ZELBORAF

5 WARNINGS AND PRECAUTIONS New Primary Cutaneous Malignancies: Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and for up to 6 months following discontinuation of ZELBORAF. Manage with excision and continue treatment without dose adjustment. ( 5.1 ) New Non-Cutaneous Squamous Cell Carcinoma: Evaluate for symptoms or clinical signs of new non-cutaneous SCC before initiation of treatment and periodically during treatment. ( 5.1 ) Other Malignancies: Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies ( 5.1 ). Tumor Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors ( 5.2 ). Serious Hypersensitivity Reactions including anaphylaxis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome): Discontinue ZELBORAF for severe hypersensitivity reactions. ( 5.3 ) Severe Dermatologic Reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Discontinue ZELBORAF for severe dermatologic reactions. ( 5.4 ) QT Prolongation: Monitor ECG and electrolytes before and during treatment. Withhold ZELBORAF for QTc of 500 ms or greater. Correct electrolyte abnormalities and control for cardiac risk factors for QT prolongation. ( 5.5 ) Hepatotoxicity: Measure liver enzymes and bilirubin before initiating ZELBORAF and monitor monthly during treatment. ( 5.6 ) Photosensitivity: Advise patients to avoid sun exposure. ( 5.7 ) Serious Ophthalmologic Reactions: Monitor for signs and symptoms of uveitis. ( 5.8 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of the potential risk to the fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 ) Radiation Sensitization and Radiation Recall: Severe cases have been reported. ( 5.10 ). Renal Failure: Measure serum creatinine before initiating ZELBORAF and monitor periodically during treatment ( 5.11 ). Dupuytren's Contracture and plantar fascial fibromatosis: Events should be managed with dose reduction, treatment interruption, or treatment discontinuation. ( 5.12 ). 5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1) ] . The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In Trial 4, in patients with ECD, the incidence of cuSCC and/or keratoacanthomas was 40.9% (9/22). The median time to first appearance of cuSCC amongst patients with at least one occurrence was 12.1 weeks. In Trial 1, in patients with unresectable or metastatic melanoma, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (non-cuSCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1) ] . Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cuSCC. Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2) ] . Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Cases of myeloid neoplasms amongst patients with ECD have been observed, including in patients who have received ZELBORAF. Monitoring complete blood count in ECD patients with co-existing myeloid malignancies is recommended. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1) ] . 5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2) ] . 5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1) ]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.2) ] . QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3) ] . 5.6 Hepatotoxicity Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF [see Adverse Reactions (6.1) ] . Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3) ] . Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1) ] . In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3) ]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1) ] . Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2) ] . 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZELBORAF and for 2 weeks after the final dose [see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ] . 5.10 Radiation Sensitization and Radiation Recall Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs have been reported in patients treated with radiation prior to, during, or subsequent to vemurafenib treatment . Fatal cases have been reported in patients with visceral organ involvement. [see Adverse Reactions (6.2) ] . Monitor patients closely when vemurafenib is administered concomitantly or sequentially with radiation treatment. 5.11 Renal Failure Renal failure, including acute interstitial nephritis and acute tubular necrosis, can occur with ZELBORAF. In Trial 1, in patients with metastatic melanoma, 26% of ZELBORAF-treated patients and 5% of dacarbazine-treated patients experienced Grade 1-2 creatinine elevations [greater than 1 and up to 3 times upper limit of normal (ULN)]; 1.2% of ZELBORAF-treated patients and 1.1% of dacarbazine-treated patients experienced Grade 3-4 creatinine elevations (greater than 3 times ULN). In Trial 4, in patients with ECD, 86% (19/22) of patients experienced Grade 1/2 creatinine elevations and 9.1% (2/22) of patients experienced Grade 3 creatinine elevations. Measure serum creatinine before initiation of ZELBORAF and periodically during treatment. 