Background

The previous SWITCH-I study explored the two possible sequences of Sunitinib and Sorafenib for the treatment of advanced/metastatic renal cell carcinoma (mRCC) and showed similar total progression-free-survival (tPFS) and overall survival (OS) times. This trial compared the sequential therapy with the multikinase inhibitors Sorafenib (So) followed by Pazopanib (Pa) or vice versa in mRCC patients (pts).

Methods

This multicentre, randomised phase 3 study assessed the sequential use of So-Pa versus Pa-So in pts with mRCC without prior systemic therapy. Pts were randomised to So 400 mg twice daily followed by Pa 800 mg once daily (So-Pa) in case of progression or intolerable toxicity or vice versa (Pa-So). The primary endpoint was non-inferiority of tPFS with So−Pa compared to Pa−So, assessed from randomisation to progression or death during second-line therapy defined as hazard ratio (HR) <1.225 as a one-sided 95% confidence interval (CI). Main secondary endpoints included OS, total time to progression (TTP), disease control rate (DCR), 1st-line and 2nd-line PFS as well as safety and tolerability.

Results

377 pts were randomised (So-Pa, n = 189; Pa-So, n = 188). Median tPFS was 8.6 mo (95% CI 7.7-10.2) for So-Pa and 12.9 mo (95% CI 10.8-15.2) for Pa-So with a HR of 1.36 (upper limit of one-sided 95% CI 1.68). Therefore, non-inferiority of So-Pa in regard to tPFS was not met. However, marked statistical differences were noted in favour of Pa-So in total TTP, 1st-line PFS and DCR but not for OS and 2nd-line PFS. In the So-Pa arm 106/189 (56%) received Pa as 2nd line and for the Pa-So arm 87/188 (46%) received So as 2nd line. The most frequent any-grade treatment-emergent first-line adverse events for So were diarrhoea (56%), fatigue (37%) and hand-foot skin reaction (35%) and for Pa diarrhoea (60%), hypertension (48%) and fatigue (45%).

Conclusions

Non-inferiority of the sequence So-Pa compared to Pa–So in terms of the primary endpoint tPFS was not met. However, superiority of the sequence Pa-So over So-Pa for tPFS was not proven either, since the study design was computed with a HR of < 1.225 as a one-sided 95% CI.

Clinical trial identification

NCT01613846, first received May 4, 2012

Legal entity responsible for the study

Technische Universität München

Funding

Bayer Vital GmbH and in part GSK/Novartis

Disclosure

M. Retz: Honoraria Advisory boards and lectures: Bristol-Myers Squib, Janssen-Cilag, Roche, MSD, Ipsen, Merck-Pfizer, Novartis, Bayer. J. Bedke: Consultancies, honoraria or study participation from Bayer, Bristol-Myers Squib, GSK, Immatics, Nektar, Novartis, Pfizer and Roche. M-O. Grimm: Consultancy fees: AstraZeneca, Amgen, Bayer Health Care, Bristol-Myers Squib, GSK, Novartis, Pfizer, Sanofi; grants: Novartis, Bristol-Myers Squib; payment for lectures: Bayer Health Care, Bristol-Myers Squib, GSK, Hexal, Janssen Cilag, JenaPharm, Novartis, Pfizer, Pierre Fabre. M. De Santis: Study Grants: Pierre Fabre; Honoraria: Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squib, Celgene, Dendreon, Eisai, ESSA, Ferring, GSK, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, SeaGen, Shionogi, Synthon, Takeda, TevaOncoGenex. J.E. Gschwend: Honoraria Advisory boards and lectures: Amgen, Astellas, Bayer, Eisai, Janssen, Novartis, Pierre-Fabre, Roche. All other authors have declared no conflicts of interest.

Background

In clinical practice, mRCC patients with the primary tumour in situ are offered CN followed by targeted therapy. This randomized trial explored a period of targeted therapy (sunitinib) prior to CN as an alternative approach.

Methods

Patients with mRCC were randomized 1:1 to immediate CN followed by sunitinib versus 3 cycles sunitinib followed by CN and sunitinib. Inclusion required histologically confirmed clear-cell subtype, resectable asymptomatic primary tumour and < = 3 surgical risk factors (Culp et al., Cancer 2010). To detect a 3 months increase in median progression free survival (Hazard ratio [HR] = 0.75) with deferred CN with a 2-sided 5% logrank test at 80% power, 380 events were needed. Due to poor accrual, the IDMC recommended to report the progression free rate (PFR) at week 28 instead (98 patients needed). Overall survival (OS), adverse events and post-operative progression in both arms were secondary endpoints.

