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The use of immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD1) and anti-programmed cell death ligand 1 (PD-L1), has changed practices in oncology, becoming a new standard of care in first or subsequent lines for several cancer subtypes. Recent data have highlighted the ability of standard chemotherapy to enhance immunogenicity and/or to break immunoresistance of the tumour and its microenvironment, leading to a rationale for the use of ICIs in combination with the standard chemotherapy regimen to improve efficacy of cancer treatment. Here, we propose to review randomised clinical trials evaluating concomitant administration of ICIs and chemotherapy, to assess clinical efficacy and safety profiles in advanced solid tumours. Association of these two modes of action on treatments has shown improved overall survival and better objective response rates than standard chemotherapy, especially in first-line treatment of non-small cell lung cancer (NSCLC) and for PD1/PD-L1 enriched tumours, highlighting a potential synergistic effect of this treatment combination in certain tumour types. However, improved survival results with the use of anti-PD-L1 avelumab as a maintenance schedule for bladder cancer raises the question of the most appropriate approach between sequential and concomitant administration of chemoimmunotherapy. To date, no trials have compared in a head-to-head protocol the administration of concomitant chemoimmunotherapy with chemotherapy, used for tumour debulking, followed by administration of ICIs. Regarding the tolerance profile, no new safety signals were found with the combination tested to date. Interestingly, recent results have shown an improved Progression Free survival 2 (PFS2) (defined as the progression after the next line of therapy) in head-and-neck cancers or NSCLC after a first-line pembrolizumab-chemotherapy combination, suggesting a potential long-lasting effect of ICIs when used in combination in the first-line setting.

Background The CARMENA trial in patients with metastatic renal cell carcinoma (mRCC) demonstrated that treatment with sunitinib alone was noninferior to cytoreductive nephrectomy (CN) followed by sunitinib (nephrectomy⬜sunitinib). Objective The objective of this study was to provide updated overall survival (OS) outcomes of CARMENA and assess whether some subgroups may still benefit from upfront CN. Design, setting, and participants CARMENA was a phase III trial in 450 patients with mRCC enrolled from 2009 to 2017. Intervention Patients in the intention-to-treat population received nephrectomy⬜sunitinib (standard of care [SOC]; n = 226) or sunitinib alone (n = 224). Outcome measurements and statistical analysis Primary endpoint was OS, assessed using an updated data cut-off (October 2018; median OS event-free follow-up, 36.6 mo). Patients were reclassified by risk using International Metastatic RCC Database Consortium (IMDC) criteria. Results and limitations Sunitinib alone was noninferior to nephrectomy⬜sunitinib (hazard ratio [HR], 0.97; 95% confidence interval, 0.79⬜1.19; p = 0.8) and demonstrated longer median OS (19.8 mo vs 15.6 mo, respectively). For patients with two or more IMDC risk factors, OS was significantly longer with sunitinib alone than with nephrectomy⬜sunitinib (31.2 mo vs 17.6 mo, respectively; HR, 0.65; p = 0.03). For patients with one IMDC risk factor, OS was longer for nephrectomy⬜sunitinib versus sunitinib alone although not significantly (31.4 mo vs 25.2 mo; HR, 1.30; p = 0.2). The post hoc nature of the subgroup analyses may limit their interpretation. Conclusions Sunitinib alone was noninferior compared with nephrectomy⬜sunitinib, suggesting that CN should not be considered SOC in patients with mRCC requiring systemic treatment. Certain subgroups, including patients with one IMDC risk factor, may still benefit from upfront CN. Patient summary We assessed the survival of patients with metastatic kidney cancer in a clinical trial. Patients treated with sunitinib on its own had the same survival as patients who had surgery before sunitinib treatment. We conclude that surgery may not be necessary for some patients with metastatic kidney cancer.

Evidence suggests that sarcopenia is a significant predictive factor of worst outcomes and treatment-associated toxicities in patients with metastatic solid tumours. The aim of this study was to explore the relationship between low muscle mass and clinical outcomes and immune-related severe toxicities (IrST) in patients treated with immune checkpoint inhibitors (ICIs).A retrospective cohort of 261 consecutive metastatic solid tumour patients treated with ICIs were included in our study. Low muscle mass was defined as skeletal muscle index41 cmThe majority of patients (No difference in outcomes and safety was observed for low muscle mass and non-low muscle mass patients treated with ICIs.

Atezolizumab is an anti–PD-L1 immune checkpoint inhibitor recommended for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) after prior platinum-containing chemotherapy, regardless of PD-L1 status, among other treatment settings. We conducted a long-term follow-up to the exploratory analysis of overall survival (OS) and safety for the IMvigor211 intent-to-treat (ITT) population. Patients with mUC and disease progression during or following platinum-based chemotherapy were randomised 1:1 to receive atezolizumab 1200 mg or chemotherapy (vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or docetaxel 75 mg/m2 according to investigator choice) intravenously every 3 wk. Although the primary analysis did not demonstrate statistically significant longer OS for patients receiving atezolizumab versus chemotherapy, updated OS showed long-term durable remission. With a median of 33 mo of follow-up, the 24-mo OS rate was 23% with atezolizumab and 13% with chemotherapy. Safety findings were consistent with the primary analysis, with no new signals detected. Chemotherapy-treated patients experienced more grade 3/4 treatment-related adverse events (AEs; 43% vs 22%) and more AEs leading to treatment discontinuation (18% vs 9%). Atezolizumab-treated patients experienced more AEs of special interest (35% vs 20%), which tended to be grade 1–2. Our findings support the use of atezolizumab in platinum-treated patients with mUC regardless of PD-L1 status. Patient summary We report follow-up results from a study of an immunotherapy treatment, atezolizumab, in patients with bladder cancer who had already received platinum-containing chemotherapy. This analysis compared the effectiveness of atezolizumab with chemotherapy over 2.5 years after starting treatment. The results show that patients who received atezolizumab lived longer and had manageable side effects compared with patients who received chemotherapy. This trial is registered at ClinicalTrials.gov as NCT02302807.

