Immunogenicity of radiotherapy on bone metastases from prostate adenocarcinoma: What is the future for the combination with radiotherapy/immunotherapy?

Bone metastatic prostate cancers (PCa) are resistant to usual immunotherapies such as checkpoint inhibitors. The main hypothesis related to this immunoresistance is the lack of antigens to stimulate anti-tumor immunity. External radiation is a potential inducer antigens presentation and thus to immunotherapy proprieties. The aim of this review is to describe the tumor microenvironment specificities, especially in bone metastasis and the immune modifications after radiation therapy on a metastatic castration-resistant PCa population. PCa microenvironment is immunosuppressive because of many tumor factors. The complex interplay between PCa cells and bone microenvironment leads to a 'vicious circle' promoting bone metastasis. Furthermore, the immune and bone systems, are connected through an osteoclastogenic cytokine: the Receptor Activator Nuclear Factor Kappa B ligand. Adapted doses of ionizing radiation play a dual role on the tumor. Indeed, radiotherapy leads to immunogenicity by inducing damage associated with molecular patterns. However, it also induces an immunosuppressive effect by increasing the number of immunosuppressive cells. Interestingly, the abscopal effect could be used to optimize immunotherapy potential, especially on bone metastasis. Radiotherapy and immunotherapy combination is a promising strategy, however further studies are necessary to determine the more efficient types of radiation and to control the abscopal effect.

Tolerability of Olaparib Combined with Abiraterone in Patients with Metastatic Castration-resistant Prostate Cancer: Further Results from the Phase 3 PROpel Trial.

BACKGROUND: The PROpel study (NCT03732820) demonstrated a statistically significant progression-free survival benefit with olaparib plus abiraterone versus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting, irrespective of homologous recombination repair mutation status. OBJECTIVE: We report additional safety analyses from PROpel to increase clinical understanding of the adverse-event (AE) profiles of olaparib plus abiraterone versus placebo plus abiraterone. DESIGN, SETTING, AND PARTICIPANTS: A randomised (1:1), double-blind, placebo-controlled trial was conducted at 126 centres in 17 countries (October 2018-January 2020). Patients had mCRPC and no prior systemic mCRPC treatment. INTERVENTION: Olaparib (300 mg bid) or placebo with abiraterone (1000 mg od) plus prednisone/prednisolone (5 mg bid). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The data cut-off date was July 30, 2021. Safety was assessed by AE reporting (Common Terminology Criteria for Adverse Events v4.03) and analysed descriptively. RESULTS AND LIMITATIONS: The most common AEs (all grades) for olaparib plus abiraterone versus placebo plus abiraterone were anaemia (46.0% vs 16.4%), nausea (28.1% vs 12.6%), and fatigue (27.9% vs 18.9%). Grade ≥3 anaemia occurred in 15.1% versus 3.3% of patients in the olaparib plus abiraterone versus placebo plus abiraterone arm. The incidences of the most common AEs for olaparib plus abiraterone peaked early, within 2 mo, and were managed typically by dose modifications or standard medical practice. Overall, 13.8% versus 7.8% of patients discontinued treatment with olaparib plus abiraterone versus placebo plus abiraterone because of an AE; 3.8% versus 0.8% of patients discontinued because of anaemia. More venous thromboembolism events were observed in the olaparib plus abiraterone arm (any grade, 7.3%; grade ≥3, 6.8%) than in the placebo plus abiraterone arm (any grade, 3.3%; grade ≥3, 2.0%), most commonly pulmonary embolism (6.5% vs 1.8% for olaparib plus abiraterone vs placebo plus abiraterone). CONCLUSIONS: Olaparib plus abiraterone has a manageable and predictable safety profile. PATIENT SUMMARY: The PROpel trial showed that in patients who had not received any previous treatment for metastatic castration-resistant prostate cancer, olaparib combined with abiraterone was more effective in delaying progression of the disease than abiraterone alone. Most side effects caused by combining olaparib with abiraterone could be managed with supportive care methods, by pausing olaparib administration for a short period of time and/or by reducing the dose of olaparib.

Prognostic Value of the Modeled Prostate-Specific Antigen KELIM Confirmation in Metastatic Castration-Resistant Prostate Cancer Treated With Taxanes in FIRSTANA.

