Phase Ib Dose-Finding Study of Axitinib Plus Pembrolizumab ... · PDF filePembrolizumab in Treatment-Naïve Patients ... and tolerability of axitinib plus pembrolizumab in...

Phase Ib Dose-Finding Study of Axitinib Plus

Pembrolizumab in Treatment-Nave 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 67, 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 13, 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-nave patients with advanced RCC

vs VEGF-pathwaydirected 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-nave 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

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)

DLTs

10

3 DLTs were reported: transient ischemic attack (n=1)

and

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 5.710 3.711.2 1.211.2

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 2.02.0 3.711.2 5.016.0

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-

nave 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.

Acknowledgments

This study is sponsored by Pfizer Inc and

Merck & Co., Inc.

Medical writing support was provided by Vardit Dror,

PhD, of Engage Scientific Solutions, and was funded

by Pfizer.