Background

Stage III (cT3-4aN0M0 or ≥cT1N+M0) urothelial cancer (UC) patients (pts) have a poor prognosis. Despite high response rates, pre-operative chemo shows limited survival benefit. Immunotherapy targeting PD-1/PD-L1 is active in metastatic UC; the combination of ipilimumab (ipi) and nivolumab (nivo) appears to increase response rates. Encouraging path Complete Response (pCR) rates are observed in trials testing neoadjuvant anti-PD-1/PD-L1 (mostly cT2-T3N0 pts). Here, we present the first clinical trial data on preoperative ipi+nivo.

Methods

This is a single-arm phase 1B trial testing the feasibility (primary endpoint) of pre-operative ipi+nivo in stage III UC pts (cis unfit/refusal). To mitigate the risk of immune-related toxicity, pts were treated with (based on melanoma data): ipi 3 mg/kg (day 1), ipi 3 + nivo 1 mg/kg (day 22), and nivo 3 mg/kg (day 43), followed by resection. Secondary endpoints were efficacy (pCR) and translational parameters: PD-L1, TMB (by WES), and immune cell infiltrates at baseline vs on-treatment using multiplex immunofluorescence (mIF; pan-CK/CD3/CD8/FOXP3/CD20/CD68).

Results

24 pts (14 cT3-4N0; 10 cN+) were enrolled, of whom 23 (96%) had resection <12 weeks from 1st cycle. 1 pt, responding radiologically, had a delay in surgery because of an irAE (hemolysis). 18/24 pts received all 3 cycles, 6 pts received 2 cycles due to irAEs. Grade 3/4 irAEs occurred in 54% of pts; 42% when excluding clinically insignificant lab deviations. 22 pts were available for efficacy assessment (1 pt resection delayed, 1 pt had resection 1 day before abstract submission). 10/22 pts (45%) achieved a pCR. 3 additional pts (14%) had noninvasive cancer at resection (2 ypTis, 1 ypTa), resulting in an overall path downstaging (≤ypT1N0) rate of 59% (13/22). In recent neoadjuvant IO studies in melanoma and NSCLC, major path response (MPR) has been defined as ≤ 10% vital tumor cells in the tumor bed. MPR was seen in 5/22 pts (23%). Nonresponse was seen in 4/22 (17%). Response was associated with massive infiltration of CD8+ T-cells in the tumour bed.

Conclusions

Preoperative ipi+nivo is feasible (96% surgery <12 weeks) and shows promising efficacy in stage III UC pts. Updated results on all 24 pts, including mIF, PDL1 and TMB, will be presented.

Clinical trial identification

NCT03387761, January 2, 2018.

Legal entity responsible for the study

Netherlands Cancer Institute - Antoni van Leeuwenhoek.

Funding

BMS.

Disclosure

M.S. Van der Heijden: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Janssen. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Scenic Biotech; Advisory / Consultancy: Third Rock Ventures; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck KGaA. P. Kvistborg: Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Personalis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: GenMab; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): NanoString. B.W. van Rhijn: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Ferring. All other authors have declared no conflicts of interest.

Background

In PURE01 study (NCT02736266), neoadjuvant pembro resulted in 42% pT0 in patients (pts) with MIBC. pT0 pts had features suggesting pre-existing immunity or higher tumor mutational burden (TMB) may promote response. In this study, we investigated potential mechanisms for resistance to pembro, including FGFR3 genomic alterations (GA).

Methods

Pts enrolled in the PURE-01, which is still recruiting pts in its amended design, had predominant urothelial carcinoma histology and stage cT ≤ 4N0 MIBC. Biomarker analyses in the expanded cohort of 96 pts included PD-L1 combined positive score and comprehensive genomic profiling (FoundationCDx assay). In addition, TCGA MIBC (n = 405) and a prospective commercial cohort (PCC) of 415 MIBC pts from the clinical use of the Decipher Bladder TURB test from the GRID registry (NCT02609269) were analyzed. A single-sample genomic classifier (GC) was trained to identify FGFR3-active tumors (FGFR3+).

Results

In PURE01 cohort, despite a linear association of TMB with ypT0 in multivariable models (p = 0.017), there was no association between FGFR3 GA and pathological response nor with PD-L1 expression. FGFR3 GA were found in 17.6% ypT0 vs 20.7% in ypT3-4 disease (corrected p = 0.82). Applying the GC to the TCGA MIBC cohort, we found 45% of FGFR3+ cases had FGFR3 mutations vs 9% for the rest of the cohort. Applying the GC to the PCC, we found that the FGFR3+ tumors were Luminal (n = 14), Luminal Infiltrated (n = 10) or Luminal Papillary (n = 30). FGFR3+ pts showed significantly lower PD-L1 (-0.03 vs. 0.109, p < 0.001) and PD-L2 (0.184 vs. 0.389, p < 0.001), but consistent PD-1 (0.175 vs. 0.163, p = 0.48) gene expression. FGFR3+ pts had lower immune and stromal infiltration as measured by the immune190 (0.227 vs. 0.348, p < 0.001) and Estimate (100.14 vs. 1099.2, p < 0.001) gene expression signatures.