Results

The study closed after 5.7 years with 99 patients entered by 19 institutions. As of May 5, 2017, median follow-up is 3.3 years. In the immediate CN arm, 46 of 50 patients had CN, 40 of 46 had post-CN sunitinib. In the deferred CN arm, 48 of 49 patients had sunitinib, 40 of 48 had CN and 26 of 40 had post-CN sunitinib (Table). PFR was 42.0% (CI: 28.2 – 56.8) and 42.9% (28.8 – 57.8) in the immediate and deferred arms, resp (p > 0.99). The OS HR (stratified by WHO PS) of intention to treat (ITT) with deferred versus immediate CN in all patients was 0.57 (CI: 0.34 – 0.95, p = 0.032) with a median OS of 32.4 (14.5-65.3) and 15.1 months (CI: 9.3, 29.5), respectively.

Table:

LBA35

Conclusions

The sequence of CN and sunitinib did not affect the PFR at 28 weeks. The sample size precludes definitive conclusions from other endpoints, although an OS signal was seen for deferred CN. CN after sunitinib appears safe.

Clinical trial identification

NCT01099423

Legal entity responsible for the study

EORTC

Funding

Pfizer

Disclosure

A. Bex: Participation in Advisory boards of Pfizer, BMS, Roche, Eisai and Ipsen. M.A.S. Jewett: Honorarium: Ipsen, Pfizer. Consultant: Pfizer, Theralase Therapeutics Inc. Ownership: Stock Theralase Therapeutics Inc. J. Wagstaff: Advisory boards for Pfizer. T. Powles: Research funds: Pfizer, Novartis, Roche, AZ. Honoraria: Pfizer, Novartis, Roche, BMS, MSD, Ipsen, Eisei.E. Boleti: Advisory board for Pfizer, Eisai, Ipsen. S. Rottey: Speaker fee from BMS, Pfizer, Roche, Bayer. C.U. Blank: Advisory board for Pfizer, BMS and Roche. J.B. Haanen: Advisory role for Pfizer. All other authors have declared no conflicts of interest.

Background

We report the updated safety and efficacy of CaboNivo and CaboNivoIpi in pts with mUC and other GU tumors (NCT02496208).

Methods

Primary objective was to determine the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D). We tested 7 dose levels (DL); 4 in part 1 (CaboNivo); 3 in part 2 (CaboNivoIpi). Part 1 pts received cabo PO daily/Nivo IV q2wks: DL1 Cabo 40mg/Nivo 1mg/kg, DL2 Cabo 40mg/Nivo 3mg/kg, DL3 Cabo 60mg/Nivo1mg/kg, DL4 Cabo 60mg/Nivo 3mg/kg. Part 2 pts received Cabo PO daily/Nivo/Ipi IV q3wks x4 cycles → Nivo IV q2wks: DL5 Cabo 40mg/Nivo1&Ipi 1mg/kg, DL6 Cabo 40mg/Nivo 3&Ipi 1mg/kg, DL7 Cabo 60mg/Nivo3&Ipi 1mg/kg. Adverse events (AEs) were graded by CTCAE v4.0. Other objectives: overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS).

Results

From 07/15/2015-04/25/2017, median(m) potential follow-up: 13.4 months(mo). 42 pts enrolled: 24 pts in part 1 (mUC n = 7; urachal (Ur) n = 4; germ cell tumor n = 4; prostate cancer (PC) n = 4; bladder squamous cell carcinoma (bSCC) n = 2; penile n = 1; sarcomatoid renal cell carcinoma (sRCC) n = 1; and trophoblastic n = 1); 18 pts in part 2 (mUC n = 8; penile n = 3; CRPC n = 5; sertoli n = 1; sRCC n = 1). Median age: 56 years (range 31-77), 90.5% male. Grade 3–4 AEs occurred in 67% of pts, mostly in part 1: hypophosphatemia (21%), neutropenia (21%), fatigue (12%), elevated lipase (12%); diarrhea, hypertension (HTN), dehydration, thrombocytopenia, proteinuria, and leukopenia (8% each); in part 2: hypophosphatemia (22%) HTN (17%); fatigue, nausea, lymphopenia, and elevated lipase (11% each). G3 immune-related AEs: aseptic meningitis (n = 1, DL1) and colitis (n = 1, DL5). No G5 toxicities or DLTs. RP2D for part 1: Cabo40mg/Nivo3mg/kg; for part 2: Cabo40mg/Nivo3&Ipi1mg/Kg. ORR=35%, 3CR (2mUC, 1SCC) & 11PR (3mUC, 2SCC, 2sRCC, 2Penile, 1Ur, 1PC). mDOR (CR+PR+SD): 7.1 mo [95% CI: 5.1-not reached], mPFS: 5.5 mo [95%CI: 4.5-12.8] and mOS was not reached. OS at 6&12 mo was 83.3%&64.3%.

