Publications by authors named "Thomas Powles"

288 Publications

Early Clinical Experience with Cabozantinib for Advanced Renal Cell Carcinoma in the UK: Real-World Treatment Pathways and Clinical Outcomes.

Clin Genitourin Cancer 2021 Oct 8. Epub 2021 Oct 8.

Barts Cancer Institute, Queen Mary University of London, London, UK.

Background: Cabozantinib monotherapy is approved in the UK for patients with treatment-naïve intermediate- or poor-risk advanced renal cell carcinoma (aRCC), or patients who received prior vascular endothelial growth factor-targeted therapy. Data are limited on the real-world use of cabozantinib for aRCC.

Patients And Methods: CERES (NCT03696407) was a retrospective study of patients with aRCC who received cabozantinib through the UK managed access programme (MAP; August 2016-July 2017), at which time cabozantinib had European regulatory approval for second- or later-line use only. The study objectives were to characterize aRCC treatment patterns and evaluate cabozantinib effectiveness. Outcomes were stratified by cabozantinib treatment line, MAP treatment date (months 0-7 vs. 8-12) and (post hoc) Charlson Comorbidity Index (CCI; ≥ 6 vs. < 6).

Results: Of 100 patients included, 99% had stage IV disease, 63% had a CCI ≥ 6 and 81% had an Eastern Cooperative Oncology Group Performance Status 0-1. Median (range) duration of follow-up was 10.8 (0.4-33.5) months. Cabozantinib was administered as second-line, third-line and fourth- or later-line in 41%, 31% and 28% of patients, respectively. Most patients (84%) initiated cabozantinib at 60 mg. Average (range) cabozantinib dose was 45.5 (19.6-59.8) mg/day; 66% of patients had ≥ 1 dose reduction. Disease progression was the most common reason for discontinuation (65.1%). Median (95% confidence interval) progression-free survival (PFS) and overall survival (OS) were 6.01 (5.16-7.85) and 10.84 (7.92-16.85) months, respectively. Overall response rate was 34.5%; disease control rate 70.1% and duration of response 6.9 (1.8-26.9) months. No significant differences in survival estimates were observed between treatment line or treatment date subgroups. Total CCI score ≤ 6 (vs. > 6) was associated with prolonged median PFS and OS.

Conclusion: Cabozantinib demonstrated clinical activity in this UK real-world aRCC population. The results provide a benchmark for future real-world studies in aRCC.
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http://dx.doi.org/10.1016/j.clgc.2021.09.005DOI Listing
October 2021

Treatment-free Survival after Immune Checkpoint Inhibitor Therapy versus Targeted Therapy for Advanced Renal Cell Carcinoma: 42-Month Results of the CheckMate 214 Trial.

Clin Cancer Res 2021 Nov 10. Epub 2021 Nov 10.

Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Purpose: Patients discontinuing immuno-oncology regimens may experience periods of disease control without need for ongoing anticancer therapy, but toxicity may persist. We describe treatment-free survival (TFS), with and without toxicity.

Patients And Methods: Data were analyzed from the randomized phase III CheckMate 214 trial of nivolumab plus ipilimumab ( = 550) versus sunitinib ( = 546) for treatment-naïve, advanced renal cell carcinoma (aRCC). TFS was estimated by the 42-month restricted mean times defined by the area between Kaplan-Meier curves for two time-to-event endpoints defined from randomization: time to protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was subdivided as TFS with and without toxicity by counting days with ≥1 grade ≥3 treatment-related adverse event (TRAE).

Results: At 42 months since randomization, 52% of nivolumab plus ipilimumab and 39% of sunitinib intermediate/poor-risk patients were alive; 18% and 5% surviving treatment-free, respectively. Among favorable-risk patients, 70% and 73% of nivolumab plus ipilimumab and sunitinib patients were alive; 20% and 9% treatment-free. Over the 42-month period, mean TFS was over twice as long after nivolumab plus ipilimumab than sunitinib for intermediate/poor-risk (6.9 vs. 3.1 months) and three times as long for favorable-risk patients (11.0 vs. 3.7 months). Mean TFS with grade ≥3 TRAEs was a small proportion of time for both treatments (0.6 vs. 0.3 months after nivolumab plus ipilimumab vs. sunitinib for intermediate/poor-risk, and 0.9 vs. 0.3 months for favorable-risk patients).

Conclusions: Patients initiating first-line nivolumab plus ipilimumab for aRCC spent more survival time treatment-free without toxicity versus those on sunitinib, regardless of risk group.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2283DOI Listing
November 2021

Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. Reply.

N Engl J Med 2021 11;385(20):1920

Royal Free Hospital, London, United Kingdom.

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http://dx.doi.org/10.1056/NEJMc2115204DOI Listing
November 2021

First-line Nivolumab plus Ipilimumab Versus Sunitinib in Patients Without Nephrectomy and With an Evaluable Primary Renal Tumor in the CheckMate 214 Trial.

