Background

The autosomal dominant hereditary disorder VHL disease is characterized by germline inactivating mutations in the VHL gene and constitutive activation of the HIF-2α transcription factor, which drives tumor growth. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, was evaluated for efficacy for treatment of VHL-associated tumors in this open-label phase II study (NCT03401788).

Methods

Eligible patients (pts) were aged ≥18 yrs and had a VHL diagnosis based on germline VHL alteration, ≥1 measurable solid RCC tumor, no prior systemic anticancer therapy, and ECOG PS 0 or 1. Pts received MK-6482 120 mg orally once daily until progression, intolerable toxicity, or investigator/pt decision to withdraw. Primary end point: ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent review committee (IRC). Secondary end points: ORR in non-RCC tumors, DOR, and safety.

Results

As of June 1, 2020, 56 of 61 (92%) enrolled pts remain on treatment with a minimum of 60 wks follow-up. All pts had ccRCC, 100% had pancreatic lesions, 70% had CNS hemangioblastomas, and 26% had retinal lesions evaluable by IRC. For ccRCC, ORR was 36% (95% CI, 24-49%) and an additional 7 (11%) unconfirmed responses (documented at single time point and pending confirmation at data cutoff) were reported by IRC; all responses were PRs. DOR in confirmed responses was not reached (NR; range, 12-62 wks). The PFS rate at 52 wks was 98% (95% CI, 89-100%). For non-RCC tumors, per IRC, the ORR was 64% (4 CRs) in pancreatic lesions and 30% (5 CRs) in CNS hemangioblastomas; median DOR was NR (range, 11-71 wks) in pts with pancreatic lesions and NR (range, 12-72 wks) in pts with central nervous system hemangioblastomas. Of 16 pts with evaluable retinal lesions at baseline, 11 (69%) showed improvement per IRC. Treatment-related AEs were reported by 98% of pts; 13% had grade 3 TRAEs. There were no grade 4-5 TRAEs. Five pts discontinued treatment (patient decision [n=3], treatment-related adverse event [n=1; grade 1 dizziness], and death [n=1; acute fentanyl toxicity]).

Conclusions

MK-6482 continued to demonstrate promising antitumor activity against VHL-associated RCC and non-RCC tumors and was well tolerated.

Clinical trial identification

NCT03401788.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

R. Srinivasan: Advisory/Consultancy, Non-remunerated: Peloton; Research grant/Funding (institution), Funds to institution to partly defray costs of clinical trials: Calithera Biosciences; Research grant/Funding (institution), Funds to institution to partly defray costs of clinical trials: Peloton/Merck. F. Donskov: Honoraria (institution): Pfizer, Ipsen. W.K. Rathmell: Research grant/Funding (self): Incyte. V.K. Narayan: Research grant/Funding (self): Merck; Research grant/Funding (self): Janssen; Research grant/Funding (self): BMS; Research grant/Funding (self): Modra. B.L. Maughan: Research grant/Funding (self): Exelixis, Bavarian-Nordic, Clovis, BMS; Travel/Accommodation/Expenses: Dava Oncology. S. Oudard: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer, Pfizer, BMS, MSD, Sanofi, Astellas, Janssen, Novartis, Roche, AstraZeneca; Honoraria (self): Ipsen. T. Else: Research grant/Funding (self): Corcept, Strongbridge; Advisory/Consultancy: Corcept, HRA. J.K. Maranchie: Research grant/Funding (self): Merck, Peleton, Roche. S.J. Welsh: Travel/Accommodation/Expenses: Ipsen, MedImmune; Speaker Bureau/Expert testimony: Pfizer. S. Thamake: Shareholder/Stockholder/Stock options: Peloton Therapeutics Inc.; Travel/Accommodation/Expenses, Full/Part-time employment: Merck. E.K. Park: Full/Part-time employment: Merck & Co., Inc. R.F. Perini: Advisory/Consultancy, Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: MSD. All other authors have declared no conflicts of interest.

