, clinical investigators have been evaluating responses to alternative combinations of B-Raf and MEK inhibitors with checkpoint inhibitors. Ribas et al. performed a phase I study combining dabrafenib, trametinib, and an anti-PD-L1 monoclonal antibody MEDI4736. Six patients with B-Raf-mutated advanced melanoma were treated with either MED14736 (3 or 10 mg/kg IV every 2 weeks), dabrafenib (150 mg twice daily) and trametinib (2 mg daily), or trametinib alone. Thrombocytopenia was the main dose limiting toxicity identified. About 100% of patients had a response to combination therapy [70]. Another phase I trial combining atezolizumab, an anti-PD-L1 antibody (800 mg every 2 weeks), cobimetinib (60 mg daily) and vemurafenib (960 mg twice a day for the first 21 days, then 720 mg daily) in 34 patients with B-Raf-mutated advanced melanoma found that this combination resulted in a manageable and reversible safety profile. Partial or complete responses were detected in 85.3% of patients [71, 72]. Combination therapy in a phase 1/2 trial with pembrolizumab (2 mg/kg every 3 weeks), dabrafenib (150 mg twice daily) and trametinib (2 mg daily) in 15 patients with advanced B-Raf mutant melanoma found manageable and reversible dose limiting toxicities and adverse events. About 60% of patients had a complete or partial response [73]. Finally, a phase I trial of pembrolizumab (2 mg/kg every 3 weeks), dabrafenib (150 mg twice a day), and trametinib (2 mg daily) was compared with dabrafenib/trametinib treatment in 60 patients with B-Raf-mutated metastatic melanoma found a median PFS in the triple therapy group of 16 months (95% CI 8.6–21.5) versus 10.3 months in the dual therapy group (95% CI 7–15.6, HR 0.66, p-0.04287). Rates of response were also more durable, 60% of patients on triple therapy had responses that lasted over 18 months compared to 26% dual therapy [74]. Many other clinical trials are ongoing evaluating the clinical benefit of treatment with combinations of B-Raf inhibitors and immunotherapy (NCT02130466, NCT02967692, NCT02908672, NCT02858921, NCT02224781, NCT01656642, NCT01673854, NCT01940809, NCT02631447, NCT03235245, and NCT02902042). Some tissue and mouse studies indicate that MEK inhibition impairs T cell proliferation and localization to the tumor tissue, suggesting combination therapies with MEK inhibitors and immunotherapy may not be synergistic. However, these findings have not been recapitulated

Additionally, immunotherapy monotherapy trials have shown that treatment with nivolumab and pembrolizumab in B-Raf mutant and B-Raf inhibitor refractory disease is associated with promising results [9, 38]. A small study of 19 pts showed an improved overall survival with a transition of therapy from vemurafenib

In addition to combination therapies, clinicians and scientists have been evaluating alternative methods to avoid or overcome resistance mechanisms after B-Raf therapy. These include using Bcl inhibitors to prevent cell escape through the YAP pathway, autophagy inhibitors that act through Bcl-2m Bcl-XL and Bcl-w, mTor inhibitors, ERK inhibitors, additional MAPK inhibitors, or Jak inhibitors to bypass

Compared to other currently approved therapies for advanced melanoma, B-Raf inhibitors are associated with a rapid onset of tumor regression, often within 1–2 weeks of treatment [9]. The speed of response is particularly beneficial in patients with a rapidly progressive or high burden of disease, as well as those with a poor performance status. The ECOG 6134 trial (NCT02224781) is accruing in an

**14**

attempt to answer whether initial treatment with checkpoint inhibitors or targeted therapy is more beneficial. This is a crucial study for which an answer will provide vital evidence for the sequencing of immunotherapy and B-Raf targeted therapy.

The introduction of B-Raf inhibitors has been an important component in the revolution of melanoma treatment that has occurred in the last decade. Vemurafenib, dabrafenib, and encorafenib in combination with MEK inhibitors such as cobimetinib, trametinib, and binimetinib, have resulted in unprecedented overall responses and increases in survival. Combination therapy has also improved patient outcomes and decreased the likelihood of significant side effects such as new cutaneous malignancies. Testing for B-Raf mutations and treatment with B-Raf inhibitors is now standard of care in oncology clinics throughout the world. However, there is still significant ongoing work in management of tumor resistance mechanisms and combination and/or sequential regimens are being studied with immuno-oncologic agents, as an example, to try to further boost the efficacy, while maintaining an acceptable safety and tolerability profile.
