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Background Avelumab is a human IgG1 monoclonal antibody against PD-L1, and axitinib is a potent inhibitor of VEGFR 1, 2, and 3. In a phase 3 study in patients (pts) with treatment-naive advanced renal cell carcinoma (aRCC; NCT02684006), avelumab in combination with axitinib (A+Ax) significantly improved progression-free survival (PFS) irrespective of PD-L1 expression vs sunitinib (S) at the preplanned interim analysis; median PFS was 13.8 mo with A+Ax vs 8.4 mo with S (HR, 0.69; p = 0.0001). Here, we report efficacy and safety in Japanese pts who were enrolled in this study. Methods Eligible pts with clear-cell aRCC, ECOG PS ≤ 1, and no prior systemic therapy were randomized 1:1 (stratified by ECOG PS and geographic region) to receive A 10 mg/kg IV Q2W + Ax 5 mg PO BID or S 50 mg PO QD on schedule 4/2. Primary endpoints were PFS by blinded independent central review (BICR) per RECIST v1.1 and overall survival (OS) in pts with PD-L1+ tumors (≥1% of immune cells). Key secondary endpoints were PFS by BICR and OS irrespective of PD-L1 expression. Other secondary endpoints included objective response rate (ORR), and safety. Results Japanese pts (N = 67) were randomized to A+Ax (n = 33) or S (n = 34); 67% vs 59% had PD-L1+ tumors; IMDC favorable/intermediate/poor risk status was 6%/64%/27% vs 6%/82%/12%. Median PFS (95% CI) was not estimable (NE) (8.1-NE) with A+Ax vs 11.2 months (1.6-NE) with S (HR, 0.49; 95%CI, 0.15-1.56) in pts with PD-L1+ tumors and 16.6 mo (8.1-NE) with A+Ax vs 11.2 mo (4.2-NE) with S (HR, 0.66; 95% CI, 0.30-1.46) in pts irrespective of PD-L1 expression. Median OS in either arm has not been reached in pts irrespective of PD-L1 expression. ORR (95% CI) was 60.6% (42.1%-77.1%) with A+Ax vs 17.6% (6.8%-34.5%) with S in pts irrespective of PD-L1 expression. Common treatment-emergent adverse events (all grade; grade ≥3) in each arm were hand-foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%), and platelet count decreased (3%; 0% vs 65%; 32%). Conclusions A+Ax was efficacious and tolerable in Japanese pts with treatment-naive aRCC, which is consistent with results in the overall population. Clinical trial identification NCT02684006, Feb 17, 2016. Editorial acknowledgement Clinical Thinking, a Nucleus Global Company, Hamilton, NJ, USA. Legal entity responsible for the study Pfizer, Inc. Funding Funding for this study was provided by Pfizer, Inc. in alliance with Merck Healthcare KGaA, Darmstadt, Germany. Disclosure 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. S. Hatakeyama: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Astellas; Honoraria (self), Research grant / Funding (institution): Kissei; Honoraria (self), Research grant / Funding (institution): Sanofi; Honoraria (self), Research grant / Funding (institution): Ono; Research grant / Funding (institution): Bristol; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Kaneka. H. Kanayama: Honoraria (self), Research grant / Funding (institution): Pfizer. K. Numakura: Honoraria (self): Pfizer; Honoraria (self): Astellas; Honoraria (self): Ono Pharm; Honoraria (self): Kyowa Kirin; Honoraria (self): AstraZeneca; Research grant / Funding (self): Grants-in-Aid for Scientific Research, the ministry of Education, Japan. T. Kato: Honoraria (self): Pfizer, Inc.; Honoraria (self): Novartis Pharma K.K; Honoraria (self): ONO Pharmaceutical Co., Ltd.; Honoraria (self): TAIHO Pharmaceutical Co., Ltd.; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria (self): Bayer Yakuhin, Ltd.; Honoraria (self): Astellas Pharma Inc. M. Eto: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer. H. Uemura: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono; Honoraria (self), Speaker Bureau / Expert testimony: BMS; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony: MSD; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Advisory / Consultancy: Sanofi; Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: Bayer; Research grant / Funding (self): Taiho; Research grant / Funding (self): Astellas; Research grant / Funding (self): Ono. 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. Y. Fujii: Full / Part-time employment: Pfizer RD Honoraria (self), Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self): Ono; Honoraria (self): BMS. All other authors have declared no conflicts of interest.