Background Pazopanib is a tyrosine kinase inhibitor given at the approved dose of 800 mg orally once daily (OD), but often requiring individual dose adjustment due to toxicity. Limited data is available to guide prescription in older patients especially the unfit according to geriatric assessment. Patients and methods VOTRAGE is a 3 + 3 dose-escalation, open-label phase I trial of continuous OD oral administration of pazopanib to evaluate safety, PK and PD data in unfit older patients with advanced solid tumors. The primary objective was to determine the maximum tolerated dose (MTD). PK data were compared with those obtained in younger adult patients in a population PK analysis. Results Eighteen patients with a median age of 82.5 years (range 75–91) were included in three dosing cohorts (400, 600, and 800 mg daily). Three dose-limiting toxicities (DLT) were observed in five patients at 800 mg and one DLT at 600 mg in six evaluable patients. MTD was defined as level 2 dose (600 mg). Individual oral clearance was not correlated with age. A relationship was observed between the occurrence of DLT and pazopanib plasma exposure. Decreased oral bioavailability of pazopanib when given with proton-pump inhibitors was confirmed in this group of patients. Conclusion We recommend performing geriatric assessment in patients older than 75 and starting pazopanib at 600 mg per day in unfit older patients. Therapeutic drug monitoring appears very helpful in this population.

Immune checkpoint inhibitors have been approved as adjuvant therapy. Adverse immune events occurred during the administration of treatment, and delayed immune-related events have low incidence. A 66-year-old man was treated for hypopharynx cancer in 2012. In 2019, he was treated for a new oropharynx cancer. After undergoing surgery and complete response, the patient received nivolumab as adjuvant treatment. 5 months after the last dose of nivolumab, he presented with grade III diarrhea and abdominal pain for 3 weeks. Rectoscopy showed infiltration of mucous by lymphocytes. Corticosteroid was started resulting in a rapid decrease in symptom severity. With the increasing immune checkpoint inhibitors in adjuvant therapy, strict surveillance and education of patient in remission is necessary.Lay abstract Immune checkpoint inhibitors have changed the outcomes of several cancers and have been approved after local treatment for melanoma or lung cancer. The toxicities of this treatment were immune-related adverse events and any organ can be involved. Usually, toxicity occurred during the administration of treatment and delayed immune-related events have low incidence. Here, we presented a case report of a patient treated with anti-programmed cell death protein 1 after loco-regional treatment for head and neck cancer and presented with severe diarrhea 5 months after the last dose of treatment. Corticosteroid was started, resulting in a rapid decrease in symptom severity. With the increasing immune checkpoint inhibitors in adjuvant therapy, strict surveillance and education of patient in remission is necessary.

Background The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. Objective To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. Design, setting, and participants IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. Intervention Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. Outcome measurements and statistical analysis The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. Results and limitations Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. Conclusions The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. Patient summary Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.

Purpose: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC. Patients and Methods: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. Results: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3–22.9); n = 65; HR, 0.45 (95% CI, 0.3–0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33–0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. Conclusions: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population. See related commentary by Hwang et al., p. 5

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for "intercurrent" events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions ("does the drug delay recurrence if no patient had received subsequent therapy?" vs "does the drug delay recurrence with or without subsequent therapy?" vs "does the drug delay recurrence or start of subsequent therapy?"). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.

OBJECTIVE To investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first-line metastatic renal cell carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti-VEGFR therapy in mRCC. PATIENTS AND METHODS SUNRISES, a randomised open-label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment-naive patients with clear-cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression-free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety. RESULTS Accrual was low due to the advent of new-generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1-year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm. CONCLUSIONS The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.

Purpose To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors. Methods In this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states. Results Compared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (Cmax) by 16% and systemic exposure (area under the plasma concentration–time curve [AUC]) by 6%; AUC0–t decreased by 7% and time to maximum plasma concentration was delayed by 1.97 h (P = 0.0009). The 90% confidence interval of the geometric least-squares mean treatment ratio for AUC and AUC0–t was contained within the no-effect limits (0.8–1.25), while that of Cmax crossed the lower bound of the no-effect limits. Adverse events (AEs) related to adavosertib treatment were reported by 20 (64.5%) of the 31 patients treated in this study. Grade ≥ 3 AEs were reported by four (12.9%) patients (one in the fed state, three in the fasted state); two of these AEs were considered treatment-related by the investigator. Three serious AEs were reported in three (9.7%) patients; these were not considered treatment-related. No patients discontinued because of treatment-related AEs, and no new safety signals were reported. Conclusion A high-fat meal did not have a clinically relevant effect on the systemic exposure of adavosertib, suggesting that adavosertib can be administered without regard to meals.

The safety profile characteristics of sunitinib were evaluated in patients who underwent nephrectomy for kidney cancer.In this literature review, safety data were evaluated from phase III trials investigating sunitinib following nephrectomy, either in the more recent adjuvant setting after nephrectomy or in the metastatic setting, with a focus on new data from the CARMENA and SURTIME trials. In particular, the aim was to determine the specificity of toxicity in the adjuvant setting.In the adjuvant setting, even if the toxicity profile of sunitinib does not differ significantly from that in the metastatic setting, the importance of the dose intensity and, thus, exposure has been emphasized. Consequently, as described mainly in the metastatic setting, management of the adverse effects of sunitinib remains critical.

Objective To evaluate patient-reported outcome (PRO) data from the IMmotion150 study. The phase 2 IMmotion150 study showed improved progression-free survival with atezolizumab plus bevacizumab vs sunitinib in patients with programmed death-ligand 1 (PD-L1)+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC). Patients and methods Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (i.v.) every 3 weeks (n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg i.v. every 3 weeks (n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). The MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6-week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. The TTD was the first ≥2-point score increase over baseline. Absolute effect size ≥0.2 suggested a clinically important difference with checkpoint inhibitor therapy vs sunitinib. Results Completion rates were >90% at baseline and ≥80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue-related interference was observed with atezolizumab (both alone and in combination) vs sunitinib. Improved TTD (hazard ratio [HR], 95% confidence interval [CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22-0.71); RCC symptoms, 0.22 (0.12-0.41); and symptom interference, 0.36 (0.22-0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy vs sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions. Conclusion PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone vs sunitinib (IMmotion150; ClinicalTrials.gov Identifier: NCT01984242).