Background

The multi-center prospective longitudinal cohort study, TRACERx Renal (NCT03226886) has revealed the evolutionary features of clear-cell renal cell carcinoma (ccRCC). However, the association of physical spatial location and genetically driven tumour subclones was unclear.

Methods

100 macroscopic tumour images taken at time of surgery were reviewed by a renal pathologist, and following quality control filtering accurate spatial data was available for 79 tumours. From these 79 cases, matched high-depth driver gene panel sequencing data was utilised from 756 individual biopsy regions (mean 9.6 biopsies per tumour). The boundaries between tumour and normal tissues were marked based on macroscopic photos by a renal pathologist, after which the positions of boundaries and biopsy regions were digitally extracted to X- and Y-coordinates. Spatial distances were calculated, with the correlations between spatial characteristics and genomic alterations investigated.

Results

We mapped the spatial location of 756 biopsies, across 79 ccRCCs, and integrated these coordinates with sequencing data. This enabled a resolution as to how genetically distinct subclones grow and evolve spatially. Compared with tumour margins, the level of somatic copy number changes was higher in tumour interiors. Moreover, metastasising clones were found to be more enriched in tumour interiors. The tumour subclones growing to largest physical size were characterised by gains of chromosomes 7q, 1q and and losses of chromosome 14q. The degree of discrepancy of genomic alterations across biopsy regions was positively correlated with spatial distances across biopsy regions. Tumour subclone growth was found to be predominantly spatially contiguous, with subclone dispersal a rare event found only in one case, which notably was associated with metastasis.

Conclusions

Spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.

Clinical trial identification

NCT03226886.

Legal entity responsible for the study

Royal Marsden Hospital.

Funding

UK Medical Research Council, the Rosetrees Trust, Cancer Research UK, UK Medical Research Council, the Wellcome Trust, the European Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital, Institute of Cancer Research, the Kidney and Melanoma Cancer Fund of The Royal Marsden Cancer Charity, Ventana Medical Systems Inc.

Disclosure

C. Swanton: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Roche-Ventana; Research grant/Funding (institution): Boehringer-Ingelheim; Research grant/Funding (institution): Ono; Advisory/Consultancy: Novartis; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: MSD; Advisory/Consultancy: Illumina; Advisory/Consultancy: Genentech; Advisory/Consultancy, Shareholder/Stockholder/Stock options: GRAIL; Advisory/Consultancy: Medicxi; Advisory/Consultancy: Celgene; Advisory/Consultancy: Sarah Cannon Research Institute; Shareholder/Stockholder/Stock options: Apogen Biotechnologies; Shareholder/Stockholder/Stock options: Epic Bioscience; Shareholder/Stockholder/Stock options, Co-founder: Achilles Therapeutics. S. Turajlic: Research grant/Funding (institution): Roche Tissue Dianostics. All other authors have declared no conflicts of interest.

Background

In mUC, avelumab has demonstrated OS improvement as maintenance treatment in patients that benefit from first line (1L) CT. Based on retrospective data (Szabados B. Eur Urol. 2018) that IO before CT was superior than the reverse sequence, we tested the hypothesis that induction avelumab followed by its combination with CG, followed by avelumab maintenance may enhance clinical benefit in patients unfit for cisplatin.

Methods

CT-naïve, unresectable/mUC patients ineligible for cisplatin, as defined by Galsky criteria, were randomized to arm A: 2 cy of induction avelumab 10mg/kg Q2W followed by 6 cy of CG + avelumab (C 5AUC day 1, G 1000mg/m² day 1 and 8 and avelumab 10mg/kg day 15) Q3W, followed by avelumab 10mg/kg Q2W (n=42) until progressive disease or intolerance, compared with arm B: CG alone for 6 cy (n=43). The primary endpoint was ORR. Secondary endpoints were PFS, OS, duration of response (DoR) and safety.