Conclusions

In our combined cohorts, FGFR3 GA did not correlate with response to pembro. FGFR3 GA are enriched in FGFR3+ tumors, which in turn tend to have lower immune activity, PD-L1 and PD-L2, suggesting FGFR3 activity may provide a potential tool for further discriminating the mechanisms underlying response and resistance to neoadjuvant pembro in MIBC.

Clinical trial identification

NCT02736266 (PURE01) NCT02609269 (GRID Registry).

Legal entity responsible for the study

The authors.

Funding

Decipher Bioscience.

Disclosure

A. Necchi: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Clovis; Advisory / Consultancy: Janssen. R. Madison: Full / Part-time employment: Foundation Medicine. J. Chung: Full / Part-time employment: Foundation Medicine. Y. Liu: Full / Part-time employment: Decipher Bioscience. J. Chung: Full / Part-time employment: Foundation Medicine. J.S. Ross: Full / Part-time employment: Foundation Medicine. S.M. Ali: Full / Part-time employment: Foundation Medicine. E. Davicioni: Full / Part-time employment: Decipher Bioscience. E.A. Gibb: Full / Part-time employment: Decipher Bioscience. All other authors have declared no conflicts of interest.

Background

In the S-TRAC trial, adjuvant sunitinib (SU) prolonged disease-free survival (DFS) versus placebo (PBO) in patients (pts) with loco-regional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy. We previously applied the 16-gene Recurrence Score and confirmed its prognostic value (Clin Cancer Res 2018;15:4407). Here, we report the results of retrospective exploratory genomic and transcriptomic analyses using nephrectomy biospecimens from the S-TRAC trial.

Methods

Formalin-fixed paraffin-embedded tumor tissue blocks from patients who provided informed consent were used for whole exome (WES) and whole transcriptome (RNAseq) sequencing (Personalis, Menlo Park, CA; Genome Med. 2015;7:71) to examine somatic mutations and analyze relevant gene expression signatures (GES) in relation to clinical outcome. GES analyses included published signatures [effector T-cell (T_eff), angiogenesis (Angio), myeloid inflammation (M_inf)] among others. Cox proportional analyses of DFS were performed for each genotype or signature in SU versus PBO groups and between genotypes or signatures within each treatment group. Estimates of related parameters were reported.

Results

In all, 171 pts (SU, n = 91; PBO, n = 80) were genotyped and 133 (SU, n = 72; PBO, n = 61) were included in the GES analyses. Differences in DFS were observed relative to wildtype when mutations in genes such as ARID1A, MTOR, or ROBO3 were present; presence or absence of mutation in BAP1, SETD2 or PBRM1, however, did not distinguish pts with respect to DFS. Low tumor mutational burden (TMB) was associated with longer DFS in PBO as compared to high TMB (hazard ratio (HR) 0.253; 95% CI: 0.119, 0.541), but not in SU. Low-Angio GES showed a modest association with shorter DFS vs high-Angio GES in PBO (HR 1.912; 95% CI: 0.829, 4.409) but did not differentiate DFS in SU. Pts with low-M_inf GES in SU had longer DFS vs those with high-M_inf GES (HR 0.304; 95% CI: 0.132, 0.702).

Conclusions

These findings define molecular features that differentiate SU-specific outcomes in adjuvant RCC and may inform personalized therapy strategies for pts at high risk of recurrence. Independent validation studies are needed to confirm these findings.

Clinical trial identification

NCT00375674.

Editorial acknowledgement

Vardit Dror and David Cope Engage Scientific Solutions, funded by Pfizer.

Legal entity responsible for the study

Pfizer.

Funding

Pfizer.

Disclosure

A. Ravaud: Advisory / Consultancy, Travel / Accommodation / Expenses, lecture fees: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses, lecture fees: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses, lecture fees: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses, lecture fees: Ipsen; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Merck Sharp & Dohme. J. Martini: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. K. Ching: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. M. Staehler: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Exelixis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche. A. Magheli: Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Janssen. B. Escudier: Advisory / Consultancy, lecture fees: Pfizer; Advisory / Consultancy, lecture fees: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Roche. X.J. Mu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. O. Valota: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. X. Lin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. R.J. Motzer: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: Incyte; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): GlaxoSmithKline.

Background

ADATPeR is the first prospective study evaluating the role of anti-PD1 agents in the neoadjuvant setting prior to cytoreductive nephrectomy in treatment-naïve patients with metastatic clear cell renal cell carcinoma (mccRCC). We performed multi-omic analyses to resolve spatial heterogeneity and temporal dynamics in putative biomarkers of response to anti-PD1 blockade.

Methods

In a single center study, patients received nivolumab (3mg/kg every 2 weeks) pre- and post-operatively until progressive disease (PD). Primary endpoint was safety, secondary endpoints were response evaluation and exploratory biomarker analysis. Multiregion tumour biopsies were obtained at baseline, on-treatment (week 9) and at PD. Whole-exome sequencing was performed to infer somatic mutations and predict candidate neoantigens (NAs). Tumour immune microenvironment was evaluated using a RNA-seq-derived immune signature and by stromal and intraepithelial tumour infiltrating lymphocytes (TILs) assessments.