Background The management of patients with locally recurrent rectal cancer (LRRC) is often complex and requires multidisciplinary input whereas only few patients are referred to a specialist centre. The aim of this study was to design a regional referral pathway for LRRC, in Nouvelle Aquitaine (South-West, France). Methods In 2016, we conducted with a Study Steering Committee (SC) a three phase mixed-methods study including identification of key factors, identification of key stakeholders and Delphi voting consensus. During three rounds of Delphi voting, a consensus was defined as favorable, if at least 80% of participating experts rate the factor, below or equal to 3/10 using a Likert scale, or consider it as “useful” using a binary scale (third round only). Finally, the SC drafted guidelines. Results Among the 423 physicians involved in 29 regional digestive Multi-Disciplinary Team (MDT) meeting, 59 participants (from 26 MDT meeting) completed all three rounds of Delphi voting. Thirteen out of twenty initially selected factors reached a favorable consensus. All patients with a LRRC need to be included into a referral pathway. Patients with a central pelvic recurrence offered curative treatment in their local hospital and patients with unresectable metastatic disease were excluded of the referral. Key performance indicators were also agreed including the time to referral and completion of pelvic MRI-, CT-, PET-scan prior to MDT referral. Conclusion The development of this referral pathway represents an innovative health service, which will improve the management of patients with LRRC in France.

Introduction: Urothelial carcinoma (UC) has a poor prognosis, with the only standard first-line metastatic treatment being platinum-based chemotherapy. Until 2018, there was no Food and Drug Administration (FDA)-approved drug for second-line setting, and only vinflunine was approved by the European Medicines Agency (EMEA) in Europe. However, targeting the programmed cell-death 1 (PD-1)/PD-ligand 1 (PD-L1) pathway with immune checkpoint inhibitor (ICI) agents has shown encouraging results. Avelumab is a human anti-PD-L1 antibody that is currently being investigated in several trials. Areas covered: In this review article, we summarise preclinical, clinical, and safety data on avelumab for UC, and describeongoing trials that are evaluating avelumab for local or advanced diseases. We also compare its place in the management of UC. Expert opinion: Avelumab has shown clinical efficacy for metastatic and advanced UC in phase I studies after the failure of platinum-based therapy with a well-tolerated safety profile. This anti-PD-L1 targeting agent has the capacity to induce antibody-dependant cellular cytotoxicity (ADCC)-mediated tumor cell lysis compared to other ICI. These results led to FDA approval of avelumab as a second-line treatment for locally advanced and metastatic UC. Avelumab is also investigated in phase II and in a randomized phase III trial as a maintenance therapy in UC as well for combination use with chemotherapy.

Resume Dans le cadre de la prise en charge du cancer du rein metastatique, les therapies systemiques ont pour la majorite une galenique orale et s’accompagnent frequemment d’effets secondaires qui peuvent compromettre l’observance. Des strategies de pause therapeutique se sont donc developpees et, en cas de maladie indolente et oligometastatique, des etudes ont egalement montre la possibilite d’une surveillance active afin de retarder l’introduction du traitement systemique. Une prise en charge multimodale associant la realisation de traitements focaux aux traitements systemiques peut avoir plusieurs objectifs : repousser l’initiation d’une therapeutique systemique, en controlant localement les localisations metastatiques, permettre la realisation d’une pause therapeutique en cas de reponse partielle au traitement systemique en controlant localement les localisations secondaires, et ne pas changer de ligne therapeutique precocement en cas de reponse dissociee au traitement systemique avec prise en charge focale de la ou des metastase(s) en progression. Les techniques de traitements focaux disponibles sont les metastasectomies, la radiologie interventionnelle (cryotherapie ou radiofrequence) et l’irradiation stereotaxique. Si les donnees, majoritairement retrospectives, de la litterature semblent valider ces differents types de traitements du fait d’un bon controle local et de toxicites gerables, peu d’etudes ont etudie la prise en charge multimodale selon les objectifs suscites. Un recueil prospectif de ces pratiques est donc primordial, notamment depuis l’avenement de l’immunotherapie dans le cancer du rein metastatique. De plus, une discussion en reunion de concertation disciplinaire reste essentielle pour valider l’agencement entre traitements systemiques et traitements focaux qui beneficiera le mieux au patient.

Aim: To examine the prognostic value of the platelet-to-lymphocyte ratio (PLR) in the adjuvant renal cell carcinoma setting. Materials & methods: Patients received adjuvant sunitinib (50 mg/day; 4 weeks on/2 weeks off) or placebo. The primary end point was disease-free survival (DFS). Results: In 609 patients, DFS was similar for baseline PLR Clinical Trials Registration: NCT00375674 ( ClinicalTrials.gov )

Adjuvant therapy with antiangiogenic agents in locoregional renal cell carcinoma did not translate into a sufficient benefit and highlight the crucial role of patient selection. Ongoing clinical trials with immune-targeted agents hold great promise for this unmet clinical need.

While many patients with non-metastatic renal cell carcinoma (RCC) can be cured with surgery alone, upward of 40% of patients recur in a short delay, raising the question of additional perioperative treatments. To address this clinical need, multiple trials have investigated the addition of systemic therapy after surgery in localized or locally advanced RCC. However, adjuvant systemic therapies in the past decades have provided disappointing results with only one positive study of antiangiogenic treatments. Debatable clinical benefit of adjuvant antiangiogenic tyrosine kinase inhibitors (TKIs) therapy at cost of high adverse event profiles have paved the way for development of alternative perioperative strategies, such as immune checkpoint inhibitors (ICIs). Further investigation into combination therapies with immunotherapy, neoadjuvant approaches and patient selection will be key to determining optimal adjuvant therapy regimens to improve outcomes and increase cure rates for patients with non-metastatic RCC. In this review, we extensively present the strong and weakness of the five adjuvant antiangiogenic TKI trials, highlight the main differences and discuss about the reasons of failure. We also expose the current ongoing clinical trials in the perioperative setting and provide new insights concerning the evolving landscape of the management of non-metastatic RCC.