Eur Urol 2021 Nov 5. Epub 2021 Nov 5.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

We present an exploratory post hoc analysis from the phase 3 CheckMate 214 trial of first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in a subgroup of 108 patients with advanced renal cell carcinoma (aRCC) without prior nephrectomy and with an evaluable primary tumor, a population under-represented in clinical trials. Patients with clear cell aRCC were randomized to NIVO+IPI every 3 wk for four doses followed by NIVO monotherapy, or sunitinib every day for 4 wk (6-wk cycle). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and primary tumor shrinkage were assessed. PFS and ORR were assessed per independent radiology review committee using RECIST version 1.1. With minimum study follow-up of 4 yr for intent-to-treat patients, OS favored NIVO+IPI (n = 53) over sunitinib (n = 55; hazard ratio 0.63, 95% confidence interval 0.40-1.0) among patients without prior nephrectomy. ORR was higher (34% vs 15%; p = 0.0041) and median duration of response was longer with NIVO+IPI versus sunitinib (20.5 vs 14.1 mo); the best overall response was partial response in either arm. A ≥30% reduction in the diameter of intact target renal tumors was achieved in 35% of patients with NIVO+IPI versus 20% with sunitinib. Safety was consistent with the global study population. In conclusion, in patients with aRCC without prior nephrectomy and with an evaluable primary tumor, NIVO+IPI showed survival benefits and renal tumor reduction versus sunitinib. This trial is registered at ClinicalTrials.gov as NCT02231749. PATIENT SUMMARY: In an exploratory analysis of a large global trial (CheckMate 214), we observed positive outcomes (both survival and tumor response to treatment) with nivolumab plus ipilimumab over sunitinib in a subgroup of patients with advanced kidney cancer who did not undergo removal of their primary kidney tumor. This subset of patients represents a population that has not been studied in clinical trials and for whom outcomes with new immunotherapy combination regimens are not yet known. We conclude that treatment with nivolumab plus ipilimumab offers these patients a survival benefit versus sunitinib, consistent with that observed in the overall study, as well as a notable kidney tumor reduction.
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http://dx.doi.org/10.1016/j.eururo.2021.10.001DOI Listing
November 2021

Beyond Chemotherapy and Checkpoint Inhibitors: Weighing the Risks and Benefits of the Novel Therapies for Metastatic Urothelial Carcinoma.

J Clin Oncol 2021 Oct 7;39(30):3411-3412. Epub 2021 Sep 7.

Thomas Powles, MD, Barts Cancer Centre, Queen Mary University of London, London, United Kingdom; Daniel P. Petrylak, MD, Smilow Cancer Center, Yale School of Medicine, New Haven, CT; and Jonathan E. Rosenberg, MD, Memorial Sloan Kettering Cancer Center, New York, NY.

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http://dx.doi.org/10.1200/JCO.21.01430DOI Listing
October 2021

Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.

N Engl J Med 2021 08;385(8):683-694

From Dana-Farber Cancer Institute, Boston (T.K.C.); Poznan University of Medical Sciences, Poznan (P.T.), and Wojewódzki Szpital Zespolony im. L. Rydygiera w Toruniu, Torun (P.S.) - both in Poland; Sungkyunkwan University, Samsung Medical Center (S.H.P.), and Asan Medical Center, University of Ulsan College of Medicine (J.L.L.) - both in Seoul, South Korea; Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow (B.V.), Edinburgh Cancer Centre and University of Edinburgh, Edinburgh (S.N.S.), and Imperial College Healthcare NHS Trust (N.S.) and the Royal Free Hospital NHS Trust, University College London (T.P.), London - all in the United Kingdom; Fiona Stanley Hospital, Perth, WA (T.F.), and Macquarie University, Sydney (H.G.) - both in Australia; Taipei Veterans General Hospital, Taipei, Taiwan (Y.-H.C.); Fakultni Nemocnice Ostrava, Ostrava (J.H.), and Palacký University and University Hospital Olomouc, Olomouc (B.M.) - both in the Czech Republic; University Hospital Jean Minjoz, Besançon (A.T.-V.), University Hospital Bordeaux-Hôpital Saint-André, Bordeaux (M.G.-G.), Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse (C.C.), Centre Hospitalier Universitaire de Montpellier, Montpellier (D.T.), and Hôpital Européen Georges Pompidou, University of Paris, Paris (S.O.) - all in France; Fundación Arturo López Pérez, Santiago, Chile (M.M.); Abramson Cancer Center, Philadelphia (N.H.); Omsk Clinical Oncology Dispensary, Omsk, Russia (E.K.); the University of Michigan, Ann Arbor (A.A.); Rocky Mountain Cancer Centers and U.S. Oncology Research, Denver (J.M.B.); Texas Oncology, U.S. Oncology Research, Woodlands (G.D.), and the University of Texas Southwestern, Dallas (H.H.); the University of Toyama, Toyama, Japan (H.K.); Eberhard Karls University Tübingen, Tübingen, Germany (J.B.); Merck, Kenilworth, NJ (R.F.P., P.Z., K.I., J.W.-R.); and USC Norris Comprehensive Cancer Center, Los Angeles (D.I.Q.).

Background: Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence.

Methods: In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point.

Results: A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred.