Results

15 patients were treated. At median follow-up of 12.5 months(m), nivolumab had an acceptable side-effect profile. Overall response rate was 37%. Preliminary transcriptome analyses of pre-treatment biopsies (33 samples from 14 patients; up to 4 regions per case) revealed enrichment for primary-resistance (defined as PD within 2m; n = 4) with immune ‘cold’ tumours, distinct from ’hot’ tumours. Histologic TILs scoring showed concordant immune phenotypic clusters. Primary-resistant cases demonstrated 0% on-treatment stromal- and IE-TILs (2 evaluable patients). In contrast, we observed heavy on-treatment stromal TILs (70-90%) and intraepithelial TILs (30-90%) across 7 regions at nephrectomy in an exceptional responder receiving ongoing treatment (>24 cycles).

Conclusions

ADATPeR is the first neoadjuvant immune checkpoint inhibitor study pre-cytoreductive nephrectomy, and incorporated multi-omic analyses of putative biomarkers. Baseline immune gene expression signature is distinct in responders compared with non-responders. On-treatment intraepithelial TILs were prominent in those deriving durable clinical benefit. Integrative analyses are ongoing.

Clinical trial identification

NCT02446860.

Legal entity responsible for the study

The authors.

Funding

Bristol-Myers Squibb; The National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research; Cancer Research UK (CRUK).

Disclosure

All authors have declared no conflicts of interest.

Background

On the basis of noninferiority outcomes for pts with metastatic disease who received S vs pts who underwent uCN followed by S (Mejean NEJM 2018), the role of uCN in pts with metastatic RCC who require systemic therapy has been revised. However, the activity of new combination treatments on the primary tumour is unknown. The JAVELIN Renal 101 trial (NCT02684006) demonstrated longer progression-free survival (median 13.8 vs 8.4 mo; HR 0.69; p < 0.001) and higher objective response rate (51% vs 26%) with A + Ax vs S in pts with aRCC; benefit was observed in all risk sugroups and in pts irrespective of prior CN (Motzer NEJM 2019; Choueiri ASCO-GU 2019).

Methods

886 eligible pts with clear cell aRCC, no prior systemic therapy for aRCC, and ECOG PS 0-1 were randomised 1:1 to receive either A + Ax (N = 442) or S (N = 444) following a standard dose and schedule. We performed a post hoc analysis to investigate the extent of primary renal tumour shrinkage in pts with renal target lesions who did not undergo uCN.

Results

Of 886 pts, 179 (20.2%) did not undergo uCN; 55/90 on the A+ Ax arm and 62/89 on the S arm had renal target lesions. Baseline characteristics were balanced between the 2 arms in this subgroup; 0.9%/59.8%/39.3% had favourable/intermediate/poor IMDC risk. Of the pts with renal target lesions who did not undergo uCN in the A + Ax vs S arms, 34.5% vs 9.7% had ≥30% shrinkage for best % change in renal target lesions from baseline. The median time to ≥ 30% shrinkage in renal target lesions was 4.4 vs 7.1 mo, respectively. The agreement rate between pts with ≥30% shrinkage in the renal target lesion and ≥30% shrinkage in all target lesions was 83.6% vs 82.3%, respectively. Results of ongoing biomarker analyses will be presented.

Conclusions

A + Ax resulted in greater shrinkage of the primary renal tumour vs S in pts with aRCC who did not undergo uCN. This is the first report of the efficacy of immuno-oncology + tyrosine kinase inhibitor therapy on the primary tumour in the context of metastatic RCC and provides insight into future neoadjuvant strategies in aRCC.

Clinical trial identification

NCT02684006 February 17, 2016.

Editorial acknowledgement

ClinicalThinking, funded by Pfizer Inc. and Merck Healthcare KGaA.

Legal entity responsible for the study

Pfizer Inc.

Funding

Pfizer Inc. in alliance with Merck Healthcare KGaA.