[Background] There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC)., [Objective] To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial., [Design, setting, and participants] ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy., [Intervention] Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC., [Outcome measurements and statistical analysis] Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed., [Results and limitations] Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue [20%], decreased appetite [6%], and transaminases increased [6%]). Treatment-related grade 3–5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1–2) and major (grade 3–5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non–treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available., [Conclusions] Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention., [Patient summary] Here, we report a comprehensive dataset of patients receiving neoadjuvant immune checkpoint inhibitors before radical cystectomy. Treatment with neoadjuvant atezolizumab is safe and does not seem to complicate surgery significantly., Queen Mary University of London was the Sponsor of the study. Roche granted QMUL funding for the study. J. Bull and M. Jacobson also provided financial support for aspects of the biomarker analysis. We acknowledge Cancer Research UK, the UK Experimental Cancer Medicine Network, and La Roche-Hoffmann for funding.

Background Avelumab is an anti–PD-L1 monoclonal antibody approved for the treatment of advanced UC after disease progression during or following platinum-based chemotherapy and as maintenance treatment in patients whose disease has not progressed with first-line platinum-based chemotherapy.1–3 M9241 is an immunocytokine composed of 2 heterodimers of IL-12 fused to the heavy chains of a human antibody targeting DNA released from necrotic tumor cells.4 During dose-escalation, avelumab + M9241 was well tolerated and showed promising antitumor activity in patients with advanced solid tumors, including 2 objective responses in patients with UC.5 We report on an interim analysis of efficacy and safety from the dose-expansion part of JAVELIN IL-12 (NCT02994953). Methods Eligible patients had locally advanced or metastatic UC that had progressed on first-line therapy, were aged =18 years, had an Eastern Cooperative Oncology Group performance status of 0/1, and were immune checkpoint inhibitor naive. Patients received the recommended phase 2 dose5 of avelumab 800 mg intravenously once weekly (QW) in combination with M9241 16.8 µg/kg subcutaneously Q4W for the first 12 weeks, then continued the combination with avelumab Q2W. The primary endpoints were confirmed best overall response (BOR) per investigator assessment (RECIST 1.1) and safety. The expansion cohort followed a 2-stage design. During stage 1 (single-arm part of the study), 16 patients were enrolled and treated. A futility analysis based on BOR was planned to determine if stage 2 (randomized controlled part of the study) would be initiated. Results At data cut-off (Jun 3, 2020), 16 patients had received avelumab + M9241 for a median duration of 8 weeks (range, 4.0–25.0 weeks). No complete or partial responses were observed; the study failed to meet the criterion (>2 responders) to initiate stage 2. Two patients (12.5%) had stable disease, 13 (81.3%) had progressive disease, and 1 (6.3%) was not evaluable. Any-grade treatment-related adverse events (TRAEs) occurred in 15 patients (93.8%); the most common (in =4 patients) were pyrexia (50.0%), nausea (37.5%), asthenia (31.3%), anemia (25.0%), and hyperthermia (25.0%); grade 4 gamma-glutamyltransferase increased occurred in 1 patient (6.3%). No TRAEs led to death. Pharmacodynamic effects on the peripheral immune system and results of pharmacokinetic and biomarker analyses will also be reported. Conclusions The predefined efficacy criterion to proceed to stage 2 was not met. The combination was well tolerated; no new safety signals emerged and the profile was consistent with the dose-escalation part of the study.5 Trial Registration NCT02994953 Ethics Approval The study was approved by each site’s independent ethics committee. Consent N/A References Bavencio(avelumab) injection [package insert]. Rockland, MA: EMD Serono, Inc; New York, NY: Pfizer Inc; 2020. Health Canada. https://www.canada.ca/en/health-canada.html. Accessed July 31, 2020. US Food and Drug Administration. FDA approves avelumab for urothelial carcinoma maintenance treatment. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment. Accessed July 31, 2020. Fallon J, Tighe R, Kradjian G, et al. The immunocytokine NHS-IL12 as a potential cancer therapeutic. Oncotarget. 2014;5:1869–1884. Strauss J, Vugmeyster Y, Sznol M, et al. Phase 1b, open-label, dose escalation study of M9241 (NHS-IL12) plus avelumab in patients (pts) with advanced solid tumours. Ann Oncol. 2019;30(5 Suppl):Abstract 4062.

Aims Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or moderate hepatic impairment to provide dosing recommendations. Methods This Phase I open-label study assessed the PK, safety and tolerability of single doses of olaparib 300-mg tablets in patients with advanced solid tumours. Patients had normal hepatic function (NHF), or mild (MiHI; Child-Pugh class A) or moderate (MoHI; Child-Pugh class B) hepatic impairment. Blood was collected for PK assessments for 96 hours. Patients could continue taking olaparib 300 mg twice daily for long-term safety assessment. Results Thirty-one patients received >= 1 dose of olaparib and 30 were included in the PK assessment. Patients with MiHI had an area under the curve geometric least-squares mean (GLSmean) ratio of 1.15 (90% confidence interval 0.72, 1.83) and a GLSmean maximum plasma concentration ratio of 1.13 (0.82, 1.56)vsthose with NHF. In patients with MoHI, GLSmean ratio for area under the curve was 1.08 (0.66, 1.74) and for maximum plasma concentration was 0.87 (0.63, 1.22)vsthose with NHF. For patients with mild or moderate hepatic impairment, no new safety signals were detected. Conclusion Patients with MiHI or MoHI had no clinically significant changes in exposure to olaparib compared with patients with NHF. The safety profile of olaparib did not differ from a clinically relevant extent between cohorts. No olaparib tablet or capsule dose reductions are required for patients with MiHI or MoHI.

Summary Background: The standard treatment in first line of advanced or metastatic urothelial bladder cancer (MBC) is the association of Gemcitabine and Cisplatin (GC). Avelumab, an anti-PD-L1 agent, has recently demonstrated efficacy. The objective is to evaluate the combination of these 3 agents. Methods: This phase II randomized open-label study, evaluated if GC-avelumab increases response rate and duration of response of patients in 1st line treatment for MBC compared to GC. Severe toxicities should not overlap and be acceptable. The two co-primary end points are the objective response rate and the incidence of severe toxicity after six cycles of treatment. The study will recruit 90 participants, randomized in two arms (1:2), GC (gemcitabine 1 000 mg/m2/j, J1,J8, Cisplatine 70 mg/m2, J1 = J21), and GC-avelumab (10 mg/Kg/3 semaines). Randomization will be stratified on Karnofsky status (≥ 80 % vs. Discussion: If both efficacy and safety of the association of GC+avelumab are in the range of acceptable through this specific study design, this will support a subsequent randomized phase III study comparing both arms with an overall survival end-point. In addition, the evaluation of predictive parameters to be confirmed (e.g. the impact of tumor PD-L1 expression) or other immunological parameters, may support a selection of the population. NCT number : NCT03324282

BackgroundAnti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma.MethodsPatients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome.Results249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24–43), and median treatment duration was 2.8 months (range 0.5–42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses.ConclusionsAfter ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.