Conclusions: Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).
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http://dx.doi.org/10.1056/NEJMoa2106391DOI Listing
August 2021

Providing an acute oncology service during the COVID-19 pandemic.

Clin Med (Lond) 2021 Sep 11;21(5):e548-e551. Epub 2021 Aug 11.

Barts Health NHS Trust, London, UK.

The COVID-19 pandemic has led to adaptations being made to all aspects of the NHS, including general practice, acute medical specialties and oncology. This has presented unique challenges to acute oncology services (AOSs) in how to provide continuity of care while maintaining the safety of patients and staff. We describe the experience of the AOS team at Barts Health NHS Trust, working across three acute hospitals in east London. Changes to the service due to COVID-19 included increased remote reviews and referrals to the specialist oncology cancer acute assessment unit. The patient population reviewed in April 2020 (at the initial peak of the pandemic in the UK) was markedly different to one reviewed in April 2019, with 55% more patients presenting with a new diagnosis of cancer via an emergency route. Finally, we suggest changes to AOSs for future waves of the pandemic.
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http://dx.doi.org/10.7861/clinmed.2020-0693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439511PMC
September 2021

Outcomes based on plasma biomarkers in METEOR, a randomized phase 3 trial of cabozantinib vs everolimus in advanced renal cell carcinoma.

BMC Cancer 2021 Aug 7;21(1):904. Epub 2021 Aug 7.

Duke Cancer Institute, Durham, NC, USA.

Background: In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced RCC after prior antiangiogenic therapy.

Methods: In this exploratory analysis, plasma biomarkers from baseline and week 4 from 621 of 658 randomized patients were analyzed for CA9, HGF, MET, GAS6, AXL, VEGF, VEGFR2, and IL-8. PFS and OS were analyzed by baseline biomarker levels as both dichotomized and continuous variables using univariate and multivariable methods. For on-treatment changes, PFS and OS were analyzed using fold change in biomarker levels at week 4. Biomarkers were considered prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and biomarker.

Results: Hazard ratios for PFS and OS favored cabozantinib versus everolimus for both low and high baseline levels of all biomarkers (hazard ratios ≤0.78). In univariate analyses, low baseline HGF, AXL, and VEGF were prognostic for improvements in both PFS and OS with cabozantinib, and low HGF was prognostic for improvements in both PFS and OS with everolimus. Low AXL was predictive of relative improvement in PFS for cabozantinib versus everolimus. Results were generally consistent when baseline biomarkers were expressed as continuous variables, although none were predictive of benefit with treatment. In multivariable analysis, low baseline HGF was independently prognostic for improved PFS for both cabozantinib and everolimus; low HGF, GAS6, and VEGF were independently prognostic for improved OS with cabozantinib. No biomarkers were independently prognostic for OS with everolimus. On-treatment increases in some biomarkers appeared prognostic for PFS or OS with cabozantinib in univariate analyses; however, none were independently prognostic in multivariable analysis.

Conclusions: PFS and OS were improved with cabozantinib versus everolimus at high and low baseline levels of all biomarkers. Low baseline HGF was consistently identified as a prognostic biomarker for improved PFS or OS with cabozantinib or everolimus, supporting further prospective evaluation of the prognostic significance of HGF in advanced RCC.

Trial Registration: ClinicalTrials.gov NCT01865747 (registered on 05/31/2013).
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http://dx.doi.org/10.1186/s12885-021-08630-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349489PMC
August 2021

Characterization and Management of Treatment-emergent Hepatic Toxicity in Patients with Advanced Renal Cell Carcinoma Receiving First-line Pembrolizumab plus Axitinib. Results from the KEYNOTE-426 Trial.

Eur Urol Oncol 2021 Jul 6. Epub 2021 Jul 6.

Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London, London, UK.

Background: Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed.

Objective: To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib.

Design, Setting, And Participants: Patients enrolled in KEYNOTE-426 were included in this study.

Outcome Measurements And Statistical Analysis: Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s).

Results And Limitations: The HEAS comprised 189/429 (44%) pembrolizumab-axitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to <3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT <3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred.

Conclusions: A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment.

Patient Summary: Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management.
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http://dx.doi.org/10.1016/j.euo.2021.05.007DOI Listing
July 2021

Learning from Crisis: a Multicentre Study of Oncology Telemedicine Clinics Introduced During COVID-19.

J Cancer Educ 2021 Jul 2. Epub 2021 Jul 2.

Barts Cancer Institute, Bart's and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, Barbican, London, EC1M 6BE, UK.

