American Society of Clinical Oncology Policy Statement on Skin Cancer Prevention

SUMMARY: Skin Cancer is the most common cancer diagnosed in the US and around the world. Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC) are the two most common types of skin cancers. It is estimated that 5.4 million cases of BCC and SCC are diagnosed each year in the US (occurring in about 3.3 million Americans, as some individuals have more than one type of skin cancer), and 8 of 10 are BCCs, whereas SCCs occur less often. Although the overall mortality rate from these cancers are low, SCCs are almost exclusively responsible for approximately 3,000 deaths per year in the US, with the greatest mortality risk among transplant recipients, who are immunocompromised. Malignant Melanoma of the skin occurs less frequently than BCC and SCC, and the American Cancer Society estimates that in the US for 2020, about 100,350 new melanomas will be diagnosed and about 6,850 people are expected to die of the disease. The rates of skin cancer have been rising rapidly over the past several years, with the economic cost estimates of $8.1 billion annually in the US.

Exposure to UltraViolet (UV) rays is a major risk factor for most skin cancers. Sunlight is the main source of UV rays. UV rays-emitting indoor tanning devices such as tanning beds, sunlamps, and UV lamps, are another source of UV rays. The risk of UV rays associated skin cancers, particularly for SCC, is dose dependent, and increases with greater duration and intensity of exposure. This risk is increased with cumulative solar UV rays exposure over an individual’s lifetime. For a given level of UV rays exposure, skin cancer risk is highest among UV ray sensitive phenotypes who typically are fair skinned, and have a propensity to sunburn, blister and/or freckle, upon exposure to UV rays. National surveys on sun exposure in the US illustrate the high rates of sunburn among adults (35%) and high school students (57%), emphasizing the importance of primary and secondary prevention strategies in the younger population. The ASCO’s 2019 National Cancer Opinion Survey found that only 49% of respondents reported using sunscreen to prevent skin cancer. Skin cancer is less common in individuals with darker skin colors (Black and Latino individuals), due to greater levels of melanin in the skin, which inherently has photoprotective ability. Nonetheless, when skin cancers do occur in individuals with darker skin tones, they tend to be more aggressive, possibly due to delayed diagnosis, as these individuals may be less aware of their skin cancer risks.

Given that skin cancer has such a major impact on society, the American Society of Clinical Oncology (ASCO) earlier this year published a policy statement aimed at lessening the burden of skin cancer through reducing exposure to UV radiation for youth and adults. This policy statement included a review of the risk factors for skin cancer, disparities in incidence, diagnosis and survival among different populations, and public health strategies for Primary and Secondary skin cancer prevention.

ASCO presented recommendations across the following four themes:

Reduce Exposure to Indoor Tanning

1) A major opportunity to prevent skin cancer is by reducing UV ray exposure through avoidance of indoor tanning.
2) Avoidance of indoor tanning holds particular promise in influencing adolescents and sexual minority men because of their higher rate of exposure to tanning.
3) The International Agency for Research on Cancer concluded that UV ray-emitting indoor tanning devices were carcinogens and there is now high-quality scientific evidence documenting strong and consistent associations between indoor tanning devices and skin cancer risk.
4) Indoor tanning is higher among non-Hispanic white females compared with all other population subgroups, and its direct association with melanoma risk likely explains the higher melanoma incidence in this group compared with male adolescents and young adults.
5) There is evidence suggesting the presence of “tanning dependence”, similar to substance use dependence, among individuals who engage in indoor tanning.
6) Recognizing that indoor tanning devices are a threat to public health, several cancer care and public health organizations support strong restrictions designed to prevent the use of UV ray-emitting tanning devices. ASCO supports strengthened laws and regulations restricting such products

Increase Public Efforts to Promote Sun Protection
1) Local, state, and federal laws should support policies that allow students to carry and use sunscreen products without physician authorization.
2) Enhance the protection of young people by encouraging the increased use of broad-spectrum sunscreen and protective clothing, through educational programs.
3) Improvement in sunscreen products and public education to prevent intentional sun exposure, for promoting Vitamin D synthesis.
4) Private and public institutions should be encouraged in their efforts to create more shaded areas in places used for outdoor recreation.
5) Development of new educational efforts, to change the social perceptions of tanned skin.

