How PET-CT is Changing the Management of Non-metastatic Castration-resistant Prostate Cancer?: Comment la TEP-TDM Peut Modifier la Prise en Charge du Cancer de la Prostate Non Métastatique Résistant à la Castration ?

INTRODUCTION: The aim of this narrative review conducted by the Prostate Cancer Committee of the French Association of Urology (CC-AFU) was to provide an update on the current evidence for the impact of PET/CT in the management of men with non-metastatic castration-resistant prostate cancer (nmCRPC). MATERIAL AND METHODS: This review is based on data available in the literature on PET/CT imaging for staging nmCRPC patients. A PubMed search and narrative review of the data were performed in March 2022. Only articles in French or English were considered. RESULTS: Current guidelines recommend bone scan and CT scan as standard imaging modalities for staging and follow-up of patients with nmCRPC. Nearly one-third of asymptomatic patients with presumed nmCRPC ultimately have metastatic disease on conventional imaging. Increasing reports have shown that conventional imaging has limited accuracy in detecting metastatic disease in nmCRPC patients, leading to the development of next-generation imaging techniques. In a retrospective study, 18F-choline PET/CT detected distant metastases in 27/58 high-risk nmCRPC patients with prior negative conventional imaging. The implementation of radiolabeled ligands of the prostate-specific membrane antigen (PSMA) PET/CT in staging strategy has resulted in metastasis detection in 45% to 98% of patients with presumptive nmCRPC on conventional imaging. Such an early diagnosis of metastatic CRPC may allow patients to be referred for metastasis-directed therapies (i.e. stereotactic body radiotherapy), aimed at prolonging the efficacy of systemic therapies and improving clinical outcomes. However, current data are not strong enough to recommend this strategy, which must be properly evaluated in clinical trials. Indeed, the use of molecular imaging may lead to inappropriate undertreatment if the second-generation androgen receptor inhibitors (darolutamide, enzalutamide, apalutamide), which prolong life, are not used in the subgroup of patients with high PSA velocity (PSA doubling time <10 months). CONCLUSION: Implementation of PSMA-PET/CT in the staging strategy would result in a migration of disease stage to extra-pelvic, M1 disease in at least half of presumed nmCRPC patients. The unprecedented accuracy of PSMA-PET/CT may pave the way for a more personalized treatment strategy. However, no data yet support this strategy for all nmCRPC patients as no oncologic benefit of early detection of M1 disease or MDT has been demonstrated. © 2022 Elsevier Masson SAS. All rights reserved.

[Tattoo hypersensitivity reaction in a patient receiving combined BRAF and MEK inhibitors]. / Hypersensibilité retardée aux tatouages induite par un traitement combiné anti-BRAF/anti-MEK.

INTRODUCTION: For inflammation of a tattoo occurring decades after its creation, sarcoidosis should be considered first of all. Two case of extremely delayed hypersensitivity tattoo reaction have been recently reported in patients treated with BRAF and MEK inhibitors. We report a similar new case strongly suggesting a specific effect of this drug combination. PATIENTS AND METHODS: A 58-year-old man bearing 20-year-old tattoos was treated with dabrafenib and trametinib for advanced melanoma. A painful erythematous swelling appeared on all the patient's tattoos two months later, while his general tolerance of the treatment was poor. Skin biopsy demonstrated perivascular lympho-histiocytic infiltrate without granuloma, but with prominent pigment-loaded macrophages. Inflammatory signs quickly regressed after drug discontinuation. DISCUSSION: Great similarity exists between this new case and the first reported case, in which a female patient presented painful infiltration of old tattoos following repeated reintroduction of dabrafenib and trametinib in a setting of advanced melanoma. The immunomodulatory properties BRAF/MEK inhibition may enhance loss of tolerance to tattoo ink, accounting for the extremely long time to reaction. This third case militates in favour of a specific drug-induced reaction, of which patients with tattoos should be informed when anti-BRAF/MEK therapy is being considered.

Recombinant protein rMBP-NAP restricts tumor progression by triggering antitumor immunity in mouse metastatic lung cancer.