PURPOSE: In a previous exploratory study, modeled early longitudinal prostate-specific antigen (PSA) kinetics observed within the 100-first treatment days with androgen deprivation therapy with or without docetaxel was associated with progression-free survival (PFS) and overall survival (OS) in patients with prostate cancer with rising PSA levels after primary local therapy. This prognostic value had to be confirmed in different settings. The objectives were to assess PSA kinetics modeling in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with chemotherapy in FIRSTANA trial and to investigate modeled PSA kinetic parameters prognostic/predictive value. MATERIALS AND METHODS: FIRSTANA phase III trial (ClinicalTrials.gov identifier: NCT01308567) assessed whether cabazitaxel is superior to docetaxel in terms of PFS/OS in patients with chemotherapy-naïve mCRPC. PSA longitudinal kinetics was assessed using the previous kinetic-pharmacodynamics model. Patient modeled ELIMination rate constant K (PSA.KELIM) was used to categorize favorable/unfavorable PSA declines (standardized PSA.KELIM < or ≥ 1.0 days-1) and further correlated with PFS/OS. RESULTS: In total, 1,050 of 1,168 enrolled patients were assessable for PSA.KELIM estimation. The median PSA.KELIM was 0.02 days-1. In univariate analyses, PSA.KELIM exhibited a significant prognostic value regarding survival: unfavorable versus favorable PSA.KELIM; median PFS, 3.6 months (95% CI, 3.0 to 4.2) versus 4.7 months (95% CI, 3.9 to 5.2), P = .002; median OS, 17.4 months (95% CI, 14.8 to 19.3) versus 28.4 months (95% CI, 26.7 to 31.6), P < .001. In multivariate analyses, PSA.KELIM was significant for PFS (hazard ratio [HR], 0.79 [95% CI, 0.67 to 0.93], P = .005) and OS (HR, 0.51 [95% CI, 0.44 to 0.60], P < .001), together with baseline radiological tumor progression and PSA doubling time. PSA.KELIM predictive value was not significant across treatment arms. CONCLUSION: This external validation study confirmed previous results about modeled PSA longitudinal kinetics prognostic value regarding PFS/OS in patients with mCRPC treated with taxanes. PSA.KELIM could be used to identify a subpopulation with poor prognosis, who may benefit from treatment intensification.

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.

Biological Biomarkers of Response and Resistance to Immune Checkpoint Inhibitors in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) represents around 2% of cancer-related deaths worldwide per year. RCC is an immunogenic malignancy, and treatment of metastatic RCC (mRCC) has greatly improved since the advent of the new immunotherapy agents, including immune checkpoint inhibitors (ICIs). However, it should be stressed that a large proportion of patients does not respond to these therapies. There is thus an urgent need to identify predictive biomarkers of efficacy or resistance associated with ICIs or ICI/Tyrosine kinase inhibitor (TKI) combinations; this is a major challenge to achieve precision medicine for mRCC in routine practice. To identify potential biomarkers, it is necessary to improve our knowledge on the biology of immune checkpoints. A lot of efforts have been made over the last decade in the field of immuno-oncology. We summarize here the main data obtained in this field when considering mRCC. As for clinical biomarkers, clinician and scientific experts of the domain are facing difficulties in identifying such molecular entities, probably due to the complexity of immuno-oncology and the constant adaptation of tumor cells to their changing environment.

A PK-PD model linking biomarker dynamics to progression-free survival in patients treated with everolimus and sorafenib combination therapy, EVESOR phase I trial.

PURPOSE: The objective was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model linking everolimus and sorafenib exposure with biomarker dynamics and progression-free survival (PFS) based on data from EVESOR trial in patients with solid tumors treated with everolimus and sorafenib combination therapy and to simulate alternative dosing schedules for sorafenib. PATIENTS AND METHODS: Everolimus (5-10 mg once daily, qd) and sorafenib (200-400 mg twice daily, bid) were administered according to four different dosing schedules in 43 solid tumor patients. Rich PK and PD sampling for serum angiogenesis biomarkers was performed. Baseline activation of RAS/RAF/ERK (MAPK) pathway was assessed by quantification of mRNA specific gene panel in tumor biopsies. The PK-PD modeling was performed using NONMEM® software. RESULTS: An indirect response PK-PD model linking sorafenib plasma exposure with soluble vascular endothelial growth factor receptor 2 (sVEGFR2) dynamics was developed. Progression-free survival (PFS) was described by a parametric time-to-event model. Higher decreases in sVEGFR2 at day 21 and higher baseline activation of MAPK pathway were associated with longer PFS (p = 0.002 and p = 0.007, respectively). The simulated schedule sorafenib 200 mg bid 5 days-on/2 days-off + continuous everolimus 5 mg qd was associated with median PFS of 4.3 months (95% CI 1.6-14.4), whereas the median PFS in the EVESOR trial was 3.6 months (95% CI 2.7-4.2, n = 43). CONCLUSION: Sorafenib 200 mg bid 5 days-on/2 days-off + everolimus 5 mg qd continuous was selected for an additional arm of EVESOR trial to evaluate whether this simulated schedule is associated with higher clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01932177.