Community Education and Outreach
1) Investing in prevention research, and continued support for the National Cancer Institute’s Division of Cancer Prevention and the Centers for Disease Control and Prevention’s National Skin Cancer Prevention Education Program, to address the burden of this disease among persons of color, lower socioeconomic status populations, and sexual minorities.
2) ASCO and the cancer care community should work together to develop effective methods for outreach and health communication, to the diverse segments of the population at risk of skin cancer.

Role of Oncology Providers
1) Research has shown that cancer survivors do not adhere to skin-protective behaviors, anymore than the lay public who have not been diagnosed with cancer.
2) Oncologists should discuss with their patients the regular use of properly applied broad-spectrum sunscreen and the use of sun-protective clothing such as hats, long sleeves, and long pants when outdoors, as well as avoidance of UV rays either from sunlight, or from UV ray-emitting indoor tanning devices.
3) Oncology providers should be vocal supporters of skin cancer prevention policies and should educate patients of color, so that they understand that they are also at risk of skin cancer.

American Society of Clinical Oncology Policy Statement on Skin Cancer Prevention. Alberg AJ, LoConte NK, Foxhall L, et al. JCO Oncology Practice. 2020;16:490-499.

Five Year Analysis of Adjuvant TAFINLAR® plus MEKINIST® in Stage III Melanoma

SUMMARY: It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death, than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas and result in constitutive activation of the MAPK pathway.

TAFINLAR® (Dabrafenib) is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. In patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, a combination of TAFINLAR® and MEKINIST® resulted in a median Overall Survival (OS) of more than 2 years, with approximately 20% of the patients remaining progression free at 3 years. These encouraging results led to the study of this combination in patients with Stage III melanoma, with BRAF V600E or V600K mutations, after complete surgical resection.

COMBI-AD, an international, multi-center, randomized, double-blind, placebo-controlled, Phase III trial, in which 870 patients with completely resected, Stage III melanoma and with BRAF V600E or V600K mutations were enrolled. Patients were randomly assigned in a 1:1 to receive TAFINLAR® 150 mg orally twice daily in combination with MEKINIST® 2 mg orally once daily (N=438) or two matched placebos (N=432). Treatment was given for 12 months. Eligible patients had undergone completion lymphadenectomy, with no clinical or radiographic evidence of residual regional node disease. None of the patients had received previous systemic anticancer treatment or radiotherapy for melanoma. BRAF V600 mutation status was confirmed in primary tumor tissue or lymph node tissue by a central reference laboratory. The median age was 50 years. Both treatment groups were well balanced and 18% had Stage IIIA disease, 41% had Stage IIIB disease, and 40% had Stage IIIC disease. Of the enrolled patients, 91% had a BRAF V600E mutation, and 9% had a BRAF V600K mutation. The Primary end point was Relapse Free Survival (RFS) and Secondary end points included Overall Survival (OS), Distant metastasis-free survival, Freedom from relapse, and Safety.

The authors had previously reported that at a median follow up of 2.8 years, the estimated 3-year RFS rate was 58% in the combination therapy group and 39% in the placebo group (HR=0.47; P<0.001), and this represented a 53% lower risk of relapse. At the time of this analysis, median RFS rate had not been reached in the combination therapy group, and was 16.6 months in the placebo group. The improved RFS benefit with the combination therapy was consistent across patient subgroups, regardless of lymph node involvement or primary tumor ulceration. The risk of distant metastases or death was reduced by 49% with the combination therapy versus placebo (HR=0.51; P<0.001).

The authors in this publication reported the results for RFS and Distant metastasis-free survival at 5 years. Overall survival was not analyzed as the data was not mature. The minimum duration of follow up was 59 months. The RFS at 5 years 52% with TAFINLAR® plus MEKINIST® and 36% with placebo (HR for relapse or death=0.51). The Distant metastasis-free survival at 5 years was 65% with TAFINLAR® plus MEKINIST® and 54% with placebo (HR for distant metastasis or death=0.55). As has been reported in previous studies, majority of relapses occurred, within the first 3 years after surgery. There were no clinically meaningful differences noted in the incidence or severity of serious Adverse Events during the follow up period.

