Background

First-line (1L) therapy for cisplatin (cis)-ineligible patients (pts) with mUC includes alternative chemotherapy or anti-PD-(L)1 monotherapy for PD-L1 positive tumors. The pan-FGFR inhibitor ERDA has established clinical benefit in 2L mUC for pts with targetable FGFRa. ERDA combined with the anti-PD-1 CET could expand 1L options for pts with FGFRa. The Ph 1b part of NORSE (NCT03473743) determined a tolerable dose of ERDA + CET in pts with 2L mUC. We report early results from the Ph 2 part of NORSE evaluating ERDA or ERDA + CET in cis-ineligible pts with 1L mUC and FGFRa.

Methods

NORSE Ph 2 is enrolling pts ≥ 18 y with mUC, select FGFRa (mutation/fusion), and measurable disease (no prior systemic therapy for mUC, cis ineligible). Pts are randomized 1:1 to receive once-daily ERDA 8 mg (with pharmacodynamically guided uptitration [UpT] to 9 mg) or ERDA 8 mg (no UpT) + IV CET 240 mg every 2 wks at cycles 1-4 and 480 mg every 4 wks thereafter. Primary end points are investigator-assessed overall response rate (ORR) per RECIST 1.1 and safety; secondary include disease control rate (DCR), time to response (TTR), and duration of response (DOR).

Results

As of July 19, 2021, 53 pts were randomized; 26 to ERDA and 27 to ERDA + CET. For ERDA vs ERDA + CET: median age was 75 vs 69 y; visceral metastases were present in 54% vs 52%; ECOG was 0-1 in 77% vs 63%. Efficacy data in response-evaluable pts are shown in the table. The safety set comprised 24 pts who received ERDA and 24 who received ERDA + CET. The most frequent treatment-emergent adverse events were hyperphosphatemia (ERDA vs ERDA + CET, 58% vs 58%), stomatitis (63% vs 54%), and diarrhea (50% vs 42%). Table: LBA27

Efficacy in response evaluable pts

Conclusions

ERDA + CET showed clinically meaningful responses in cis-ineligible patients with 1L mUC and FGFRa. Safety was generally consistent with ERDA alone. Enrollment is ongoing.

Clinical trial identification

NCT03473743.

Editorial acknowledgement

Medical writing assistance was provided by Benjamin Ricca, PhD, Autumn Kelly, MA, and Khalida Rizi, MPharm, PhD, of Parexel, and was funded by Janssen Global Services, LLC.

Legal entity responsible for the study

Janssen Research & Development, LLC.

Funding

Janssen Research & Development, LLC.