The COVID-19 pandemic has necessitated adaptation of cancer patient care. Oncology patients who contract COVID-19 have poor outcomes. Telemedicine clinics (teleclinics) have been introduced for cancer patients to reduce the risk of horizontal transmission at St. Bartholomew's Hospital and The Royal Free Hospital in London. Teleclinics have become routine in many specialities; however, inclusion in oncology care was not standard prior to the pandemic. A mixed-methods survey was designed and delivered to cancer patients (n = 106) at St. Bartholomew's Hospital and The Royal Free Hospital who had transitioned to teleclinics in March 2020. The survey explored patients' perceptions of this format. In total, 96 (90.5%) patients consented to take part, across a range of tumour types. Overall, respondents reacted favourably to the format of the teleclinics, with 90.6% of respondents (87/96) stating they would utilise teleclinics beyond the pandemic. Additionally, a survey was distributed to clinicians delivering these teleclinics (n = 16) to explore previous training in, perceptions of, and lessons learned from the introduction of telemedicine. Results suggest patients are accepting of teleclinic use for most clinical purposes. Teleclinic implementation affords benefits to cancer patient care both during and after COVID-19, but there is an urgent need for telemedicine education in oncology specialty training.
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http://dx.doi.org/10.1007/s13187-021-02053-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249430PMC
July 2021

Enfortumab Vedotin in Advanced Urothelial Carcinoma. Reply.

N Engl J Med 2021 07;385(1):93-94

Memorial Sloan Kettering Cancer Center, New York, NY.

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http://dx.doi.org/10.1056/NEJMc2106975DOI Listing
July 2021

Molecular determinants of response to PD-L1 blockade across tumor types.

Nat Commun 2021 06 25;12(1):3969. Epub 2021 Jun 25.

Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, UK.

Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC). Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications. Signatures described previously for immune checkpoint inhibitors also failed to validate. At the pathway level, significant heterogeneity is observed between indications, in particular within the PD-L1 tumors. mUC and NSCLC are molecularly aligned, with cell cycle and DNA damage repair genes associated with response in PD-L1- tumors. At the gene level, the CDK4/6 inhibitor CDKN2A is identified as a significant transcriptional correlate of response, highlighting the association of non-immune pathways to the outcome of checkpoint blockade. This cross-indication analysis reveals molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.
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http://dx.doi.org/10.1038/s41467-021-24112-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233428PMC
June 2021

Differences in oncological and toxicity outcomes between programmed cell death-1 and programmed cell death ligand-1 inhibitors in metastatic renal cell carcinoma: A systematic review and meta-analysis.

Cancer Treat Rev 2021 Sep 12;99:102242. Epub 2021 Jun 12.

Department of Urology, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Research Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria. Electronic address:

Background: The programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) pathway is important in metastatic renal cell carcinoma (mRCC). However, some dissimilarities between anti-PD-1 and anti-PD-L1 inhibitors have emerged. We aimed to assess differences between anti-PD-1 and anti-PD-L1 combination immunotherapies as first-line treatments in mRCC patients.

Methods: Multiple databases (PubMed, Web of Science, and Scopus) were searched for articles published until March 2021. Studies were eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORR), complete response rates (CRR), and adverse events.

Results: Five studies met the eligibility criteria. PD-1 combination therapy was associated with significantly better OS and PFS and higher ORR and CRR than sunitinib (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.40-0.89; HR: 0.52, 95% CI: 0.37-0.75; odds ratio [OR]: 3.20, 95% CI: 2.18-4.68; and OR: 3.05, 95% CI: 2.13-4.37, respectively; P < 0.001). For all oncological outcomes, anti-PD-1 agents were superior to anti-PD-L1 agents based on HR and OR (OS: HR = 0.88, PFS: HR = 0.76, ORR: OR = 1.85, and CRR: OR = 2.24). Conversely, anti-PD-L1 agents were superior to anti-PD-1 agents in their safety profiles. In network meta-analyses, pembrolizumab plus lenvatinib seemed the worst tolerated anti-PD-1 combination therapy.

Conclusions: Our analysis indicates the superior oncologic benefits of first-line anti-PD-1 combination therapies over anti-PD-L1 combination therapies in mRCC patients. This biological difference is of vital importance for clinical treatment decision making and the design of future rational combination therapy trials in mRCC.
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http://dx.doi.org/10.1016/j.ctrv.2021.102242DOI Listing
September 2021

ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.

Nature 2021 07 16;595(7867):432-437. Epub 2021 Jun 16.

Roche/Genentech, South San Francisco, CA, USA.

Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFβ signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.
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http://dx.doi.org/10.1038/s41586-021-03642-9DOI Listing
July 2021

The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor-based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care.

Eur Urol 2021 10 29;80(4):393-397. Epub 2021 May 29.

The Royal Free London NHS Foundation Trust, London, UK; UCL Division of Surgery and Interventional Science, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

The recent randomized controlled phase III CLEAR trial results are the last to complement immune checkpoint inhibitor (ICI)-based doublet combination therapies for treatment-naïve metastatic clear-cell renal cell carcinoma. The CLEAR trial demonstrated an improved progression-free survival (PFS), overall survival (OS), and an objective response rate (ORR) benefit for the combination of lenvatinib plus pembrolizumab over sunitinib. The CheckMate-9ER trial update demonstrated an ongoing PFS, OS, and quality-of-life benefit for cabozantinib plus nivolumab over sunitinib as did the update of Keynote-426 for axitinib plus pembrolizumab in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups. In the IMDC intermediate- and poor-risk groups, the CheckMate-214 trial of ipilimumab plus nivolumab confirmed the OS benefit with a PFS plateauing after 30 months. The RCC Guidelines Panel recommends three tyrosine kinase inhibitors + ICI combinations of axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab across all IMDC risk groups in advanced first-line RCC, and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate- and poor-risk groups. PATIENT SUMMARY: New data from combination trials with immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit for lenvatinib plus pembrolizumab, cabozantinib plus nivolumab (with improved quality-of-life), axitinib plus pembrolizumab, and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.
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http://dx.doi.org/10.1016/j.eururo.2021.04.042DOI Listing
October 2021

Immune Checkpoint Inhibition in Advanced Bladder and Kidney Cancer: Responses and Further Management.