It was concluded that in this 5-year analysis of extended follow up from the COMBI-AD trial, 12 months of adjuvant therapy with a combination of TAFINLAR® and MEKINIST® resulted in longer Relapse Free and Distant metastasis-free Survival, compared to placebo, in patients with resected Stage III melanoma with BRAF V600 mutations.

Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. Dummer R, Hauschild A, Santinami M, et al. N Engl J Med 2020; 383:1139-1148

Association Between Immune Related Adverse Events and Recurrence Free Survival in Stage III Melanoma

SUMMARY: It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death, than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types.

Immune-related Adverse Events (irAEs) are commonly observed following treatment with ICIs. An association between irAEs and improved outcomes has been reported, among patients with malignant melanoma and lung cancer, treated with ICIs such as anti-CTLA-4 and anti-PD-1 antibodies. It however remains unclear whether immune-related Adverse Events (irAEs) indicate drug activity in patients treated with ICIs.

The European Organization for Research and Treatment of Cancer (EORTC) 1325/(KEYNOTE-054) trial is a randomized, double-blind, placebo-controlled Phase III study which enrolled 1019 patients with completely resected, Stage IIIA, IIIB or IIIC Melanoma. Patients were randomly assigned 1:1 to receive KEYTRUDA® 200 mg IV every three weeks (N=514) or placebo (N=505) as adjuvant therapy, for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxicity. KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1 monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response, and unleashing the tumor-specific effector T cells.

This study met the Primary end point of Recurrence-Free Survival (RFS), in this high-risk Stage III melanoma patients. KEYTRUDA® was associated with significantly longer Recurrence-Free Survival (RFS) compared to placebo in the overall intent-to-treat population, with a 1-year RFS rate of 75.4% versus 61.0% respectively (HR for recurrence or death=0.57; P<0.001). This suggested that the risk of recurrence or death in the total population was 43% lower in the KEYTRUDA® group than in the placebo group.

The authors in this publication investigated the association between immune-related Adverse Events (irAEs) and Recurrence-Free Survival (RFS) in the KEYNOTE-054 clinical trial, adjusting for age, sex and stage of the disease and also investigated the influence of systemic steroid use on outcome. Of 1011 patients who received treatment with KEYTRUDA® therapy or placebo, 61.5% were men and 38.5% were women. About 25% were 65 years and older and 37% of patients were younger than 50 years. The onset of the first irAE occurred within the first 6 months of treatment for majority of the patients who experienced an irAE and the common irAEs included endocrine disorders such as hypothyroidism or hyperthyroidism, and vitiligo. The incidence of irAEs was 37.4% in the KEYTRUDA® group and 9% in the placebo group, and in each treatment group, the incidence of irAEs was similar for men and women, for younger and older patients, and across different disease stages.

Consistent with previously published results in the intent-to-treat population, a prolonged RFS was observed in the KEYTRUDA® group compared with the placebo group, among patients who started the treatment allocated at the time of randomization (HR=0.56). The occurrence of an irAE was associated with a longer RFS in the KEYTRUDA® group (HR=0.61; P=0.03), but not in the placebo group (HR=1.37; P=0.21). Compared with the placebo arm, the reduction in the hazard of recurrence or death was substantially higher (P=0.03) after the onset of an irAE (HR=0.37), than without or before the onset of an irAE (HR=0.62), in patients who started KEYTRUDA® treatment. Similar results were obtained in each sex group and when only endocrine AEs were considered. Steroid are known to be immune-suppressive and treatment with KEYTRUDA® was less effective when steroids were used after the onset of an irAE.

It was concluded from this secondary analysis that the occurrence of an irAE was associated with a longer Relapse-Free Survival, among patients treated with KEYTRUDA®.

Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo. A Secondary Analysis of a Randomized Clinical Trial. Eggermont AM, Kicinski M, Blank CU, et al. JAMA Oncol. 2020;6:519-527.

FDA Approves IO in Combination with Targeted Therapies for BRAF Positive Advanced Melanoma

SUMMARY: The FDA on July 30, 2020, approved TECENTRIQ® (Atezolizumab), in combination with COTELLIC® (Cobimetinib) and ZELBORAF® (Vemurafenib), for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. Patients with locally advanced or metastatic melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and result in constitutive activation of the MAPK pathway.

