PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort.

INTRODUCTION: Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors (ICI) are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its interactions with angiogenesis pathways, to search for potential therapeutic targets. METHODS: The expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 68 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to estimate the prevalence of PD-L1 expression and its prognostic impact in metastatic pRCC. Secondary endpoints included the evaluation of other immune markers (PD-1, PD-L2, and LAG-3) and their association with PD-L1. We also assessed angiogenic markers and their association with PD-L1. RESULTS: Overall, 27.9 % of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.6 %), PD-1 and LAG-3 were positive in 17.6 % and 19.1 % respectively. None of these markers was correlated with PD-L1 expression. 66 % (45/68) expressed at least one immune marker, and 43 % (29/68) were "double-positive", as they expressed both immune and angiogenic markers. OS was significantly shorter for patients with PD-L1 positive pRCC. A multivariate analysis confirmed a significant association between PD-L1 expression and shorter overall survival (HR = 4.0, p = 0.01). CONCLUSION: These results reinforce clinical data on the expected benefit of ICI in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in this multicenter cohort.

Activity of Lutetium-177 Prostate-specific Membrane Antigen and Determinants of Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Cabazitaxel: The PACAP Study.

BACKGROUND: Both cabazitaxel and lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improve survival in metastatic castration-resistant prostate cancer (mCRPC) after an androgen receptor pathway inhibitor and docetaxel, but there are limited data regarding Lu-PSMA activity after cabazitaxel. OBJECTIVE: To assess the activity of Lu-PSMA and determinants of outcomes after cabazitaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of consecutive mCRPC patients from eight European centers treated with Lu-PSMA after cabazitaxel. INTERVENTION: Lu-PSMA every 6-8 wk at a dose of 6-7.6 GBq. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was radiographic progression-free survival (rPFS). The secondary endpoints included time to prostate-specific antigen (PSA) progression (TTPSA), overall survival (OS), PSA decline, objective response rate (ORR), clinical benefit, and safety. RESULTS AND LIMITATIONS: Of 126 patients, 68% had International Society of Urological Pathology (ISUP) grade 4-5 disease, 21% had visceral metastases, and 7% had lymph node disease only. DNA damage repair (DDR) alterations were detected in 11/50 (22%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (interquartile range 2-4). With a median follow-up of 12.0 mo, the median rPFS was 4.4 mo (95% confidence interval [CI] 3.2-5.4), TTPSA 3.5 mo (95% CI 3.0-4.6), and OS 8.9 mo (95% CI 6.5-12.7). The ORR was 35%, and 55 patients (44%) experienced a PSA decline of ≥50%. The time to castration resistance of <12 mo was associated with shorter rPFS (p = 0.01). A similar trend was observed for ISUP grade 4-5 (p = 0.08), and baseline positron-emission tomography parameters including PSMA mean standardized uptake value (SUV) and maximum SUV (respectively, p = 0.06 and 0.05). The duration of previous cabazitaxel or DDR status did not impact outcomes. Patients experiencing a PSA decline of ≥ 50% on therapy demonstrated longer rPFS, TTPSA, and OS (all p < 0.0001). Limitations include retrospective data collection and investigator-based rPFS assessment. CONCLUSIONS: Lu-PSMA demonstrated a substantial PSA decline but limited rPFS after cabazitaxel in a real-life setting. Adverse baseline characteristics, baseline positron-emission tomography parameters, and quality of PSA response may help identify patients less likely to benefit from Lu-PSMA. PATIENT SUMMARY: Lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improved outcomes in patients with castration-resistant prostate cancer, but there are limited data about its activity after cabazitaxel, a chemotherapy that is also the standard of care in this setting. We conducted a study across eight European centers and showed substantial responses on Lu-PSMA after cabazitaxel, although activity was short lived in a heavily pretreated population. Our findings prompt for real-life evaluation of Lu-PSMA in earlier settings to define the best therapeutic sequence.

Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma.

BACKGROUND: Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets. METHODS: We performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort. RESULTS: Unsupervised clustering identified two "TME subtypes", in each of the cohorts: the "immune-enriched" and the "immune-low". Within AXIPAP trial cohort, the "immune-enriched" cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the "immune-enriched" group (adjusted p<0.05). Finally, five differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations. CONCLUSION: For the first time, using RNA-seq and immunohistochemistry, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and B immune population. This "immune-enriched" group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and in combination with targeted therapies. TRIAL REGISTRATION NUMBER: NCT02489695.

Efficacy and safety of cabozantinib rechallenge in metastatic renal cell carcinoma: A retrospective multicentric study.