Conclusions

CaboNivo and CaboNivoIpi showed durable clinical activity in mUC and rare GU malignancies with manageable toxicity.

Clinical trial identification

Trial Protocol Number: NCT02496208, release date: 07/15/2015

Legal entity responsible for the study

National Cancer Institute, National Health Institutes.

Funding

Cancer Therapy Evaluation Program

Disclosure

All authors have declared no conflicts of interest.

Background

Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1 − 3, fibroblast growth factor receptor 1 − 4, platelet-derived growth factor receptor α, RET, and KIT. LEN was approved in combination with everolimus to treat advanced renal cell carcinoma (RCC) after 1 prior VEGF-targeted treatment. We report results for the RCC cohort of a phase 1b/2 trial of LEN+pembrolizumab (pembro) in patients (pts) with selected solid tumors (NCT02501096).

Methods

This was a multicenter open-label study. Pts had metastatic clear cell RCC, measurable disease according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status ≤1. LEN 20 mg/d plus pembro 200 mg intravenously every 3 weeks was assessed as the maximum tolerated dose and recommended phase 2 dose in phase 1b. Tumor assessments were performed by trial investigators using irRECIST. The primary phase 2 endpoint was objective response rate (ORR) at 24 weeks. Secondary endpoints included ORR, progression-free survival (PFS), and duration of response (DOR).

Results

30 Pts were enrolled in either the phase 1b (8 pts) or phase 2 cohort (22 pts). Data cutoff Feb 15, 2017. 11 (37%) Pts had 0, 11 (37%) pts had 1, and 8 (27%) pts had ≥2 prior anti-cancer therapies. Of pts who received prior medication (n = 19, 63%), 16 (53%) received prior VEGF-targeted therapy. Efficacy outcomes are summarized in the Table. At data cutoff, 17 (57%) pts were still receiving treatment, 8 (27%) completed treatment due to disease progression, and 5 (17%) discontinued treatment. The most common any-grade treatment-emergent adverse events were diarrhea, fatigue, hypothyroidism, nausea, and stomatitis. Toxicities were manageable with dose interruption and/or modification and no new safety signals were found. Updated data will be presented.

Conclusions

Combination treatment with LEN+pembro showed promising antitumor activity and an acceptable safety profile. A phase 3 trial of LEN+pembro and LEN+everolimus, vs sunitinib in first-line treatment for metastatic clear cell RCC is ongoing.Table:

847O

Clinical trial identification

NCT02501096

Legal entity responsible for the study

Eisai Inc

Funding

Eisai Inc

Disclosure

C-H. Lee: Research funds to institute from Eisai, Bristol-Myers Squib, Pfizer, Exelixis, Calithera, and consulting fees from Exelixis. D. Rasco: Research funding from Aeglea, Asana, Ascentage, Bayer, Celgene, Eisai, Five Prime Therapeutics, GlaxoSmithkline, Macrogenics, Merck, Millennium Pharmaceuticals, OncoMed Pharmaceuticals, Pharmacyclics, Rexahn Pharmaceuticals, Santa Maria Biotherapeutics. M. Taylor: Honoraria from/held consulting advisory role with: Eisai, Bristol-Myers Squib, Blueprint Medicine, and Trillium Pharma; participated in speakers\' bureau for Eisai Inc. C. Dutcus, R. Shumaker, D. Stepan, D. Li: Employee of Eisai Inc. E.V. Schmidt: Employee of/stockholder: Merck Research Labs. R.J. Motzer: Grants from Pfizer, Eisai, Exelixis, Novartis, and Bristol-Myers Squib. Served as a consultant to Pfizer, Eisai, Exelixis, and Novartis. All other authors have declared no conflicts of interest.