5.12 Dupuytren's Contracture and Plantar Fascial Fibromatosis Dupuytren's contracture and plantar fascial fibromatosis have been reported with ZELBORAF. The majority of cases were mild to moderate, but severe, disabling cases of Dupuytren's contracture have also been reported [see Dosage and Administration (2.3) , Adverse Reactions (6.1 , 6.2) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: New Primary Malignancies [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Dermatologic Reactions [see Warnings and Precautions (5.4) ] QT Prolongation [see Warnings and Precautions (5.5) ] Hepatotoxicity [see Warnings and Precautions (5.6) ] Photosensitivity [see Warnings and Precautions (5.7) ] Ophthalmologic Reactions [see Warnings and Precautions (5.8) ] Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.10) ] Renal Failure [see Warnings and Precautions (5.11) ] Dupuytren's Contracture and Plantar Fascial Fibromatosis [see Warnings and Precautions (5.12) ] Melanoma: Most common adverse reactions (≥ 30%) are arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. ( 6.1 ) Erdheim-Chester Disease: Most common adverse reactions (>50%) are arthralgia, rash maculo-papular, alopecia, fatigue, electrocardiogram QT interval prolonged, and skin papilloma. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. Unresectable or Metastatic Melanoma with BRAF V600E Mutation This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14) ] . Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m 2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Table 1 presents adverse reactions reported in at least 10% of unresectable or metastatic melanoma patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2. Table 1 Adverse Reactions Reported in ≥ 10% of Unresectable or Metastatic Melanoma Patients Treated with ZELBORAF Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. ADRs Trial 1: Treatment-Naïve Patients Trial 2: Patients with Failure of at Least One Prior Systemic Therapy ZELBORAF n=336 Dacarbazine n=287 ZELBORAF n=132 All Grades (%) Grade 3 Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2). (%) All Grades (%) Grade 3 (%) All Grades (%) Grade 3 (%) Skin and subcutaneous tissue disorders Rash 37 8 2 0 52 7 Photosensitivity reaction 33 3 4 0 49 3 Alopecia 45 < 1 2 0 36 0 Pruritus 23 1 1 0 30 2 Hyperkeratosis 24 1 < 1 0 28 0 Rash maculo-papular 9 2 < 1 0 21 6 Actinic keratosis 8 0 3 0 17 0 Dry skin 19 0 1 0 16 0 Rash papular 5 < 1 0 0 13 0 Erythema 14 0 2 0 8 0 Musculoskeletal and connective tissue disorders Arthralgia 53 4 3 < 1 67 8 Myalgia 13 < 1 1 0 24 < 1 Pain in extremity 18 < 1 6 2 9 0 Musculoskeletal pain 8 0 4 < 1 11 0 Back pain 8 < 1 5 < 1 11 < 1 General disorders and administration site conditions Fatigue 38 2 33 2 54 4 Edema peripheral 17 < 1 5 0 23 0 Pyrexia 19 < 1 9 < 1 17 2 Asthenia 11 < 1 9 < 1 2 0 Gastrointestinal disorders Nausea 35 2 43 2 37 2 Diarrhea 28 < 1 13 < 1 29 < 1 Vomiting 18 1 26 1 26 2 Constipation 12 < 1 24 0 16 0 Nervous system disorders Headache 23 < 1 10 0 27 0 Dysgeusia 14 0 3 0 11 0 Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma 21 < 1 0 0 30 0 Cutaneous SCC Includes both squamous cell carcinoma of the skin and keratoacanthoma. Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. 24 22 < 1 < 1 24 24 Seborrheic keratosis 10 < 1 1 0 14 0 Investigations Gamma-glutamyltransferase increased 5 3 1 0 15 6 Metabolism and nutrition disorders Decreased appetite 18 0 8 < 1 21 0 Respiratory, thoracic and mediastinal disorders Cough 8 0 7 0 12 0 Injury, poisoning and procedural complications Sunburn 10 0 0 0 14 0 Clinically relevant adverse reactions reported in < 10% of unresectable or metastatic melanoma patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, panniculitis, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis, Dupuytren's contracture Nervous system disorders: neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change from Baseline to Grade 3/4 Liver Laboratory Abnormalities in Trial 1 For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. Parameter Change From Baseline to Grade 3/4 ZELBORAF (%) Dacarbazine (%) GGT 11.5 8.6 AST 0.9 0.4 ALT 2.8 1.9 Alkaline phosphatase 2.9 0.4 Bilirubin 1.9 0 Erdheim-Chester Disease (ECD) This section describes adverse reactions identified from analyses of Trial 4 [see Clinical Studies (14) ] . In Trial 4, 22 patients with BRAF V600 mutation-positive ECD received ZELBORAF 960 mg twice daily. The median treatment duration for ECD patients in this study was 14.2 months. Table 3 presents adverse reactions reported in at least 20% of BRAF V600 mutation-positive ECD patients treated with ZELBORAF. In Trial 4, the most commonly reported adverse reactions (> 50%) in patients with BRAF V600 mutation- positive ECD treated with ZELBORAF were arthralgia, rash maculo-papular, alopecia, fatigue, electrocardiogram QT interval prolonged, and