Recombinant Helicobacter pylori neutrophil-activating protein fused with maltose-binding protein (rMBP-NAP), a potential TLR2 ligand, was reported to possess immunomodulatory effects on in situ tumors in our previous study. In the present work, we attempt to elucidate the effect of rMBP-NAP at the local immune modulation in B16-F10-induced metastatic lung cancer. Our results demonstrated that growth of B16-F10 melanoma metastases in the lung was significantly arrested after rMBP-NAP treatment, along with marked reduction in metastatic lung nodules and significant increase in survival. The treatment induced both local and systemic immune responses, which were associated with higher influx of CD4+/CD8+ T cells and drove toward Th1-like and cytotoxic immune environment. Moreover, rMBP-NAP also showed significant anti-angiogenic activity by reducing vascularization in lung tumor sections. rMBP-NAP could induce antitumor immunity through activating Th1 cells and producing pro-inflammatory cytokines, which are responsible for the effective cytotoxic immune response against cancer progression. Our findings indicate that rMBP-NAP might be a novel antitumor therapeutic strategy.

[Immunohistochemistry using clone VE1 is an economic, specific and sensitive method for detecting the presence of BRAFV600E mutations in melanoma]. / L'immunohistochimie (clone VE1) est une méthode économique, spécifique et sensible pour détecter la présence d'une mutation BRAFV600E dans le mélanome.

BACKGROUND: Determination of BRAF mutation status is mandatory in the management of patients with inoperable stage IIIC or stage IV melanoma. Currently, molecular biology (MB) has been validated for detecting the presence of BRAF mutations. OBJECTIVE: To compare the sensitivity, specificity and cost of immunohistochemistry (IHC) (clone VE1) versus BM methods (qPCR and Sanger sequencing). PATIENTS AND METHODS: All the samples for which BRAF mutation status was requested between March 2013 and February 2015 at the cellular and molecular analysis laboratory of the Angers Hospital were included retrospectively and consecutively. The IHC (clone VE1) and BM analyses were performed with the same formalin-fixed paraffin embedded tumour samples. The cost of these two methods was determined on the basis of the cost for the French Health Insurance. RESULTS: Two hundred and seven samples were subjected to a determination of BRAF mutational status in IHC and BM. Only one sample was discordant between these two methods (positive in IHC, negative in BM). The sensitivity and specificity of the IHC was 100% and 99.25% respectively. The ratio of the cost of IHC/BM testing was 1:2.1. CONCLUSION: IHC (clone VE1) is a specific, sensitive and economic method for determining BRAFV600E mutation status. Nevertheless, this method must be validated in order to be integrated into a decisional algorithm, alongside BM methods, to determine whether targeted BRAF-inhibitor therapy is indicated.

[Management of metastatic renal cell carcinomass]. / Prise en charge des métastases du cancer du rein.

The management of metastatic renal cell carcinoma had changed over the last ten years with the apparition of new treatments and advances in surgery and ablative techniques. The therapies for metastatic patients have also been personalized and different prognostic groups have been established to adapt the treatment to the severity of the disease. Surgical excision, radiotherapy or ablative therapy could be proposed for patients with isolated metastasis and good condition to delay the systemic therapy initiation. Until 2006, in case of metastatic renal cell carcinoma, immunotherapy (IL-2 and TNF-alpha) was proposed. Targeted therapies acting on angiogenesis mechanisms have also been developed. Recently, immunotherapy has revolutionized the therapeutic management and has improved the overall survival of patients with metastatic renal carcinoma. For each patient, a multidisciplinary management is organized with a personal therapeutic project. This global management needs coordination with the medical team and also need a good communication with the patient, his entourage and his doctor.

[Prognostic factors for metastatic renal cell carcinoma treated with second-line targeted therapies]. / Étude des facteurs pronostiques pour le carcinome rénal métastatique traité par une deuxième ligne de thérapies ciblées.

OBJECTIVE: To assess the prognostic value of clinical and biological features in patients treated with second-line targeted therapies (TT) for a metastatic renal cell carcinoma (mRCC). MATERIAL AND METHODS: A retrospective study was performed including 60 patients treated with second-line TT from 2006 to 2013. Clinical and biological features were collected, including TT-induced toxicities, Heng and MSKCC prognostic scores, and renal function. Overall survival (OS) and progression-free survival (PFS) were assessed using univariate and multivariate analysis. RESULTS: The median age was 61 years [39-81]. MSKCC and Heng scores were significantly prognostic for OS and PFS (P<0.05). Hypo-albuminemia, anemia and brain metastasis were associated with poorer OS and PFS (P<0.05). Severe induced toxicities had a prognostic impact with higher OS (26 months vs 10 months, P=0.003) and PFS (5 months vs 4 months, P=0.047). Renal function impairment at the initiation of the second line was also associated with higher survival (OS=24 months vs 9 months, P=0.035 and PFS=7 months vs 4 months, P=0.043). On multivariate analysis, induced toxicity was found as an independent factor of good prognosis for OS (HR=0.36; P=0.01). CONCLUSION: Our results suggested that renal function impairment and TT-induced toxicities in the second line of treatment for mRCC have a potential prognostic interest as it had previously been reported for the first line of TT. LEVEL OF EVIDENCE: 5.