Three drug combinations, ipilimumab-nivolumab (Ipi-Nivo), pembrolizumab-axitinib (Pembro-Axi), and avelumab-axitinib (Ave-Axi), have received regulatory approval in the USA and Europe for the treatment of metastatic renal cell carcinoma with clear cell component (mRCC). However, no head-to-head comparison data are available to identify the best option. Therefore, we aimed to compare these new treatments in a first-line setting. We conducted a systematic search in PubMed, the Cochrane Library, and clinicaltrials.gov for any randomized controlled trials of treatment-na&iuml, ve patients with mRCC, from January 2015 to October 2019. The process was performed according to PRISMA guidelines. We performed a Bayesian network meta-analysis with two different approaches, a contrast-based model comparing HRs and ORs between studies and arm-based using parametric modeling. The outcomes for the analysis were overall survival, progression-free survival (PFS), and objective response rate. Our search identified 3 published phase 3 randomized clinical trials (2835 patients). In the contrast-based model, Ave-Axi (SUCRA = 83%) and Pembro-Axi (SUCRA = 80%) exhibited the best ranking probabilities for PFS. For overall survival (OS), Pembro-Axi (SUCRA = 96%) was the most preferable option against Ave-Axi and Ipi-Nivo. Objective response rate analysis showed Ave-Axi as the best (SUCRA: 94%) and Pembro-Axi as the second best option. In the parametric models, the risk of progression was comparable for Ave-Axi and Ipi-Nivo, whereas Pembro-Axi exhibited a lower risk during the first 6 months of treatment and a higher risk afterwards. Furthermore, Pembro-Axi exhibited a net advantage in terms of OS over the two other regimens, while Ave-Axi was the least preferable option. Overall evidence suggests that pembrolizumab plus axitinib seems to have a slight advantage over the other two combinations.

Osimertinib is a third‐generation, irreversible, oral epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR‐TKI sensitizing and EGFR T790M and has demonstrated efficacy in non‐small cell lung cancer (NSCLC) central nervous system metastases. In this phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL

Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC)1. AUC is characterized by several recurrent targetable genomic alterations2–5. This study ( NCT02546661 , BISCAY) combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory AUC populations including: (1) fibroblast growth factor receptor (FGFR) inhibitors in tumors with FGFR DNA alterations (FGFRm); (2) pharmacological inhibitor of the enzyme poly-ADP ribose polymerase (PARP) in tumors with and without DNA homologous recombination repair deficiency (HRRm); and (3) TORC1/2 inhibitors in tumors with DNA alteration to the mTOR/PI3K pathway3–5.This trial adopted a new, biomarker-driven, multiarm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms. Response rates (RRs) ranged 9–36% across the study arms, which did not meet efficacy criteria for further development. Overall survival (OS) and progression-free survival (PFS) were similar in the combination arms and durvalumab monotherapy arm. Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFRm. Sequential circulating tumor DNA analysis showed that changes to FGFRm correlated with clinical outcome. Our data support the clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations. These findings question the targeted/immune therapy approach in AUC. The adaptive, biomarker-driven BISCAY trial evaluating durvalumab with targeted agents in patients with metastatic urothelial carcinoma based on tumor genomic alterations finds no added clinical benefit over durvalumab monotherapy.

BackgroundThe extent to which response and survival benefits with immunotherapy-based regimens persist informs optimal first-line treatment options. We provide long-term follow-up in patients with advanced renal cell carcinoma (aRCC) receiving first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the phase 3 CheckMate 214 trial. Survival, response, and safety outcomes with NIVO+IPI versus SUN were assessed after a minimum of 42 months of follow-up.MethodsPatients with aRCC were enrolled from October 16, 2014, through February 23, 2016. Patients stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk and region were randomized to nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or SUN (50 mg) once per day for 4 weeks (6-week cycle). Primary endpoints: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) per independent radiology review committee in IMDC intermediate-risk/poor-risk patients. Secondary endpoints: OS, PFS, and ORR in the intention-to-treat (ITT) population and safety. Favorable-risk patient outcomes were exploratory.ResultsAmong ITT patients, 550 were randomized to NIVO+IPI (425 intermediate/poor risk; 125 favorable risk) and 546 to SUN (422 intermediate/poor risk; 124 favorable risk). Among intermediate-risk/poor-risk patients, OS (HR, 0.66; 95% CI, 0.55–0.80) and PFS (HR, 0.75; 95% CI, 0.62–0.90) benefits were observed, and ORR was higher (42.1% vs 26.3%) with NIVO+IPI versus SUN. In ITT patients, both OS benefits (HR, 0.72; 95% CI, 0.61–0.86) and higher ORR (39.1% vs 32.6%) were observed with NIVO+IPI versus SUN. In favorable-risk patients, HR for death was 1.19 (95% CI, 0.77–1.85) and ORR was 28.8% with NIVO+IPI versus 54.0% with SUN. Duration of response was longer (HR, 0.46–0.54), and more patients achieved complete response (10.1%–12.8% vs 1.4%–5.6%) with NIVO+IPI versus SUN regardless of risk group. The incidence of treatment-related adverse events was consistent with previous reports.ConclusionsNIVO+IPI led to improved efficacy outcomes versus SUN in both intermediate-risk/poor-risk and ITT patients that were maintained through 42 months’ minimum follow-up. A complete response rate >10% was achieved with NIVO+IPI regardless of risk category, with no new safety signals detected in either arm. These results support NIVO+IPI as a first-line treatment option with the potential for durable response.Trial registration numberNCT02231749.