BACKGROUND: Despite metastatic renal cell carcinoma (mRCC) expanded treatment options, disease progression ultimately occurs for most patients. Rechallenge may be a compelling strategy in a refractory setting. Cabozantinib is the standard of care in first and later lines of therapy, but its activity in rechallenge is unknown. METHODS: This retrospective study assessed the efficacy and safety of cabozantinib rechallenge, as defined by a second exposure after an interval of ≥3 months without treatment or ≥1 other treatment line, in patients with mRCC. The primary endpoint was median progression-free survival (PFS) at rechallenge. Secondary endpoints included overall survival, objective response rate, and safety at rechallenge. RESULTS: We included 51 mRCC patients who received cabozantinib in a rechallenge setting between 2017 and 2022. Median age at diagnosis was 54 years, 78% were male, 90% had clear cell mRCC, and 92% had prior nephrectomy. 15 patients (29%) were rechallenged after a pause in treatment, whereas 36 (70.6%) had ≥1 other treatment lines between first cabozantinib exposure (CABO-1) and rechallenge (CABO-2). Median PFS was 15.1 months (mo, 95% Confidence interval 11.2-22.1) at CABO-1 and 14.4mo (95%CI 9.8-NR) at CABO-2. Median overall survival was 67.6mo for CABO-1 (95% CI 52.2-NR) and 27.4mo for CABO-2 (95%CI 17.2-NR); objective response rate was 70.6% for CABO-1 and 60% for CABO-2. CABO-2 PFS was higher for patients with CABO-1 PFS > 12 months, and for those who discontinued CABO-1 because of toxicity, without statistical significance. There were no unexpected adverse events. CONCLUSIONS: Cabozantinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients.

Impact of Iron-Deficiency Management on Quality of Life in Patients with Cancer: A Prospective Cohort Study (CAMARA Study).

BACKGROUND: Iron deficiency (ID) is very common in patients with solid tumors and may cause symptoms such as fatigue. However, its impact on clinical outcomes is poorly described. The aim of this prospective monocentric cohort study was to evaluate the evolution of quality of life (QoL) of these patients after iron supplementation. METHODS: We included patients treated for a solid tumor, which were diagnosed with a functional (ferritin <800 ng/mL) or absolute (ferritin <300 ng/mL) ID (transferrin saturation coefficient <20%). The primary endpoint was patients' QoL evolution between baseline and intermediate visit, 15-30 days after initial intravenous iron supplementation, assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale. Secondary endpoints were the same assessment between baseline, intermediate, and final visit at 6 months and the evolution of functional capacities. RESULTS: From 02/2014 to 12/2016, 248 patients were enrolled, of whom 186 were included in the analyses, including 140/186 (75.3%) with absolute ID. Anemia was detected in 141/174 (81.0%) patients at baseline. The FACT-An scores improved significantly between inclusion and intermediate visit (P = .001) and also between the 3 times of evaluation (P < .001). The most improved dimensions were those assessing physical, emotional well-being, and fatigue. Patients who performed the functional tests in all 3 phases had a significant improvement in performance on the majority of tests. CONCLUSION: The supplementation of ID was associated with an improvement of the QoL and functional capacities in patients with cancer. A randomized control trial is necessary to confirm our results. Our findings underline the importance of supportive care, including screening for ID, in oncology. CLINICAL TRIAL REGISTRATION NUMBER: NCT03625661.

Are immune checkpoint inhibitors a valid option for papillary renal cell carcinoma? A multicentre retrospective study.

BACKGROUND: Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC). Pivotal studies evaluating immune checkpoint inhibitors mostly excluded nccRCC. The aim of this retrospective and multicentre study was to evaluate the activity of programmed death-1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors specifically in metastatic pRCC. METHODS: The primary end-point was time to treatment failure (TTF). Secondary endpoints included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). RESULTS: From 02/2016 to 01/2019, 57 patients with pRCC were included. Histology included 16 (28%) type 1 pRCC, 34 (60%) type 2 pRCC and 7 (12%) unclassified pRCC. Treatment with immune checkpoint inhibitors was used in the first-line setting in 4 patients (7%), in the second-line setting in 32 patients (56%) and in the third-line setting or more in 21 patients (37%). With a median follow-up of 12 months (95% confidence interval [CI]: 9.9-21.0), the median TTF was 3.1 months (95% CI: 2.7-5.0). Among the 55 patients evaluable for ORR, best response was complete response/partial response in 6 patients (11%), stable disease in 18 patients (33%) and progressive disease in 31 patients (56%). The median OS was 14.6 months (95% CI: 9.0- not reached). TRAEs of grade III-IV were noted in 6 patients (10%) leading to treatment discontinuation, and no grade V TRAEs were observed. CONCLUSION: PD-1/PD-L1 inhibitors exhibit limited activity as monotherapy in this pRCC population, which remains an unmet need. Our findings underline the need for further prospective clinical trials evaluating immune checkpoint inhibitor combinations in patients with pRCC.