Patient Treated with Nivolumab After Previous Failure of BRAF Inhibitor Therapy

The patient, a 62-year-old man, presented at our dermatological oncology clinic in December 2014 following a non-wide excision of nodular malignant melanoma, Breslow 6.4, Clark not specified, with ulceration, no regression on the left auricle, which had been performed at the surgery in his hometown. According to histology, the tumor reached one lateral margin. During the examination, the patient reported that he did not know how long he had the lesion on his left auricle; he noticed it in October 2014 when it started bleeding. From his personal medical history, the patient only reported long-term treatment for hypertension.

Due to the localization on the auricle, we indicated only reexcision without sentinel node mapping for the patient. The operation was performed in January 2015 at the ENT clinic of VFN with a margin of 1.5 cm. Residual tumor infiltration by malignant melanoma was still detected histologically in the resectate of the left auricle. During another clinical examination at the beginning of January 2015, a palpable resistance was found on the left side of the neck, which could be differentially diagnosed as a reactive node given the short time since the surgery but also as a node infiltrated by melanoma metastasis due to the high Breslow value. A PET CT scan was planned for the patient, which took place in early February 2015 and concluded: soft tissue nodosity around the left ear and lymphadenopathy on the left side of the neck - very likely malignant melanoma infiltration. Subsequently, during another clinical examination, a new nodule measuring 6×6×2 mm was found on the posterior surface of the left auricle with a crust on the surface and a palpable indefinite resistance behind the angle of the mandible. The patient was referred again to the ENT clinic, where in February 2017 an excision of the nodule on the posterior surface of the left ear was performed. Histological examination confirmed that it was a recurrence of malignant melanoma. Sonographically, infiltated nodes were subsequently confirmed behind the angle of the mandible, retroauricularly, and in the left parotid gland. Therefore, the patient was offered participation in the Columbus study, which he agreed to. The examination for BRAF mutation from the tumor tissue confirmed V600E positivity. In April 2015, treatment with the BRAF inhibitor encorafenib at a dose of 300 mg/day in combination with the MEK inhibitor binimetinib at a dose of 45 mg daily was initiated for the patient. During this treatment, metastases regressed, but in March 2016, a metastasis reappeared on CT scans behind the left auricle, and node infiltration behind the left angle of the mandible; progression was confirmed by control CT of the head, neck, and trunk in May 2017, with a newly described 8 mm metastatic lesion paracardially in the left lung. Therefore, treatment with the BRAF and MEK inhibitors was terminated, and we requested the patient's insurance company to approve the administration of the anti-PD-1 antibody - nivolumab under paragraph 16. The treatment was approved and started in June 2016 at a dose of 3 mg/kg every 2 weeks in the form of an intravenous infusion. A control CT performed in August 2016 showed partial regression of the lung metastasis, and the other findings were unchanged. In November 2016, according to CT, there was further regression of the metastases; in February 2017, only a decreasing metastasis behind the left ear was described (Figure 1), and the CT from April 2017 confirmed further regression of the metastasis behind the left auricle. During another control CT exam performed in July 2017 (Figure 2), and also according to the clinical examination, the lesion behind the left ear had increased (Figure 3), the lesion in the lungs was still regressing (Figure 4). From August 23, palliative radiotherapy of the metastasis behind the left auricle was initiated, planned for 10 fractions.

Considering the size of the lesion before starting nivolumab treatment and the ongoing regression of the lung lesion, we evaluated the disease as stable, did not discontinue the treatment, and the patient has been approved to continue under paragraph 16. Currently, he has been treated for 14 months. The patient is in very good clinical condition and has no side effects from the treatment.

LD values in this patient fluctuated during the treatment; at the start of nivolumab treatment, the value was within the normal range, during treatment it increased several times to a maximum value of 6.9 ukat/l (normal up to 3.8), and now the patient’s value is again within the normal range.

MUDr. Taťána Šuková

Department of Dermatology and Venereology, VFN and 1st Faculty of Medicine, Charles University