Background

The phase 3 CLEAR study showed statistically significant PFS (primary endpoint) and OS benefits, and improved ORR with LEN + PEMBRO vs SUN in pts with aRCC in the 1L setting. We report updated efficacy and describe pts who completed 2 years of PEMBRO and continued on LEN monotherapy.

Methods

Pts with aRCC and no prior systemic therapy were randomized (1:1:1) to receive LEN 20 mg PO QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + EVE 5 mg PO QD; or SUN 50 mg PO QD (4 weeks on/2 weeks off). Randomization was stratified by geographic region and MSKCC prognostic group. In this descriptive follow-up analysis (data cutoff March 31, 2021), we report updated PFS, ORR, and duration of response (DOR) as assessed by independent imaging review per RECIST v1.1 for LEN + PEMBRO and SUN, as well as an exploratory subgroup analysis of pts who completed 2 yrs of PEMBRO per protocol and continued LEN. Updated OS was previously reported.

Results

Updated efficacy results are in the table. Median survival follow-up was 33.7 mos for pts randomized to LEN + PEMBRO (N = 355) and 33.4 mos for pts randomized to SUN (N = 357). PFS (median 23.3 vs 9.2 mos) and ORR (71.0% vs 36.1%) continued to be improved with LEN + PEMBRO vs SUN. DOR was longer with LEN + PEMBRO vs SUN (median, 26.0 vs 14.7 mos). Of the pts who completed 2 yrs of PEMBRO (n = 101 of 355 pts), most (n = 65) had IMDC intermediate/poor risk disease and fewer (n = 36) had favorable risk disease, consistent with the intention-to-treat population. PEMBRO completers had a 36-mos OS rate of 94.5%; 69 (68.3%) of these pts had treatment-related treatment-emergent adverse events. Table: 1449MO

Conclusions

With longer follow-up, LEN + PEMBRO continued to show a clinically meaningful benefit vs SUN, consistent with prior results of the CLEAR study. A large proportion of pts treated with LEN + PEMBRO completed 2 yrs of PEMBRO and continued with LEN monotherapy with ongoing clinical benefit. The results further support LEN + PEMBRO as a standard of care in 1L aRCC.

Clinical trial identification

NCT02811861.

Editorial acknowledgement

Medical writing support was provided by Irene Minkina, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, with funding by Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