BACKGROUND This study aimed to determine the clinical benefit of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. PATIENTS AND METHODS Patients with MIBC (T2-4aN0M0) were randomised to receive two cycles of neoadjuvant MVAC followed by radical cystectomy (NAC arm) or radical cystectomy alone (RC arm). The primary end point was overall survival (OS). Secondary end points were progression-free survival, surgery-related complications, adverse events during chemotherapy, proportion with no residual tumour in the cystectomy specimens, and quality of life. To detect an improvement in 5-year OS from 45% in the RC arm to 57% in the NAC arm with 80% power, 176 events were required per arm. RESULTS Patients (N = 130) were randomly assigned to the RC arm (N = 66) and the NAC arm (N = 64). The patient registration was terminated before reaching the initially planned number of patients because of slow accrual. At the second interim analysis just after the early stoppage of patient accrual, the Data and Safety Monitoring Committee recommended early publication of the results because the trial did not have enough power to draw a confirmatory conclusion. OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant [hazard ratio 0.65, multiplicity adjusted 99.99% confidence interval 0.19-2.18, one-sided P = 0.07]. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (P < 0.01). In subgroup analyses, OS in almost all subgroups was in favour of NAC. CONCLUSIONS This trial showed a significantly increased pT0 proportion and favourable OS of patients who received neoadjuvant MVAC. NAC with MVAC can still be considered promising as a standard treatment. UMIN CLINICAL TRIALS REGISTRY IDENTIFIER C000000093.

Background Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1–3. In the phase III AXIS study in second-line metastatic renal cell carcinoma (mRCC), axitinib demonstrated significant improvement in progression-free survival (PFS) compared with sorafenib (median PFS, 6.7 versus 4.7 months; hazard ratio [HR] 0.665; one-sided P Methods Eligible patients had clear-cell mRCC; progressive disease per RECIST after one prior systemic first-line therapy; and Eastern Cooperative Oncology Group performance status (PS) of 0 or 1. Patients were stratified by PS and prior therapy, then randomized 1:1 to receive axitinib or sorafenib. Tumour imaging was assessed by an independent review committee. Results Of the 723 enrolled patients, 158 were Asian (axitinib arm: n = 77; sorafenib arm: n = 81). Of the Asian patients, 74% were male, median age was 61 years, and 59% had PS = 0; prior therapies were 54% cytokine-, 41% sunitinib-, 4% bevacizumab-, and 1% temsirolimus-based regimens. Median PFS in the Asian patients was 10.3 months in the axitinib arm and 4.7 months in the sorafenib arm (HR 0.578; 95% confidence interval, 0.362–0.924; one-sided P = 0.0096). The objective response rate (ORR) was 31.2% versus 7.4% (one-sided P = 0.0003) in the Asian patients receiving axitinib and sorafenib, respectively. Common adverse events (AEs) in the Asian patients receiving axitinib were hypertension (53%), diarrhoea (53%), hand-foot syndrome (47%), fatigue (45%), decreased appetite (36%), dysphonia (36%), and hypothyroidism (31%). Common AEs in the Asian patients receiving sorafenib were hand-foot syndrome (70%), diarrhoea (46%), hypertension (34%), and alopecia (30%). Conclusions Axitinib is effective and well tolerated in the Asian patients with mRCC. Consistent with global phase III trial results, PFS and ORR were higher with axitinib versus sorafenib in the Asian patients.