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

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)

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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.

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.