[Management of patients with metastatic cutaneous melanoma: French national guidelines. French National Cancer Institute]. / Prise en charge thérapeutique des patients atteints d'un mélanome cutané métastatique : recommandations nationales françaises. L'Institut national du cancer.

BACKGROUND: Recent years have seen the emergence of new molecules for the treatment of patients with metastatic cutaneous melanoma, with significant benefits in terms of survival and the opening of new therapeutic perspectives. In addition, many techniques are currently being developed for locoregional treatment of metastatic sites. Management of metastatic melanoma is thus fast-changing and is marked by innovative therapeutic approaches. However, the availability of these new treatments has prompted debate among healthcare professionals concerning their use and their place in therapeutic strategy. AIMS: Since 2008, the French National Cancer Institute (INCa) has been leading a project to define and diffuse national clinical practice guidelines. It has performed a review of these treatment methods, which it aims to circulate, and it is seeking to develop recommendations in order to allow nationwide implementation of innovative approaches while promoting good use thereof. METHODS: The clinical practice guidelines development process is based on systematic literature review and critical appraisal by experts within a multidisciplinary working group, with feedback from specialists in cancer care delivery. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery. RESULTS: This article presents the national recommendations for first- and second-line systemic treatment and for locoregional treatment of metastatic sites in patients presenting metastatic cutaneous melanoma.

[Stage IV prostate cancer in Guadeloupe, a French Caribbean archipelago]. / Cancer de prostate non localisé au diagnostic en Guadeloupe.

OBJECTIVES: To study clinical characteristics, in terms of survival and response to treatment, of patients with non-localized prostate cancer at diagnosis in an Afro-Caribbean population from Guadeloupe. METHODS: Cases of stage IV prostate cancer (T4N0M0, TxN1M0 and TxNxM1) at diagnosis in the Pointe à Pitre Hospital were selected from 1995 to 2012 and studied. RESULTS: One hundred and eighty-three patients were included. Median age at diagnosis was 70.3 years old (79.2% were more than 65 years). A total of 81.5% of them was TxNxM1 and 11.5% was TxN1M0. Median disease free survival was 18.5 months. Median overall survival was 49.0 months. CONCLUSION: This study about non-localized prostate cancer at diagnosis in an Afro-Caribbean population from a French Caribbean archipelago seemed to show no difference with general population suffering from the same disease, although prostate cancer incidence in this area is one of the highest in the world.

[Prognostic value of toxicities induced by targeted therapies in patients treated for a metastatic renal cell carcinoma]. / Valeur pronostique de la toxicité induite par les thérapies ciblées dans le carcinome rénal métastatique.

OBJECTIVE: To assess the prognostic value of clinical and biological variables in the era of targeted therapies, especially induced toxicity in patients treated for metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: A retrospective single-center study was performed in patients treated in our center from 2006 to 2012. The clinical and biological variables and toxicity data were retrospectively collected. Survival rates were calculated using the Kaplan-Meier method and compared by the Log-Rank test. Multivariate analysis was also performed using the Cox model. RESULTS: One hundred and two patients were included, with a median follow-up of 20 months. The median overall survival (OS) was 21 months, and 6 months for the progression free survival (PFS). As expected, the variables included in the Mozter prognostic score had a significant impact on OS (P < 0.0001) and PFS (P < 0.0001). However, hypoalbuminemia (P < 0.0001), brain metastasis (P = 0.003) and the absence of nephrectomy (P < 0.0001) were found as poor prognosis factors for OS. In addition, severe toxicity (grade 3-4) was significantly associated with higher OS (P < 0.0001) and PFS (P = 0.0003) and appeared as an independent factor in multivariate analysis for OS (P = 0.02) and PFS (P = 0.01). CONCLUSION: Severe toxicity induced by targeted therapies was found as a prognostic factor increasing significantly the survival. Further studies are needed to assess the real value of this factor in the development of sequential therapies for the treatment of RCC.

