Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer.

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.

Exposure-response relationship of cabozantinib in patients with metastatic renal cell carcinoma treated in routine care.

BACKGROUND: Interindividual pharmacokinetic variability may influence the clinical benefit or toxicity of cabozantinib in metastatic renal cell carcinoma (mRCC). We aimed to investigate the exposure-toxicity and exposure-response relationship of cabozantinib in unselected mRCC patients treated in routine care. METHODS: This ambispective multicenter study enrolled consecutive patients receiving cabozantinib in monotherapy. Steady-state trough concentration (Cmin,ss) within the first 3 months after treatment initiation was used for the PK/PD analysis with dose-limiting toxicity (DLT) and survival outcomes. Logistic regression and Cox proportional-hazards models were used to identify the risk factors of DLT and inefficacy in patients, respectively. RESULTS: Seventy-eight mRCC patients were eligible for the statistical analysis. Fifty-two patients (67%) experienced DLT with a median onset of 2.1 months (95%CI 0.7-8.2). In multivariate analysis, Cmin,ss was identified as an independent risk factor of DLT (OR 1.46, 95%CI [1.04-2.04]; p = 0.029). PFS and OS were not statistically associated with the starting dose (p = 0.81 and p = 0.98, respectively). In the multivariate analysis of PFS, Cmin, ss > 336 ng/mL resulted in a hazard ratio of 0.28 (95%CI, 0.10-0.77, p = 0.014). By contrast, Cmin, ss > 336 ng/mL was not statistically associated with longer OS. CONCLUSION: Early plasma drug monitoring may be useful to optimise cabozantinib treatment in mRCC patients treated in monotherapy, especially in frail patients starting at a lower than standard dose.

Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas.

BACKGROUND: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). METHODS: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. RESULTS: There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. CONCLUSION: In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.

Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial.

BACKGROUND: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. METHODS: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. FINDINGS: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. INTERPRETATION: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. FUNDING: Bristol Myers Squibb, ARTIC.

Cabozantinib-nivolumab sequence in metastatic renal cell carcinoma: The CABIR study.

Nivolumab and cabozantinib are approved agents in mRCC patients after sunitinib/pazopanib (TKI) failure. However, the optimal sequence, cabozantinib then nivolumab (CN) or nivolumab then cabozantinib (NC), is still unknown. The CABIR study aimed to identify the optimal sequence between CN and NC after frontline VEGFR-TKI. In this multicenter retrospective study, we collected data from mRCC pts receiving CN or NC, after frontline VEGFR-TKI. A propensity score (PrS) was calculated to manage bias selection, and sequence comparisons were carried out with a cox model on a matched sample 1:1. The primary endpoint was progression-free survival (PFS) from the start of second line to progression in third line (PFS2-3 ). Key secondary endpoints included overall survival from second line (OS2 ). Out of 139 included mRCC patients, 38 (27%) and 101 (73%) received CN and NC, respectively. Overlap in PrS allowed 1:1 matching for each CN pts, with characteristics well balanced. For both PFS2-3 and OS2 , NC sequence was superior to CN (PFS2-3 : HR = 0.58 [0.34-0.98], P = .043; OS2 : 0.66 [0.42-1.05], P = .080). Superior PFS2-3 was in patients treated between 6 and 18 months with prior VEGFR-TKI (P = .019) and was driven by a higher PFSL3 with cabozantinib when given after nivolumab (P < .001). The CABIR study shows a prolonged PFS of the NC sequence compared to CN in mRCC after first line VEGFR-TKI failure. The data suggest that cabozantinib may be more effective than nivolumab in the third-line setting, possibly related to an ability of cabozantinib to overcome resistance to PD-1 blockade.

MiTF/TFE Translocation Renal Cell Carcinomas: From Clinical Entities to Molecular Insights.