Am Soc Clin Oncol Educ Book 2021 Jun;41:e182-e189

Barts Health NHS Trust and the Royal Free NHS Foundation Trust, Barts Cancer Institute, and Queen Mary University of London, London, United Kingdom.

Immune checkpoint inhibitors have an established role in the treatment of newly diagnosed metastatic kidney cancer. Treatment regimens combining nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib have demonstrated superior overall survival compared with sunitinib in randomized studies. Response rates vary from 42% to 71.1% with these combinations. Atezolizumab and pembrolizumab have been approved for the treatment of cisplatin-ineligible patients with metastatic bladder cancer. These and other checkpoint inhibitors have been studied in metastatic bladder cancer and are routinely used after progression on platinum-based chemotherapy. Durable responses are observed in bladder and kidney cancer. Although some patients may experience immune-related adverse events requiring treatment discontinuation, a portion of these patients will continue to experience a response off-therapy. At the time of progression, patients with metastatic kidney cancer may be treated with antiangiogenesis agents, and there are data suggesting that they may also be treated with a rechallenge of immunotherapy. In patients with metastatic bladder cancer who have progression after immune checkpoint inhibition, there are considerable data supporting the use of enfortumab vedotin. Ongoing studies are evaluating novel combinations of immune checkpoint inhibitors with other agents; thus, the treatment landscape of metastatic bladder and kidney cancer is expected to continue to evolve rapidly.
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http://dx.doi.org/10.1200/EDBK_323835DOI Listing
June 2021

Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial.

Lancet Oncol 2021 07 26;22(7):931-945. Epub 2021 May 26.

University of Michigan Health System, Ann Arbor, MI, USA.

Background: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma.

Methods: KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305.

Findings: Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group.

Interpretation: The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma.

Funding: Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
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http://dx.doi.org/10.1016/S1470-2045(21)00152-2DOI Listing
July 2021

Radiomics for Renal Cell Carcinoma: Predicting Outcomes from Immunotherapy and Targeted Therapies-A Narrative Review.

Eur Urol Focus 2021 Jul 11;7(4):717-721. Epub 2021 May 11.

Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK.

T-cell immunotherapy and molecular targeted therapies have become standard-of-care treatments for renal cell carcinoma (RCC). There is a need to develop robust biomarkers that predict patient outcomes to targeted therapies to personalise treatment. In recent years, quantitative analysis of imaging features, termed radiomics, has been used to extract tumour features. This narrative mini review summarises the evidence for radiomics prediction of immunotherapy and molecular targeted therapy outcomes in RCC. Radiomics may predict survival, treatment response, and disease progression in RCC treated with tyrosine kinase inhibitors (eg, sunitinib) and immune checkpoint inhibitors (eg, nivolumab). Further validation is necessary in large-scale studies. PATIENT SUMMARY: We summarise evidence on the ability of features extracted from CT (computed tomography) scans to predict patient outcomes from new treatments for kidney cancer. Although these features can predict treatment outcomes for patients, including survival, treatment response, and cancer progression, further research is necessary before this technology can be applied clinically.
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http://dx.doi.org/10.1016/j.euf.2021.04.024DOI Listing
July 2021

Impact of the first surge of the COVID-19 pandemic on a tertiary referral centre for kidney cancer.

BJU Int 2021 12 25;128(6):752-758. Epub 2021 May 25.

Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, UK.

Objective: To analyse the impact of the COVID-19 pandemic on a centralized specialist kidney cancer care pathway.

Materials And Methods: We conducted a retrospective analysis of patient and pathway characteristics including prioritization strategies at the Specialist Centre for Kidney Cancer located at the Royal Free London NHS Foundation Trust (RFH) before and during the surge of COVID-19.

Results: On 18 March 2020 all elective surgery was halted at RFH to redeploy resources and staff for the COVID-19 surge. Prioritizing of patients according to European Association of Urology guidance was introduced. Clinics and the specialist multidisciplinary team (SMDT) meetings were maintained with physical distancing, kidney surgery was moved to a COVID-protected site, and infection prevention measurements were enforced. During the 7 weeks of lockdown (23 March to 10 May 2020), 234 cases were discussed at the SMDT meetings, 53% compared to the 446 cases discussed in the 7 weeks pre-lockdown. The reduction in referrals was more pronounced for small and asymptomatic renal masses. Of 62 low-priority cancer patients, 27 (43.5%) were deferred. Only one (4%) COVID-19 infection occurred postoperatively, and the patient made a full recovery. No increase in clinical or pathological upstaging could be detected in patients who underwent deferred surgery compared to pre-COVID practice.

