Surgical or Radiotherapeutic Intervention Concerning Large Singular Stable to Progressive Metastases in Patients With BRAFV600-mutated Melanoma Receiving Treatment With Encorafenib + Binimetinib

Inclusion Criteria: Patients may be included in the study only if they meet all the following criteria: 1. Signed informed consent form 2. Female and male patients ≥ 18 years of age 3. Ability to comply with the study protocol, in the investigator's judgement 4. Ongoing treatment with Encorafenib plus Binimetinib (EB) in accordance with the current Summary of Product Characteristics (SmPC) for a minimum of 3 months 5. ECOG performance status 0-2 6. Life expectancy ≥ 12 weeks 7. Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous or unknown primary melanoma (inoperable stage III or metastatic stage IV, per AJCC 8 staging) 8. Presence of a BRAFV600-mutation according to a validated test 9. Measurable disease according to RECIST v.1.1, i.e. 1 to 3 locally untreated target lesion(s) to treat with a longest diameter of ≥ 10 mm (lymph node metastases smallest diameter ≥ 15 mm) \[TLT; target lesion(s) to treat which are stable or progressive under EB and subject to surgery or electrochemotherapy or radiotherapy within the study\] plus ≥ 1 additional target lesion \[target lesion(s), which are not subject to surgery or electrochemotherapy or radiotherapy within the study\] for continuous measurement Note: Localization of TLTs will be cohortly observed. 10. Availability of RECIST-v1.1-compliant imaging (CT or MRT chest/ abdomen/pelvis and MRT head) within 28 days before initiation of EB treatment outside of the study (= "EB pretreatment") and within 28 days before initiation of surgery or electrochemotherapy or radiotherapy, to assess treatment response under EB pretreatment Note: Steering committee approval is required for older imaging (however, imaging older than 2 months prior to EB initiation is not allowed). 11. Patient must fulfill one of the following conditions (= mixed tumor response) for TLT: 1. EB in palliative 1st line i. with current response of all metastases according to RECIST v1.1 with exception of 1 to 3 TLT that are stable ii. with current response or stability of all metastases according to RECIST v1.1 with exception of 1 to 3 TLT that are progressing 2. EB in palliative 2nd line after progression upon checkpoint inhibition in palliative 1st line i. with current response of all metastases according to RECIST v1.1 with the exception of 1 to 3 TLT that are stable ii. with current response or stability of all metastases according to RECIST v1.1 with the exception of 1 to 3 TLT that are progressing Notes: * Adjuvant BRAFi/MEKi pretreatment with \> 6 months of treatment free interval between end of adjuvant and start of palliative 1st line treatment is allowed; any other prior adjuvant therapy is allowed. * Inclusion of patients switching from other BRAFi/MEKi to EB within the study treatment line is not allowed. * Only for b): BRAFi/MEKi pretreatment in palliative 1st line with direct switch to checkpoint inhibition within this line and without progression is allowed. * Mixed tumor response is defined as: some metastases decreasing in size (=responding), some metastases increasing in size (=growing) and/or new metastases appearing, some metastases are stable. 12. TLT must be eligible for treatment with radiotherapy or surgery (R0) or electrochemotherapy; if both, radiotherapy and surgery, required according to national guidelines (e.g., brain metastases) authorization of steering committee is required. 13. Patients must have recovered from all prior treatment related toxicities to NCI CTCAE v5.0 grade ≤ 1, at the time of registration (except for: toxicities not considered a safety risk such as alopecia; stable and non-EB overlapping immune-related (ir) toxicities grade ≤ 2 which are controlled, except ir colitis) 14. Patient with toxicities related to E and/or B \[NCI CTCAE v5.0\] must have recovered to grade ≤ 1 and be in a stable situation concerning such toxicities 15. Adequate bone marrow, organ function and lab parameters: 1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 2. Hemoglobin ≥ 9 g/dL without transfusion 3. Platelet count ≥ 100 x 109/L without transfusion 4. Creatinine ≤ 1.5 mg/dL, or calculated creatinine clearance (Cockroft-Gault) ≥ 50 mL/min 5. Serum albumin ≥ 25 g/L 6. Serum bilirubin ≤ 2.0 x ULN, exception in case of known Gilbert's disease: ≤ 3.0 x ULN 7. AST/ALT ≤ 2.5 x ULN, exception in case of liver metastases: ≤ 5.0 x ULN 8. INR/PTT ≤ 1.5 x ULN 16. Adequate cardiac function: 1. Left ventricular ejection fraction (LVEF) ≥ 50 % as determined by echocardiogram 2. Triplicate average baseline QTcF interval ≤ 480 msec 17. Negative serum β-hCG test (female patient of childbearing potential only) within 72 hours prior to registration and use of a highly effective contraception for both male and female patients if the risk of conception exists throughout the study and for 4 weeks after study drug discontinuation. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, should use a highly effective contraception method including: * Total abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation \>6 weeks prior to registration; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male sterilization (\>6 months prior to registration); for female patients on the study, the vasectomized male partner must be the sole partner for that patient * Combination of two of the following: 1. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1 %), for example hormone vaginal ring or transdermal hormone contraception 2. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 3. Barrier methods of contraception: Condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository Note: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. Exclusion Criteria: Inclusion Criteria: Patients may be included in the study only if they meet all the following criteria: 1. Signed informed consent form 2. Female and male patients ≥ 18 years of age 3. Ability to comply with the study protocol, in the investigator's judgement 4. Ongoing treatment with Encorafenib plus Binimetinib (EB) in accordance with the current Summary of Product Characteristics (SmPC) for a minimum of 3 months 5. ECOG performance status 0-2 6. Life expectancy ≥ 12 weeks 7. Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous or unknown primary melanoma (inoperable stage III or metastatic stage IV, per AJCC 8 staging) 8. Presence of a BRAFV600-mutation according to a validated test 9. Measurable disease according to RECIST v.1.1, i.e. 1 to 3 locally untreated target lesion(s) to treat with a longest diameter of ≥ 10 mm (lymph node metastases smallest diameter ≥ 15 mm) \[TLT; target lesion(s) to treat which are stable or progressive under EB and subject to surgery or electrochemotherapy or radiotherapy within the study\] plus ≥ 1 additional target lesion \[target lesion(s), which are not subject to surgery or electrochemotherapy or radiotherapy within the study\] for continuous measurement Note: Localization of TLTs will be cohortly observed. 10. Availability of RECIST-v1.1-compliant imaging (CT or MRT chest/ abdomen/pelvis and MRT head) within 28 days before initiation of EB treatment outside of the study (= "EB pretreatment") and within 28 days before initiation of surgery or electrochemotherapy or radiotherapy, to assess treatment response under EB pretreatment Note: Steering committee approval is required for older imaging (however, imaging older than 2 months prior to EB initiation is not allowed). 11. Patient must fulfill one of the following conditions (= mixed tumor response) for TLT: 1. EB in palliative 1st line i. with current response of all metastases according to RECIST v1.1 with exception of 1 to 3 TLT that are stable ii. with current response or stability of all metastases according to RECIST v1.1 with exception of 1 to 3 TLT that are progressing 2. EB in palliative 2nd line after progression upon checkpoint inhibition in palliative 1st line i. with current response of all metastases according to RECIST v1.1 with the exception of 1 to 3 TLT that are stable ii. with current response or stability of all metastases according to RECIST v1.1 with the exception of 1 to 3 TLT that are progressing Notes: * Adjuvant BRAFi/MEKi pretreatment with \> 6 months of treatment free interval between end of adjuvant and start of palliative 1st line treatment is allowed; any other prior adjuvant therapy is allowed. * Inclusion of patients switching from other BRAFi/MEKi to EB within the study treatment line is not allowed. * Only for b): BRAFi/MEKi pretreatment in palliative 1st line with direct switch to checkpoint inhibition within this line and without progression is allowed. * Mixed tumor response is defined as: some metastases decreasing in size (=responding), some metastases increasing in size (=growing) and/or new metastases appearing, some metastases are stable. 12. TLT must be eligible for treatment with radiotherapy or surgery (R0) or electrochemotherapy; if both, radiotherapy and surgery, required according to national guidelines (e.g., brain metastases) authorization of steering committee is required. 13. Patients must have recovered from all prior treatment related toxicities to NCI CTCAE v5.0 grade ≤ 1, at the time of registration (except for: toxicities not considered a safety risk such as alopecia; stable and non-EB overlapping immune-related (ir) toxicities grade ≤ 2 which are controlled, except ir colitis) 14. Patient with toxicities related to E and/or B \[NCI CTCAE v5.0\] must have recovered to grade ≤ 1 and be in a stable situation concerning such toxicities 15. Adequate bone marrow, organ function and lab parameters: 1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 2. Hemoglobin ≥ 9 g/dL without transfusion 3. Platelet count ≥ 100 x 109/L without transfusion 4. Creatinine ≤ 1.5 mg/dL, or calculated creatinine clearance (Cockroft-Gault) ≥ 50 mL/min 5. Serum albumin ≥ 25 g/L 6. Serum bilirubin ≤ 2.0 x ULN, exception in case of known Gilbert's disease: ≤ 3.0 x ULN 7. AST/ALT ≤ 2.5 x ULN, exception in case of liver metastases: ≤ 5.0 x ULN 8. INR/PTT ≤ 1.5 x ULN 16. Adequate cardiac function: 1. Left ventricular ejection fraction (LVEF) ≥ 50 % as determined by echocardiogram 2. Triplicate average baseline QTcF interval ≤ 480 msec 17. Negative serum β-hCG test (female patient of childbearing potential only) within 72 hours prior to registration and use of a highly effective contraception for both male and female patients if the risk of conception exists throughout the study and for 4 weeks after study drug discontinuation. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, should use a highly effective contraception method including: * Total abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation \>6 weeks prior to registration; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male sterilization (\>6 months prior to registration); for female patients on the study, the vasectomized male partner must be the sole partner for that patient * Combination of two of the following: 1. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1 %), for example hormone vaginal ring or transdermal hormone contraception 2. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 3. Barrier methods of contraception: Condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository Note: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. Exclusion Criteria: Patients will be excluded from the study for any of the following reasons: 1. Uveal or mucosal melanoma 2. Presence of untreated brain metastases (exception if this is TLT) Note: Treated brain metastases (stereotactic or surgical intervention) are allowed, if these are stable for \> 4 weeks and off corticosteroids for \> 3 weeks. 3. Presence of any symptomatic brain and/or leptomeningeal metastases 4. Any previous radiation \[including stereotactic radiosurgery (SRS)\] therapy involving \> 25 % of bone marrow and/or ongoing ≤ 28 days prior to registration (local/surgical intervention excluded) 5. Any major surgery, open biopsy, or significant traumatic injury ≤ 14 days prior to screening Note: Minor surgical procedures should be completed \> 7 days prior to registration. 6. Prior treatment with a BRAF- and/or MEK-inhibitor other than EB 1. in the adjuvant setting and fast relapse (i.e., treatment free interval between adjuvant and palliative 1st line ≤ 6 months) is not allowed 2. in the palliative setting is not allowed Exception: Pretreatment with BRAF- plus MEK-inhibition in palliative 1st line and direct switch to checkpoint-inhibition within this line without progression 7. Any prior systemic chemotherapy for the current melanoma disease Note: Chemotherapy given as part of isolated limb perfusion, regional or intralesional treatment will not be considered systemic treatment 8. Any use of an investigational agent ≤ 28 days or ≤ 5 half-lives (minimum 14 days) or an approved medication except of E + B prior to registration, whichever is shorter 9. Any intake of the following foods/supplements within ≤ 7 days prior to registration: 1. St. John's wort or hyperforin 2. Grapefruit and Grapefruit juice 10. Any condition that would interfere with the planned radiotherapy or surgery or electrochemotherapy of TLT Note: If one of these therapies is without interference this should be performed in the study. 11. Any contraindication against the radiotherapy or surgery or electrochemotherapy of TLT Note: If one of these therapies is without contraindication this should be performed in the study. 12. Known hypersensitivity to any components of the study treatment 13. Any malabsorption condition that would alter the absorption of orally administered medications 14. Inability to swallow oral medication 15. History of allogeneic bone marrow or organ transplant requiring use of immunosuppressive medication 16. Known positive serology for HBV, HCV and/or HIV 17. Any active infection requiring systemic antibiotic therapy ≤ 2 weeks prior to registration 18. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma with intraocular pressures \> 21 mm HG or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) 19. Impaired cardiovascular function or clinically significant cardio-vascular diseases, including the following: 1. Myocardial infarction ≤ 6 months prior to registration 2. Severe/unstable angina pectoris ≤ 6 months prior to registration 3. Cerebrovascular accident or transient ischemic attack ≤ 6 months prior to registration 4. History of symptomatic congestive heart failure (NYHA stage ≥ 2) 5. History of congenital long QT syndrome or mean QTcF \> 480 msec or uncorrectable electrolyte abnormalities 6. Uncontrolled arterial hypertension despite medical treatment (patients with a history of hypertension controlled to ≤ grade 1 with anti-hypertensives are eligible) 7. Uncontrolled or clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular \[AV\] block without a pacemaker) 20. Neuromuscular disorders that are associated with elevated creatine phosphokinase (CK) (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) 21. Previous or concurrent malignancy with the following exceptions: 1. Adequately treated basal cell or squamous cell skin cancers (adequate wound healing prior to registration) 2. in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to registration 3. or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to registration 22. Known alcohol or drug abuse 23. Any medical, psychiatric, cognitive or other conditions that would, in the investigator's judgement, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results 24. Participation in another trial (non-interventional studies are allowed) within 30 days prior to screening 25. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive β-hCG laboratory test 26. Legal incapacity or limited legal capacity