Phase Ib Dose-Finding Study of Axitinib Plus Pembrolizumab ... · Pembrolizumab in Treatment-Naïve Patients ... and tolerability of axitinib plus pembrolizumab in treatment-naïve
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Phase Ib Dose-Finding Study of Axitinib Plus
Pembrolizumab in Treatment-Naïve Patients
With Advanced Renal Cell Carcinoma
TK Choueiri1, ER Plimack2, S Gupta3, I Puzanov4,
DF McDermott5, J Tarazi6, S Keefe7, B Rosbrook6, MB Atkins8
1Dana-Farber Cancer Institute, Boston, MA; 2Fox Chase Cancer Center, Philadelphia, PA;3Masonic Cancer Center, University of Minnesota, Minneapolis, MN; 4Vanderbilt University
Medical Center, Nashville, TN; 5Beth Israel Deaconess Medical Center, Boston, MA; 6Pfizer Oncology, San Diego, CA; 7Merck & Co., Inc., Kenilworth, NJ;
8Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC
Kidney Cancer Association 14th International Symposium, November 6–7, 2015, Miami, FL
Disclosures
2
● TK Choueiri has received institutional research funding
from Pfizer and has an advisory role at Pfizer, Novartis,
GlaxoSmithKline, Genentech, Merck, Bayer, and Onyx
Background
3
1. Grepin R, Pages G. J Oncol 2010;2010:1-8.
2. Bergers G, Hanahan D. Nature Rev Cancer 2008;8:592-603.
3. Hutson TE, et al. Lancet Oncol 2013;14:1287-94.
4. Rini BI, et al. Lancet Oncol 2013;14(12):1233-42.
5. Motzer RJ, et al. N Engl J Med. 2015 Sep 25 [Epub ahead of print].
6. Atkins MB, et al J Clin Oncol 2015;33 (suppl; abstr 3009).
● Most patients with renal cell carcinoma (RCC) treated
with vascular endothelial growth factor receptor
(VEGFR) inhibitors eventually progress on therapy.1,2
● Axitinib, an inhibitor of VEGFR 1–3, is approved for
2nd-line treatment of advanced RCC and has shown
clinical activity and an acceptable safety profile in the
first-line setting.3,4
● Agents that block the PD-1/PD-L1 interaction have
shown efficacy in patients whose disease has
progressed following VEGF-pathway inhibitor therapy.5
● Pembrolizumab inhibits PD-1 and has antitumor activity
in several malignancies, including RCC.6
Background (II)
4
● We hypothesize that a combination therapy regimen of
axitinib plus pembrolizumab may provide clinical
benefit in treatment-naïve patients with advanced RCC
vs VEGF-pathway–directed therapy alone.
● This ongoing, open-label phase Ib, multicenter study*
consists of a dose-finding phase to determine the maximum
tolerated dose (MTD) and a dose-expansion phase.
● The primary objectives:
● To assess the safety and tolerability of axitinib plus
pembrolizumab in treatment-naïve patients with advanced RCC.
● To estimate MTD and select the recommended Phase 2 dose
(RP2D).
● Here we report the results from the dose-finding phase.
* ClinicalTrials.gov identifier: NCT02133742
Study Design and Endpoints
5
BID=twice daily; BL assess=baseline assessment; C=cycle; D=day; DLT=dose-limiting toxicity; EOT=end of
treatment; IV=intravenous; LD1=lead-in Day 1; LD7=lead-in Day 7; q3w=every 3 weeks
• Primary endpoint: dose-limiting toxicities during the first 2
cycles (6 weeks).
• Secondary endpoints: safety, objective response rate, other
efficacy endpoints, pharmacokinetics, biomarkers.
Patient Population
6
● Histologically or cytologically confirmed clear-cell
advanced RCC with primary tumor resected.
● Mandatory archival tumor biospecimen.
● ≥1 measureable lesion, as defined by RECIST v1.1.
● ECOG performance status 0 or 1.
● Controlled hypertension.
ECOG PS=Eastern Cooperative Oncology Group performance status; RCC=renal cell carcinoma;
RECIST=Response Evaluation Criteria in Solid Tumors
Key inclusion criteria
Key exclusion criteria
● Prior treatment with systemic therapy for advanced
RCC.
Treatment
7
● Axitinib 5 mg BID orally (starting dose) beginning on Day –7.
● Pembrolizumab 2 mg/kg IV q3w up to 2 years.
● Dose levels (DL)
DL 1: axitinib 5 mg BID + pembrolizumab 2 mg/kg q3w.
DL –1 (if DL 1 beyond MTD): axitinib 3 mg BID +
pembrolizumab 2 mg/kg q3w.
● Dose-finding component of the trial is completed when 10
DLT-evaluable patients have been treated at the highest dose
of axitinib + pembrolizumab associated with DLT rate <0.33.
● Treatment continues until confirmed disease progression or
unacceptable toxicity.
BID=twice daily; DL= dose level; DLT= dose-limiting toxicity; IV=intravenous; q3w= 3-week cycle ;
MTD=maximum tolerated dose.
DLT Definition
8
● Any of the following AEs occurring during the DLT
observation period (the first 6 weeks):
Grade 4 neutropenia or thrombocytopenia, grade ≥3
neutropenic infection or thrombocytopenia with
bleeding, or febrile neutropenia.
Nonhematologic grade ≥3 toxicity.