This study was sponsored by Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

C.G. Porta: Financial Interests, Personal, Invited Speaker: Angelini Pharma, AstraZeneca, BMS, Eisai, General Electric, Ipsen, Merck, MSD; Financial Interests, Personal, Speaker’s Bureau: Angelini Pharma, BMS, Eisai, Ipsen, Merck, MSD, Angelini Pharma, AstraZeneca, BMS, Eisai, Ipsen, Merck, MSD; Financial Interests, Personal, Advisory Role: Angelini Pharma, AstraZeneca, BMS, Eisai, Ipsen, Merck, MSD; Financial Interests, Personal, Other, Protocol Steering Committee Member: BMS, Eisai, EUSA Pharma, MSD. M. Eto: Financial Interests, Personal, Other, Speaker’s Bureau: MSD, ONO, Takeda, Merck; Financial Interests, Personal, Research Grant: Sanofi, ONO, Takeda. R.J. Motzer: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Eisai, Exelixis, Merck, Genentech/Roche, Incyte, Lilly Oncology, AstraZeneca, EMD Serono, Aveo Pharmaceuticals, AVEO; Financial Interests, Institutional, Invited Speaker, funding for trial conduct from sponsor to my employer MSKCC: Pfizer, Eisai, Genentech/Roche, Merck, Bristol Myers Squibb, Exelixis, AVEO. U.F.F. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, EISAI, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, Clovis Oncology, AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca, Sanofi, Roche. T. Buchler: Financial Interests, Personal, Invited Speaker: Roche, Bayer, Bristol Myers Squibb, Astellas, Janssen, Ipsen, Merck; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Ipsen, Merck, Servier, Eli Lilly, Pfizer; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, Merck, Bayer, Exelixis, Eisai, Eli Lilly, MSD; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Servier, Roche; Non-Financial Interests, Advisory Role: Leram Pharmaceuticals. N.S. Basappa: Financial Interests, Personal, Advisory Board: Merck, Eisai, Ipsen, Pfizer, BMS, AstraZeneca, Bayer, Seagen, Janssen, EMD Serono, Roche; Financial Interests, Personal, Sponsor/Funding: Eisai; Financial Interests, Personal, Advisory Role: Janssen, Ipsen. M.J. Mendez Vidal: Financial Interests, Personal, Speaker’s Bureau: Astellas Pharma, Bristol Myers Squibb, Ipsen, EUSA Pharma, Janssen-Cilag, Pfizer, Roche; Financial Interests, Personal, Advisory Role: Astellas Pharma, Bristol Myers Squibb, EUSA Pharma, Ipsen, Eisai, Janssen-Cilag, Novartis, Pfizer, Roche, Sanofi. S. Tjulandin: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Eli Lilly, BioCad, Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca, R-Pharm, Merck Sharp Dohme, Roche, Pierre Fabre, Servier; Financial Interests, Personal, Ownership Interest: RusPharmTech; Financial Interests, Personal and Institutional, Invited Speaker: Merck Sharp Dohme, Eisai, AbbVie, Novartis, Bristol Myers Squibb; Other, The Chair: Russian Society of Clinical Oncology (RUSSCO). B. Melichar: Financial Interests, Personal, Invited Speaker: Roche, Pfizer, BMS, Astellas, Novartis, Bayer, MSD, Merck Serono, Sanofi, Servier, AstraZeneca, Amgen, Janssen, Eisai, Eli Lilly, Pierre Farbre; Financial Interests, Personal, Advisory Role: Roche, Pfizer, BMS, Astellas, Novartis, Bayer, MSD, Merck Serono, Sanofi, Servier, AstraZeneca, Amgen, Janssen, Eisai, Eli Lilly, Pierre Farbre. T.E. Hutson: Financial Interests, Personal, Speaker’s Bureau: Astellas Pharma, Bristol Myers Squibb, Eisai, Exelixis, Johnson & Johnson, Pfizer; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Eisai, Exelixis, Johnson & Johnson, Pfizer; Financial Interests, Personal, Advisory Role: Astellas Pharma, Bayer/Onyx, Bristol Myers Squibb, Exelixis, Johnson & Johnson, Novartis, Pfizer. C. Alemany: Financial Interests, Personal, Speaker’s Bureau: Alexion, Bristol Myers Squibb; Non-Financial Interests, Institutional, Funding: Merck, Janssen, Sanofi, Novartis, Pfizer, Olema. B. McGregor: Financial Interests, Personal, Advisory Board: Exelixis, BMS, Dendreon, SeaGen, Astellas, Eisai, Merck, Nektar; Financial Interests, Personal, Invited Speaker: EMD Serono, SeaGen; Financial Interests, Institutional, Invited Speaker: Pfizer, Exelixis, Exelixis, Calithera, BMS, SeaGen, Aveo; Non-Financial Interests, Member: ASCO. C.S. He: Financial Interests, Personal, Full or part-time Employment: Eisai. R. Perini: Financial Interests, Personal, Full or part-time Employment: Merck; Financial Interests, Personal, Stocks/Shares: Merck. K. Mody: Financial Interests, Personal, Full or part-time Employment: Eisai. J. McKenzie: Financial Interests, Personal, Full or part-time Employment, Full time employee: Eisai Inc. T.K. Choueiri: Financial Interests, Personal, Advisory Board, Advice on GU/RCC drugs: BMS, Pfizer, Merck, Exelixis, AstraZeneca; Financial Interests, Personal, Advisory Board, Advice on Onc drugs: Lilly, EMD Serono, Infinity; Financial Interests, Personal, Advisory Board, Advice on RCC drug: Calithera; Financial Interests, Personal, Invited Speaker, RCC drug: Ipsen; Financial Interests, Personal, Advisory Board, Advice on GU Onc drugs: Surface Oncology; Financial Interests, Personal, Other, Consultant on onc drugs: Analysis Group; Financial Interests, Personal, Invited Speaker, CME, ww2.peerview.com: Peerview; Financial Interests, Personal, Invited Speaker, CME, gotoper.com: PER; Financial Interests, Personal, Invited Speaker, CME, researchtopractice.com: ResearchToPractice; Financial Interests, Personal, Invited Speaker, National Association of Managed Care: NAMC; Financial Interests, Personal, Invited Speaker, ASCO-related event: ASCO-SITC; Financial Interests, Personal, Other, Grant review to Orien Network ($400): ORIEN; Financial Interests, Personal, Advisory Board, Advising oncology strategy: Aptitude Health; Financial Interests, Personal, Invited Speaker, Best of ASCO19 talk: Advent health; Financial Interests, Personal, Invited Speaker, Best of ESMO20 talk ($1000): UAE Society of Onc; Financial Interests, Personal, Invited Speaker, CME, mjhlifesciences.com (OncLive): MJH life sciences; Financial Interests, Personal, Invited Speaker, Grand Rounds: MDACC; Financial Interests, Personal, Invited Speaker, RCC webinar: Cancernet; Financial Interests, Personal, Invited Speaker, CME, Kidney Cancer Association ($1300): France Foundation; Financial Interests, Personal, Invited Speaker, CME, RCC: Springer, WebMed; Financial Interests, Personal, Invited Speaker, CME, ImmunoOncology in RCC: ASiM, CE; Financial Interests, Personal, Invited Speaker, CME, PodCast in RCC ($500.00): Caribou Publishing; Financial Interests, Personal, Invited Speaker, Reimbursement ($432.00): Kidney Cancer Association; Financial Interests, Personal, Other, member of the DSMB for clinical trial: Aravive; Financial Interests, Personal, Invited Speaker, unpaidhttps://www.accru.org/main/public/index.xhtml: ACCRU; Financial Interests, Personal, Invited Speaker, Unpaidhttps://kidneycan.org: KidneyCan; Financial Interests, Personal, Other, External Advisory Board Member: Gustave Roussy; Financial Interests, Personal, Stocks/Shares: Pionyr (not publicly traded), Tempest (publicly traded), Osel (not publicly traded), Nuscan (not publicly traded); Financial Interests, Personal, Royalties, For writing and updating chapters in GU Oncology: Up-To-Date online textbook; Financial Interests, Institutional, Funding, National Chair: BMS, Merck, Exelixis, AstraZeneca, Takeda, Tracon, Peloton; Financial Interests, Institutional, Invited Speaker: Roche, Surface Oncology, GSK; Financial Interests, Institutional, Funding, National co-chair: Pfizer, EMD-Serono; Financial Interests, Institutional, Funding, Chair of trial: Lilly; Financial Interests, Institutional, Funding, SC member: Eisai; Financial Interests, Institutional, Funding, National co-chair on 3 ongoing trials: ALLIANCE Cooperative Group; Financial Interests, Institutional, Research Grant, for GU oncology translational research through IION program: BMS; Financial Interests, Institutional, Research Grant, for GU oncology translational research: Exelixis; Financial Interests, Institutional, Research Grant, For Health outcomes research: Roche; Financial Interests, Institutional, Invited Speaker, leads trials as PI: Nikang; Non-Financial Interests, Leadership Role, Co-Chair of the meeting, 2019-: Kidney Cancer Research Summit of KidneyCAN; Non-Financial Interests, Principal Investigator, Trial Global and National PI with GU Cancers, mostly Kidney Cancer: Multiple Academic and Industry entities; Non-Financial Interests, Personal, Other, Track Leader/Session chair/Speaker/Discussant: ASCO; Non-Financial Interests, Personal, Other, Speaker/Discussant/Track Leader: ESMO; Non-Financial Interests, Institutional, Other, Access to genomic database: Foundation Med, Guardant, Invitae; Non-Financial Interests, Personal, Other, Grants reviewers: AACR; Non-Financial Interests, Personal, Other, Reviewer of papers: Various journals (e.g. NEJM, Lancet, JCO); Non-Financial Interests, Personal, Other, Medical writing and editorial assistance support (e.g. ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, pharmagenesis, and others). However, first draft frequently initiated by myself when I am 1st author: Medical Communication; Non-Financial Interests, Member: ASCO, AACR; Non-Financial Interests, Other, Political vote usually as “independent”, not a member of any political party. I am an issue voter: General US Politics; Other, No financial interest. Institutional.Filed patents related to biomarkers of immune checkpoint blockers, and circulating free methylated DNA. No money made and some patents were abandoned: Filed patents; Other, Employee at DFCI. Please see https://www.dana-farber.org/ for mission statement (non-profit hospital). I am also the past President of Medical Staff at DFCI 2015-2018: Dana-Farber Cancer Institute (DFCI); Other, Professor at HMS, Please see https://hms.harvard.edu/ for mission statement (non-profit school): Harvard Medical School (HMS). All other authors have declared no conflicts of interest.