Patients with metastatic renal cell carcinoma with sarcomatoid features (sRCC) have a poor prognosis and have shown limited responsiveness to inhibition of the VEGF pathway. We conducted a prespecified analysis of the randomised, phase 3 IMmotion151 trial in previously untreated patients with advanced or metastatic RCC to assess the effectiveness of atezolizumab + bevacizumab versus sunitinib in a subgroup of patients with sarcomatoid features. Patients whose tumour had any component of sarcomatoid features were included and received atezolizumab + bevacizumab (n = 68) or sunitinib (n = 74). Baseline characteristics were similar between the groups. Median progression-free survival was significantly longer in the group receiving atezolizumab + bevacizumab overall (8.3 vs 5.3 mo; hazard ratio [HR] 0.52 95% confidence interval [CI] 0.34–0.79) and in the subset of patients with PD-L1–positive tumours (8.6 vs 5.6 mo; HR 0.45, 95% CI 0.26–0.77). More patients receiving atezolizumab + bevacizumab achieved an objective response (49% vs 14%), including complete responses (10% vs 3%), and reported greater symptom improvements versus sunitinib. Safety was consistent with the known profiles of each drug and with that reported in the overall safety-evaluable population of IMmotion151. This analysis supports enhanced activity of atezolizumab + bevacizumab in patients with sRCC. Patient summary In this report, we looked at patients with a specific type of kidney cancer (tumours with sarcomatoid features) that has been hard to treat. A treatment with two drugs (atezolizumab and bevacizumab) appeared to help patients live longer without the disease getting worse than another drug (sunitinib) that is often used. Patients who took the two drugs also said they were better able to carry out their everyday activities than patients who took sunitinib. The combination of these two drugs may work better in patients with this type of advanced kidney cancer.

Purpose: In the S-TRAC trial, adjuvant sunitinib improved disease-free survival (DFS) compared with placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence. This post hoc exploratory analysis investigated the neutrophil-to-lymphocyte ratio (NLR) for predictive and prognostic significance in the RCC adjuvant setting. Experimental Design: Kaplan–Meier estimates and Cox proportional analyses were performed on baseline NLR and change from baseline at week 4 to assess their association with DFS. Univariate P values were two-sided and based on an unstratified log-rank test. Results: 609 of 615 patients had baseline NLR values; 574 patients had baseline and week 4 values. Sunitinib-treated patients with baseline NLR Conclusions: In the postnephrectomy high-risk RCC patient cohort, low baseline NLR may help identify those most suitable for adjuvant sunitinib. A ≥25% NLR decrease at week 4 may be an early indicator of those most likely to tolerate treatment and derive DFS benefit.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

New cancer treatments, in particular targeted therapy or immunotherapy, have increased outcomes in recent years [1,2]. As a result, there is an increasing demand for critical care and recent studie...

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.

Background To determine safety and efficacy of radiofrequency ablation (RFA) for local treatment of lung metastases of renal cell carcinoma (RCC), sequenced or combined with systemic treatments. Methods Retrospectively, we studied 53 patients treated by RFA for a maximum of six lung metastases of RCC. The endpoints were local efficacy, overall (OS), disease-free (DFS), pulmonary progression-free (PPFS) and systemic treatment-free (STFS) survivals, complications graded by the CTCAE classification and factors associated with survivals. Potential factors analysed were: clinical and pathological data, tumoral staging of TNM classification, primary tumor histology, Fuhrman’s grade, age, number and size of lung metastases and extra-pulmonary metastases pre-RFA. Results One hundred metastases were treated by RFA. Median follow-up time was 61 months (interquartile range 90–34). Five-year OS was 62% (95% confidence interval (CI): 44–75). Median DFS was 9.9 months (95% CI: 6–16). PPFS at 1 and 3 years was 58.9% (95%CI: 44.1–70.9) and 35.2% (95%CI: 21.6–49.1), respectively. We observed 3% major complications (grade 3 and 4 of CTCAE classification). Local efficacy was 91%. Median STFS was 28.3 months. Thirteen patients (25%) with lung recurrence could be treated by another RFA. T3/T4 tumors had significantly worse OS, PPFS and STFS. Having two or more lung metastases increased the risk of pulmonary progression more than threefold. Conclusion Integrated to systemic treatment strategy, RFA is safe and effective for the treatment strategy of lung metastasis from RCC with good OS and long systemic treatment-free survival. RFA offers the possibility of repeat procedures, with low morbidity.

Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4-7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials. gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-beta and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.

International audience; Introduction: Papillary renal cell carcinoma (PRCC) represents 10%e15% of renal carcinomas. No standard treatments exist for metastatic PRCC (mPRCC) patients. Axitinib is indicated as second-line treatment in metastatic clear cell renal carcinoma, and we aim to assess the efficacy of this vascular endothelial growth factor receptor inhibitor in front line for mPRCC. Methods: This French multicentre phase II study AXIPAP enrolled untreated mPRCC patients, with measurable disease, Eastern Cooperative Oncology Group performance status 1 and Vascular endothelial growth factor; VEGF inhibitor; Targeted therapy adequate organ functions. PRCC had to be confirmed by histology expert central review. Axi-tinib was administered orally 5 mg twice daily. Primary end-point was progression-free rate at 24 weeks (24w-PFR) by central review. Results: Fifty-six patients were screened, and 44 included (13 type 1, 30 type 2 and 1 non-specified). The median follow-up was 32.0 (13.1e39.9) months. The 24w-PFR was 45.2% (95% confidence interval [CI], 32.6% to þN), the objective response rate was 28.6% (95% CI, 15.7%e44.6%) (type 1: 7.7%; type 2: 35.7%). The overall median progression free survival was 6.6 months (95% CI, 5.5e9.2), 6.7 months (95% CI, 5.5e9.2) and 6.2 months (95% CI, 5.4 e9.2) for type 1 and 2, respectively. Median overall survival was 18.9 months (95% CI, 12.8enot reached). Adverse events were as expected; grade 3e4 treatment-related adverse events were rare except hypertension (27%). Conclusions: Axitinib demonstrated encouraging efficacy in mPRCC patients, especially in type 2 PRCC. Toxicity was manageable. Axitinib appears as an interesting option for first-line treatment and to be worth further investigation in combination with immunotherapy in these patients. Expert pathology review should be recommended in this setting. Clinical trial registration: ClinicalTrials.gov, NCT02489695.