Disclosure

L. Albiges: Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Peloton Therapeutics; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis. B.I. Rini: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): GNE/Roche; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Peloton. J.B.A.G. Haanen: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Bayer; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Gadeta DV; Advisory / Consultancy: Celsius Therapeutics; Advisory / Consultancy: AstraZeneca/MedImmune. R.J. Motzer: Advisory / Consultancy, Research grant / Funding (institution): Pfizer Inc.; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Incyte; Research grant / Funding (institution): Bristol-Myers Squibb (BMS); Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Merck. C.K. Kollmannsberger: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Astellas; Advisory / Consultancy: EMD Serono. S. Negrier: Honoraria (self): Pfizer; Honoraria (self): BMS; Honoraria (self): Novartis; Honoraria (self): Ipsen; Honoraria (self): Eusa Pharma. J. Bedke: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: Eusa Pharma; Advisory / Consultancy: Nektar. M.A. Bilen: Advisory / Consultancy: Exelixis; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Tricon Pharmaceuticals; Research grant / Funding (institution): Peleton; Research grant / Funding (institution): Pfizer. P. Nathan: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Immunocore; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer. Y. Tomita: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono; Honoraria (self): Sanofi-Aventis; Honoraria (self): BMS; Advisory / Consultancy: Taiho; Advisory / Consultancy: MSD; Research grant / Funding (institution): Takeda. B. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. K.A. Ching: Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Pfizer Inc. A. Chudnovsky: Full / Part-time employment: Pfizer, Inc. P.B. Robbins: Full / Part-time employment: Pfizer, Inc. A. di Pietro: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer, Inc. D. Thomaidou: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer, Inc. T.K. Choueiri: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Cerulean Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Prometheus Laboratories; Honoraria (self), Advisory / Consultancy: Alligent; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Corvus Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Alexion Pharmaceuticals; Research grant / Funding (institution): Seattle Genetics/Astellas; Honoraria (self), Advisory / Consultancy: Sanofi/Aventis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Peloton Therapeutics; Honoraria (self), Advisory / Consultancy: EMD Serono; Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy, Leadership role: NCCN; Leadership role: Kidney Cancer Association; Honoraria (self), Advisory / Consultancy: UptoDate; Honoraria (self), Advisory / Consultancy: Michael J. Hennessy Associates; Honoraria (self), Advisory / Consultancy: ASCO; Honoraria (self), Advisory / Consultancy: Harborside Press; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Analysis Group; Honoraria (self), Advisory / Consultancy: PlatformQ Health; Honoraria (self), Advisory / Consultancy: Clinical Care Options; Honoraria (self), Advisory / Consultancy: Navinta Healthcare; Honoraria (self), Advisory / Consultancy: Kidney Cancer Journal; Honoraria (self), Advisory / Consultancy: Lpath; Honoraria (self), Advisory / Consultancy: NEJM; Honoraria (self), Advisory / Consultancy: Lancet Oncology; Honoraria (self), Advisory / Consultancy: HERON; Honoraria (self), Advisory / Consultancy: Lilly; Research grant / Funding (institution): TRACON Pharma; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Calithera Biosciences; Full / Part-time employment: Dana Farber Cancer Hospital. All other authors have declared no conflicts of interest.

Background

The NIVOREN GETUG-AFU 26 study reported safety and efficacy of N in mccRCC pts in a “real world setting”. A translationnal research program was launched to characterize immune cell populations in and around the tumor by immunohistochemistry (IHC) and correlate them with outcome on N.

Methods

All pts treated with N in the GETUG AFU 26 NIVOREN trial who consented for translational program and with available archived paraffin-embedded (FFPE) tumor tissue samples were eligible. Tumor were centrally reviewed. Densities of CD3-, CD8- and CD20-cells and tertiary lymphoid structures (TLS) were estimated by IHC. PD-L1 expression was quantified as percentage of positive tumor cells (TC) and immune cells (IC).

Results

Overall 324 pts were included. Pts had similar baseline characteristics (IMDC Good, Intermediate, Poor in 18%, 60% and 22%, respectively) than overall trial population. Median PFS was 4.5 (2.9-5.2) months and median OS 25.4 (23.6-NE) months. Highest density of CD8 T cells at the invasive margin (IM) was associated with worse PFS (2.3 vs 4.6 months, HR = 3.96 (1.84-8.51), p = 0.0001) and OS (8.6 vs 25.4 months, HR = 2.43 (0.99-5.95), p = 0.0451). PD-L1 expression on TC (³1%) was associated with worse OS (22.7 vs 29.1 months, HR = 1.51 (1.06-2.15), p = 0.0232) but not PFS (3.5 vs 4.6 months, p = 0.5121). PD-L1 expression on IC (³1%) was associated with numerically shorter median OS (24.7 months vs NR, HR = 1.34 (0.95-1.88), p = 0.0955). CD8 densities, either in the T or at the IM were associated with high PD-L1 expression (>1%) by TC or by IC (all p < 0.0001). Densities of CD3, CD20 and TLS were not significantly associated with OS or PFS. More data such as response rates and combinations of markers will be presented at the meeting.

Conclusions

We report the largest translational analysis supporting that highest CD8 density at the IM is associated with worse OS and PFS while PD-L1 expression by ³1% TC or IC is associated with worse OS in pts with mccRCC receiving N.

Clinical trial identification

NCT03013335.

Legal entity responsible for the study

UNICANCER.

Funding

Institut National du Cancer, Direction Générale de l’Offre de Soins, Bristol-Myers-Squibb.

Disclosure

Y. Vano: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Astellas. N. Rioux-Leclercq: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Ipsen. B. Beuselinck: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS. M. Gross-Goupil: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: GSK. S. Negrier: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Eusa Pharma. D. Borchiellini: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen-Cilag; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy: Sanofi. B. Escudier: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Eusa Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Aveo. L. Albiges: Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: Ipsen; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Novartis. All other authors have declared no conflicts of interest.