Conclusion: The first surge of the COVID-19 pandemic severely impacted diagnosis, referral and treatment of kidney cancer at a tertiary referral centre. With a policy of prioritization and COVID-protected pathways, capacity for time-sensitive oncological interventions was maintained and no immediate clinical harm was observed.
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http://dx.doi.org/10.1111/bju.15441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239749PMC
December 2021

First-line immune-checkpoint inhibitor combination therapy for chemotherapy-eligible patients with metastatic urothelial carcinoma: A systematic review and meta-analysis.

Eur J Cancer 2021 07 4;151:35-48. Epub 2021 May 4.

Department of Urology, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Research Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria; European Association of Urology Research Foundation, Arnhem, Netherlands. Electronic address:

Introduction: Platinum-based combination chemotherapy is the standard treatment for patients with chemotherapy-eligible metastatic urothelial carcinoma (mUC). Immune-checkpoint inhibitors (ICIs) are currently assessed in this setting. This review aimed to assess the role of ICIs alone or in combination as first-line treatment in chemotherapy-eligible patients with mUC.

Methods: Multiple databases were searched for articles published until November 2020. Studies were deemed eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), durations of response (DORs) and adverse events (AEs) in chemotherapy-eligible patients with mUC.

Results: Three studies met our eligibility criteria. ICI combination therapy was associated with significantly better OS and PFS, higher CRR and longer DOR than chemotherapy alone (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.76-0.94, P = 0.002; HR: 0.80, 95% CI: 0.71-0.90, P = 0.0002; odds ratio [OR]: 1.48, 95% CI: 1.12-1.96, P = 0.006; and mean difference: 1.39, 95% CI: 0.31-2.46, P = 0.01, respectively). ICI-chemotherapy combination therapy was also associated with significantly better OS and PFS, higher ORR and CRR and longer DOR than chemotherapy alone. Although OS and PFS benefits of ICI combination therapy were larger in patients with high expression of programmed death-ligand 1 (PD-L1), PD-L1 low expression patients also had a benefit; HR for OS (high PD-L1: HR 0.79 versus low PD-L1: HR 0.89) and PFS (high PD-L1: HR 0.74 versus low PD-L1: HR 0.82). ICI monotherapy was not associated with better oncological outcomes but was associated with better safety outcomes than chemotherapy alone.

Conclusions: Our analysis indicates a superior oncologic benefit to first-line ICI combination therapies in patients with chemotherapy-eligible mUC over standard chemotherapy. In contrast, ICI monotherapy was associated with favorable safety outcomes compared with chemotherapy but failed to show its superiority over chemotherapy in oncological benefits. PD-L1 status alone cannot help guide treatment decision-making. However, caution should be exercised in interpreting the conclusions drawn from this study, given that there is the heterogeneity of the population of interest, risk of bias and the nature of the studies evaluated whose data remain immature or unpublished.
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http://dx.doi.org/10.1016/j.ejca.2021.03.049DOI Listing
July 2021

An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer.

Nat Med 2021 05 3;27(5):793-801. Epub 2021 May 3.

CRUK Manchester Institute Cancer Biomarker Centre, Manchester, UK.

Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC). AUC is characterized by several recurrent targetable genomic alterations. 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 pathway.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.
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http://dx.doi.org/10.1038/s41591-021-01317-6DOI Listing
May 2021

Atezolizumab Versus Chemotherapy in Patients with Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: A Long-term Overall Survival and Safety Update from the Phase 3 IMvigor211 Clinical Trial.

Eur Urol 2021 07 23;80(1):7-11. Epub 2021 Apr 23.

Barts Cancer Institute, Queen Mary University of London, London, UK.

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/m, paclitaxel 175 mg/m, or docetaxel 75 mg/m 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.
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http://dx.doi.org/10.1016/j.eururo.2021.03.024DOI Listing
July 2021

Clinical Effectiveness of Second-line Sunitinib Following Immuno-oncology Therapy in Patients with Metastatic Renal Cell Carcinoma: A Real-world Study.

Clin Genitourin Cancer 2021 08 17;19(4):354-361. Epub 2021 Mar 17.

Tom Baker Cancer Centre, University of Calgary, Department of Oncology, Calgary, Canada. Electronic address:

Background: Limited data exist on the clinical effectiveness of second-line (2L) vascular endothelial growth factor (receptor) targeted inhibitor (VEGF(R)i) sunitinib after first-line (1L) immuno-oncology (IO) therapy for patients with metastatic renal cell carcinoma (mRCC) in real-world settings.

Methods: A retrospective cohort study among adult patients with mRCC treated with 2L sunitinib following 1L IO was conducted from select International mRCC Database Consortium (IMDC) centers. All analyses were performed overall and by 1L ipilimumab + nivolumab (IPI+NIVO) or 1L IO+VEGF(R)i. Median overall survival (mOS) and time-to-treatment discontinuation (mTTD) in 2L were estimated using Kaplan-Meier analysis. The 2L objective response rate (ORR) (complete/partial response) was reported.