BACKGROUND: Antibodies targeting programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) have shown clinical activity in the treatment of metastatic renal cell carcinoma (mRCC). This phase Ib cohort of the JAVELIN Solid Tumor trial assessed the efficacy and safety of avelumab (anti-PD-L1) monotherapy in patients with mRCC as either first-line (1 L) or second-line (2 L) treatment. METHODS: Patients with mRCC with a clear-cell component who were treatment naive (1 L subgroup) or had disease progression after one prior line of therapy (2 L subgroup) received avelumab 10 mg/kg intravenous infusion every 2 weeks. Endpoints included confirmed best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), PD-L1 expression, and safety. RESULTS: A total of 62 patients were enrolled in the 1 L subgroup, and 20 patients were enrolled in the 2 L subgroup. In the 1 L and 2 L subgroups, confirmed objective response rates were 16.1 and 10.0%, median DOR was 9.9 months (95% confidence interval [CI], 2.8-not evaluable) and not evaluable (95% CI, 6.9-not evaluable), median PFS was 8.3 months (95% CI, 5.5-9.5) and 5.6 months (95% CI, 2.3-9.6), and median OS was not evaluable (95% CI, not evaluable) and 16.9 months (95% CI, 8.3-not evaluable), respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 51 patients in the 1 L subgroup (82.3%) and 14 patients in the 2 L subgroup (70.0%). Grade ≥ 3 TRAEs occurred in eight patients in the 1 L subgroup (12.9%) and one patient in the 2 L subgroup (5.0%). No treatment-related deaths occurred. CONCLUSION: Avelumab showed clinical activity and a manageable safety profile in both the 1 L and 2 L treatment setting in patients with mRCC. These data support the use of avelumab in combination with other agents in mRCC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01772004 ; registered 21 January, 2013. ispartof: JOURNAL FOR IMMUNOTHERAPY OF CANCER vol:7 issue:1 ispartof: location:England status: published

Background Papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC). Pivotal studies evaluating immune checkpoint inhibitors mostly excluded nccRCC. PD-1/PD-L1 inhibitors exhibit limited activity in metastatic pRCC. The immune microenvironment in pRCC is unknown. Methods In silico, we studied the expression of cytotoxic lymphocyte infiltration (CYT), using a descriptive (by CIBERSORT) and specific quantitative approach, as well as the expression of inhibitors checkpoint immune markers (ICI), in 258 localized papillary renal cell tumors using RNA-seq data from The Cancer Genome Atlas (TCGA) as training set. Based on previous report, we selected 8 genes of interest (CD8a, CD8b, GZMA, PRF1, PD1, PDL1, PDL2 and CTLA4). An independent data set of 34 localized pRCC (gene expression) was used as a validation set. Results Using a clustering method based on the expression level of 8 predefined genes of interest, we identified 3 groups, differentiated by CYT and ICI expression. In validation cohort, we observed similar clustering. Cluster 3, characterized by a CYT and ICI high expression, was significantly associated with increased population of TCD8, TCD4 helper, M1 macrophages and dendritic cells in CIBERSORT analysis. Additionally, these immune clusters were not associated with indels neo-antigen load but were significantly correlated with the MHC class I antigen presenting machinery expression (APM) (p = 1.1.10-11) and interferon-gamma gene expression (p = 1.6.10-13). Conclusions We characterized cytotoxic immune infiltration in pRCCs. Cluster 3 could correspond to a population of immunotherapy responders. Transcriptomic immune signature validation in pRCCs patients treated with immunotherapy is warranted. Legal entity responsible for the study Manon de Vries-Brilland. Funding Has not received any funding. Disclosure M. Gross-Goupil: Honoraria (institution), Advisory / Consultancy: Ipsen; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (institution), Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Amgen. A. Ravaud: Research grant / Funding (institution), Travel / Accommodation / Expenses, Officer / Board of Directors: Pfizer; Travel / Accommodation / Expenses, Officer / Board of Directors: BMS; Travel / Accommodation / Expenses, Officer / Board of Directors: AstraZeneca; Travel / Accommodation / Expenses, Officer / Board of Directors: Roche; Travel / Accommodation / Expenses, Officer / Board of Directors: MSD; Travel / Accommodation / Expenses, Officer / Board of Directors: Ipsen. B. Escudier: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (self): Aveo; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: EUSA. L. Albiges: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.

Background Androgen deprivation therapy (ADT) plus docetaxel is the standard of care in fit men with metastatic castration-naive prostate cancer (mCNPC) following results from GETUG-AFU 15, CHAARTED, and STAMPEDE. No data are available on the efficacy of treatments used for metastatic castration-resistant prostate cancer (mCRPC) in men treated upfront with ADT plus docetaxel for mCNPC. Objective To investigate the efficacy and tolerance of subsequent treatments in patients treated upfront with chemo-hormonal therapy for mCNPC. Design, setting, and participants Retrospective data from the GETUG-AFU 15 phase 3 trial were collected for treatments received for mCRPC. Outcome measurements and statistical analysis For the first three lines of salvage treatment for mCRPC we investigated the biochemical progression-free survival, maximum prostate-specific antigen (PSA) decline, overall survival, and tolerance. Results and limitations Overall, 245 patients received at least one treatment for mCRPC. For docetaxel used in first-line, a PSA decline ≥50% was observed in 25/66 (38%) and in 4/20 patients (20%) who had received upfront ADT alone and ADT plus docetaxel ( p =0.14). The median biochemical progression-free survival was 6.0 mo (95% confidence interval: 3.6–7.7) and 4.1 mo (95% confidence interval: 1.3–4.9), respectively. For docetaxel used in first- or second-line, a PSA decline ≥50% was observed in 36/80 (45%) and in 4/29 patients (14%) who had received upfront ADT alone and ADT plus docetaxel ( p =0.07). PSA declines ≥50% were observed with bicalutamide in 12/28 (43%) and 4/23 patients (17%) who had received upfront ADT alone and ADT plus docetaxel. Among men treated upfront with ADT plus docetaxel who received abiraterone or enzalutamide for mCRPC, 10/19 patients (53%) achieved a PSA decline ≥50%. Few grade 3–4 events occurred. Study limitations include the observational design and retrospective characteristics of this analysis, without standardized therapeutic salvage protocols, and the limited number of patients in some of the treatment subgroups. Conclusions Docetaxel rechallenge following progression to mCRPC after upfront ADT plus docetaxel for mCNPC was active only in a limited number of patients. Available data on abiraterone and enzalutamide support maintained efficacy in this setting. The lack of standardized therapeutic protocols for men developing mCRPC limits the comparability between patients. Patient summary Rechallenging docetaxel at castration-resistance was active only in a limited number of patients treated upfront with chemo-hormonal therapy for metastatic castration-naive prostate cancer. Anticancer activity was suggested with abiraterone or enzalutamide in this setting.