Results

Baseline characteristics were generally balanced: median age 74 years, visceral metastasis (65%), renal impairment (60%) and ECOG-PS 2 (35%). The ORR was 57% (24/42) in arm A and 53% (23/43) in arm B (p= 0.73). 13 p (31%) in arm A progressed or died before the 1^st response assessment (including 6 deaths in the 1^st month) vs. 4 p (9.3%) in arm B. Median PFS was 6.9 m (95% CI, 2.2 to 8.4) in arm A vs. 7.4 m (95% CI, 5.8 to 9.7) in arm B (p=0.712). Median OS was 10.5 m (95% CI, 6.9 to NR) with avelumab/CG and 13.2 m (95% CI, 12.5 to 18.4) with CG (p=0.264). The 15-months OS rate was 45% (95% CI, 29 to 60) with avelumab/CG vs. 39% with CG (95% CI, 22 to 56). Treatment-related adverse event of ≥ Grade 3 occurred in 71% of patients in arm A and in 65% in arm B.

Conclusions

The previous hypothesis that IO before CT might optimize subsequent CT response was not proven. Early progression was higher in the induction avelumab arm (31% vs. 9.3%). However, despite the follow-up being immature, superior percentual OS benefit was observed in the avelumab/CT arm followed by avelumab maintenance. Induction IO alone before CT/IO is not an adequate strategy. Ongoing phase III trials are looking at different sequencing/combination approaches.

Clinical trial identification

NCT03390595; EudraCT: 2017-004260-36.

Legal entity responsible for the study

Associació per a la Reserca Oncològica Associació per a la Reserca Oncològica.

Funding

Merck AG, Pfizer.

Disclosure

B. Perez Valderrama: Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas Pharma; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Eusa Pharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: MSD Oncology; Advisory/Consultancy: Novartis; Travel/Accommodation/Expenses: Pfizer. M.A. Climent Duran: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Astra. M. Domènech: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony: Astellas Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Janssen. J.L. Perez Gracia: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Eisai; Research grant/Funding (self): Incyte; Research grant/Funding (self): Janssen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Seattle Genetics. X. Garcia del Muro: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Ipsen; Advisory/Consultancy: Lilly; Advisory/Consultancy: Eusa Pharma; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: PharmaMar; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Speaker Bureau/Expert testimony: Astellas Pharma; Research grant/Funding (self): AstraZeneca. P. Maroto: Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Astellas; Advisory/Consultancy: Janssen; Advisory/Consultancy: Bristol-Myers Squib; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Novartis. J. Bellmunt: Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: MSD; Advisory/Consultancy: Merck; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Roche-Genentech; Advisory/Consultancy: Pierre-Fabre; Licensing/Royalties: UpToDate. All other authors have declared no conflicts of interest.

Background

In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab (anti–PD-L1) 1L maintenance + BSC significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with advanced UC without disease progression with 1L induction CTx (gemcitabine + cisplatin [GemCis] or carboplatin [GemCar]) in all randomized pts (hazard ratio [HR] 0.69; p=0.0005) and pts with PD-L1+ tumors (HR 0.56; p=0.0003). We report prespecified subgroup analyses.

Methods

Pts were randomized 1:1 to avelumab + BSC or BSC alone, stratified by best response to 1L CTx (complete/partial response [CR/PR] vs stable disease [SD]) and by visceral vs nonvisceral disease. The primary endpoint was OS (from randomization). PD-L1 status was assessed using the Ventana SP263 assay.

Results

700 pts were randomized to either avelumab + BSC (n=350) or BSC alone (n=350); median follow-up was >19 mo. An OS benefit with avelumab + BSC vs BSC alone (median [95% CI], mo) was observed across prespecified subgroups, including pts with objective response (CR/PR; 23.8 [19.0, not estimable (NE)] vs 15.0 [13.0, 18.7]; HR 0.69 [0.53, 0.89]) or SD (19.9 [18.2, NE] vs 14.0 [10.7, 19.4]; HR 0.70 [0.46, 1.05]) as best response to 1L CTx; and pts with visceral (18.9 [16.5, 21.4] vs 14.0 [11.7, 17.4]; HR 0.82 [0.62, 1.09]) and nonvisceral metastases (28.3 [23.8, NE] vs 15.2 [13.4, 20.2]; HR 0.54 [0.38, 0.76]). OS in other subgroups is shown (Table). No significant treatment-by-subgroup interaction (at 0.05 level) was observed for any subgroup variable. Additional subgroups, progression-free survival, objective response endpoints, and safety data will also be presented.