Background

Despite advances in clear cell RCC treatment, pts with sRCC have poor prognosis and are more resistant to VEGF-targeted therapy. In JAVELIN Renal 101 (NCT02684006), progression-free survival (PFS) was longer (median 13.8 vs 8.4 mo; HR 0.69; p < 0.001) and objective response rate (ORR) was higher (51% vs 26%) with A + Ax vs S; benefit was observed in pts irrespective of PD-L1 expression and across all prognostic risk groups (Motzer NEJM 2019; Choueiri ASCO-GU 2019). We report data from a post hoc analysis of JAVELIN Renal 101 pts with sRCC.

Methods

886 eligible pts with clear cell aRCC, no prior systemic therapy for aRCC, and ECOG PS 0-1 were randomised 1:1 to receive either A + Ax (N = 442) or S (N = 444) following a standard dose and schedule. PFS and ORR were assessed by independent review committee in pts irrespective of PD-L1 expression. Pts whose pathology report indicated sarcomatoid features were included in this post hoc analysis. Biomarker analyses included expression of PD-L1, genes and signatures, whole exome sequencing, and classification per criteria reported previously (Chen Cell Rep 2016).

Results

Of the 886 randomised pts, 108 (12.2%; 47 on A + Ax and 61 on S arm) had sRCC. Baseline characteristics were balanced between the 2 arms in this subgroup; 10.2%/62.0%/27.8% had favourable/intermediate/poor IMDC risk. In pts with sRCC, A + Ax improved PFS (median [95% CI], 7.0 [5.3, 13.8] vs 4.0 [2.7, 5.7] mo; HR 0.57 [95% CI, 0.325,1.003]) and ORR [95% CI] (46.8% [32.1, 61.9] vs 21.3% [11.9, 33.7]; complete response in 4.3% vs 0%) vs S. Ongoing biomarker analyses suggest that pts with sRCC have higher median expression levels of key immune markers, including PD-L1 and IFNG, and most are defined molecularly by the differentially expressed genes in M1-M4 TCGA subtypes as the M3 classification with historically poor prognosis.

Conclusions

Pts with sRCC who received A + Ax had PFS and ORR benefit over S, supporting the results in the overall trial population. This analysis provides insight into the biology of an aggressive subtype of RCC and suggests a potential new treatment option.

Clinical trial identification

NCT02684006 February 17, 2016.

Editorial acknowledgement

ClinicalThinking, funded by Pfizer Inc. and Merck Healthcare KGaA.

Legal entity responsible for the study

Pfizer Inc.

Funding

Pfizer Inc. in alliance with Merck Healthcare KGaA.

Disclosure

T.K. Choueiri: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Cerulean Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Prometheus Laboratories; Honoraria (self), Advisory / Consultancy: Alligent; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Corvus Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Alexion Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Peloton Therapeutics; Honoraria (self), Advisory / Consultancy: Sanofi/Aventis; Honoraria (self), Advisory / Consultancy: EMD Serono; Research grant / Funding (institution): Seattle Genetics/Astellas; Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy, Leadership role: NCCN; Leadership role: Kidney Cancer Association; Honoraria (self), Advisory / Consultancy: UptoDate; Honoraria (self), Advisory / Consultancy: Michael J. Hennessy Associates; Honoraria (self), Advisory / Consultancy: ASCO; Honoraria (self), Advisory / Consultancy: Harborside Press; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Analysis Group; Honoraria (self), Advisory / Consultancy: PlatformQ Health; Honoraria (self), Advisory / Consultancy: Clinical Care Options; Honoraria (self), Advisory / Consultancy: Navinta Healthcare; Honoraria (self), Advisory / Consultancy: Kidney Cancer Journal; Honoraria (self), Advisory / Consultancy: Lpath; Honoraria (self), Advisory / Consultancy: NEJM; Honoraria (self), Advisory / Consultancy: Lancet Oncology; Honoraria (self), Advisory / Consultancy: HERON; Honoraria (self), Advisory / Consultancy: Lilly; Research grant / Funding (institution): TRACON Pharma; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Calithera Biosciences; Leadership role, Full / Part-time employment: Dana Farber Cancer Hospital. J.M.G. Larkin: Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: GSK; Advisory / Consultancy: Kymab; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Secarna; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: EUSA Pharma. S.K. Pal: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Research grant / Funding (self): Medivation; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Aveo; Advisory / Consultancy: Myriad Pharmaceuticals; Advisory / Consultancy: Genentech; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai. R.J. Motzer: Honoraria (self), Research grant / Funding (institution): Pfizer Inc.; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Incyte; Research grant / Funding (institution): Bristol-Myers Squibb (BMS); Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Merck. B. Venugopal: Honoraria (self), Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self): Eusa Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb. B.Y. Alekseev: Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Ferring; Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi. G. Gravis: Travel / Accommodation / Expenses: Janssen Oncology; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Astellas Pharma; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Ipsen. M.A. Bilen: Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy: GenomicHealth; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Incyte; Speaker Bureau / Expert testimony: AstraZeneca; Research grant / Funding (institution): Tricon Pharmaceuticals; Research grant / Funding (institution): Peleton; Research grant / Funding (institution): Pfizer. A. Chudnovsky: Full / Part-time employment: Pfizer Inc. K.A. Ching: Research grant / Funding (self), Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Pfizer Inc. M. Mariani: Full / Part-time employment: Pfizer Inc. P.B. Robbins: Full / Part-time employment: Pfizer Inc. B. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. A. di Pietro: Full / Part-time employment: Pfizer Inc. L. Albiges: Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Peloton Therapeutics; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis. All other authors have declared no conflicts of interest.