Management of oligometastatic/metastatic sarcomas and place of local treatments with focus on modern radiotherapy approaches.

Soft tissue sarcomas are a rare and heterogeneous disease. For localized disease, treatment is based on surgery and radiotherapy with or without chemotherapy depending on risk factors. Upfront metastases are present in 7 to 20% of cases, and are localized to the lungs in most of cases. Disseminated disease is generally considered incurable but in selected cases, aggressive local treatment of metastases allowed long survival. Treatment of primary tumour is often debated. Our purpose is to evaluate the literature concerning the role of radiotherapy in the management of primary metastatic soft tissue sarcomas.

Indication and perspectives of radiation therapy in the setting of de-novo metastatic prostate cancer.

Prostate cancer is the most common cancer and the third leading cause of cancer mortality in men. Each year, approximately 10% of prostate cancers are diagnosed metastatic at initial presentation. The standard treatment option for de-novo metastatic prostate cancer is androgen deprivation therapy with novel hormonal agent or with chemotherapy. Recently, PEACE-1 trial highlighted the benefit of triplet therapy resulting in the combination of androgen deprivation therapy combined with docetaxel and abiraterone. Radiotherapy can be proposed in a curative intent or to treat local symptomatic disease. Nowadays, radiotherapy of the primary disease is only recommended for de novo low-burden/low-volume metastatic prostate cancer, as defined in the CHAARTED criteria. However, studies on stereotactic radiotherapy on oligometastases have shown that this therapeutic approach is feasible and well tolerated. Prospective research currently focuses on the benefit of intensification by combining treatment of the metastatic sites and the primary all together. The contribution of metabolic imaging to better define the target volumes and specify the oligometastatic character allows a better selection of patients. This article aims to define indications of radiotherapy and perspectives of this therapeutic option for de-novo metastatic prostate cancer.

Radiation therapy of the primary tumour and oligometastatic sites in patients with breast cancer with synchronous metastases: A literature review.

De novo metastatic breast cancer represents 5 to 8% of all breast cancers (2500 new cases per year in France). Systemic treatment is the cornerstone of treatment, whereas radiation therapy usually has a palliative intent. Advances in systemic and local treatments (surgery and radiation therapy) have substantially improved overall survival. In the recent breast cancer statistics in the United States, the 5-year relative survival for patients diagnosed during 2012-2018 was 29% for stage IV (Breast Cancer Statistics). Thus, an increasing proportion of metastatic breast cancers present a prolonged complete response to systemic therapy, which raises the question of the impact of local treatment on patient survival. Radiation therapy has shown its value for early breast cancer, but its place in the local management of the primary tumour or oligometastatic sites for de novo metastatic breast cancer remains under debate. This article is a literature review assessing the role of radiation therapy directed to the primary tumour and oligometastatic sites of breast cancer in patients with synchronous metastases, in order to highlight clinicians in their therapeutic decision.

[Cellular and molecular mechanisms of carcinogenic side effects and resistance to BRAF inhibitors in metastatic melanoma with BRAFV600 mutation: state of the knowledge]. / Effets secondaires carcinogènes et résistances aux thérapies ciblées anti-BRAF.

Cutaneous melanoma is a malignant tumor with a high metastatic potential. If an early treatment is associated with a favorable outcome, the prognosis of metastatic melanoma remains poor. Advances in molecular characterization of cancers, notably the discovery of BRAF gene mutations in metastatic melanoma, allowed to the recent development of targeted therapies against mutated BRAF protein. Despite high tumor response rates observed in clinical trials, these new drugs are associated with frequent secondary tumor resistance occurrence and paradoxical carcinogenic side effects. The cellular and molecular mechanisms of these carcinogenic side effects and secondary resistance are not yet fully elucidated and are actually intensely studied. This review of the literature focus on the mechanisms of these carcinogenic side effects and on the tumor resistance associated with anti-BRAF targeted therapies.

Recommandations francophones pour la pratique clinique concernant la prise en charge des cancers du sein de Saint-Paul-de-Vence 2022-2023.

