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

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.