Background

The combination of nivolumab 3 mg/kg + ipilimumab 1 mg/kg (nivo+ipi) is an approved 1^st line (1L) therapy for patients with metastatic renal cell carcinoma (mRCC) and intermediate / poor risk. TITAN-RCC investigated a response-based approach with nivo induction and nivo+ipi boost in non-responders. We report final study results for 1L and 2L (after TKI) patients.

Methods

From OCT 2016 to DEC 2018 207 patients with intermediate/poor risk mRCC started nivo induction (Q2W, 240 mg). Patients with early progressive disease (PD, week 8) or non-responders at week 16 (stable disease [SD]/PD) received 2-4 doses nivo+ipi. Responders to nivo induction (complete/partial response [CR/PR]) continued with nivo maintenance but could receive nivo+ipi for later PD. The primary endpoint was confirmed objective response rate (ORR) per RECIST in 1L and 2L. Secondary endpoints included efficacy of nivo induction, response to boost, progression free (PFS) and overall survival (OS), and safety.

Results

Of the 207 patients, 109 were 1L and 98 2L. Median age was 65 yr, 71 % of patients had intermediate and 25 % poor risk. Confirmed response to nivo induction was 28 % in 1L and 18 % in 2L. After 33.6 months from last patient first treatment and 15.9 months median follow-up, ORR for nivo ± nivo+ipi was 36 % in 1L (significant >25 %, p<0.05) and 32 % in 2L. Irrespective of time point, 44% (1L) and 53% (2L) of patients receiving boosts for PD upon nivo improved in best response. PFS was 6.3 months (95 % CI 3.7-10.1) in 1L and 3.7 months (95 % CI 1.8-4.5) in 2L. OS was 32.0 months (95 % CI 22.9-39.4) in 1L and 25.9 months (95 % CI 17.8-33.7) in 2L. No new safety signals emerged. Table: 1450MO

Response to nivo+ipi boost

Conclusions

Nivo+ipi boosts improve outcomes compared to nivo monotherapy. Responses were also observed after progression during nivo maintenance suggesting a potential role as rescue strategy. However, overall efficacy of our tailored approach appears to be inferior compared to upfront nivo+ipi treatment.

Clinical trial identification

EudraCT: 2016-002307-26, NCT02917772.

Legal entity responsible for the study

AIO-Studien-gGmbH.

Funding

Bristol Myers Squibb.

Disclosure

M. Grimm: Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Bristol Myers Squibb, Ipsen Pharma, Merck Serono, MSD, Pfizer, EUSA, Janssen, Oncinfo, Deutsche Gesellschaft für Urologie; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, EUSA Pharma, Ipsen Pharma, Merck Serono, MSD, Pfizer, Roche, Eisai, Takeda, Astellas, Ingress Health, Janssen Cilag; Financial Interests, Personal and Institutional, Invited Speaker: Bristol Myes Squibb; Financial Interests, Institutional, Invited Speaker: Intuitive Surgical. P. Barthelemy: Financial Interests, Personal, Advisory Board: BMS, MSD, Merck, Pfizer, Ipsen, Bayer, Janssen Cilag, Astellas, Novartis, Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Seagen. M. Schmidinger: Financial Interests, Personal, Advisory Board, advisory boards or lectures: BMS, MSD, Merck, Ipsen; Financial Interests, Personal, Invited Speaker: EUSA, Janssen; Financial Interests, Personal, Advisory Board: Alkermes, Exelixis; Financial Interests, Personal, Advisory Board, Advisory board or lectures: Eisai; Financial Interests, Institutional, Research Grant, Research grant for retropsective study: Ipsen. J. Busch: Financial Interests, Personal, Invited Speaker: BMS, Merck, Ipsen, Pfizer, Janssen, Astellas; Financial Interests, Personal, Advisory Board: MSD, Merck, Ipsen, BARD, AstraZeneca. B. Perez Valderrama: Financial Interests, Personal, Advisory Board: Pfizer, Astellas Pharma, Bristol Myers Squibb, Ipsen, EUSA Pharma, Sanofi-Aventis, Merck, MSD, AstraZeneca; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Roche, Bayer, EUSA Pharma, MSD, Merck, Pfizer, Janssen, Astellas Pharma. N. Charnley: Financial Interests, Institutional, Funding: BMS; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Funding: Ipsen, EUSA. G. Baretton: Financial Interests, Personal, Advisory Role: BMS, MSD, AstraZeneca, Roche, Novartis; Financial Interests, Institutional, Funding: BMS, MSD; Financial Interests, Personal, Other, Honoria: Pfizer, Roche, MSD, BMS, AstraZeneca. I. Duran Martinez: Financial Interests, Personal, Advisory Board, I have served as an advisor for this company in the last two years: Roche Genentech, MSD, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker, I have participated in different compensated educational activities sponsored by Jansen over the last two years: Jansen; Financial Interests, Personal, Invited Speaker, I have participated in different compensated educational activities sponsored by Pfizer over the last two years: Pfizer; Financial Interests, Personal, Advisory Board, I have collaborated as an advisor in different occasions over the last two years: ipsen; Financial Interests, Personal, Invited Speaker, I have participated in different compensated educational activities sponsored by this company over the last two years: IPSEN, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, I have collaborated as an advisor for this company in the last two year: Merck; Financial Interests, Personal, Advisory Board, I have participated in different compensated advisory boards over the last two years: Astellas; Financial Interests, Personal, Advisory Board, I have collaborated as an advisor for this company over the last two years: Immunomedics, Inc.; Financial Interests, Personal, Invited Speaker, I have participated in educational activities sponsored by this company in the last two years: EUSA Pharma, MSD; Financial Interests, Personal, Invited Speaker, I have participated in educational activities sponsored by Novartis in the last 2 years: Novartis; Financial Interests, Personal, Invited Speaker, I have participated in compensated educational activities for this company in the last two years: Astellas; Financial Interests, Personal and Institutional, Research Grant, Roche has funded research in my institution to projects under my coordination: Roche Genentech; Financial Interests, Personal, Invited Speaker, I serve as a member of a SC for a trial sponsored by this company: Immunomedics, Inc.; Financial Interests, Personal and Institutional, Research Grant, AZ has funded research conducted in my institution related to a project where I am the PI: AstraZeneca; Non-Financial Interests, Leadership Role, I am the president of an independent cooperative group of GU Oncologist from the north of Spain: GO NORTE; Non-Financial Interests, Invited Speaker, I belong as a external advisor to the board of directors of the Spanish Association of cancer research since 2021: ASEICA. G.A. De Velasco Oria: Financial Interests, Personal, Advisory Board: Pfizer, astellas, BMS, MSD, Ipsen, Bayer, Eusa P., Merck; Financial Interests, Personal, Invited Speaker: Pfizer, astellas, BMS, MSD, Roche, Ipsen, Merck; Financial Interests, Institutional, Research Grant: Roche. F. Priou: Financial Interests, Personal, Advisory Board: MSD, AstraZeneca. J.P. Maroto Rey: Non-Financial Interests, Advisory Role: Bayer, MSD, Astellas, Merck. L. Albiges: Financial Interests, Institutional, Other, Consulting: Astellas, AstraZeneca, BMS, Eisai, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer; Non-Financial Interests, Principal Investigator: Pfizer, BMS, Ipsen, AVEO, AstraZeneca, MSD; Non-Financial Interests, Other, Clinical trial steering committee: Roche, Exelixis; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Other, Medical Steering Committee: Kidney Cancer Association; Non-Financial Interests, Other, Member of the Renal Cell Carcinoma Guidelines Panel: European Association of Urology (EAU); Non-Financial Interests, Other, Member of the Kidney Cancer Research Summit scientific committee 2021: Kidney Can; Other, Scientific Committee: BMS France. All other authors have declared no conflicts of interest.