Disclosure

T.B. Powles: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Honoraria/Consultant fees: Astellas; Financial Interests, Personal, Other, Honoraria/Consultant fees: AstraZeneca; Financial Interests, Personal, Other, Honoraria/Consultant fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria/Consultant fees: Eisai; Financial Interests, Personal, Other, Honoraria/Consultant fees: Exelixis; Financial Interests, Personal, Other, Honoraria/Consultant fees: F. Hoffmann-La Roche; Financial Interests, Personal, Other, Honoraria/Consultant fees: Johnson & Johnson; Financial Interests, Personal, Other, Honoraria/Consultant fees: Incyte; Financial Interests, Personal, Other, Honoraria/Consultant fees: Ipsen; Financial Interests, Personal, Other, Honoraria/Consultant fees: Merck; Financial Interests, Personal, Other, Honoraria/Consultant fees: Pfizer; Financial Interests, Personal, Other, Honoraria/Consultant fees: Seattle Genomics; Financial Interests, Personal, Other, Travel reimbursement: AstraZeneca; Financial Interests, Personal, Other, Travel reimbursement: F. Hoffmann-La Roche; Financial Interests, Personal, Other, Travel reimbursement: Ipsen; Financial Interests, Personal, Other, Travel reimbursement: Pfizer; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Exelixis; Financial Interests, Institutional, Research Grant: F. Hoffmann-La Roche; Financial Interests, Institutional, Research Grant: Johnson & Johnson; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer. V. Moreno: Financial Interests, Personal, Advisory Role: Bayer, Bristol Myers Squibb. Y. Vano: Financial Interests, Personal, Advisory Role: BMS, MSD, Pfizer, Novartis, Ipsen, Roche, Astellas, Sanofi, Janssen. Y. Loriot: Financial Interests, Personal, Advisory Role: Janssen, Astellas Pharma, Roche, AstraZeneca, MSD Oncology, Clovis Oncology, Seattle Genetics, Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role: Janssen, MSD Oncology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Astellas, Pharma, Janssen Oncology, Roche, AstraZeneca, MSD Oncology, Clovis Oncology, Seattle Genetics, Bristol Myers Squibb; Financial Interests, Personal, Other, Honorria: Sanofi, Pfizer; Financial Interests, Institutional, Funding: Sanofi, Jnssen Oncology, MSD Oncolofy, AstraZeneca, Clovis oncology, Exelixis, Boehringer Ingelheim, Incyte, Pfizer, Oncogenex, Medivation, CureVac, Nektar. T.W. Kang: Financial Interests, Personal, Full or part-time Employment: Chonnam National University Medical School, Chonnam National University Hospital; Financial Interests, Personal, Advisory Role: Janssen Pharmaceuticals, Astellas Pharma; Financial Interests, Personal, Research Grant: Alvogen Korea. M. Tammaro: Financial Interests, Personal, Full or part-time Employment: Janssen Pharmaceuticals. A. O'Hagan: Financial Interests, Personal, Full or part-time Employment: Janssen Pharmaceuticals . M. Hosseini: Financial Interests, Personal, Full or part-time Employment: Janssen Pharmaceuticals. S. Triantos: Financial Interests, Personal, Full or part-time Employment: Janssen Pharmaceuticals. H. Chhabra: Financial Interests, Personal, Full or part-time Employment: Janssen Pharmaceuticals. A. Santiago-Walker: Financial Interests, Personal, Full or part-time Employment: Janssen Pharmaceuticals. A.O. Siefker-Radtke: Financial Interests, Personal, Advisory Role: Janssen, Merck, NCCN, Bristol Myers Squibb, AstraZeneca, Bavarian Ndic, Seattle Genetics, Nektar, Genentech, EMD Serono, Mirati Therapeutics, Basilea; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: Methods of Characterizing and treatng molecular subsets of Muscle-Invsive Bladder Cancer; Financial Interests, Personal, Funding: NH, Michael and Sherry Sutton Fund for Urothelial Cancer, Janssen, Takeda, Bristol Myers Squibb, BioClin Therapeutics, Nektar, Merck Sharp & Dohme, Basilea. All other authors have declared no conflicts of interest.

Background

EphrinB2 (B2) expressed in mUC is a gatekeeper blocking immune cell (IC) traffic. Blocking B2 with B4 facilitates IC traffic into the tumor and may be synergistic with PD1/PDL1 treatment (tx). This trial investigated the safety and efficacy of B4 + P in mUC.

Methods

Patients (pts) with mUC previously treated with platinum chemotherapy (PC) were eligible. Prior PD1/PDL1 was excluded. Tx consisted of P 200mg IV q3 weeks + B4 10mg/kg IV weekly in a 21 day cycle until progression (PD) or unacceptable toxicities (tox). Response was measured q6 weeks using RECIST 1.1. Primary endpoint was overall survival (OS), secondary endpoints were progression free survival (PFS) and duration of response (DOR), and objective response rate (ORR). Pts who did not complete 1 cycle of tx or did not get the first imaging were inevaluable for response. Tumor tissue for all evaluable pts were tested for B2 by Immunohistochemical (IHC) staining.