Background

Hypoxia-inducible factor (HIF)-2α is a transcription factor that is a key oncogenic driver in renal cell carcinoma (RCC). PT2977 is a potent and selective small molecule HIF-2α inhibitor that prevents HIF-2α from heterodimerizing with HIF-1β, blocking the expression of HIF-2α target genes in tumour cells, and inducing regressions in mouse xenograft RCC models.

Methods

Patients with advanced solid tumours were treated with PT2977 in a dose-escalation design to determine the recommended Phase 2 dose (RP2D). Patients with advanced clear cell RCC who had received at least one prior therapy were enrolled in an expansion cohort at the RP2D of 120 mg orally once daily.

Results

55 pts were treated with PT2977 120 mg (three in dose escalation; 52 in expansion). Median number of prior therapies was 3 (1-9). 73% of patients were intermediate risk and 18% were poor risk by IMDC criteria. As of March 15, 2019, the most common all-grade, all-cause adverse events (AEs) > 25% are anemia (75%), fatigue (64%), dyspnea (44%), nausea (33%), peripheral edema (29%) and cough (27%). Anemia (20%) and hypoxia (11%) are the most common Grade 3 AEs and on-target effects of HIF2α inhibition. Discontinuation due to a treatment-related AE was reported in 2 patients (4%). 13 patients (24%) experienced a confirmed PR and 30 patients (54%) had SD, with a clinical benefit rate of 78%. Follow-up for all patients has been at least 40 weeks and the probability of PFS at 40 weeks is 50.1%.

Conclusions

PT2977 is well tolerated and has a favorable safety profile. The clinical activity of PT2977 shows promise for the treatment of RCC. A PT2977 monotherapy Phase 3 trial in previously treated advanced RCC patients is planned.

Clinical trial identification

NCT02974738.

Legal entity responsible for the study

Peloton Therapeutics, Inc.

Funding

Peloton Therapeutics, Inc.

Disclosure

E. Jonasch: Advisory / Consultancy, Research grant / Funding (self): Exelixis; Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen. E.R. Plimack: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Incyte; Advisory / Consultancy: Janssen; Advisory / Consultancy: AstraZeneca. T. Bauer: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): Foundation Medicine; Research grant / Funding (institution): Phosplatin Therapeutics; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Top Alliance BioScience; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Moderna Therapeutics; Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Aileron Therapeutics; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Calithera Biosciences; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Immugen. J.R. Merchan: Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy: Exelixis; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): Vyriad; Research grant / Funding (institution): Silagen; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): RepImmune; Research grant / Funding (institution): Rexahn. K.P. Papadopoulos: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): ARMO Biosciences; Advisory / Consultancy, Research grant / Funding (institution): ArQule; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): 3D Medicines; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Syros Pharmaceuticals; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Jounce Therapeutics; Research grant / Funding (institution): MabSpace Biosciences; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Regereron; Research grant / Funding (institution): Sanofi. D.F. McDermott: Advisory / Consultancy, Research grant / Funding (institution): Peloton Therapeutics; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Exelixis; Honoraria (self), Advisory / Consultancy: Array BioPharm; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: EMD Serono; Research grant / Funding (institution): Prometheus Laboratories; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Jounce Therapeutics. M.D. Michaelson: Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Advisory / Consultancy: Exelixis. L.J. Appleman: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Acerta; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Tokai; Research grant / Funding (institution): AVEO; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Inovio; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Eli Lilly. S. Thamake: Shareholder / Stockholder / Stock options, Full / Part-time employment: Peloton Therapeutics. N. Zojwalla: Shareholder / Stockholder / Stock options, Full / Part-time employment: Peloton Therapeutics. T.K. Choueiri: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Tracon; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Foundation Medicine; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Prometheus Labs; Research grant / Funding (self), Research grant / Funding (institution): Calithera; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Analysis Group; Research grant / Funding (self), Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy: Alexion.

Background

Endoglin is an essential angiogenic receptor expressed on proliferating tumor vessels and RCC stem cells that is implicated as a mechanism of VEGF resistance. TRC105 is an endoglin monoclonal antibody that potentiates the anti-tumor activity of VEGF inhibitors in preclinical models and demonstrated a 29% RECIST response rate when combined with AX in patients with mRCC in a Phase 1b trial.

Methods

TRAXAR was a multicenter, randomized 1:1 (stratified by ECOG, 0 vs. 1), Phase 2 study of TRAX vs AX in patients with mRCC who had progressed following one prior VEGF inhibitor at 33 centers in the US and EU. The primary endpoint was progression-free survival (PFS) assessed by RECIST by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), and safety. PFS and ORR were also assessed by Investigator review (INV) and according to Choi criteria (CC).