ZELBORAF® (Vemurafenib), a selective oral inhibitor of mutated BRAF, demonstrated significant improvement in Progression Free Survival (PFS) and Overall Survival (OS), compared to Dacarbazine. Squamous cell carcinomas were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. MEK gene is downstream from RAF in the MAPK pathway. The addition of a selective inhibitor of MEK gene such as COTELLIC® (Cobimetinib) to a BRAF inhibitor such as ZELBORAF® has addressed some of these limitations, in previously published studies, with improvement in Objective Response Rates (ORR) and decrease in the incidence of cutaneous secondary cancers. coBRIM is a multicenter, randomized, Phase III study in which the efficacy and safety of COTELLIC® combined with ZELBORAF®, was evaluated in previously untreated patients, with advanced BRAF-mutated melanoma. The final analysis of this trial evaluated the 5-year survival data, and the OS was over 30% in patients who received the combination therapy, with a Complete Response (CR) rate was about 20%.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells. The 5 year OS among patients receiving PD1 targeted immunotherapy is about 34%, with a median OS of 17-20 months. With the approval of multiple therapeutic options for the management of patients with BRAF-mutant melanoma, treatment decisions have become increasingly complex. In patients with limited disease burden, immunotherapy with checkpoint inhibitors is favored by most clinicians, based on the long term data supporting the durability of responses with immunotherapies, but response rates are lower. On the contrary, BRAF-targeted agents are utilized in patients with extensive, symptomatic disease and active brain metastases, as the response rates are higher but are short lived. The optimal sequence of these therapeutic strategies in order to improve long-term patient outcome, has remained unclear.

Preclinical studies suggested that combining these two targeted therapies with a checkpoint inhibitor might overcome the limitations of each class and potentially lead to more durable responses. The safety and efficacy of combining TECENTRIQ® with COTELLIC® (MEK inhibitor) and ZELBORAF® (BRAF inhibitor), in patients with BRAFV600-mutated metastatic melanoma, was evaluated in a Phase I study, with promising results, and a 28-day run-in period with COTELLIC® and ZELBORAF® was associated with an increase in proliferating CD4+ T-helper cells, without increasing the T-regulatory cells (Tregs). Tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response and Tregs remain a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. The aim of IMspire 150 trial was to determine if combining checkpoint inhibitor with two targeted therapies would improve efficacy.

IMspire150 is a pivotal, placebo-controlled, international, multicenter, double-blinded, Phase III trial, in which 514 treatment-naive patients with Stage IIIc and Stage IV, BRAF V600–mutant malignant melanoma were enrolled. Patients were randomly assigned 1:1 to treatment with the doublet combination or the triplet therapy. Doublet therapy given to the control group of patients consisted of ZELBORAF® 960 mg orally twice daily plus COTELLIC® at 60 mg orally, on days 1 to 21 of a 28 day cycle. In the experimental or triplet therapy group, there was a 28-day run-in with ZELBORAF® plus COTELLIC® alone, dosed similar to the control group (cycle 1), following which patients received TECENTRIQ® 840 mg IV on Days 1 and 15 of each 28 day cycle starting cycle 2, in combination with ZELBORAF® at a lower dose of 720 mg orally twice daily and COTELLIC® 60 mg orally once daily. Treatment was continued until disease progression, or unacceptable toxicity. Both treatment groups were well balanced, median patient age was 54 years, 58% were male and 94% of patients had Stage IV disease. The Primary endpoint was investigator-assessed Progression Free Survival (PFS). Secondary end points included Objective Response Rates (ORR), Duration of Response (DOR), and Overall Survival (OS).

The combination of immunotherapy with targeted therapies was significantly superior to targeted therapies alone. At a median follow up of 18.9 months, the median PFS with the triplet combination was 15.1 months versus 10.6 months with the doublet therapy (HR=0.78; P=0.025). This represented a 22% reduction in the risk of disease progression. This benefit was observed across all subgroups including age, disease burden, LDH level, and extent of tumor involvement by organ site. Although Objective Response Rates were similar in both treatment groups, the median Duration of Response was 21.0 months with triplet combination versus 12.6 months for the doublet therapy. The OS data were not mature at the time of this analysis, but interim analysis however showed a median OS of 28.8 months with the triplet combination versus 25.1 months with doublet therapy. Both treatment groups had comparable toxicities. Among those patients receiving triplet combination, the most common toxicities were rash, fever, fatigue, nausea, pruritus, stomatitis, musculoskeletal pain, hepatotoxicity, edema, hypothyroidism, and photosensitivity.