MiTF/TFE translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of RCC representing the most prevalent RCC in the pediatric population (up to 40%) and making up 4% of all RCCs in adults. It is characterized by translocations involving either TFE3 (TFE3-tRCC), TFEB (TFEB-tRCC) or MITF, all members of the MIT family (microphthalmia-associated transcriptional factor). TFE3-tRCC was first recognized in the World Health Organization (WHO) classification of kidney cancers in 2004. In contrast to TFEB-tRCC, TFE3-tRCC is associated with many partners that can be detected by RNA or exome sequencing. Both diagnoses of TFE3 and TFEB-tRCC are performed on morphological and immunohistochemical features, but, to date, TFE break-apart fluorescent in situ hybridization (FISH) remains the gold standard for diagnosis. The clinical behavior of tRCC is heterogeneous and more aggressive in adults. Management of metastatic tRCC is challenging, especially in the younger population, and data are scarce. Efficacy of the standard of care-targeted therapies and immune checkpoint inhibitors remains low. Recent integrative exome and RNA sequencing analyses have provided a better understanding of the biological heterogeneity, which can contribute to a better therapeutic approach. We describe the clinico-pathological entities, the response to systemic therapy and the molecular features and techniques used to diagnose tRCC.

MET alterations in biphasic squamoid alveolar papillary renal cell carcinomas and clinicopathological features.

Biphasic squamoid alveolar papillary renal cell carcinoma (BSA-PRCC) is a recently studied lesion considered a morphologic variant of papillary renal cell carcinoma (RCC), more closely related to type 1. Considering the role of proto-oncogene MET in both sporadic type 1 papillary RCC and hereditary papillary RCC, we aimed to explore the role of MET activation in the oncogenesis of BSA-PRCC. We identified 17 patients with either unique (n = 14) or multiple (n = 3) BSA-PRCC, all localized, and performed an integrative analysis of MET status in 18 formalin-fixed paraffin-embedded tumors combining next-generation sequencing analysis, fluorescent in situ hybridization and immunohistochemistry. Trisomy 7 was found in 86% of tumors (14/16) without MET amplification at 7q31 (15/15). A pathogenic MET genetic variant was identified in 60% (9/15) of cases, at the germline level in 57% (4/7) of tested patients or at the somatic level (5/11). MET expression was observed in all tumors with a higher value of combined score in large cells (mean 97%, range 80-100%) than in small cells (mean 74%, range 10-100%) and was lower in two cases without MET copy number gain. In conclusion, our study provides additional evidence to consider biphasic squamoid alveolar papillary RCC as a morphological variant of type 1 papillary renal RCC. Our data strongly suggest that MET represents a major oncogenic driver gene in BSA-PRCC, harboring a higher frequency of MET mutation that encourages to further explore the benefice of anti-MET targeted therapies for aggressive BSA-PRCC.

Update on the most promising biomarkers of response to immune checkpoint inhibitors in clear cell renal cell carcinoma.

In the last few years, the standard of care for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically with the emergence of the immune checkpoint inhibitors (ICI): anti-PD(L)-1 used as a monotherapy or as in combination either with an anti CTLA-4 or with an anti-angiogenic molecule (VEGFR tyrosine kinase inhibitor (TKI)). These combinations are now recommended in first line setting for mccRCC, according to the last European recommendations. In the face of these new therapeutic options, the question of selecting the best treatment arises as well as the optimal sequence. Predictive biomarkers are required to guide the therapeutic choice and provide a personalized treatment for each patient. This narrative review will provide an overview of the main predictive biomarkers assessed in mccRCC treatment, with a particular focus on mRNA panel signatures.

Cabazitaxel schedules in metastatic castration-resistant prostate cancer: a review.

Cabazitaxel (25 mg/m2 every 3 weeks) is the standard second-line chemotherapy for patients with metastatic castration-resistant prostate cancer previously treated with docetaxel. It is associated with a risk of neutropenic complications, which may be a barrier to its use in daily clinical practice, particularly in frail elderly patients. Here the authors reviewed key studies conducted with cabazitaxel (TROPIC, PROSELICA, AFFINITY, CARD and the European compassionate use program) and pilot studies with adapted schedules. Based on this review, the use of prophylactic granulocyte colony-stimulating factor from cycle 1 appears crucial to maximize the benefit-risk ratio of cabazitaxel in metastatic castration-resistant prostate cancer. Preliminary data with alternative schedules look promising, especially for frail patients. Results of the ongoing Phase III CABASTY trial (ClinicalTrials.gov: NCT02961257) are awaited.

The clinical role of the TME in solid cancer.