Results

Of 150 pts (TRAX, 75; AX, 75), 106 (71%) were male, 142 (95%) were white; median age was 64 years (range, 38-82). Treatment with TRAX did not prolong PFS compared to AX. ORR was not different based on IRC, INV or CC (Table). Most all-grade common adverse events (AEs) in TRAX vs AX: headache (65.8% vs. 16.2%), epistaxis (63.0% vs. 8.1%), and diarrhea (60.3% vs. 59.5%); most common serious AEs included: anemia (6.9% vs. 1.4%) and dehydration (4.1% vs. 0%).Table:

912PD

Conclusions

TRC105 did not demonstrate activity when combined with AX in patients with mRCC who had received prior VEGF inhibitor treatment, whether assessed using RECIST or Choi criteria. TRAX was generally well tolerated in pts with advanced or metastatic RCC.

Clinical trial identification

NCT01806064.

Legal entity responsible for the study

TRACON Pharmaceuticals.

Funding

TRACON Pharmaceuticals.

Disclosure

T.K. Choueiri: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: TRACON; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Cerulean; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche Products Limited; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): GSM; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Peloton; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Prometheus; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Corvus; Honoraria (institution): Calithera. R.K. Pachynski: Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy: Jounce Therapeutics; Speaker Bureau / Expert testimony: Dendreon; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Speaker Bureau / Expert testimony: Genomic Health; Advisory / Consultancy: Bayer. Y. Zakharia: Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jansen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Castle Bioscience; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array. T.H. Ho: Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: ipensenlivemeetings; Advisory / Consultancy: cardinal health; Advisory / Consultancy: Exelixis. B.E. Simpson: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON Pharmaceuticals. B. Adams: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON. L. Robertson: Shareholder / Stockholder / Stock options, Full / Part-time employment: TRACON. M. Darif: Advisory / Consultancy: TRACON. C. Theuer: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: TRACON. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Exelixis; Advisory / Consultancy: EMD Serono; Advisory / Consultancy, Research grant / Funding (self): Ely Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy: Genentech; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy: Medivation; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: Nektar; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Pharmacyclics; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (self): TRACON. All other authors have declared no conflicts of interest.

Background

Interim results from APACHE (NCT03081923) have been presented, with the monotherapy arm stopped for futility (Necchi, Eur Urol 2018). Updated results with the expanded combination therapy cohort are presented.

Methods

Apache is an open-label, randomized, 3-stage, phase 2 study. Pts who have failed ≥2 chemotherapy (CT) regimens received Durva, 1.5 gr q4w, x 13 cycles (arm A) or Durva plus with Treme, 75 mg q4w, x 4 cycles, followed by Durva alone x total 13 cycles (arm B). The primary endpoint is the modified objective response-rate (mORR=RECIST 1.1 complete or partial response [PR] or stable disease [SD]+STM reduction >10%). H0: mORR rate ≤10%, H1: mORR ≥25% (α and β = 10%). The total sample size of 120 pts is split into 3 stages: in stage 1, each arm is terminated whenever no response is observed in 11 pts/arm. In stage 2, 29 additional pts/arm are enrolled. Biomarker analyses include: PD-L1 expression on immune cells (Ventana SP142) and comprehensive genomic profiling (CGP) with FoundationOne assay.

Results

From 02/17-11/18, 29 pts were enrolled (11 arm A and 18 arm B). 22 had gonadal and 7 extragonadal GCT, 19 had received >/=3 prior CT regimens. Median tumour mutational burden (TMB) was 4 mutations (mut)/mb, 1 pt showed microsatellite instability in arm A. 10 pts (34.5%) experienced any-Grade AEs, without differences between arms. In the expanded arm B, 2 responses (11.1%, 1 RECIST-PR in seminoma and 1 SD with STM reduction in nonseminoma) and 2 SD were observed. PD occurred regardless of PD-L1 expression and TMB. After median follow-up of 16.3 months, 12-month OS in arm A was 30% (95%CI: 7.2-57.7) and in arm B was 29.6% (95%CI: 10.2-52.2). Further CT post-PD was administered in 8 pts (27.6%), but was mostly ineffective (7/8 SD/PD).

Conclusions

Despite objective responses were rare with IO, long-term OS results are encouraging in very highly pre-treated GCT pts, suggesting a role for maintenance approach in earlier setting (2^nd-line CT), and privileging Durva+Treme due to more responses. Conventional IO biomarkers did not allow for patient selection, and further research is warranted.

Clinical trial identification

NCT03081923.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

S.M. Ali: Full / Part-time employment: Foundation Medicine. J. Chung: Full / Part-time employment: Foundation Medicine. J.S. Ross: Full / Part-time employment: Foundation Medicine. A. Necchi: Honoraria (institution), Advisory / Consultancy: Merck; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy, Spouse / Financial dependant: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Clovis; Honoraria (institution), Advisory / Consultancy: Janssen; Honoraria (institution), Advisory / Consultancy: Roche. All other authors have declared no conflicts of interest.