Conclusions

Avelumab 1L maintenance + BSC provided OS benefit vs BSC alone across prespecified subgroups of pts whose disease had not progressed with 1L induction CTx and is an important advance for 1L treatment of advanced UC. Table: 704MO

Clinical trial identification

NCT02603432.

Editorial acknowledgement

Medical writing support was provided by Kelly Bryant of ClinicalThinking (Hamilton, NJ, USA) and funded by Pfizer and Merck KGaA, Darmstadt, Germany.

Legal entity responsible for the study

Pfizer.

Funding

This study was sponsored by Pfizer, and is part of an alliance between Pfizer and Merck KGaA, Darmstadt, Germany.

Disclosure

P. Grivas: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): Bavarian Nordic; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Biocept; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, Educational unbranded activity with Bristol-Myers Squibb (2017): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Clovis Oncology; Research grant/Funding (institution): Debiopharm; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Driver; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: EMD Serono; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Exelixis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Foundation Medicine; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Honoraria (self), Advisory/Consultancy: GlaxoSmithKline; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Heron Therapeutics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Mirati Therapeutics; Research grant/Funding (institution): Oncogenex; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Research grant/Funding (institution): Immunomedics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Seattle Genetics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: QED Therapeutics; Honoraria (institution): KureIT. C. Caserta: Advisory/Consultancy: Janssen; Advisory/Consultancy: Merck; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Novartis Pharma SAS; Advisory/Consultancy: Pfizer Pharmaceuticals Israel. B. Perez Valderrama: Advisory/Consultancy, Non-remunerated activity/ies: Astellas Pharma; Advisory/Consultancy, Non-remunerated activity/ies: Bristol-Myers Squibb; Advisory/Consultancy, Non-remunerated activity/ies: Ipsen; Advisory/Consultancy: Pierr-Fabre; Advisory/Consultancy: Bayer; Advisory/Consultancy, Non-remunerated activity/ies: Roche; Advisory/Consultancy: Sanofi; Advisory/Consultancy: EUSA Pharma; Advisory/Consultancy: MSD Oncology; Advisory/Consultancy: Novartis Pharma SAS; Non-remunerated activity/ies: Pfizer Pharmaceuticals Israel. H. Gurney: Advisory/Consultancy: BMS; Advisory/Consultancy: MSD; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Ipsen; Advisory/Consultancy: AstraZeneca. Y. Loriot: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy: Janssen; Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas. S.S. Sridhar: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy: Sanofi; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Merck; Advisory/Consultancy, Research grant/Funding (institution): Pfizer. N. Tsuchiya: Honoraria (self): Astellas; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Janssen; Honoraria (self): Novartis; Honoraria (self): Ono; Honoraria (self): Bayer; Honoraria (self): Sanofi; Honoraria (self): Takeda; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MDS. S. Gupta: Honoraria (self), Speaker Bureau/Expert testimony: Exelixis; Honoraria (self), Speaker Bureau/Expert testimony: Janssen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy: AstraZeneca; Research grant/Funding (institution): Astellas. B. Huang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. N. Costa: Full/Part-time employment: Pfizer. J.A. Blake-Haskins: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. A. di Pietro: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. T.B. Powles: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Incyte; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Research to Practice; Honoraria (self), Travel/Accommodation/Expenses: Ferring; Honoraria (self): Gerson Lehrman Group; Honoraria (self): Janssen Research & Development. All other authors have declared no conflicts of interest.

Background

Sitra is a spectrum-selective TKI which targets TAM receptors (Tyro3, Axl, MerTK), split family receptors (VEGFR2 and c-Kit) and c-Met. Sitra has demonstrated antitumor activity as well as the reduction of Type 2 tumor-associated macrophages, regulatory T-cells and myeloid-derived suppressor cells and enhancement of T cell-mediated anti-tumor immune response in nonclinical studies and patients. Given these pleiotropic immune-enhancing effects, we hypothesized that the combination of sitra with a CPI will augment clinical activity of CPI alone in UC.