It was concluded that in treatment-naive patients with advanced BRAF V600-mutant malignant melanoma, TECENTRIQ® in combination with ZELBORAF® and COTELLIC® significantly and clinically improved Progression Free Survival, when compared to placebo in combination with ZELBORAF® and COTELLIC®.

Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial. McArthur GA, Stroyakovskiy D, Gogas H, et al. Presented at: the 2020 AACR Annual Virtual Meeting I; April 27-28, 2020. Abstract CT012.

Adjuvant Therapy with Low Dose YERVOY® Improves Overall Survival in Resected High Risk Melanoma 

SUMMARY: It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death, than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.
Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system, prevent uncontrolled immune reactions and suppress antitumor immunity. Antibodies that target these membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), PD-1 (Programmed cell Death-1) and PD-L1 (Programmed cell Death-Ligand1) block the Immune checkpoint proteins and ligands, unleash T cells, resulting in T cell proliferation, activation and a therapeutic response. Several agents are presently approved by the FDA for the adjuvant treatment of high-risk Melanoma and they include YERVOY® (Ipilimumab), OPDIVO® (Nivolumab), KEYTRUDA® (Pembrolizumab), high-dose Interferon alfa-2b, as well as TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) combination for BRAF-mutant Melanoma.Unleashing-T-Cell-Function-with-YERVOY-(Ipilimumab)
YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4. Overall Survival however has only been established for adjuvant high-dose Interferon alfa-2b or high dose YERVOY® given at 10 mg/kg. However, the use of YERVOY® at 10mg/kg as adjuvant therapy in clinical practice has been limited by the high incidence of severe toxicities. YERVOY® at 3 mg/kg was approved in 2011 for unresectable metastatic melanoma. To further address the relative efficacy and safety of YERVOY® at the 2 dose levels, the authors in the present study compared high-dose Interferon (HDI), a standard adjuvant treatment for high-risk melanoma available since 1996, with YERVOY® given at 3 mg/kg (Ipi3) and YERVOY® given at a dose of 10 mg/kg (Ipi10). Adjuvant high dose Interferon has been shown to improve Relapse Free Survival (RFS) and Overall Survival (OS) in ECOG and several intergroup trials. 
Intergroup trial E1609 is an open-label, multicenter, multinational, 3-arm, Phase III study in which 1,670 adult patients were randomly assigned 1:1:1 to receive Ipi3 (N = 523), HDI (N = 636), or Ipi10 (N = 511). Eligible patients had completely resected Stage IIIB, IIIC, or IV (M1a or M1b) cutaneous malignant melanoma, and patients with Stage IIIB or IIIC disease were required to have complete lymph node dissection. Both Ipi3 or Ipi10 were administered IV every 3 weeks for 4 doses (induction), followed by the same dose every 12 weeks for up to 4 additional doses (maintenance). HDI was administered IV at 20 million units/m2 daily, 5 days a week, for 4 weeks (induction), followed by 10 million units/m2 subcutaneously every other day, 3 days per week, for 48 weeks (maintenance). Treatment was continued for a maximum of 60 weeks with YERVOY® or 52 weeks with HDI, or until unacceptable toxicities or disease progression. The two Coprimary end points were Overall Survival (OS) and Relapse Free Survival (RFS) of patients in the Ipi3 or Ipi10 group, each compared with outcomes of those patients in the HDI group. Secondary end points were Safety and tolerability of adjuvant YERVOY® and Quality of Life assessments.
Patients in the Ipi3 (YERVOY® 3 mg/kg) group had superior Overall Survival compared with patients in the HDI (high dose Interferon) group (HR=0.78; P=0.044). The 5 year Overall Survival rate was 72% with ipi3 and 67% with HDI. For RFS, the HR was 0.85 (P=0.065), with a median RFS of 4.5 years for Ipi3 and 2.5 years for HDI, and these study outcomes were positive and favored Ipi3, based on the protocol criteria.
When Ipi10 (YERVOY® 10 mg/kg) was compared with HDI, there were trends toward improvement in OS and RFS in favor of Ipi10, but these findings were not statistically significant. More patients in the HDI group required salvage therapy with YERVOY® or YERVOY®/PD-1 combination, compared to the Ipi3 and Ipi10 groups (P<0.001).
It was concluded that adjuvant therapy with YERVOY®, given at a dose of 3 mg/kg, was significantly less toxic and demonstrated a significant improvement in OS against an active control regimen (high dose Interferon), among patients with high-risk resected melanoma. The authors added that the current approved adjuvant YERVOY® dose of 10 mg/kg was more toxic and not superior in efficacy to high dose Interferon. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. Tarhini AA, Lee SJ, Hodi FS, et al. DOI: 10.1200/JCO.19.01381 Journal of Clinical Oncology 38, no. 6 (February 20, 2020) 567-575.