Background

Seminomas do not express specific tumour markers, but in ∼30% of the patients (pts) serum HCG levels are elevated. This study investigates the prognostic impact of HCG levels and other characteristics in metastatic HCG-positive seminoma patients.

Methods

Patients with seminomatous histology, metastatic disease, serum HCG levels above normal without AFP elevations at diagnosis were eligible. Uni- and multivariable analyses were conducted to identify risk factors associated with survival outcomes. Cut-off values were determined by ROC curve analysis. Primary and secondary endpoints were overall survival (OS) and recurrence free survival (RFS), respectively.

Results

Our study identified 407 eligible patients diagnosed between 1984 and 2018 (334 pts good and 48 pts intermediate prognosis according to IGCCCG). The 5-year OS and 3-year RFS rates were 91% and 83%, respectively. HCG levels ranged from 1 IU/l to 283.782 IU/l (median: 33; IQR 142.5) pre- and 0 IU/l to 36.700 IU/l (median: 37; IQR 156.2) post-orchiectomy. Serum HCG levels pre-orchiectomy correlated with the UICC stage: mean HCG 826.9 IU/l in stage IIA-C vs. mean 4764.4 IU/l in stage IIIA-C (p < 0.001) and metastatic burden assessed by the largest axial diameter of metastasis: mean HCG 57.4 IU/l if < 7cm vs. mean 4.685 IU/l if ≥ 7cm (p = 0.012), respectively. Univariable analysis revealed LDH ≥1.5 UNL pre-orchiectomy (5-year OS: 87% vs. 97%, n = 91) (p = 0.019), age ≥40 years (5-year OS: 87% vs. 94%, n = 152) (p = 0.007), and HCG ≥2.000 IU/l pre-orchiectomy (5-year OS: 76% vs. 94%, n = 17) (p = 0.019) as poor prognostic factors concerning OS. Multivariable analysis confirmed LDH ≥1.5 UNL pre-orchiectomy (HR 3.88, 95%CI 1.97-16.25; p = 0.01), age ≥40 years (HR 5.97, 95%CI 1.82-17.15; p = 0.02), and HCG levels ≥2.000 IU/l pre-orchiectomy (HR 3.59, 95%CI 1.01-12.77; p = 0.048) as independent negative prognosticators for OS. No significant correlations were found between patient characteristics and the recurrence free survival.

Conclusions

HCG values correlate with the tumour stage and levels ≥2.000 IU/l are associated with an impaired outcome concerning OS. Our results should be considered for the risk stratification of HCG positive seminoma patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

T. Hermanns: Advisory / Consultancy: Bayer und MSD. U. De Giorgi: Research grant / Funding (self): AstraZeneca, Roche, Sanofi; Travel / Accommodation / Expenses: BMS, Ipsen, Janssen, Pfizer; Advisory / Consultancy: Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Pfizer, Sanofi. R. Cathomas: Advisory / Consultancy: AstraZeneca, Astellas, Bayer, Janssen, Sanofi, BMS, MSD, Roche, Pfizer; Speaker Bureau / Expert testimony: Debiopharm, Astellas. C. Oing: Honoraria (self), Travel / Accommodation / Expenses: IPSEN, Medac; Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.

Background

The International Kidney Cancer Coalition (IKCC) is a federation of 38 affiliated patient organizations representing 1.2 million patients worldwide that is committed to reduce the global burden of kidney cancer. A large-scale global survey of RCC patients to capture real world experiences (RWE) has never been undertaken.

Methods

The 35-question survey was designed to identify geographic variations in patient education, experience and awareness, access to care, best practices, quality of life, involvement in clinical trials and to highlight unmet needs. The survey was conducted in Sept-Oct 2018 and completed online or in paper form by kidney cancer patients and /or their caregivers identified by IKCC’s 38 Affiliate Organizations and through social media in 14 languages.

Results

1,983 responses were recorded from 43 countries. Analysis revealed that at diagnosis, 43% of all respondents had no understanding of their RCC sub-type; patients with clear cell carcinoma (64%) had a notably poorer understanding of their RCC subtype than did patients with rarer RCC subtypes. While 96% of respondents reported psychosocial impacts, surprisingly, only 50% disclosed them to their healthcare team. Of the 70% of patients who were never asked to participate in a clinical trial, 89% responded they would have “fairly likely” done so if asked. RCC patients <45 years old reported nearly twice as many barriers to treatment as patients >45 at diagnosis. Females reported longer delays to diagnosis than males. Shared decision making remains aspirational across major cancer centers and community hospitals: globally 29% of all patients reported no involvement in their treatment decision, responding ‘my doctor decided for me’.

Conclusions

This exploratory research sheds light on the unmet needs in the RCC patient experience and warrants further analysis. This first-ever global survey serves as a benchmark for longitudinal data collection. RWE indicates opportunities to improve communication about diagnosis, psychosocial impacts, and clinical trials.

Legal entity responsible for the study

The International Kidney Cancer Coalition.

Funding

International Kidney Cancer Coalition.

Disclosure

All authors have declared no conflicts of interest.