Complete Response in Metastatic Clear Cell Renal Cell Carcinoma Patients Treated with Immune-Checkpoint Inhibitors: Remission or Healing? How to Improve Patients' Outcomes?

Renal-cell carcinoma (RCC) accounts for 2% of cancer diagnoses and deaths worldwide. Clear-cell RCCs represent the vast majority (85%) of kidney cancers and are considered morphologically and genetically as immunogenic tumors. Indeed, the RCC tumoral microenvironment comprises T cells and myeloid cells in an immunosuppressive state, providing an opportunity to restore their activity through immunotherapy. Standard first-line systemic treatment for metastatic patients includes immune-checkpoint inhibitors (ICIs) targeting PD1, in combination with either another ICI or with antiangiogenic targeted therapy. During the past few years, several combinations have been approved with an overall survival benefit and overall response rate that depend on the combination. Interestingly, some patients achieve prolonged complete responses, raising the question of whether these metastatic RCC patients can be cured. This review will focus on recent therapeutic advances in RCC and the clinical and biological aspects underpinning the potential for healing.

Clinical results of the EVESOR trial, a multiparameter phase I trial of everolimus and sorafenib combination in solid tumors.

PURPOSE: Everolimus (EVE) and sorafenib (SOR) combination was associated with synergistic activity in preclinical models. However, previous clinical studies were hampered by cumulative toxicities when both were given continuously. The academic EVESOR trial (NCT01932177) was designed to assess alternative doses and intermittent dosing schedules of EVE and SOR combination therapy to improve the benefit-risk ratio for patients with solid tumors. METHODS: EVESOR is a multiparameter dose-escalation phase I trial investigating different doses and dosing schedules, with the final objective of generating data for modeling and simulation. Patients were allocated into continuous (A and B) or intermittent (C and D) schedules to determine the recommended phase II dose (RP2D). The clinical outcomes are presented here. RESULTS: Forty-three patients were included from 2013 to 2019. Most of them had gynecological (25.6%), cholangiocarcinomas (23.2%), colorectal (14.0%), and breast cancers (11.6%). Dose-escalation up to EVE 10 mg QD and SOR 400 mg BID was possible on intermittent schedules. Five dose-limiting toxicities were observed, and dose reductions were required in 39.5% patients, stabilizing at EVE 5 mg and SOR 200 mg BID for 58.1% of them. The overall response rate was 6.3%, and disease control rate was 75.0%. The median progression-free survival (PFS) was 3.6 months. The longest median PFS were observed in cholangiocarcinomas (9.9 months), and gynecological adenocarcinomas (9.2 months). CONCLUSION: Intermittent arms were associated with improved efficacy/toxicity profiles; and EVE 5 mg QD and SOR 200 mg BID was defined a clinically feasible dose. Strong signs of efficacy were found in cholangiocarcinomas and gynecologic carcinomas. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01932177.

Impact of Bone Metastases on Patients with Renal Cell Carcinoma or Melanoma Treated with Combotherapy Ipilimumab Plus Nivolumab.

(1) Background: Ipilimumab plus nivolumab (combo-ICI) improves overall survival (OS) in patients with advanced renal cell carcinoma (RCC) or melanoma. The impact of bone metastases (BM) on survival outcomes of combo-ICI-treated patients is unknown. (2) Methods: This single-center retrospective observational study involved 36 combo-ICI-treated patients with advanced RCC and 35 with melanoma. Clinical and laboratory data preceding the initiation of combo-ICI were collected. Univariate and multivariate Cox proportional hazard models were used to assess the effect of BM on overall survival (OS) and progression-free survival (PFS). (3) Results: zNine RCC and 11 melanoma patients had baseline BM. In unadjusted analysis, baseline BM was associated with a poorer OS in the RCC cohort. Baseline BM did not have any impact on survival outcomes in melanoma patients. After adjustment on baseline performance status and on neutrophil-to-lymphocyte ratio (NLR), the impact of BM was no longer significant, but a NLR ≥ 3 was significantly associated with a poorer OS in the RCC cohort. (4) Conclusions: The presence of baseline BM seems to be associated with worse outcomes in RCC combo-ICI-treated patients, while its effect might not be independent from the inflammatory state (approximated by the NLR). BM seems to have no impact on the outcomes of melanoma combo-ICI-treated patients.

Embryonated Chicken Tumor Xenografts Derived from Circulating Tumor Cells as a Relevant Model to Study Metastatic Dissemination: A Proof of Concept.