Biomarkers May Predict Response to BRAF and MEK inhibitors in Malignant Melanoma

Biomarkers May Predict Response to BRAF and MEK inhibitors in Malignant Melanoma 
SUMMARY: It is estimated that in the US, approximately 100,350 new cases of malignant melanoma will be diagnosed in 2020 and about 6850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. Patients with locally advanced or metastatic melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes. In treatment naïve patients receiving anti-PD-1 therapies such as KEYTRUDA® (Pembrolizumab) or OPDIVO® (Nivolumab) in Phase III trials, the Progression Free Survival (PFS) rates have ranged from 27-31%, with an Overall Survival (OS) rate of 46% at 4 years. The 5-year OS among patients receiving KEYTRUDA® was 43%, and in those treated with a combination of OPDIVO® plus YERVOY® (Ipilimumab), 4-year PFS and OS rates were 37% and 53%, respectively.BRAF-MEK-Inhibition-in-MAPK-Pathway
The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and result in constitutive activation of the MAPK pathway.
TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. Long term survival data pooled from two randomized Phase III COMBI-d and COMBI-v trials, which involved previously untreated, unresectable or metastatic melanoma patients, with BRAFV600E or V600K mutation who had received TAFINLAR® along with MEKINIST® showed PFS rates of 21% at 4 years and 19% at 5 years. The OS rates were 37% at 4 years and 34% at 5 years. The 5-year OS rate was 71% among patients who had a Complete Response and 55% among those who had a normal LDH level plus fewer than three metastatic organ sites at baseline.
With the approval of multiple therapeutic options for the management of patients with BRAF-mutant melanoma, treatment decisions have become increasingly complex. In patients with limited disease burden, immunotherapy with checkpoint inhibitors is favored by most clinicians based on the long term data supporting the durability of responses with immunotherapies. On the contrary, BRAF-targeted agents are utilized in patients with extensive, symptomatic disease and active brain metastases. The optimal sequence of these therapeutic strategies in order to improve long-term patient outcome, has remained unclear. 
COMBI-AD is an international, multi-center, randomized, double-blind, placebo-controlled, Phase III trial, in which 870 patients with completely resected, Stage III melanoma and with BRAF V600E or V600K mutations were enrolled. Patients were randomly assigned in a 1:1 to receive TAFINLAR® 150 mg orally twice daily in combination with MEKINIST® 2 mg orally once daily (N=438) or two matched placebos (N=432). Treatment was given for 12 months. At a median follow up of 2.8 years, the estimated 3-year Relapse Free Survival (RFS) rate was 58% with a combination of TAFINLAR® and MEKINIST® and 39% in the placebo group (HR=0.47; P<0.001), and this represented a 53% lower risk of relapse. The risk of distant metastases or death was reduced by 49% with the combination therapy versus placebo (HR=0.51; P<0.001). A prespecified exploratory outcome of this trial was assessment of biomarkers. The authors assessed intrinsic tumor genomic features in 368 patients using Next-Generation DNA sequencing, and tumor microenvironment characteristics were assessed in 507 patients by use of a NanoString RNA assay, in an attempt to provide prognostic and predictive information. Median follow up at data cutoff was 44 months in the TAFINLAR® plus MEKINIST® group and 42 months in the placebo group.
Baseline MAPK pathway genomic alterations did not affect treatment benefit or outcomes in either treatment groups. An Interferon Gamma gene expression signature higher than the median was prognostic for prolonged RFS in both treatment groups. Tumor Mutational Burden (TMB) was independently associated with better RFS in the placebo group (HR for top third versus bottom third of TMB values=0.56; P=0.0056), but this benefit was not seen in the TAFINLAR® plus MEKINIST® group (HR= 0.83; P=0.44). However, patients with TMB in the lower two terciles who received TAFINLAR® plus MEKINIST® combination had improved RFS compared to those who received placebo (HR=0.49: P<0.0001). Patients with high TMB appeared to have a less pronounced benefit with TAFINLAR® plus MEKINIST® targeted therapy, compared to placebo, especially if they had an Interferon Gamma gene expression signature lower than the median. 
It was concluded from this biomarker analysis that high Tumor Mutational Burden was independently associated with better Relapse Free Survival in the placebo group but not in the TAFINLAR® plus MEKINIST® combination group, and an Interferon Gamma gene expression signature higher than the median was prognostic for prolonged RFS in both treatment groups. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Dummer R, Brase JC, Garrett J, et al. The Lancet Oncology. Published:January 30, 2020DOI:https://doi.org/10.1016/S1470-2045(20)30062-0