Results: Among 102 patients on 2L sunitinib, mean age was 61.3 years. IMDC risk scores at 2L initiation was available for 83 patients: 8 (9.6%) were favorable, 45 (54.2%) were intermediate, and 30 (36.1%) were poor risk. The 1L consisted of IPI+NIVO in 62 (60.8%), IO+VEGF(R)i therapy in 27 (26.5%), and IO monotherapy in 13 (12.7%) patients. Among all patients, mOS was 15.6 months (95% confidence interval [CI], 9.8-21.7), with a 1-year OS rate of 57.5% (95% CI, 45.2-68.0). mTTD was 5.4 months (95% CI, 4.2-7.2) and ORR was 22.5%.

Conclusion: Despite availability of effective 1L therapies in recent years, 2L sunitinib continues to have clinical activity after failure of 1L IO. Further studies on optimal treatment sequencing after 1L IO progression are needed.
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http://dx.doi.org/10.1016/j.clgc.2021.03.006DOI Listing
August 2021

Safety and Efficacy of Atezolizumab in Understudied Populations with Pretreated Urinary Tract Carcinoma: Subgroup Analyses of the SAUL Study in Real-World Practice.

J Urol 2021 08 9;206(2):240-251. Epub 2021 Apr 9.

San Camillo and Forlanini Hospitals, Rome, Italy (present address: Englander Institute for Precision Medicine, Weill Cornell Medicine, Meyer Cancer Center, New York, USA).

Purpose: Atezolizumab is an established treatment option for pretreated urothelial carcinoma, demonstrating efficacy in phase II/III trials. The SAUL study enrolled a broader patient population to determine safety and efficacy in underrepresented subgroups.

Materials And Methods: Patients with metastatic urinary tract carcinoma received atezolizumab 1,200 mg every 3 weeks until disease progression, unacceptable toxicity, loss of clinical benefit, or patient/physician decision. The primary endpoint was safety. Efficacy was a secondary endpoint. Analyses by programmed cell death ligand-1 (PD-L1) status, age, Eastern Cooperative Oncology Group performance status (ECOG PS) and renal impairment were prespecified; post hoc analyses explored outcomes by tumor location.

Results: A total of 1,004 patients were enrolled. Subgroup analyses in patients with older age, renal impairment, or upper tract urothelial carcinoma showed safety and efficacy similar to those in patients without these characteristics. Patients with ECOG PS 2 had clinical features typically associated with aggressive disease; median overall survival was 2.3 months versus 10.0 months in patients with ECOG PS0/1. Patients with PD-L1 expression on ≥5% of tumor-infiltrating immune cells tended to have better outcomes than those with <5% PD-L1 expression, although conclusions on the relative efficacy of atezolizumab cannot be drawn from this single-arm study.

Conclusions: The understudied populations included in the SAUL study had similar outcomes to those in more selected populations included in phase II/III trials of atezolizumab, except for those with ECOG PS 2. Age ≥80 years and/or creatinine clearance <30 ml/minute does not preclude administration of atezolizumab; however, treatment risk versus benefit must be carefully assessed in patients with ECOG PS 2.
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http://dx.doi.org/10.1097/JU.0000000000001768DOI Listing
August 2021

Intratumoral CD103+ CD8+ T cells predict response to PD-L1 blockade.

J Immunother Cancer 2021 04;9(4)

Department of OMNI Biomarker Development, Genentech Inc, South San Francisco, California, USA

Background: CD8+ tissue-resident memory T (T) cells, marked by CD103 () expression, are thought to actively suppress cancer progression, leading to the hypothesis that their presence in tumors may predict response to immunotherapy.

Methods: Here, we test this by combining high-dimensional single-cell modalities with bulk tumor transcriptomics from 1868 patients enrolled in lung and bladder cancer clinical trials of atezolizumab (anti-programmed cell death ligand 1 (PD-L1)).

Results: was identified as the most significantly upregulated gene in inflamed tumors. Tumor CD103+ CD8+ T cells exhibited a complex phenotype defined by the expression of checkpoint regulators, cytotoxic proteins, and increased clonal expansion.

Conclusions: Our analyses indeed demonstrate that the presence of CD103+ CD8+ T cells, quantified by tracking intratumoral CD103 expression, can predict treatment outcome, suggesting that patients who respond to PD-1/PD-L1 blockade are those who exhibit an ongoing antitumor T-cell response.
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http://dx.doi.org/10.1136/jitc-2020-002231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032254PMC
April 2021

Immune Checkpoint Inhibitors in Front-line Therapy for Urothelial Cancer.

Eur Urol Oncol 2021 Mar 30. Epub 2021 Mar 30.

Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, UK. Electronic address:

Immune checkpoint inhibitors are the standard-of-care front-line treatment option for PD-L1-positive, cisplatin-ineligible metastatic urothelial carcinoma. The data supporting this are based on two single-arm trials. Randomised trials to confirm these findings and test new combinations have recently been performed. It was hoped that these trials would clarify some of the previous uncertainties. In this report we summarise the findings from these trials and perform a combined analysis. The results show that immune checkpoint inhibitor monotherapy is not superior to chemotherapy as things currently stand. The chemoimmunotherapy combination shows a probable efficacy signal, but this appears to be insufficient to change practice. PATIENT SUMMARY: In this report, we summarise the outcomes of three recent trials that investigated immunotherapy (IMT) on its own and combined with chemotherapy (CT) for patients with metastatic bladder cancer who had not previously received any treatment. We show that IMT on its own is not better than CT for these patients. There is a sign that combined CT and IMT probably has a benefit, but it does not seem to be large enough to justify a change in treatment recommendations.
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http://dx.doi.org/10.1016/j.euo.2021.02.010DOI Listing
March 2021

Should patients with low-risk renal cell carcinoma be followed differently after nephron-sparing surgery vs radical nephrectomy?

BJU Int 2021 09 26;128(3):386-394. Epub 2021 Apr 26.

UCL Division of Surgical and Interventional Science, Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, UK.

Objective: To investigate whether pT1 renal cell carcinoma (RCC) should be followed differently after partial (PN) or radical nephrectomy (RN) based on a retrospective analysis of a multicentre database (RECUR).

Subjects: A retrospective study was conducted in 3380 patients treated for nonmetastatic RCC between January 2006 and December 2011 across 15 centres from 10 countries, as part of the RECUR database project. For patients with pT1 clear-cell RCC, patterns of recurrence were compared between RN and PN according to recurrence site. Univariate and multivariate models were used to evaluate the association between surgical approach and recurrence-free survival (RFS) and cancer-specific mortality (CSM).

Results: From the database 1995 patients were identified as low-risk patients (pT1, pN0, pNx), of whom 1055 (52.9%) underwent PN. On multivariate analysis, features associated with worse RFS included tumour size (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.14-1.39; P < 0.001), nuclear grade (HR 2.31, 95% CI 1.73-3.08; P < 0.001), tumour necrosis (HR 1.5, 95% CI 1.03-2.3; P = 0.037), vascular invasion (HR 2.4, 95% CI 1.3-4.4; P = 0.005) and positive surgical margins (HR 4.4, 95% CI 2.3-8.5; P < 0.001). Kaplan-Meier analysis of CSM revealed that the survival of patients with recurrence after PN was significantly better than those with recurrence after RN (P = 0.02). While the above-mentioned risk factors were associated with prognosis, type of surgery alone was not an independent prognostic variable for RFS nor CSM. Limitations include the retrospective nature of the study.

Conclusion: Our results showed that follow-up protocols should not rely solely on stage and type of primary surgery. An optimized regimen should also include validated risk factors rather than type of surgery alone to select the best imaging method and to avoid unnecessary imaging. A follow-up of more than 3 years should be considered in patients with pT1 tumours after RN. A novel follow-up strategy is proposed.
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http://dx.doi.org/10.1111/bju.15415DOI Listing
September 2021

Perioperative therapy in renal cancer in the era of immune checkpoint inhibitor therapy.

Curr Opin Urol 2021 05;31(3):262-269

Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust.

Purpose Of Review: Immune checkpoint inhibitor (ICI) combination therapy has revolutionized therapy of metastatic renal cancer. The success of immunotherapy has renewed an interest to study these agents in adjuvant and neoadjuvant settings and prior to cytoreductive nephrectomy. This narrative review will give an overview of ongoing trials and early translational research outcomes.

Recent Findings: In nonmetastatic renal cell carcinoma (RCC), five phase 3 adjuvant and neoadjuvant trials with ICI monotherapy or combinations are ongoing with atezolizumab (IMmotion 010; NCT03024996), pembrolizumab (KEYNOTE-564; NCT03142334), nivolumab (PROSPER; NCT03055013), nivolumab with or without ipilimumab (CheckMate 914; NCT03138512) and durvalumab with or without tremelimumab (RAMPART; NCT03288532). Phase 1b/2 neoadjuvant trials demonstrate safety, efficacy and dynamic changes of immune infiltrates and provide rationales for neoadjuvant trial concepts as well as prediction of response to therapy. In primary metastatic RCC, two phase 3 trials investigate the role of deferred cytoreductive nephrectomy following pretreatment with ICI combination (NORDICSUN; NCT03977571 and PROBE; NCT04510597).

Summary: The outcomes of the major phase 3 trials are awaited as early as 2023. Meanwhile, translational data from phase 1b/2 studies enhance our understanding of the tumour immune microenvironment and its dynamic changes.
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http://dx.doi.org/10.1097/MOU.0000000000000868DOI Listing
May 2021

Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial.

Lancet Oncol 2021 04 12;22(4):525-537. Epub 2021 Mar 12.

Barts Cancer Institute, Queen Mary University of London, St Bartholomew's Hospital, London, UK.

Background: Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma.

Method: In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2-4a or ypN+ tumours following neoadjuvant chemotherapy or pT3-4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients.

Findings: Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2-29·8). Median disease-free survival was 19·4 months (95% CI 15·9-24·8) with atezolizumab and 16·6 months (11·2-24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group.

Interpretation: To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time.

Funding: F Hoffmann-La Roche/Genentech.
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http://dx.doi.org/10.1016/S1470-2045(21)00004-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495594PMC
April 2021
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