With more than 60,000 new cases of breast cancer in mainland France in 2023 and 8% of all cancer deaths, breast cancer is the leading cancer in women in terms of incidence and mortality. While the number of new cases has almost doubled in 30 years, the percentage of patients at all stages alive at 5 years (87%) and 10 years (76%) testifies to the major progress made in terms of screening, characterisation and treatment. However, this progress, rapid as it is, needs to be evaluated and integrated into an overall strategy, taking into account the characteristics of the disease (stage and biology), as well as those of the patients being treated. These are the objectives of the St Paul-de-Vence recommendations for clinical practice. We report here the summary of the votes, discussions and conclusions of the Saint-Paul-de-Vence 2022-2023 RPCs.

[Interest of focal radiotherapy in case of oligoprogression under immunotherapy in the treatment of metastatic non-small cell lung cancer]. / Oligroprogression sous nivolumab du cancer bronchique non à petites cellules métastatiques traitées par radiothérapie.

INTRODUCTION: The prognosis of metastatic non-small cell lung cancer (NSCLC) has been improved by the use of immune checkpoint inhibitors (ICI). Unfortunately, in some cases, cancer cells will develop resistance mechanisms. In case of progression in a limited number of lesions (oligoprogression), focal treatment with radiotherapy is proposed while continuing the ICI therapy. METHODS: A cohort of 37 patients with metastatic NSCLC treated with nivolumab (anti-PD-1) in second or subsequent line and who received focal radiotherapy for oligoprogression with continuation of nivolumab was compared with a control cohort of 87 patients no oligoprogressor treated par immunotherapy. RESULTS: After a median follow-up of 37 months [18; 62], the median progression free survival (PFS) in the radiotherapy-treated cohort was 15.04 versus 5.04 months in the control cohort, with a statistically significant difference (P=0.048). The median PFS following focal radiotherapy in the oligoprogressor group was 7.5 months. In univariate analysis, the presence of lung metastasis was associated with increased PFS, in contrast to the presence of brain metastases, which were associated with decreased PFS in the radiotherapy group. The median overall survival was not reached in both groups, with no significant difference between the two cohorts. CONCLUSION: The combination of focal radiotherapy in case of oligoprogression and continued treatment with nivolumab in the treatment of metastatic NSCLC in the second or subsequent line of treatment seems to be with an increase in PFS.

[Real-world study of the consumption between 2017 and 2020 of anti-cancer medications that inhibit cyclin- dependent kinases 4 and 6]. / Étude en vie réelle de la consommation de médicaments anticancéreux inhibiteurs des kinases cycline-dépendantes 4 et 6 entre 2017 et 2020.

The real-world study of data from the Système National des Données de Santé (French System of Health Data) in relation to therapeutic indications that give entitlement to having Assurance Maladie (Health-Insurance Fund) pay for, or reimburse the cost of, inhibitors of cyclin-dependent kinases 4 and 6 (iCDK4/6) shows that the target population defined by the Haute Autorité de santé (HAS-National Health Authority) has been significantly exceeded ; in addition, there is a gap with respect to reimbursable indications and therapeutic strategy. The HAS has set the upper limit of the eligible population at 5 320 new patients per year, but in 2019, Assurance Maladie reimbursed iCDK4/6-related costs for 10 894 patients, i.e. double the number. Therapeutic strategies are found that do not comply with the opinions of the commission de la transparence (transparency commission) in 30 % of cases, and that do not comply with reimbursable therapeutic indications in 22 % of cases. Patient profiles are not in line with reimbursable indications in terms of age (women aged under 50 and, a priori, non-menopausal) and sex (men) in 14 % of cases. Furthermore, treatment seems to be started at an advanced stage of the disease, based on the number of deaths observed after treatment is started: 13% of patients died in the year following the start of treatment, including 26 % in the first three months. There is a significant volume of treatment being started, but there is also a significant volume of stoppage. One third of patients for whom treatment was started in 2019 had their treatment stopped after less than one year, including half after less than three months.

Safety and efficacy of immunotherapy according to the age threshold of 80 years.