Five-Year Outcomes with TAFINLAR® plus MEKINIST® in Metastatic Melanoma

SUMMARY: It is estimated that in the US, approximately 96,480 new cases of Melanoma will be diagnosed in 2019 and about 7,230 patients are expected to die of the disease. The incidence of Melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage Melanoma, with a 5-year survival rate of 98% for stage I disease and 90% for stage II disease. Patients with locally advanced or metastatic Melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes. In treatment naïve patients receiving anti-PD-1 therapies such as KEYTRUDA® (Pembrolizumab) or OPDIVO® (Nivolumab) in phase 3 trials, the Progression Free Survival (PFS) rates have ranged from 27-31%, with an Overall Survival (OS) rate of 46% at 4 years. The 5-year OS among patients receiving KEYTRUDA® was 43%, and in those treated with a combination of OPDIVO® plus YERVOY® (Ipilimumab), 4-year PFS and OS rates were 37% and 53%, respectively.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in Melanoma is at the V600E/K site and is detected in approximately 50% of Melanomas, and result in constitutive activation of the MAPK pathway.

TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. It has been well established that patients who have unresectable or metastatic Melanoma with a BRAFV600E or V600K mutation have prolonged PFS and OS when treated with a combination of BRAF and MEK inhibitors. However, long-term 4 and 5-year clinical outcomes in these patient’s have not been reported.

Two randomized Phase III trials helped address this issue. COMBI-d involved 423 patients randomized to TAFINLAR® plus MEKINIST® (N=211) or to TAFINLAR® plus placebo (N=212). In COMBO-v, 704 patients were randomized to TAFINLAR® plus MEKINIST® (N=352) or to single-agent ZELBORAF® (Vemurafenib; N=352). In a previously published pooled analysis of patients treated in the COMBI-d and COMBI-v trials, 3-year PFS and OS were 23% and 44% respectively. Further, there was a significant association between several baseline factors such as performance status, age, sex, number of organ sites with metastasis, serum LDH level and both PFS as well as OS.

In this review, the researchers analyzed pooled long term survival data from two randomized Phase III COMBI-d and COMBI-v trials, which involved previously untreated, unresectable or metastatic Melanoma patients, with BRAFV600E or V600K mutation, who had received BRAF inhibitor TAFINLAR® 150 mg orally twice daily along with a MEK inhibitor MEKINIST® 2 mg orally once daily. These two trials evaluated the efficacy and safety of TAFINLAR® plus MEKINIST®, as compared with BRAF inhibitor monotherapy. The long term, 5-year survival data from these two trials was reported, along with clinical characteristics of the patients who derived long-term benefit from this treatment. The Primary end points in the COMBI-d and COMBI-v trials were PFS and OS, respectively. The median patient age in these trials was 55 years, 3% of patients had nonmetastatic disease and two-thirds had M1c metastatic disease.