Background

Patients (Pts) with locally advanced bladder cancer (BC) have a poor prognosis despite radical surgical therapy. Early data on neoadjuvant immunotherapy in muscle invasive BC is promising, while there are indications of synergistic effects of radiation and immunotherapy. This trial evaluates the feasibility, safety and efficacy of neoadjuvant radio-immunotherapy (RIT) following radical cystectomy (RCX) in patients with locally advanced, muscle invasive BC.

Methods

Patients with locally advanced urothelial BC (cT3/4 cN0/N+ cM0, eligible for RCX, unfit for or refusing neoadjuvant chemotherapy) were included in this prospective, single arm, phase II-trial. Pts were treated with Nivolumab 240mg intravenously every two weeks for 4 cycles, starting one week before radiotherapy of the bladder/pelvis with 50.4 Gy, followed by RCX with standardized pelvic lymphadenectomy. Primary endpoint is the rate of Pts with completed treatment (RIT and RCX) at the end of week 15. Secondary endpoints include overall response rate (ORR), pathological response rates, disease free survival (DFS) and toxicity.

Results

Of 33 treated Pts, 32 (97%) were ≥cT3/4 and 10 (30.3%) were lymph node positive (cN+). For primary endpoint and efficacy analysis, 31 Pts were eligible. Primary endpoint of completed treatment (RIT and RCX) in time at the end of week 15 was reached in 27/31 (87.1%) Pts. Median number of nivolumab cycles was 4. The radiological ORR was 70.9% (CR 16.1%, PR 54.8%, SD 25.8% and PD 3.2%). Pathological response rate was ypT0 38.7% and ≤ ypT1 58.1%. While survival data is immature, DFS rate at 12 months was 90.6%. Any-grade treatment-related AEs (TRAEs) occurred in 54.5 % of all 33 patients. TRAEs were mostly grade 1-2. Most common TRAEs were thyroid and gastrointestinal disorders (each 15.2%) and skin reactions (33.3%). TRAEs led to Nivolumab discontinuation in 8 (25.8%) Pts.