The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and a variety of immune cells that control tumour growth and invasion. It is well established that anti-tumour immunity is a critical hurdle that must be overcome for tumours to initiate, grow and spread and that anti-tumour immunity can be modulated using current immunotherapies to achieve meaningful anti-tumour clinical responses. Pioneering studies in melanoma, ovarian and colorectal cancer have demonstrated that certain features of the tumour immune microenvironment (TME)-in particular, the degree of tumour infiltration by cytotoxic T cells-can predict a patient's clinical outcome. More recently, studies in renal cell cancer have highlighted the importance of assessing the phenotype of the infiltrating T cells to predict early relapse. Furthermore, intricate interactions with non-immune cellular players such as endothelial cells and fibroblasts modulate the clinical impact of immune cells in the TME. Here, we review the critical components of the TME in solid tumours and how they shape the immune cell contexture, and we summarise numerous studies evaluating its clinical significance from a prognostic and theranostic perspective.

Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies.

Tumors are highly heterogeneous tissues where malignant cells are surrounded by and interact with a complex tumor microenvironment (TME), notably composed of a wide variety of immune cells, as well as vessels and fibroblasts. As the dialectical influence between tumor cells and their TME is known to be clinically crucial, we need tools that allow us to study the cellular composition of the microenvironment. In this focused research review, we report MCP-counter, a methodology based on transcriptomic markers that assesses the proportion of several immune and stromal cell populations in the TME from transcriptomic data, and we highlight how it can provide a way to decipher the complex mechanisms at play in tumors. In several malignancies, MCP-counter scores have been used to show various prognostic impacts of the TME, which we also show to be linked with the mutational burden of tumors. We also compared established molecular classifications of colorectal cancer and clear-cell renal cell carcinoma with the output of MCP-counter, and show that molecular subgroups have different TME profiles, and that these profiles are consistent within a given subgroup. Finally, we provide insights as to how knowing the TME composition may shape patient care in the near future.

Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer.

OBJECTIVES: To evaluate the safety and efficacy of a 2-weekly cabazitaxel schedule in patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: During the period October 2013 to February 2016, 43 patients with mCRPC were treated with cabazitaxel (16 mg/m2 , on days 1 and 15 of a 4-week cycle) together with prophylactic granulocyte colony-stimulating factor (G-CSF). The safety profile and efficacy (prostate-specific antigen [PSA] response; biological, clinical or radiological progression-free survival [PFS] and overall survival [OS]) of the treatment were analysed. RESULTS: All patients had received prior docetaxel and 79.1% abiraterone acetate. At inclusion, 46.5% were aged >70 years and 27.9% had an Eastern Cooperative Oncology Group performance status ≥2. Six patients stopped treatment because of toxicity. Grade ≥3 toxicities were: asthenia (16.3%); neutropenia (11.6%); thrombocytopenia (9.3%); diarrhoea (7%), anaemia (4.7%), febrile neutropenia (4.7%) and haematuria (2.3%). In all, 52.4% achieved a ≥30% PSA response and 40.5% had a ≥50% PSA response. The median OS was 15.2 months. CONCLUSION: This prospective pilot study suggests that cabazitaxel 16 mg/m² given 2-weekly has a manageable toxicity profile in docetaxel- and abiraterone acetate-pretreated patients with mCRPC. A prospective phase III trial comparing this regimen with the standard cabazitaxel regimen is planned to confirm these results.

The role of rechallenge with targeted therapies in metastatic renal-cell carcinoma.

PURPOSE OF REVIEW: To explore the accumulating evidence and feasibility of rechallenge with agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways for incorporation into the evolving management algorithm for metastatic renal-cell carcinoma (mRCC). RECENT FINDINGS: The current standard of care after the development of resistance to first-line targeted therapies in mRCC is sequential treatment with subsequent lines of alternative anti-VEGF agents or mTOR inhibitors, with optimal sequencing being the focus of ongoing research. Recent evidence from case study and retrospective reports suggests that mRCC patients can achieve important clinical benefits from rechallenge at later lines of therapy with the same targeted therapy used for previous line treatment. Further, the results of REchallenge with SUnitinib in MEtastatic, the first study of sunitinib rechallenge to include a prospective component, reinforce the potential for prolonged survival with this treatment approach for mRCC patients. SUMMARY: Rechallenge represents an important and feasible therapeutic option for the future treatment of mRCC patients. The results of ongoing prospective studies are expected to further evaluate the benefits of rechallenge and better inform wherein this approach fits in the treatment algorithm for mRCC.