A total of 563 patients (211 in the COMBI-d trial and 352 in the COMBI-v trial) were randomly assigned to receive TAFINLAR® plus MEKINIST®. The PFS rates were 21% at 4 years and 19% at 5 years. The OS rates were 37% at 4 years and 34% at 5 years. The 5-year OS rate was 71% among patients who had a Complete Response and 55% among those who had a normal Lactate Dehydrogenase level plus fewer than three metastatic organ sites at baseline.

It was concluded that first-line treatment with TAFINLAR® plus MEKINIST® led to long-term benefit in approximately one third of the patients who had unresectable or metastatic Melanoma with a BRAF V600E or V600K mutation. The authors added that this is the largest data set and longest follow-up in this patient population treated with BRAF and MEK inhibitors. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. Robert C, Grob JJ, Stroyakovskiy D, et al. June 4, 2019. DOI: 10.1056/NEJMoa1904059

FDA Approves KEYTRUDA® for Adjuvant Treatment of Melanoma

SUMMARY: The FDA on February 15, 2019, approved KEYTRUDA® (Pembrolizumab) for the adjuvant treatment of patients with Melanoma with involvement of lymph node(s) following complete resection. It is estimated that in the US, approximately 96,480 new cases of Melanoma will be diagnosed in 2019 and about 7,230 patients are expected to die of the disease. The incidence of Melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage Melanoma, with a 5-year survival rate of 98% for stage I disease and 90% for stage II disease. Stage III malignant Melanoma however is a heterogeneous disease, and the risk of recurrence is dependent on the number of positive nodes, as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78% whereas those patients with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively. Several agents are presently approved by the FDA for the adjuvant treatment of high-risk Melanoma and they include YERVOY® (Ipilimumab), OPDIVO® (Nivolumab), TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) for BRAF-mutant Melanoma and Interferon alfa. Unleashing-T-Cell-Function-with-Combination-Immunotherapy

KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

The present FDA approval was based on the European Organization for Research and Treatment of Cancer (EORTC) 1325/(KEYNOTE-054) trial which is a randomized, double-blind, placebo-controlled Phase III study which involved high-risk patient population of patients with Stage III Melanoma. This study included 1019 patients with completely resected, Stage IIIA (more than 1 mm lymph node metastasis), IIIB or IIIC Melanoma. Patients were randomly assigned 1:1 to receive KEYTRUDA® 200 mg IV every three weeks (N=514) or placebo (N=505), as adjuvant therapy, for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxicity. Enrolled patients required complete resection of Melanoma with negative margins and lymph node dissection. Patients with mucosal or ocular Melanoma were excluded. The Primary end points were Recurrence-Free Survival (RFS) in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-L1, as well as Safety.

At a median follow up of 15 months, KEYTRUDA® was associated with significantly longer Recurrence-Free Survival (RFS) compared to placebo in the overall intent-to-treat population, with a 1-year RFS rate of 75.4% versus 61.0% respectively (HR for recurrence or death=0.57; P<0.001). This suggested that the risk of recurrence or death in the total population was 43% lower in the KEYTRUDA® group than in the placebo group. Patients receiving KEYTRUDA® experienced fewer recurrences/deaths, 26% compared with 43% in the placebo group. The RFS benefit with KEYTRUDA® compared with placebo was observed regardless of tumor PD-L1 expression. In the subgroup of 853 patients with PD-L1-positive tumors, the 1-year RFS rate was 77.1% in the KEYTRUDA® group and 62.6% in the placebo group (HR=0.54; P<0.001). This suggested that the risk was 46% lower in the KEYTRUDA® group than in the placebo group, among patients with PD-L1-positive tumors. KEYTRUDA® was also consistently effective in patients with PD-L1-negative tumors and in those with undetermined tumor PD-L1 expression The Median RFS was 20.4 months in the placebo arm and not reached for those receiving KEYTRUDA®. The most common adverse reactions were rash, asthenia, influenza-like illness, diarrhea, pruritus, nausea, arthralgia and hypothyroidism.

It was concluded that KEYTRUDA® as adjuvant therapy for high-risk Stage III Melanoma, resulted in significantly longer Recurrence-Free Survival than placebo, with no new toxic effects identified. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. Eggermont AM, Blank CU, Mandala M, et al. N Engl J Med 2018;378:1789-1801