Results

69 pts enrolled between 12/2016 - 09/2020. Median age 67, male/female 58/11, prior lines of tx 1/1+ 63/6. Sites of disease at baseline: nodes 43 (62%), lungs 24 (35%), liver 16 (23%), bone 9 (13%). ECOG 0 39 (57%) vs. 1 30 (43%). Bellmunt risk groups 0/1/2-3 were 41/43/16%. 23% upper tract primary. Among all enrolled at a median follow up 25.4 mo (range 1.3-48.3), the median OS was 14.4 mo (95% CI 6.4, 21.4). The ORR was 38%, median PFS 4.0 mo (95% CI 2.3, 5.5) and median DOR 8.0 mo. Among 62 evaluable pts ORR was 42% (95% CI 30-55, 9 CR, 17 PR), 40 pts expressed B2 (65%). Among B2+ pts ORR was 57.5% (95% CI 42-74, 8CR, 15 PR), median OS 15.3 mo (95% CI 12.0- NE), PFS 6.5 mo (95% CI 26-12.8), DOR 27 mo (range 10.4, NE). Median cycles of tx 5 (range 1-36). 6 pts still on tx, 5 pts off tx without PD. 36 (52%) off tx due to PD, 4 tox 1 grade (G) 3 arthralgia, 1 G3 edema, 1 G3 abdominal pain and 1 G3 supraventricular tachycardia, 4 died on tx (1 organ failure attributed to P, 1 aspiration pneumonia, 2 decline in health status). Hypertension was the most common tox attributed to B4, 72% all G, 42 % G3-4. Other tox ≥10%: fatigue, anorexia, nausea, headache, proteinuria, hyperuricemia, rash, ↑AST, anemia.

Conclusions

B4 + P is well tolerated and may have synergistic efficacy in mUC. B2 was expressed in the majority of pts and predicted for improved tx outcome.

Clinical trial identification

NCT02717156.

Legal entity responsible for the study

USC.

Funding

Merck and Vasgene.

Disclosure

All authors have declared no conflicts of interest.

Background

The optimal perioperative chemotherapy regimen for patients (pts) with MIBC is not defined.

Methods

Between February 2013 and February 2018, 500 pts were randomized in 28 French centres and received either 4 cycles of GC every 3 weeks or 6 cycles of dd-MVAC every 2 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). The primary endpoint of the VESPER trial was the progression-free survival (PFS) at 3 years (clinicaltrials.gov NCT 018 12369).

Results

437 patients (88%) received neoadjuvant chemotherapy, 60% of pts received the planned 6 cycles in the dd-MVAC arm and 84% received 4 cycles in the GC arm. Thereafter, 91% and 90% of pts underwent surgery, respectively. Organ-confined response (< ypT3N0) was observed more frequently in the dd-MVAC arm (77% vs 63%, p=0.001). In the adjuvant group, 40% of pts received 6 cycles in the dd-MVAC arm, 81% received 4 cycles in the GC arm. In the perioperative setting of the VESPER trial, PFS at 3 years was improved in the dd-MVAC arm (64% vs 56%, HR=0.77 (95% CI, 0.57-1.02), p=0.066), as was also time to progression (TTP) (3-year rate: 69% vs 58%, HR=0.68 (95% CI, 0.50-0.93), p=0.014). In the neoadjuvant group, the PFS at 3 years was significantly higher for the dd-MVAC arm (66% vs 56%, HR=0.70 (95% CI, 0.51-0.96), p=0.025). In the adjuvant group, the results were not conclusive due to the limited sample size (n=56).

Conclusions

In the VESPER phase III trial, we reported a benefit on PFS at 3 years for the dd-MVAC arm. In the neoadjuvant group, a better bladder tumour local control with a significant improvement on PFS at 3 years were observed in the dd-MVAC arm.

Clinical trial identification

NCT 018 12369.

Editorial acknowledgement

NA

Legal entity responsible for the study

The authors.

Funding

Grant from the French Ministry of Health (PHRC 2011-037).

Disclosure

All authors have declared no conflicts of interest.