Prognostic impact of baseline serum C-reactive protein in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib.

OBJECTIVE: To evaluate the impact of baseline serum C-reactive protein (CRP) level on outcome in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib. PATIENTS AND METHODS: We reviewed the charts of patients with mRCC who started sunitinib as a first targeted treatment between 2005 and 2012 in three hospitals in Belgium and France. Collected data included known prognostic factors for mRCC, anatomical location of metastatic sites, response rate (RR), progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 200 eligible patients were identified by retrospective chart review. The median PFS and OS were 12 and 20 months, respectively. We observed a clear impact of baseline CRP levels on outcome: the median PFS was 25 months in the group with baseline CRP ≤5 mg/L and 8 months in the group with baseline CRP >5 mg/L (hazard ratio [HR] 2.48, 95% CI 1.74-3.59). The median OS in each group was 50 vs 12 months, respectively (HR 3.17, 2.20-4.68). In the group with baseline CRP ≤5 mg/L, 61% of patients experienced a partial response compared with 32% of patients in the group with baseline CRP >5 mg/L (difference = 29%, 95% CI 15-42). When adding baseline CRP (with a log transformation) to the six variables of the International Metastatic RCC Database Consortium (IMDC) model in a multivariable Cox regression model, baseline CRP was independently associated with poor PFS (HR for each doubling in CRP level: 1.14, 95% CI 1.03-1.26; P = 0.01) and OS (HR: 1.29, 95% CI 1.16-1.43; P < 0.001). Adding baseline CRP to the model increased the c-statistic of PFS at 5 years from 0.63 (0.59-0.68) to 0.69 (0.65-0.73), and the c-statistic of OS at 5 years from 0.65 (0.60-0.69) to 0.70 (0.66-0.74). Patients with elevated baseline CRP levels had a poor prognosis independent of the IMDC risk group, whereas patients with a low baseline CRP in the IMDC favourable risk group had a very good outcome. CONCLUSION: Baseline serum CRP level is a strong independent variable linked with RR, PFS and OS in patients with mRCC treated with sunitinib.

Évolution de la prise en charge du cancer du rein : place des biomarqueurs et facteurs pronostiques.

Evolution of the support kidney cancer: place of biomarkers and prognostic factors.

Humoral complementomics - exploration of noninvasive complement biomarkers as predictors of renal cancer progression.

Despite the progress of anti-cancer treatment, the prognosis of many patients with solid tumors is still dismal. Reliable noninvasive biomarkers are needed to predict patient survival and therapy response. Here, we propose a Humoral Complementomics approach: a work-up of assays to comprehensively evaluate complement proteins, activation fragments, and autoantibodies targeting complement proteins in plasma, which we correlated with the intratumoral complement activation, and/or local production, focusing on localized and metastatic clear cell renal cell carcinoma (ccRCC). In two prospective ccRCC cohorts, plasma C2, C5, Factor D and properdin were elevated compared to healthy controls, reflecting an inflammatory phenotype that correlated with plasma calprotectin levels but did not associate with CRP or with patient prognosis. Conversely, autoantibodies against the complement C3 and the reduced form of FH (a tumor neo-epitope reported in lung cancer) correlated with a favorable outcome. Our findings pointed to a specific group of patients with elevated plasma C4d and C1s-C1INH complexes, indicating the initiation of the classical pathway, along with elevated Ba and Bb, indicating alternative pathway activation. Boostrapped Lasso regularized Cox regression revealed that the most predictive complement biomarkers were elevated plasma C4d and Bb levels at the time of surgery, which correlated with poor prognosis. In conclusion, we propose Humoral Complementomics as an unbiased approach to study the global state of the complement system in any pathological plasma sample and disease context. Its implementation for ccRCC revealed that elevated C4d and Bb in plasma are promising prognostic biomarkers, correlating with shorter progression-free survival.