Conclusions

The trial met its primary endpoint. Neoadjuvant radio-immunotherapy followed by radical cystectomy in locally advanced bladder cancer patients is feasible and safe.

Clinical trial identification

NCT03529890, first posted: May 18, 2018.

Legal entity responsible for the study

Faculty of Medicine, Technical University of Munich.

Funding

Bristol Myers Squibb.

Disclosure

S.C. Schmid: Financial Interests, Personal, Invited Speaker: Ipsen, Astellas; Financial Interests, Institutional, Funding: Bristol-Myers Squibb; Non-Financial Interests, Personal, Travel expenses: Janssen; Financial Interests, Personal, Travel expenses: Novartis. A.K. Seitz: Financial Interests, Personal, Congress invitation: Bristol Myers Squibb. F. Zengerling: Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Invited Speaker, Travel: Bayer Health; Financial Interests, Personal, Invited Speaker, Advisory Boards: Bristol-Myers Squibb, Novartis, Roche, Sanofi-Aventis; Financial Interests, Personal, Invited Speaker, Advisory Boards, Travel: Ipsen, Pfizer, Merck Healthcare; Financial Interests, Personal, Advisory Board, Travel: Janssen-Cilag; Financial Interests, Personal, Advisory Board: MSD. C. Bolenz: Financial Interests, Personal, Invited Speaker: Janssen-Cilag GmbH, AstraZeneca GmbH, Medac GmbH, Takeda Pharma GmbH, Roche Pharma AG, Ipsen Pharma GmbH; Financial Interests, Personal, Advisory Board: Roche Pharma AG, ERBE Elektromedizin GmbH. J. Gschwend: Financial Interests, Institutional, Sponsor/Funding: Bristol Myers Squibb. M. Retz: Financial Interests, Institutional, Sponsor/Funding: Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Background

Transurethral resection of bladder tumour (TURBT) has been the mainstay of bladder cancer staging for a century. The objective of the trial was to assess the feasibility and efficacy of the substitution of TURBT with MRI and biopsy in the staging of patients with suspected muscle invasive bladder cancer (MIBC). The hypothesis being tested was that image directed staging would shorten time to correct treatment for MIBC patients.

Methods

Patients with suspected bladder cancer were identified via the haematuria clinic. Those with possible muscle invasive disease (assessed on a Likert scale at flexible cystoscopy) were randomised to standard TURBT assessment (Pathway 1) or MRI based assessment (Pathway 2) with tumour biopsy. Patients with probable non-muscle invasive disease (NMIBC) all underwent TURBT. Primary outcome for Feasibility Phase: proportion of patients completing allocated pathway (target 80%). Primary outcome, Efficacy Phase: time to correct treatment, defined as TURBT for NMIBC or the first of chemotherapy, radiotherapy, surgery or decision for palliative care for MIBC (target: 30 day improvement).

Results

Between May 2018 and December 2021, 143 patients were randomised, median age 74 years, 47.9% probable NMIBC, 52.1% possible MIBC. Feasibility phase: 37/39 (95% (95% CI 83-99%)) patients with MIBC followed correct pathway. Efficacy phase: Pathway 1, median time to correct MIBC treatment 98 (95% CI 72-174) days; Pathway 2 53 (95% CI 20-89) days, hazard ratio (HR) 3.4 (95% CI 1.4-8.3). Logrank test: p-value= 0.0046. Secondary outcomes include median time to correct treatment all patients: Pathway 1 37 days, Pathway 2 31 days; HR 1.3 (95% CI 0.9-1.8).

Conclusions

An MRI directed pathway led to substantial shortening of time to correct treatment for MIBC patients with no detrimental effect of time to treatment for NMIBC patients. Consideration should be given to incorporation of MRI into the standard pathway for all patients with suspected invasive bladder cancer.

Clinical trial identification

ISRCTN 35296862.

Legal entity responsible for the study

University of Birmingham.

Funding

NHS Health Technology Agency.

Disclosure

All authors have declared no conflicts of interest.

Background

Radical treatment for muscle-invasive bladder cancer (MIBC) involves radiotherapy with radiosensitiser or cystectomy currently selected subjectively (patient/clinician preference). The West 24-gene bladder cancer hypoxia signature predicted benefit from hypoxia-modifying radiosensitisation (carbogen+nicotinamide, CON) in BCON trial. The BC2001 trial showed combining chemotherapy (5-FU, mitomycin-C) with radiotherapy (RT) improves loco-regional progression free survival. Both BCON and BC2001 allowed conventional (62Gy/32 fractions) or hypofractionated (55Gy/20 fractions) RT. We tested two hypotheses: (1) our hypoxia signature does not predict benefit from concurrent chemotherapy; and (2) accelerated treatment reduces reoxygenation and is less favourable for patients with hypoxic tumours.