Methods

This is a multi-cohort phase 2 Study (516-003) to evaluate the efficacy and safety of the nivo+sitra combination in UC. This Cohort (C5) enrolled CPI-naïve pts who have disease progression on or after prior platinum-based chemotherapy. Sitra is administered orally, daily; nivo intravenously, 240mg every 2 weeks or 480mg every 4 weeks. Based on the Predictively Probability Design, a target sample size of 26 pts in Stage 1 allows advancement to Stage 2 if clinically active. Other objectives include pharmacokinetics (PK) and correlative biomarkers.

Results

C5 met its prespecified clinical activity with 8 confirmed responses in the first 26 evaluable pts, and advanced to Stage 2 (ongoing). As of May 8, 2020, C5 has enrolled 36 pts with 26 having had ≥1 on-study tumor assessment. Preliminary confirmed investigator-assessed ORR per RECIST 1.1 was 31% (4% CR). Disease control rate (CR/PR/SD) was 77%. With median follow-up of 6.1 months, median PFS was 3.9 months (95% CI 1.9, 7.3). Most common (≥20%) treatment-related adverse events (TRAEs) included fatigue (49%), diarrhea (43%), decreased appetite (41%), dysphonia (30%), increased ALT (30%), hypertension (24%), nausea (22%) and palmar-plantar erythrodysesthesia syndrome (22%). Grade 3/4 TRAEs occurred in 46% of pts. There were no Grade 5 TRAEs. Updated safety, PK and efficacy data will be presented.

Conclusions

Sitra with nivo combination is clinically active with manageable side effects in CPI-naïve, platinum-experienced pts with UC.

Clinical trial identification

NCT03606174.

Legal entity responsible for the study

Mirati Therapeutics, Inc.

Funding

Mirati Therapeutics, Inc.

Disclosure

P. Msaouel: Honoraria (self): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Mirati Therapeutics; Honoraria (self): Exelixis; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Gateway for Cancer Research. A.O. Siefker-Radtke: Advisory/Consultancy: Merck; Advisory/Consultancy: Bavarian Nordic; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Genentech; Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen; Advisory/Consultancy: Mirati Therapeutics; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Nektar Therapeutics; Advisory/Consultancy: Pfizer. R. Sweis: Honoraria (self): Aduro; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Exelixis; Honoraria (self): Eisai; Honoraria (self): Mirati; Honoraria (self): Puma. S. Mao: Speaker Bureau/Expert testimony: Bristol-Myers Squibb. J.E. Rosenberg: Advisory/Consultancy, Research grant/Funding (institution): Mirati Therapeutics; Advisory/Consultancy: Adicet Bio; Advisory/Consultancy: Agensys; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: BioClin Therapeutics; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol Myers Squibb; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Fortress Biotech; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: Inovio Pharma; Advisory/Consultancy: Janssen; Advisory/Consultancy: Lilly; Advisory/Consultancy: Merck; Advisory/Consultancy: Pharmacyclics; Advisory/Consultancy, Research grant/Funding (institution): QED Therapeutics; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy: Sensei Biotherapeutics; Advisory/Consultancy: Western Oncolytics; Advisory/Consultancy: Boerhinger Ingelheim; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Jounce Therapeutics; Research grant/Funding (institution): Novartis; Travel/Accommodation/Expenses: Chugai. U.N. Vaishampayan: Advisory/Consultancy, Research grant/Funding (institution): Alkermes; Advisory/Consultancy: Bayer; Advisory/Consultancy: Exelixis; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb. A. Rezazadeh Kalebasty: Shareholder/Stockholder/Stock options: ECOM Medical; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Exelixis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: EMD Serono; Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Astellas; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eisai; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Merck; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Beyond Spring; Research grant/Funding (institution): BioClin Therapeutics; Research grant/Funding (institution): Clovis Oncology; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Epizy; Travel/Accommodation/Expenses: Prometheus Laboratories. N. Davis: Research grant/Funding (institution): Mirati Therapeutics. T. Zhang: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Acerta; Research grant/Funding (institution): Abbvie; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Merrimack; Research grant/Funding (institution): OmniSeq; Research grant/Funding (institution): PGDx; Advisory/Consultancy, Research grant/Funding (institution): Merck; Research grant/Funding (institution): Mirati Therapeutics; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Regeneron; Advisory/Consultancy, Speaker Bureau/Expert testimony: Genentech; Advisory/Consultancy, Speaker Bureau/Expert testimony: Exelixis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Genomic Health; Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi Aventis; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Amgen; Advisory/Consultancy: MJH Associates; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Pharmacyclics; Advisory/Consultancy: Seattle Genetics. J. Christensen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics. R. Shazer: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics. X. Yan: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics. M. Winter: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics. H. Der-Torossian: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics. G. Vasudeva Iyer: Honoraria (self), Research grant/Funding (institution): Mirati Therapeutics; Honoraria (self), Research grant/Funding (institution): Janssen; Research grant/Funding (institution): DeBioPharm; Research grant/Funding (institution): Novartis. All other authors have declared no conflicts of interest.