skin papilloma. The most common (≥ 10%) Grade ≥ 3 adverse reactions were squamous cell carcinoma of the skin, hypertension, rash maculo-papular, and arthralgia. The incidence of adverse reactions resulting in permanent discontinuation of study medication was 32%. Table 3 Adverse Reactions Reported in ≥ 20% of ECD Patients Treated with ZELBORAF Adverse drug reactions, graded using NCI-CTCAE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. Trial 4: Patients with ECD n=22 Body System Adverse Reactions All Grades (%) Grade 3-4 (%) Skin and subcutaneous tissue disorders Rash maculo-papular 59 18 Alopecia 55 - Hyperkeratosis 50 5 Dry skin 45 - Photosensitivity reaction 41 - Palmar-plantar erythrodysaesthesia syndrome 41 - Pruritus 36 - Actinic keratosis 32 5 Keratosis pilaris 32 - Rash papular 23 - Musculoskeletal and connective tissue disorders Arthralgia 82 14 General disorders and administration site conditions Fatigue 55 5 Gastrointestinal disorders Diarrhea 50 - Nausea 32 - Vomiting 23 - Nervous system disorders Peripheral sensory neuropathy 36 - Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Skin papilloma 55 - Seborrhoeic keratosis 41 - SCC of skin Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. 36 36 Melanocytic nevus 23 _ Cardiac disorders Electrocardiogram QT interval prolonged 55 5 Respiratory, thoracic and mediastinal disorders Cough 36 - Vascular disorders Hypertension 36 23 Injury, poisoning and procedural complications Sunburn 23 - Clinically relevant adverse reactions reported in < 20% of ECD patients treated with ZELBORAF in Trial 4 include: Neoplasms benign, malignant and unspecified (includes cysts and polyps): keratoacanthoma Musculoskeletal and connective tissue disorders: Dupuytren's contracture Table 4 shows the incidence of worsening liver laboratory abnormalities in Trial 4 summarized as the proportion of ECD patients who experienced a shift from baseline to Grade 3 or 4. Table 4 Change from Baseline to Grade 3 Liver Laboratory Abnormalities in Trial 4 Change From Baseline to Grade 3 Parameter Vemurafenib (%) AST 0 ALT 9.1 Alkaline phosphatase 4.5 Bilirubin 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1) ] . Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3) ] . Blood and lymphatic systems disorder: Neutropenia Injury, poisoning and procedural complications: Radiation sensitization and recall [see Warnings and Precautions (5.10) ]. Gastrointestinal disorders: Pancreatitis Renal and urinary disorders: Acute interstitial nephritis, acute tubular necrosis [see Warnings and Precautions (5.11) ]. Musculoskeletal and connective tissue disorders: Dupuytren's contracture and plantar fascial fibromatosis [see Warnings and Precautions (5.12) ]. Immune system disorders: Sarcoidosis

<table width="90%" ID="t1"><caption>Table 1 Adverse Reactions Reported in &#x2265; 10% of Unresectable or Metastatic Melanoma Patients Treated with ZELBORAF<footnote>Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.</footnote></caption><col width="30%" align="left" valign="top"/><col width="10%" align="center" valign="top"/><col width="11%" align="center" valign="top"/><col width="10%" align="center" valign="top"/><col width="11%" align="center" valign="top"/><col width="14%" align="center" valign="top"/><col width="14%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" rowspan="3" align="center" valign="middle">ADRs</th><th styleCode="Botrule Rrule" colspan="4">Trial 1: Treatment-Na&#xEF;ve Patients</th><th styleCode="Botrule Rrule" colspan="2">Trial 2: Patients with Failure of at Least One Prior Systemic Therapy</th></tr><tr styleCode="Botrule"><th styleCode="Rrule" colspan="2" align="center">ZELBORAF n=336</th><th styleCode="Rrule" colspan="2">Dacarbazine n=287</th><th styleCode="Rrule" colspan="2">ZELBORAF n=132</th></tr><tr><th align="center">All Grades (%)</th><th styleCode="Rrule">Grade 3<footnote ID="t1f2">Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (&lt; 1% in Trial 1 and 4% in Trial 2).</footnote> (%)</th><th>All Grades (%)</th><th styleCode="Rrule">Grade 3 (%)</th><th>All Grades (%)</th><th styleCode="Rrule">Grade 3<footnoteRef IDREF="t1f2"/> (%)</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Rash</td><td>37</td><td styleCode="Rrule">8</td><td>2</td><td styleCode="Rrule">0</td><td>52</td><td styleCode="Rrule">7</td></tr><tr><td styleCode="Lrule Rrule">Photosensitivity reaction</td><td>33</td><td styleCode="Rrule">3</td><td>4</td><td styleCode="Rrule">0</td><td>49</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule Rrule">Alopecia</td><td>45</td><td styleCode="Rrule">&lt; 1</td><td>2</td><td styleCode="Rrule">0</td><td>36</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Pruritus</td><td>23</td><td styleCode="Rrule">1</td><td>1</td><td styleCode="Rrule">0</td><td>30</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule">Hyperkeratosis</td><td>24</td><td