Summary Background Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population. Methods We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged ≥18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m 2 , paclitaxel 175 mg/m 2 , or 75 mg/m 2 docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on vs ≥5% of tumour-infiltrating immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver metastases (yes vs no), and number of prognostic factors (none vs one, two, or three). Patients and investigators were aware of group allocation. Patients, investigators, and the sponsor were masked to PD-L1 expression status. The primary endpoint of overall survival was tested hierarchically in prespecified populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. This study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT02302807. Findings Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11·1 months [95% CI 8·6–15·5; n=116] vs 10·6 months [8·4–12·2; n=118]; stratified hazard ratio [HR] 0·87, 95% CI 0·63–1·21; p=0·41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15·9 months [95% CI 10·4 to not estimable] vs 8·3 months [5·6–13·2]; HR 0·57, 95% CI 0·26–1·26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3–4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients). Interpretation Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting. Funding F Hoffmann-La Roche, Genentech.

Simple Summary First-line treatment options for metastatic clear cell renal cell carcinoma have significantly increased. The current recommended therapeutic strategy is based on a combination, but monotherapy remains an alternative. However, the choice of the type of combination, i.e., dual immunotherapy or immunotherapy combined with an antiangiogenic drug, has not been clearly standardized. A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. This review summarizes all recent data from the main combinations evaluated in first-line treatment and discusses the choice of drugs according to the patient’s profile and the benefit/risk balances of each combination. Abstract The development of antiangiogenic treatments, followed by immune checkpoint inhibitors (ICI), has significantly changed the management of metastatic clear cell renal cell cancer. Several phase III trials show the superiority of combination therapy, dual immunotherapy (ICI-ICI) or ICI plus tyrosine kinase inhibitors (TKI) of the vascular endothelium growth factor (VEGF) over sunitinib monotherapy. The question is therefore what is the best combination for a given patient? A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. However, several issues remain unresolved and require further investigation, such as the PD-L1 status, the relevance of possible options based on the patient’s profile, and consideration of second-line and subsequent treatments.

Objectif Cette video la prise en charge en chirurgie robotique d’un patient de 45 ans presentant une TGNS testiculaire avec volumineuse atteinte retroperitoneale. Le scanner realise apres chimiotherapie revele un volumineux amas de masses residuelles comprenant un envahissement de la veine cave, responsable de 2 episodes d’embolie pulmonaire. L’objectif d’une telle approche mini-invasive est de limiter la morbidite perioperatoire. Methodes Un filtre cave a ete positionne avant la chirurgie afin d’eviter une recidive d’embolie pulmonaire. Le patient a ete installe an decubitus lateral droit, avec un roulis de 70°. L’espace retroperitoneal a ete aborde de maniere transmesocolique, puis le decollement duodenal a ete realise. Le curage a debute par la liberation du nodule envahissant la veine cave. Celle-ci a ete controlee des deux cotes du thrombus. La cavotomie a necessite 20 min de clampage. L’intervention s’est poursuivie en completant le curage pre-cave, puis inter-aortico-cave jusqu’aux vaisseaux renaux. Resultats La duree operatoire fut de 6 h 14, les pertes sanguines estimees a 500 mL. Aucune transfusion n’a ete necessaire. Le patient est sorti a j4 sans complication postoperatoire. L’examen anatomopathologique montre la presence de tissus necrotiques et de multiples foyers teratomateux, sans persistance de tumeur viable. Le filtre cave a ete retire au 14e jour postoperatoire. Apres 9 mois de suivi, le patient n’a presente aucun signe clinique ou biologique de recidive. Conclusion La chirurgie de masses residuelles est habituellement realisee en centres experts et necessite une laparotomie xyphopubienne. La voie robotique mini-invasive s’impose peu a peu comme une alternative reduisant la morbidite. Neanmoins, plus de publications dans la litterature, avec un suivi oncologique prolonge, sont necessaires pour confirmer l’interet de cette voie d’abord.

ObjectivesTo evaluate the prevalence and type of rheumatic immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs), as well as the correlation with tumour response.MethodsThis was a single-centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs and tumour response was assessed on a regular basis. Patients who experienced musculoskeletal symptoms were referred to the department of rheumatology for clinical evaluation and management.ResultsFrom September 2015 to May 2017, 524 patients received ICIs and 35 were referred to the department of rheumatology (6.6%). All but one of the rheumatic irAEs occurred with anti-programmed cell death protein 1(PD-1)/PD-1 ligand 1(PD-L1) antibodies, with a median exposure time of 70 days. There were two distinct clinical presentations: (1) inflammatory arthritis (3.8%) mimicking either rheumatoid arthritis (n=7), polymyalgia rheumatica (n=11) or psoriatic arthritis (n=2) and (2) non-inflammatory musculoskeletal conditions (2.8%; n=15). One patient with rheumatoid arthritis was anti-cyclic citrullinated peptide (anti-CCP) positive. Nineteen patients required glucocorticoids, and methotrexate was started in two patients. Non-inflammatory disorders were managed with non-steroidal anti-inflammatory drugs, analgesics and/or physiotherapy. ICI treatment was pursued in all but one patient. Patients with rheumatic irAEs had a higher tumour response rate compared with patients without irAEs (85.7% vs 35.3%; PConclusionSince ICIs are used with increasing frequency, knowledge of rheumatic irAEs and their management is of major interest. All patients were responsive either to low-to-moderate doses of prednisone or symptomatic therapies and did not require ICI discontinuation. Furthermore, tumour response was significantly higher in patients who experienced rheumatic irAEs.