Patient-Derived Xenografts (PDXs) in the Chorioallantoic Membrane (CAM) are a representative model for studying human tumors. Circulating Tumor Cells (CTCs) are involved in cancer dissemination and treatment resistance mechanisms. To facilitate research and deep analysis of these few cells, significant efforts were made to expand them. We evaluated here whether the isolation of fresh CTCs from patients with metastatic cancers could provide a reliable tumor model after a CAM xenograft. We enrolled 35 patients, with breast, prostate, or lung metastatic cancers. We performed microfluidic-based CTC enrichment. After 48-72 h of culture, the CTCs were engrafted onto the CAM of embryonated chicken eggs at day 9 of embryonic development (EDD9). The tumors were resected 9 days after engraftment and histopathological, immunochemical, and genomic analyses were performed. We obtained in ovo tumors for 61% of the patients. Dedifferentiated small tumors with spindle-shaped cells were observed. The epithelial-to-mesenchymal transition of CTCs could explain this phenotype. Beyond the feasibility of NGS in this model, we have highlighted a genomic concordance between the in ovo tumor and the original patient's tumor for constitutional polymorphism and somatic alteration in one patient. Alu DNA sequences were detected in the chicken embryo's distant organs, supporting the idea of dedifferentiated cells with aggressive behavior. To our knowledge, we performed the first chicken CAM CTC-derived xenografts with NGS analysis and evidence of CTC dissemination in the chicken embryo.

Chemotherapy following immune checkpoint inhibitors in patients with locally advanced or metastatic urothelial carcinoma.

BACKGROUND: Recent studies suggest improvements in response to salvage chemotherapy (CT) after immune checkpoint inhibitors (ICIs) in several types of cancer. Our objective was to assess the efficacy of chemotherapy re-challenge after ICI, compared with second-line chemotherapy without previous ICI in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). METHODS: In this multicentre retrospective study, we included all patients with la/mUC initiating second or third-line chemotherapy from January 2015 to June 2020. We compared patients treated with second-line chemotherapy without previous ICI (CT2) and patients treated with third-line chemotherapy after ICI (CT3). The primary end-point was objective response rate (ORR) in CT3 compared with CT2. Secondary end-points included progression-free survival (PFS) and toxicities. RESULTS: Overall, 553 patients were included. ORRs were 31.0% (95% CI, 26.5 to 35.5) and 29.2% (95% CI, 21.9 to 36.6), respectively, in CT2 and CT3, with no statistically significant differences (P = 0.62). In subgroup analyses, no differences in ORR were observed by Bellmunt risk group, type of chemotherapy (platinum or taxanes), duration of response to first-platinum-based chemotherapy (< or ≥ 12 months) or FGFR-status. Median PFS was 4.6 months (95% CI, 3.9 to 5.1) and 4.9 months (95% CI, 4.1 to 5.5) in CT2 and CT3, respectively, and grade 3-4 hematologic toxicity occurred in 35.0% and 22.4% of patients. CONCLUSION: This large multicentre retrospective study provides clinically relevant real-world data. Chemotherapy re-challenge after ICI in la/mUC achieves ORR and PFS comparable with those obtained in CT2 with an acceptable safety profile. These updated results offer more promising outcomes than historically reported with second-line chemotherapy data.

[Metastatic renal cell carcinoma: Management of toxicities of combinations]. / Cancer du rein métastatique : gestion des toxicités des combinaisons.

New combinations of antiangiogenic tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) or dual ICI have been shown to be effective in phase III trials compared to sunitinib in the first-line treatment of metastatic renal cell cancer. While ICI doublet is already used in other indications, TKI/ICI combinations are more recent and the management of their adverse effects (AEs) are less well known, particularly with regard to the accountability of each therapeutic class. The objective of this article is to analyze the safety data from the main phase III studies to provide clinicians with practical advice for managing the AEs from these combinations. Their management depends largely on the type of combination and their grade. In the case of a TKI/ICI combination, discontinuation of the 2 molecules is considered from grade 2. Rapid improvement in symptoms suggests that the AE is related to the TKI. It is then possible, after resolution, to reintroduce the TKI, if needed by reducing the dose, and to continue the ICI. Otherwise, the blame falls on the ICI and treatment usually involves corticosteroids. Management also depends on the type of AE and its severity. In some cases (dysthyroidism), treatment with TKI/ICI may be continued. In other situations (cardiac or neurological toxicity), it should be discontinued from grade 1 and hospitalization and corticosteroid therapy should be considered immediately. In all cases, information and education are integral parts of the prevention and proper management of potential AEs.