Background

Data related to the impact of human papillomavirus (HPV) infection status and the outcome of perioperative treatments in patients with lymph node-involved penile squamous-cell carcinoma (PSCC) are lacking. We aimed to analyze the benefit from perioperative radiotherapy (RT) according to HPV infection status.

Methods

Within an international, multicenter database of 1,254 patients (pts) with PSCC who received inguinal lymph node dissection (ILND) from Europe, United States, Brazil, United Kingdom and China, 507 had suitable clinical information. Kaplan-Meier and restricted mean survival time (RMST) examined the overall survival (OS) differences among HPV+ and HPV- patients according to the use of perioperative RT to involved regional lymph nodes. The analyses were also made after propensity score-matching (PSM; N=136). Multivariable Cox regression analyses for OS were also done. Finally, we looked at the genomic alterations landscape of PSCC from the Foundation Medicine database (N=199) to characterize HPV+ PSCC.

Results

Pts with HPV+ PSCC exhibited a lower clinical N-stage (p<0.001) and ILNM density (p<0.001). HPV+ patients had similar median OS (p=0.1) but longer RMST than HPV- patients at different time-points. Nevertheless, HPV+ patients treated with perioperative RT exhibited longer median OS (p=0.015) and longer RMST compared to HPV- pts. These findings were not confirmed with perioperative chemotherapy (p=0.19). In the PSM cohorts, HPV+ status remained significantly associated with longer OS after RT. In multivariable Cox regression analyses, pts with HPV+ PSCC exhibited a significantly improved OS compared with those with HPV- PSCC (HR: 0.12, 95%CI: 0.03-0.48; p=0.003). Among the several different genomic alterations frequencies, the top-altered genes (>20%) in HPV+ cases were PI3KCA (38.7%) and KMT2D(25.8%), whereas in HPV- cases these were TP53 (75.2%), CDKN2A (65%) and TERT (promoter region, 60.2%).

Conclusions

Perioperative RT was more effective in the subgroup of HPV+ PSCC. Reasons for enhanced RTsensitivity may also be related to the different landscape of genomic alterations. These results should be considered as hypothesis-generating and may inspire future prospective trials.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Metastatic penile squamous carcinoma (mSCC) is a very rare disease with poor outcomes despite the use of platinum-based chemotherapy agents. There is limited real-world data on how these patients are managed in clinical practice and their outcomes. To our knowledge this is the largest review of such patients to date.