Methods

Pre-treatment biopsy samples were obtained from 312 patients from BC2001. RNA was extracted and full transcriptomic data generated using Affymetrix Clariom S arrays. Patients were stratified using the cohort median of the median expression of 24-signature genes hypoxia score into hypoxia-high and -low groups. Data for BCON (n=151) were available from a published study.

Results

Hypoxia score was prognostic for overall survival in the combined BC2001 cohort in univariable and multivariable (HR=1.29; 95% CI 0.97-1.71; p=0.075) analyses with no interaction between hypoxia score and treatment arm (p=0.92) Patients with hypoxic tumours had a poorer prognosis following hypofractionated compared with conventional fractionation in both BC2001 (n=298, HR 1.80 95% CI 1.08-2.91; p=0.023) and the BCON RT only arm (n=75; HR 14.2; 95% CI 1.7-119; p=0.015). CON abrogated the detrimental effect of hypoxia with hypofractionated RT.

Conclusions

Hypoxic MIBC has a poor prognosis and exhibits fraction sensitivity, which is mitigated with hypoxia modification. Use of hypoxia score to personalise treatment needs testing in a biomarker-stratified trial.

Legal entity responsible for the study

The authors.

Funding

NIHR CRUK.

Disclosure

All authors have declared no conflicts of interest.

Background

The efficacy of NAPC in locally advanced PSCC was suggested in prior small case series. Although the phase III randomized InPACT trial is expected to report results for this disease space within the next 4 years, we are currently left with scant evidence-based guidance in managing these patients. Thus, we aimed to bridge that gap and provide evidence on real-world outcomes of patients with PSCC who received NAPC prior to surgical resection.

Methods

After internal review board approval, patients from eight tertiary care centers who had undergone NAPC prior to surgical resection for PSCC were analyzed. Patients had locally advanced (cTany, cN+) disease. Outcomes analyzed included clinicopathologic data, agents utilized, and surgical modalities. The primary outcome, overall survival (OS), was analyzed using Kaplan-Meier Method and compared using Cox Proportional Hazard Modelling. Secondary outcomes included the best overall response measured with RECIST 1.1 criteria.

Results

One hundred and fifty-six patients treated with NAPC for PSCC were included. The median age of the cohort was 59 years (range, 48-67), and 109 (70%) had an Eastern Cooperative Oncology Group score of 0-1. The clinical stages prior to NAC were cIIA-IIB (12%), cIIIa (16%), cIIIb (22%), and cIV (47%). 123 (79%) of patients received TIP (Paclitaxel - Ifosfamide - Cisplatin) NAC prior to surgical resection. 76% of patients underwent penile-sparing surgical procedures, 24% had a radical penectomy and 84% had inguinal lymphadenectomy. The median (95% CI) OS was 39 months (20.9 – 57.1), while the median progression free survival was 23 months (10.4 – 35.5). On serial imaging after NAPC, 20.7% had progressive disease (PD), 23.3% had stable disease, 48.4% had partial response, and 7.6% had complete response. On Cox Regression, significant predictors (hazard ratio (HR), p<0.05) for OS included PD (HR 2.1, p=0.02) following administration of NAPC.

Conclusions

NAPC is efficacious in PSCC. This study represents the largest conglomeration of multi-institutional PSCC patients treated with systemic chemotherapy, which will guide management strategies while we await prospective clinical trial data.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Chahoud: Financial Interests, Personal, Advisory Role: Pfizer, Aveo, Exelixis. P.E. Spiess: Non-Financial Interests, Leadership Role, Vice-Chair of NCCN Bladder and Penile Cancer Panel: NCCN; Non-Financial Interests, Leadership Role, President of Global Society of Rare GU Tumors: Global Society of Rare GU Tumors; Financial Interests, Leadership Role, Member of the ASCO/EAU Panel on penile cancer: ASCO/EAU. A. Schneider: Financial Interests, Institutional, Invited Speaker, for Prostate Cancer: NCCN. All other authors have declared no conflicts of interest.

Background

Between 60-70% of patients with germ-cell tumors (GCT) present with clinical stage I (CSI) disease. Active surveillance after orchiectomy is the preferred management but is associated with a 15 to 30% relapse rate. We compared the outcomes of patients relapsing from CSI to the ones of similar patients presenting with de novo metastatic disease.

