Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases. METHODS: TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAFV600 wild-type cohort and a BRAFV600 mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, brain metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAFV600 wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAFV600 mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAFV600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141. FINDINGS: Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAFV600 mutation-positive cohort; the BRAFV600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3-15·0) for the BRAFV600 mutation-positive cohort and 6·2 months (3·5-23·0) for the BRAFV600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29-54) by IRC assessment in the BRAFV600 mutation-positive cohort and 27% (95% CI 8-55) by investigator assessment in the BRAFV600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAFV600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (11 [18%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAFV600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients who received triplet therapy in the BRAFV600 mutation-positive cohort and two (13%) of 15 in the BRAFV600 wild-type cohort. No treatment-related deaths occurred. INTERPRETATION: Atezolizumab plus vemurafenib and cobimetinib provided intracranial activity in patients with BRAFV600-mutated melanoma with CNS metastases. FUNDING: F Hoffmann-La Roche.

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases. METHODS: TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAFV600 wild-type cohort and a BRAFV600 mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, CNS metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAFV600 wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAFV600 mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAFV600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141. FINDINGS: Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAFV600 mutation-positive cohort; the BRAFV600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3-15·0) for the BRAFV600 mutation-positive cohort and 6·2 months (3·5-23·0) for the BRAFV600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29-54) by IRC assessment in the BRAFV600 mutation-positive cohort and 27% (95% CI 8-55) by investigator assessment in the BRAFV600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAFV600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (ten [17%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAFV600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients in the BRAFV600 mutation-positive cohort and two (13%) of 15 in the BRAFV600 wild-type cohort. One death in the BRAFV600 mutation-positive cohort (limbic encephalitis) was considered to be related to atezolizumab treatment. INTERPRETATION: Adding atezolizumab to vemurafenib plus cobimetinib provided promising intracranial activity in patients with BRAFV600-mutated melanoma with CNS metastases. FUNDING: F Hoffmann-La Roche.

Melanoma primario de ganglio linfático. A propósito de 3casos con comportamiento biológico favorable / Primary lymph node melanoma. With regard to 3 cases with favourable biological behaviour

Antecedentes: Los melanomas afectando inicialmenteganglios linfáticos, sin lesión primaria identificada, se hanincluido tradicionalmente dentro del grupo de melanomasmetastáticos de origen desconocido (MMOD). Hay variaciónen los datos aportados en diferentes artículos de la literatura.Su historia natural no está bien definida y no hay guías clarasde tratamiento. El objetivo de nuestro trabajo es revisar loscasos que constan en el Instituto Oncológico de Gipuzkoa(IOG) con más de 8 años de seguimiento, para tener una perspectivade supervivencia, y mostrar los hallazgos de mayorinterés. Material y Métodos: Se estudian las historias depacientes codificados como MMOD en el Registro de Tumoresdel (IOG) desde 1980 a 1999. Resultados: Siguiendo criteriosestrictos para su inclusión se han encontrado 8 casos deMMOD (1,52% del total de 523 melanomas) de los que 3 sonmujeres con debut inicial afectando un ganglio linfático(0,57%). Caso 1: 30 años, localización supraclavicular. Caso2: 31 años, ganglio intramamario. Caso 3: 58 años, adenopatíainguinal. Se realizó linfadenectomía cervical radical, extirpaciónlocal con ampliación mamaria y resección de una adenopatíarecidivada y resección local de la adenopatía inguinalrespectivamente. Las tres se encuentran libres de enfermedaddespués de un periodo de seguimiento superior a 20 años sintratamiento de quimioterapia. Conclusiones: Aunque sonpocos casos, los hallazgos nos plantean la posibilidad de quehaya un subgrupo de melanomas, hasta ahora consideradoscomo MMOD, que sean verdaderos primarios de ganglioslinfáticos con una evolución biológica favorable diferente a lahabitual por razones todavía no establecidas. No deben serconsiderados como Estadio III o IV de melanoma y podríanser tratados solamente con cirugía local de forma individualizada (AU)

Background: Melanomas that initially affect lymphnodes, with no identified primary lesion, have traditionallybeen included within the group of metastatic melanomas ofunknown origin (MMUO).There are variations between thevarious data presented in the literature. Its natural history isnot well defined and there are no clear guidelines for treatment.The aim of our work is to review the cases that havebeen monitored in the Gipuzkoa Oncological Institute(GOI) for more than 8 years, in order to gain a perspectivewith regard to survival, and to present those findings thatmay be of interest. Material and Methods: A study of thehistories of patients coded as having MMUO in the TumourRegistry of the GOI from 1980 to1999. Results: Followingstrict inclusion criteria, we found 8 cases of MMUO (1.52%of 523 total melanomas), of which 3 women correspond tomelanomas initially affecting a lymph node (0.57%). Case1: Thirty-year-old, supraclavicular location. Case 2: Thirtyone-year-old, intramammary node. Case 3: Fifty-eight-yearold,inguinal adenopathy. A radical cervical lymphadenectomy;local removal with mammary extension and resectionof a relapsed adenopathy; and local resection of the inguinaladenopathy respectively were done. All 3 patients are free ofdisease after a follow-up period of more than 20 years, withno chemotherapy treatment. Conclusions: While the groupof cases is small, the findings raise the possibility that theremay be a subgroup of melanomas, up to now consideredas MMUO, that are true primary lymph node tumours withfavourable biological development different to the normalevolution for reasons that have not yet been established.They should not be considered as Stage III or IV of melanomaand could be treated on an individual basis, with localsurgery alone (AU)