BACKGROUND: To compare safety and efficacy of ICIs among patients<80 and those ≥80 years of age. METHODS: A single-center retrospective observational cohort study comparing patients<80 and ≥80 years of age matched for cancer site (lung vs others) and participation in a clinical trial. PRIMARY ENDPOINT: grade ≥2 toxicity during the first three months of ICI therapy. The two groups were compared using univariate and multivariate regression. RESULTS: Two hundred and ten consecutive patients were recruited, with the following characteristics: mean age: 66.5±16.8, 20% aged ≥80 years, 75% male, 97% ECOG-PS ≤ 2, 78% G8-index ≤ 14/17, 80% lung or kidney cancer, and 97% metastatic cancer. The grade ≥2 toxicity rate during the first three months of ICI therapy was 68%. Patients aged ≥80 years of age had a more significant (P<0.05) proportion of grade ≥2 non-hematological toxicities (64% vs 45%) than those aged<80 years: rash (14% vs 4%), arthralgia (7.1% vs 0.6%), colitis (4.7% vs 0.6%), cytolysis (7.1% vs 1.2%), gastrointestinal bleeding (2.4% vs 0%), onycholysis (2.4% vs 0%), oral mucositis (2.4% vs 0%), psoriasis (2.4% vs 0%), or other skin toxicities (25% vs 3%). Efficacy among patients ≥80 and<80 years of age was comparable. CONCLUSIONS: Although non-hematological toxicities affected 20% more patients aged ≥80 years, hematological toxicities and efficacy were comparable between patients aged ≥80 and<80 years with advanced cancer and treated with ICIs.

[Adapted physical activity and metastatic cancer: What needs and expectations?] / Activité Physique Adaptée et cancer métastatique : quels besoins et quelles attentes ?

This French study aimed to evaluate oncologists' and patients' perception of physical activity, particularly adapted physical activity, in order to identify the obstacles and levers to its practice in patients with metastatic cancer. METHOD: Between October 2019 and March 2020, 60 medical oncologists and 305 patients with metastatic cancer were asked to fill in a self-completed questionnaire. RESULTS: The benefits of physical activity are recognised by most oncologists and patients. These benefits were perceived more by oncologists in prevention (78%) or in the early stage (72%) of the disease than in the metastatic stage (55%) (P=0.01). Patient's physical condition (45%) and age (37%) but also the lack of time during the consultation to explain supportive care (35%) are the main obstacles identified by the oncologist to the integration of physical activity into patient care. Furthermore, lack of knowledge of adapted programmes is the main reason given by the physicians who have never prescribed physical activity (51%). On the patient side, while 88% of them had heard of the benefits of physical activity, only 11% had received a prescription. Most oncologists and patients were very interested in receiving information on where and what types of activities to practice, as well as what to avoid. CONCLUSION: Efforts in terms of information for both oncologists and patients seem necessary to increase the level of physical activity prescription and practice for patients followed for metastatic cancer.

[Metastatic Crohn's disease of the umbilicus: An exceptional location]. / Maladie de Crohn métastatique ombilicale : une localisation exceptionnelle.

INTRODUCTION: Cutaneous manifestations of Crohn's disease are frequent and include metastatic lesions. These are separated from the digestive tract and affect particularly the limbs and major folds. Umbilical involvement is exceptional. CASE REPORT: A 93-year-old woman followed for 6 years for Crohn's disease, in remission on infliximab, 5mg/kg every 8 weeks, consulted for a fissured and painful omphalitis. Histology revealed epithelioid granulomas without necrosis in the dermis, leading to the diagnosis of umbilical cutaneous metastasis of Crohn's disease. Infliximab intensification every 6 weeks led to a positive outcome. CONCLUSION: We report a unique case of umbilical metastatic localization of Crohn's disease occurring during treatment with anti-TNF alpha. The diagnosis was based on skin biopsy and histology which found epithelioid granulomas without caseous necrosis.

Clinical activity of immunotherapy-based combination first-line therapies for metastatic renal cell carcinoma: the right treatment for the right patient.

Immunotherapy (IO) with checkpoint inhibitors with or without anti-angiogenic tyrosine kinase inhibitor (TKI)-based combinations have demonstrated superior efficacy over sunitinib for treatment-naive patients with metastatic clear-cell renal cell carcinoma (mRCC). Four of these combinations (nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib and pembrolizumab plus lenvatinib) represent new front-line standard-of-care options for mRCC patients, according to the International Metastatic RCC Database Consortium (IMDC) subgroups. Questions over the optimal treatment between IO-IO or IO-TKI combinations for mRCC patients in intermediate/poor IMDC risk groups and the optimal IO-TKI regimen for all IMDC risk groups remain unanswered. This review will focus on the biological pathways that have driven the hypothesis of a synergistic combination of such agents and their efficacy results, with consideration of response and survival outcomes in the overall population of phase three pivotal trials as well as in specific subgroups of interest.