Kidney Cancer Journal 21
location n=3, other n=5), and 16 patients had sccRCC. 17
patients received prior systemic therapy, 16 of whom had
nccRCC. The ORR was 31% in the overall cohort. 10 patients
(19%) developed grade 3 treatment-related adverse
events (AEs), half of which were immune-related. There
were no grade 4-5 AEs.
Conclusions: In this study, we show that therapy with
atezolizumab and beva-cizumab was safe and demonstrated
anti-tumor activity in nccRCC and sccRCC.
Further analyses will report ORR by histologic subtype
and PD-L1 expression status. Analysis of tissue and bloodbased
biomarkers of response are ongoing. Clinical trial
information: NCT02724878
Pembrolizumab (pembro) plus axitinib (axi) versus
sunitinib as first-line therapy for locally advanced or
metastatic renal cell carcinoma (mRCC): phase III
KEYNOTE-426 study.
Thomas Powles, Elizabeth R. Plimack, Viktor Stus, et al.
Background: A phase 1b study of pembro (anti–PD-1)
plus axi (VEGFR-TKI) showed promising antitumor
activity and manageable safety in patients (pts) with
previously untreated mRCC. The global, open-label,
phase 3 KEYNOTE-426 study assessed the efficacy and
safety of pembro + axi vs sunitinib as first-line therapy
for mRCC (NCT02853331).
Methods: Eligible pts with clear-cell mRCC, no previous
systemic therapy for mRCC, and KPS ≥70% were
randomized 1:1 to pembro 200 mg IV Q3W for a
maximum of 35 cycles plus axi 5 mg orally BID or
sunitinib 50 mg orally QD (4-wk on/2-wk off schedule).
Treatment was given until PD, intolerable toxicity, or
pt/investigator decision. Randomization was stratified by
IMDC risk group and geographic region. Primary endpoints
were OS and PFS (RECIST v1.1 by blinded,
independent central review BICR). ORR was the key
secondary endpoint. At the protocol-specified first
interim analysis, the superiority thresholds were P =
0.0001 for OS, 0.0013 for PFS, and 0.025 for ORR (if OS
and PFS were significant).
Results: 861 pts were randomized: 432 to pembro + axi,
429 to sunitinib. After a 12.8-mo median follow-up,
59.0% of pts in the pembro + axi arm and 43.1% in the
sunitinib arm remained on treatment. Pembro + axi
significantly improved OS (HR 0.53 95% CI 0.38-0.74;
P< 0.0001; 12-mo rate 89.9% vs 78.3%), PFS (HR 0.69
95% CI 0.57-0.84; P = 0.0001; median 15.1 vs 11.1 mo),
and ORR (59.3% vs 35.7%; P< 0.0001). Duration of
response was prolonged with pembro + axi (median not
reached vs 15.2 mo). The pembro + axi benefit was
observed in all subgroups tested, including all IMDC risk
and PD-L1 expression subgroups. Treatment-related AEs
were grade 3-5 in 62.9% of pts in the pembro + axi arm
vs 58.1% in the sunitinib arm and led to regimen
discontinuation in 6.3% vs 10.1%.
Conclusions: Pembrolizumab + axitinib provided superior
OS, PFS, and ORR compared with sunitinib and had
manageable safety in pts with previously untreated,
advanced or metastatic clear-cell RCC. These data suggest
that pembrolizumab + axitinib should be a new standard
of care for this population. Clinical trial information:
NCT02853331
Subgroup analysis from JAVELIN Renal 101:
Outcomes for avelumab plus axitinib (A + Ax) versus
sunitinib (S) in advanced renal cell carcinoma
(aRCC).
Toni K. Choueiri, Robert J. Motzer, Matthew T. Campbell, et al.
Background: In the ongoing phase 3 JAVELIN Renal 101
trial, progression-free survival (PFS) was longer (median,
13.8 vs 8.4 mo; hazard ratio, 0.69; p=0.0001) and the
objective response rate (ORR) was higher (51% vs 26%)
with A + Ax vs S in patients with previously untreated
aRCC. Here we report outcomes from an analysis of
several prespecified subgroups.
Methods: Patients were randomized 1:1 to receive A (10
mg/kg) IV every 2 weeks + Ax (5 mg) PO twice daily or S
(50 mg) PO once daily for 4 wk (6-wk cycle). Primary and
key secondary endpoints were PFS per independent
review committee (IRC; RECIST v1.1) and OS in patients
with PD-L1+ tumors (≥1% of immune cells) and in
patients irrespective of PD-L1 expression; other secondary
endpoints included OR per IRC (RECIST v1.1).
Results: A total of 886 patients were randomized; 560
(63%) had PD-L1+ tumors. At data cut-off (Jun 2018),
median follow-up was 12.0 vs 11.5 mo for A + Ax vs S
groups.
Conclusions: A + Ax demonstrated PFS and OR benefit
across all prognostic risk groups and PD-L1 subgroups vs
S in aRCC. Clinical trial information: NCT02684006
A phase II study investigating the safety and
efficacy of savolitinib and durvalumab in metastatic
papillary renal cancer (CALYPSO).
Thomas Powles, James M. G. Larkin, Poulam Patel, et al
Methods: This single arm phase I/II trial explored durvalumab
and savolitinib at starting doses of 1500mg
Q4W and 600mg OD respectively, with a 4wk savolitinib
run-in. Treatment naïve or previously treated patients
with metastatic PRC were included. Response rate (RR)
(RECIST v1.1) was the primary endpoint. Progression free
survival (PFS), tolerability (CTCAE v4) and overall survival
were secondary endpoints.
Results: Dose escalation work identified a dose of
durvalumab of 1500mg Q4W and savolitinib 600mg OD
to take forward to phase II. Between Jan 2017 and Jul
2018, 42 patients were enrolled at this dose. 1 patient did
not receive study treatment. The following analyses were
performed on the remaining 41 patients. 12% of patients
did not receive the combination (3 PD, 1 death, 1 PS
deterioration). The median follow up was 8.9 months
(95% CI: 6.9-10.9 months). IMDC good, intermediate and
poor risk disease occurred in 29% (n=12), 63% (n=26),
and 7% (n=3) patients respectively. Overall RR was 27%
(11/41), while median PFS was 3.3 months (95% CI: 1.5-
NR months). RR and median PFS in the previously
untreated cohort (N=28) were 29% (8/28) and 12.0
months (95% CI: 1.5-NR months) respectively. Grade 3/4
toxicity occurred in 15 patients.
Conclusions: The combination of savolitinib and durvalumab
appears safe and associated with clinical activity
in PRC. Clinical trial information: NCT02819596. KCJ