Methods

A prospective database of over 1200 patients referred to the supra-regional penile multi-disciplinary team (MDT) at St George’s Hospital London was collected from 2006 to 2020. Patients were treated at St George’s Hospital or at other centres with oncology guidance from the St George’s MDT. Metastatic disease was defined as the presence of disease outside the pelvis or those in whom curative therapy for the metastasis was not possible and hence treated with palliative intent. Indication of treatment was to treat symptoms and prolong survival. Clinical benefit rate (CBR), median progression free survival (mPFS) and median overall survival (mOS) were analyzed retrospectively.

Results

101 patients (median age 63, IQR (56-72), 73% ECOG 0/1) were included. 32% (32/101) received adjuvant chemotherapy prior to metastatic recurrence of disease. 59% (59/101) patients received chemotherapy and 42% (42/101) received best supportive care (BSC). 17% (17/101) patients received subsequent second-line systemic therapy and 3% (3/101) patients received third-line systemic therapy.

For first-line systemic-therapy (n=59), there was a 46% (27/59) CBR with 9% (5/59) complete response, 15% (9/59) partial response and 22% (13/59) stable disease. Patients receiving 2nd line subsequent- therapy (n=17) had a 29% (5/17) CBR. mPFS for first- and second-line treatment was 3.2 (95% CI: 2.0-4.5) and 2.2 (95% CI: 1.9-2.4) months respectively. mOS for all patients was 6.2 months (95% CI: 5.1-7.2). mOS for first-line chemotherapy, second-line chemotherapy and BSC patients was 7.2 (95% CI: 5.9-8.5), 4.5 (95% CI: 2.5-6.5) and 2.0 (95% CI: 1.1-2.9) months respectively.

Conclusions

First-line platinum-based chemotherapy is associated with notable response rates in mSCC patients. Subsequent therapy can be beneficial but outcomes remain sub-optimal. Agents with better response rates are needed urgently potentially in combination with platinum-based chemotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

It is hypothesized that cisplatin-based chemotherapy (CT) reduces the occurrence of a metachronous contralateral (second) germ cell testicular cancer (TC). However, data regarding treatment details are lacking in previous publications. The aim of this study was to investigate the risk of a second TC in relation to previous TC treatment, in particular the number of cisplatin-based CT cycles.

Methods

A population-based cohort of 5622 men diagnosed with first TC 1980-2009, as well as second TC, was identified by the Cancer Registry of Norway. Treatment data were based on medical records. Cumulative incidence of metachronous contralateral TC was estimated, and standardized incidence ratios (SIRs) were calculated to compare the risk to the general population. The effect of treatment intensity on the second TC risk was investigated using Cox regression.

Results

Median follow-up was 16.3 years, during which 206 men were diagnosed with a second TC after median 5.9 years. Median time to second TC was shorter after CT (5.5 years) than after surgery only (6.6 years). Overall, the 20-year crude cumulative incidence was 4.0% (95% CI 3.5-4.6), with lower incidence after CT (3.1 %, 95% CI 2.4-3.9) than after surgery only (5.7%, 95% CI 4.4-7.3). The second TC incidence was also lower for those >=30 years (2.8%, 95% CI 2.2-3.4) at first TC diagnosis than those <30 years (6.0 %, 95% CI 4.9-7.1). Overall, the risk of a second TC was 13-fold higher compared with the risk of developing TC in the general population (SIR 13.3, 95% CI 11.6-15.3). The SIR was lower after CT (9.1, 95% CI 7.1-11.6) than after surgery only (17.1, 95% CI 13.6-21.7). With surgery only as reference, treatment with CT significantly reduced the risk of a second TC (HR 0.52, 95% CI 0.37-0.73). For each cisplatin-based CT cycle administered, the risk for a second TC decreased monotonously, with significantly reduced risks after 3, 4 and >4 cycles (HRs 0.45, 0.41, and 0.21 respectively).

Conclusions

The overall 20-year cumulative incidence of a second TC was 4.0%. Age at first TC diagnosis as well as treatment intensity influenced the risk of a second TC, with a monotonic risk reduction for each additional cisplatin-based CT cycle administered.

Legal entity responsible for the study

Translational Cancer Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway.

Funding

Helse Nord RHF.

Disclosure

All authors have declared no conflicts of interest.