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.

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.

Final Results of Neoadjuvant Atezolizumab in Cisplatin-ineligible Patients with Muscle-invasive Urothelial Cancer of the Bladder.

BACKGROUND: Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC). OBJECTIVE: To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and circulating tumor DNA (ctDNA) in the ABACUS trial. DESIGN, SETTING, AND PARTICIPANTS: ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy. INTERVENTION: Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements. RESULTS AND LIMITATIONS: The median follow-up time was 25 mo (95% confidence interval [CI] 25-26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21-41). Two-year DFS and OS were 68% (95% CI 58-76) and 77% (95% CI 68-85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65-94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio [HR] 0.60 [95% CI 0.24-1.5], p = 0.26, and 0.72 [95% CI 0.31-1.7], p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 [95% CI 0.09-0.68], p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 [95% CI 1.3-13], p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work. CONCLUSIONS: Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future. PATIENT SUMMARY: We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy.

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.

Metastatic Renal Medullary and Collecting Duct Carcinoma in the Era of Antiangiogenic and Immune Checkpoint Inhibitors: A Multicentric Retrospective Study.

Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11−16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7−100 months and an objective response rate (ORR) of 39% (95% CI, 26−52%). Patients received a median of two (1−5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10−15% and disease control rates ranging 24−50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets.

Modeled Early Longitudinal PSA Kinetics Prognostic Value in Rising PSA Prostate Cancer Patients after Local Therapy Treated with ADT +/- Docetaxel.

BACKGROUND: In metastatic prostate cancer (PCa) patients, androgen-deprivation therapy (ADT) combined with chemotherapy or next-generation androgen receptor targeted agents is a new standard treatment. The objective of the present study is to assess longitudinal PSA kinetics during treatment using mathematical modeling, to identify the modeled PSA kinetic parameters able to exhibit early prognostic/predictive values. METHODS: Phase III clinical trial dataset (NCT00764166) comparing ADT +/- docetaxel in 250 locally treated patients for PCa with rising PSA levels, who were at high risk of metastatic disease was assessed. A kinetic-pharmacodynamic (K-PD) model was used to fit PSA kinetics during the first 100 treatment days, to estimate the modeled PSA production rate K (KPROD) and elimination constant rate K (KELIM). The prognostic value of these parameters, considered as categorized (favorable vs. unfavorable) covariates regarding PSA progression-free survival (PSA-PFS) and overall survival (OS), was assessed using univariate/multivariate analyses. RESULTS: Data from 177/250 patients was assessed. KELIM exhibited a significant prognostic value regarding PSA-PFS and KPROD regarding OS (univariate analysis). In the PSA-PFS final multivariate model, KELIM and the primary therapy type were significant. The OS multivariate model integrated both KPROD and baseline PSA doubling-time. CONCLUSION: In this first study assessing the modeled PSA kinetics prognostic value in PCa patients treated with systemic treatments, KELIM and KPROD exhibited respective prognostic values regarding PSA-PFS and OS.

Impact of Liver Metastases and Number of Metastatic Sites on Immune-Checkpoint Inhibitors Efficacy in Patients with Different Solid Tumors: A Retrospective Study.

Background: ICIs have dramatically improved patient outcomes in different malignancies. However, the impact of liver metastases (LM) and number of metastatic sites (MS) remains unclear in patients treated with single-agent anti-PD(L)1. Methods: We aimed to assess the prognostic impact of LM and MS number on progression-free survival (PFS) and overall survival (OS) in a large single-arm retrospective multicentric cohort (IMMUCARE) of patients treated with anti-PD(L)-1 for different solid tumors. Results: A total of 759 patients were enrolled from January 2012 to October 2018. The primary tumor types were non-small cell lung cancer (71%), melanoma (19%), or urologic cancer (10%). At the time of ICI initiation, 167 patients (22%) had LM and 370 patients (49%) had more than MS. LM was associated with a shorter median PFS of 1.9 months (95% CI: 1.8−2.5) vs. 4.0 months (95% CI: 3.6−5.4) in patients without LM (p < 0.001). The median OS of patients with LM was of 5.2 months (95% CI: 4.0−7.7) compared with 12.8 months (95% CI: 11.2−15.1) (p < 0.001). Interestingly, LM were not associated with shorter PFS, or OS compared to other MS types (brain, bone, or lung) in patients with only one MS. Patients with multiple MS also had poor clinical outcomes compared to patients with only one MS. The presence of LM and MS number were independent prognostic factors on overall survival. Conclusion: The presence of LM or multiple MS were associated with poorer survival outcomes in patients treated with anti-PD(L)-1.