Methods

We identified in the IGCCCG Updated database all patients with gonadal disseminated GCT who had complete information on initial tumor stage whether CSI or de novo metastatic. Patients relapsing from initial CSI were compared to patients with de novo metastatic GCT. Progression-free survival and overall survival at 5 years (5y-PFS and 5y-OS) were estimatedby the Kaplan-Meier method and compared with the hazard ratio (HR).

Results

A total of 1014 seminoma (S) [298 (29.4%) relapsing from CSI, 716 (70.6%) de novo] and 3103 non-seminoma (NS) [626 (20.2%) relapsing from CSI, 2477 (79.8%) de novo] patients were identified. No statistically significant differences in PFS and OS were found between patients relapsing from CSI and de novo metastatic disease for S patients (5y-PFS 87.6% versus 88.5% and 5y-OS 93.2% versus 96.1%). For NS patients there was no difference in outcome between relapsing and de novo patients within the same IGCCCG group (HR=0.89; 95% CI: 0.70-1.12). IGCCCG group was more favorable in NS patients relapsing from CSI: (good risk: 82.1% vs 51.4%) and equal in S patients (good risk: 96.3% vs 96.4%). Nevertheless 112/626 (18%) NS and 11/298 (4%) S CSI patients relapsed with intermediate or poor IGCCCG group.

Conclusions

We found no differences in PFS or OS at 5 years in patients relapsing from initial CSI as compared to de novo metastatic patients within the same IGCCCG prognostic group. However, a substantial proportion of CSI patients relapsed with intermediate or poor prognostic features with a need of intensified treatment. The study underlines the importance of improving active surveillance techniques and schedules to detect recurrence as early as possible in CSI patients and to avoid unnecessary toxicity.

Legal entity responsible for the study

The International Germ Cell Cancer Collaborative Group (IGCCCG).

Funding

EORTC.

Disclosure

All authors have declared no conflicts of interest.

Background

Clinical observations indicate a higher prevalence of psychiatric disorders, in particular neurodevelopmental disorders, among testicular germ cell cancer (TGCC) patients. Our aim was to investigate if history of specific psychiatric disorders is associated with increased risk of TGCC and/or increased mortality.

Methods

We conducted a nested case-control study including 6,250 TGCC patients diagnosed 1992-2014, individually matched to 62,500 controls. Using conditional logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the association between history of psychiatric diagnoses and TGCC risk. Among the cases only, we used a cohort study design and Cox regression to calculate hazard ratios (HRs) with 95% CIs of the association between psychiatric diagnosis and all-cause and TGCC-specific mortality.

Results

History of a neurodevelopmental disorder (i.e., attention deficit hyperactivity disorder, autism spectrum disorder and intellectual disabilities) was associated with an increased risk of seminoma (OR 1.54; 95% CI 1.09-2.19). Seminoma patients with neurodevelopmental disorders were also younger (34 versus 38 years, p=0.004) and more often presented with stage IV disease (5.4% versus 1.2%) than those without. A decreased risk of seminoma was seen for patients with psychotic disorders (OR 0.62; 95% CI 0.40-0.96). Psychiatric history overall was not associated with TGCC. Patient history of any psychiatric disorder was associated with an increased all-cause mortality (HR 2.91; 95% CI 2.11-4.02) and an increased TGCC-specific mortality (HR 1.79; 95% CI 1.04-3.08).

Conclusions

We report, for the first time, an association between neurodevelopmental disorders and testicular seminoma. Furthermore, we found an increased TGCC-specific mortality for TGCC-patients with psychiatric disorders.

Legal entity responsible for the study

Uppsala University, Research group Ingrid Glimelius.

Funding

Swedish Cancer Society (CAN 19 0123 Pj).

Disclosure

A. Pettersson: Financial Interests, Personal, Other, Honoraria: Capio St. Göran; Financial Interests, Personal, Other, Honararia: Astellas Pharma; Financial Interests, Personal, Other, Honoraria: Mediahuset i Göteborg; Financial Interests, Personal, Other, Advisor: Janssen-Cilag; Financial Interests, Personal, Other, Grants: Merck & Co.; Financial Interests, Personal, Other, CEO and Co-Founder: Levo Prevention AB. I. Glimelius: Financial Interests, Institutional, Other, I participate as Scientific Board on an Educational Event: Janssen-Cilag; Financial Interests, Personal, Other, I participate in a Real-World Initiative to Study Register-Based Data Supported by: Takeda; Financial Interests, Personal, Other, Safety Board for Evaluation of Side-Effects from the Viral Vector Developed within the Company: Lokon Pharma. All other authors have declared no conflicts of interest.