styleCode="Rrule">1</td><td>&lt; 1</td><td styleCode="Rrule">0</td><td>28</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Rash maculo-papular</td><td>9</td><td styleCode="Rrule">2</td><td>&lt; 1</td><td styleCode="Rrule">0</td><td>21</td><td styleCode="Rrule">6</td></tr><tr><td styleCode="Lrule Rrule">Actinic keratosis</td><td>8</td><td styleCode="Rrule">0</td><td>3</td><td styleCode="Rrule">0</td><td>17</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Dry skin</td><td>19</td><td styleCode="Rrule">0</td><td>1</td><td styleCode="Rrule">0</td><td>16</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Rash papular</td><td>5</td><td styleCode="Rrule">&lt; 1</td><td>0</td><td styleCode="Rrule">0</td><td>13</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Erythema</td><td>14</td><td styleCode="Rrule">0</td><td>2</td><td styleCode="Rrule">0</td><td>8</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Arthralgia</td><td>53</td><td styleCode="Rrule">4</td><td>3</td><td styleCode="Rrule">&lt; 1</td><td>67</td><td styleCode="Rrule">8</td></tr><tr><td styleCode="Lrule Rrule">Myalgia</td><td>13</td><td styleCode="Rrule">&lt; 1</td><td>1</td><td styleCode="Rrule">0</td><td>24</td><td styleCode="Rrule">&lt; 1</td></tr><tr><td styleCode="Lrule Rrule">Pain in extremity</td><td>18</td><td styleCode="Rrule">&lt; 1</td><td>6</td><td styleCode="Rrule">2</td><td>9</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Musculoskeletal pain</td><td>8</td><td styleCode="Rrule">0</td><td>4</td><td styleCode="Rrule">&lt; 1</td><td>11</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain</td><td>8</td><td styleCode="Rrule">&lt; 1</td><td>5</td><td styleCode="Rrule">&lt; 1</td><td>11</td><td styleCode="Rrule">&lt; 1</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Fatigue</td><td>38</td><td styleCode="Rrule">2</td><td>33</td><td styleCode="Rrule">2</td><td>54</td><td styleCode="Rrule">4</td></tr><tr><td styleCode="Lrule Rrule">Edema peripheral</td><td>17</td><td styleCode="Rrule">&lt; 1</td><td>5</td><td styleCode="Rrule">0</td><td>23</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Pyrexia</td><td>19</td><td styleCode="Rrule">&lt; 1</td><td>9</td><td styleCode="Rrule">&lt; 1</td><td>17</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia</td><td>11</td><td styleCode="Rrule">&lt; 1</td><td>9</td><td styleCode="Rrule">&lt; 1</td><td>2</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Nausea</td><td>35</td><td styleCode="Rrule">2</td><td>43</td><td styleCode="Rrule">2</td><td>37</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule">Diarrhea</td><td>28</td><td styleCode="Rrule">&lt; 1</td><td>13</td><td styleCode="Rrule">&lt; 1</td><td>29</td><td styleCode="Rrule">&lt; 1</td></tr><tr><td styleCode="Lrule Rrule">Vomiting</td><td>18</td><td styleCode="Rrule">1</td><td>26</td><td styleCode="Rrule">1</td><td>26</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td>12</td><td styleCode="Rrule">&lt; 1</td><td>24</td><td styleCode="Rrule">0</td><td>16</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Headache</td><td>23</td><td styleCode="Rrule">&lt; 1</td><td>10</td><td styleCode="Rrule">0</td><td>27</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dysgeusia</td><td>14</td><td styleCode="Rrule">0</td><td>3</td><td styleCode="Rrule">0</td><td>11</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Neoplasms benign, malignant and unspecified (includes cysts and polyps)</content></td><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Skin papilloma</td><td>21</td><td styleCode="Rrule">&lt; 1</td><td>0</td><td styleCode="Rrule">0</td><td>30</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Cutaneous SCC<footnote>Includes both squamous cell carcinoma of the skin and keratoacanthoma.</footnote><footnote>Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.</footnote></td><td>24</td><td styleCode="Rrule">22</td><td>&lt; 1</td><td styleCode="Rrule">&lt; 1</td><td>24</td><td styleCode="Rrule">24</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Seborrheic keratosis</td><td>10</td><td styleCode="Rrule">&lt; 1</td><td>1</td><td styleCode="Rrule">0</td><td>14</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Investigations</content></td><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gamma-glutamyltransferase increased</td><td>5</td><td styleCode="Rrule">3</td><td>1</td><td styleCode="Rrule">0</td><td>15</td><td styleCode="Rrule">6</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Metabolism and nutrition disorders</content></td><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased appetite</td><td>18</td><td styleCode="Rrule">0</td><td>8</td><td styleCode="Rrule">&lt; 1</td><td>21</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td>8</td><td styleCode="Rrule">0</td><td>7</td><td styleCode="Rrule">0</td><td>12</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Injury, poisoning and procedural complications</content></td><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Sunburn</td><td>10</td><td styleCode="Rrule">0</td><td>0</td><td styleCode="Rrule">0</td><td>14</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="85%" ID="t2"><caption>Table 2 Change from Baseline to Grade 3/4 Liver Laboratory Abnormalities in Trial 1<footnote>For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.