Inability to complete ≥75% of axitinib dosing or 2
infusions of pembrolizumab due to treatment-
related toxicity.
AE=adverse event; DLT=dose-limiting toxicity
Results: Patients
9
● As of September 11, 2015, 11 patients were enrolled.
Patient Demographics
and Baseline Characteristics
Age, yr
Median (range) 63.0 (28-75)
<65 / ≥65; n (%) 7 (63.6) / 4 (36.4)
Male/Female, n (%) 8 (72.7) / 3 (27.3)
ECOG PS, n (%)
0 9 (81.1)
1 2 (18.2)
ECOG PS=Eastern Cooperative Oncology Group performance status
DLTs
10
● 3 DLTs were reported: transient ischemic attack (n=1)
and <75% of planned axitinib dose received due to
treatment-related toxicity (n=2).
● MTD was determined to be axitinib 5 mg BID +
pembrolizumab 2 mg/kg q3w.
● 9 patients remain on treatment and without confirmed
progression.
BID=twice daily; DLT=dose-limiting toxicity; MTD=maximum tolerated dose; q3w=3-week cycle;
RP2D=recommended phase II dose
Administered Dose and Duration of Treatment
11
Axitinib
DL 1*
Average
Daily Dose (mg) Months on Treatment Months on Drug
n 11 11 11
Median 9.4† 7.4 6.1
Range 5.7–10 3.7–11.2 1.2–11.2
Pembrolizumab
DL 1*
Average Administered
Dose Per Cycle (mg/kg) Months on Treatment
Total No. of Cycles
Received
n 11 11 112
Median 2.0 7.4 10.0
Range 2.0–2.0 3.7–11.2 5.0–16.0
BID=twice daily; DL=dose level; IV=intravenous; q3w=every 3 weeks
* Dose level 1: axitinib 5 mg BID + pembrolizumab 2 mg/kg IV q3w.
† 6 (54.5%) patients had the axitinib dose reduced (ie, decreased below 5mg BID
for ≥2 consecutive doses).
Treatment-emergent, All-causality AEs
occurring in ≥15% of patients* (1/2)
12
n (%)
Adverse Event All Grades Grade 3
Any AEs 11 (100.0) 8 (72.7)
Diarrhea 8 (72.7) 1 (9.1)
Hypertension 6 (54.5) 3 (27.3)
Hypothyroidism 6 (54.5) 0
Fatigue 5 (45.5) 0
Oral pain 5 (45.5) 0
Increased ALT 4 (36.4) 1 (9.1)
Arthralgia 4 (36.4) 0
Headache 4 (36.4) 1 (9.1)
Rash 4 (36.4) 0
Cough 4 (36.4) 0
Decreased appetite 3 (27.3) 0
Increased AST 3 (27.3) 1 (9.1)
Dizziness 3 (27.3) 0
AE=adverse event; ALT=alanine transaminase; AST=aspartate transaminase
*2 patients discontinued treatment due to treatment-emergent AEs: diarrhea during cycle 11 (n=1)
and arthralgia after cycle 6 (n=1).
Treatment-emergent, All-causality AEs
occurring in ≥15% of patients* (2/2)
13
n (%)
Adverse Event All Grades Grade 3
Dry skin 3 (27.3) 0
Epistaxis 3 (27.3) 0
Weight decreased 3 (27.3) 0
Dysphonia 3 (27.3) 0
Dyspepsia 2 (18.2) 0
Dyspnea exertional 2 (18.2) 0
Hyperthyroidism 2 (18.2) 0
Hyperuricemia 2 (18.2) 1 (9.1)
Nausea 2 (18.2) 0
Pain in extremity 2 (18.2) 0
PPE syndrome 2 (18.2) 0
Pneumonia 2 (18.2) 0
Urinary tract infection 2 (18.2) 0
PPE=palmoplantar erythrodysesthesia
*2 patients discontinued treatment due to treatment-emergent AEs: diarrhea during cycle 11 (n=1)
and arthralgia after cycle 6 (n=1).
Efficacy● 6 patients had confirmed partial response.
● 5 patients had stable disease with some degree of tumor
shrinkage.
● After median follow up time of 7.4 months on treatment, 9
patients remain on treatment and without confirmed
progression.Tumor Response Measured by
Percentage Change in Lesion Diameters
* Discontinued from treatment due to AEs.
P=patient; PR=partial response; SD=stable disease; SLDs=sum of the longest tumor diameters
0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8
- 6 0
- 4 0
- 2 0
0
2 0
W e e k s o n S t u d y
Ch
an
ge
in
S
LD
s F
ro
m B
as
elin
e (
%)
P - 1 ( S D )
P - 2 ( S D ) *
P - 6 ( P R )
P - 3 ( S D )
P - 4 ( P R ) *
P - 5 ( S D )
P - 7 ( P R )
P - 8 ( P R )
P - 9 ( P R )
P - 1 0 ( P R )
P - 1 1 ( S D )
15
Conclusions
15
● Preliminary results indicate combination axitinib plus
pembrolizumab is well tolerated at standard doses of
each agent and exhibits antitumor activity in treatment-
naïve patients with advanced RCC.
● There were no treatment discontinuations due to
hepatotoxicity.
● Enrollment completed with 41 additional patients
enrolled in the dose expansion phase to confirm the
RP2D and further evaluate safety and antitumor activity
of this combination.
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