</footnote></caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2" valign="bottom">Parameter</th><th styleCode="Botrule Rrule" colspan="2">Change From Baseline to Grade 3/4</th></tr><tr><th styleCode="Rrule" align="center">ZELBORAF (%)</th><th styleCode="Rrule">Dacarbazine (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">GGT</td><td styleCode="Rrule">11.5</td><td styleCode="Rrule">8.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">AST</td><td styleCode="Rrule">0.9</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">ALT</td><td styleCode="Rrule">2.8</td><td styleCode="Rrule">1.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alkaline phosphatase</td><td styleCode="Rrule">2.9</td><td styleCode="Rrule">0.4</td></tr><tr><td styleCode="Lrule Rrule">Bilirubin</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="85%" ID="t3"><caption>Table 3 Adverse Reactions Reported in &#x2265; 20% of ECD Patients Treated with ZELBORAF<footnote>Adverse drug reactions, graded using NCI-CTCAE v 4.0 (NCI common toxicity criteria) for assessment of toxicity.</footnote></caption><col width="36%" align="left" valign="top"/><col width="28%" align="center" valign="top"/><col width="36%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" colspan="3" align="center">Trial 4: Patients with ECD</th></tr><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule" colspan="2">n=22</th></tr><tr><th styleCode="Lrule Rrule" align="center">Body System Adverse Reactions</th><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3-4 (%)</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Rash maculo-papular</td><td styleCode="Rrule">59</td><td styleCode="Rrule">18</td></tr><tr><td styleCode="Lrule Rrule">Alopecia</td><td styleCode="Rrule">55</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule">Hyperkeratosis</td><td styleCode="Rrule">50</td><td styleCode="Rrule">5</td></tr><tr><td styleCode="Lrule Rrule">Dry skin</td><td styleCode="Rrule">45</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule">Photosensitivity reaction</td><td styleCode="Rrule">41</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule">Palmar-plantar erythrodysaesthesia syndrome</td><td styleCode="Rrule">41</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule">Pruritus</td><td styleCode="Rrule">36</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule">Actinic keratosis</td><td styleCode="Rrule">32</td><td styleCode="Rrule">5</td></tr><tr><td styleCode="Lrule Rrule">Keratosis pilaris</td><td styleCode="Rrule">32</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash papular</td><td styleCode="Rrule">23</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">82</td><td styleCode="Rrule">14</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">55</td><td styleCode="Rrule">5</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">50</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">32</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">23</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Peripheral sensory neuropathy</td><td styleCode="Rrule">36</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Neoplasms benign, malignant and unspecified (incl. cysts and polyps)</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Skin papilloma</td><td styleCode="Rrule">55</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule">Seborrhoeic keratosis</td><td styleCode="Rrule">41</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule">SCC of skin<footnote>Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.</footnote></td><td styleCode="Rrule">36</td><td styleCode="Rrule">36</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Melanocytic nevus</td><td styleCode="Rrule">23</td><td styleCode="Rrule">_</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Cardiac disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Electrocardiogram QT interval prolonged</td><td styleCode="Rrule">55</td><td styleCode="Rrule">5</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td styleCode="Rrule">36</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Vascular disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">36</td><td styleCode="Rrule">23</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Injury, poisoning and procedural complications</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Sunburn</td><td styleCode="Rrule">23</td><td styleCode="Rrule">-</td></tr></tbody></table>