Fig. 3. Patient #3 NSCLC with right lung and abdominal nodules

• 76 year old female with stage IIIB adenocarcinoma of the right upper lobe and atelectasis of the right middle lobe, diagnosed in 10/15 • Prior treatments included cisplatin/etoposide/carboplatin, and nivolumab (no prior clinical benefit).• Patient continues on study in Cycle 4.

Fig. 2. Patient #2 NSCLC with upper lobe nodule, upper abdominal and retroperitoneal lymphadenopathy

• 71 year old female with stage IV adenocarcinoma of the right upper lobe, diagnosed in 9/14.• Prior treatments included carboplatin/pemetrexed, pemetrexed maintenance, and nivolumab (no prior clinical benefit).• Patient continues on study in Cycle 5.

BACKGROUND• Combination therapy with agents that target the molecular and cellular

mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant non-small cell lung cancer (NSCLC).

• Sitravatinib is a spectrum-selective tyrosine kinase inhibitor (TKI) which targets receptor tyrosine kinases (RTKs) including TAM receptors (Tyro, Axl, MER), split family receptors (VEGFR2, KIT), RET and MET.

• Inhibition of these target classes by sitravatinib may enhance anti-tumor activity through targeted depletion of immunosuppressive Type 2 tumor associated macrophages, regulatory T cells and myeloid-derived suppressor cells (MDSCs) and increasing antigen presentation capacity of dendritic cells in the tumor microenvironment (TME).

• Given these pleiotropic immune activating effects, the combination of sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC.

Rationale for Targeting TAM and Split RTKs to Enhance Response to Immune Checkpoint Inhibitors 1, 2

STUDY OBJECTIVESPRIMARY OBJECTIVE• To evaluate the clinical activity of the combination regimen in non-squamous

NSCLC using Objective Response Rate (ORR) by RECIST

SECONDARY OBJECTIVES• To evaluate safety and tolerability

• To evaluate secondary efficacy endpoints including duration of response (DR), progression free survival (PFS), and overall survival (OS)

• To evaluate pharmacokinetics (PK)

EXPLORATORY OBJECTIVES • To assess effects on circulating PD-L1 levels, immune cell populations

and cytokines

• To assess effects on tumor cell PD-L1 expression, tumor infiltrating immune cell populations and gene expression signatures

• To assess correlation of tumor gene alterations in circulation and tumor tissue with treatment outcome

METHODS• MRTX-500 is a Phase 2 study evaluating the tolerability and clinical

activity of sitravatinib in combination with nivolumab in patients with non-squamous NSCLC who have experienced progression of disease on or after treatment with CIT.

• Patients receive oral sitravatinib once daily (QD) in combination with nivolumab 240 mg intravenously every 2 weeks, as continuous 28 day cycles.

• The study began with a limited dose escalation evaluation of sitravatinib in combination with nivolumab to determine the dose levels to be used in Phase 2.

• Enrollment into the Phase 2 is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤ 12 weeks).

LEAD-IN PHASE• mTPI method for dose escalation decisions

PHASE 2 • Sample size based on Predictive Probability Design

• Stage 1 – 9 patients in each strata

• Stage 2 – if ≥ 1 response, enroll 8 additional patients in each strata

• If at least 3 objective responses, further investigation may be warranted

• Enrollment may be expanded to as many as 100 patients

METHODSKEY INCLUSION CRITERIA • Histologically confirmed non-squamous NSCLC with metastatic or unresectable,

locally advanced disease, non amenable to treatment with curative intent

• Prior treatment:

At least one prior treatment in the advanced disease setting including a platinum-based doublet

Most recent treatment included checkpoint inhibitor (anti-PD-1 or anti-PD-L1) with the result of progression of disease on or after treatment

• Measureable disease as per RECIST v1.1

• ECOG performance status of 0, 1 or 2

• Adequate bone marrow and organ function

KEY EXCLUSION CRITERIA • Brain metastases or spinal cord compression unless asymptomatic,

treated and stable.

• History of tumors that test positive for EGFR, ROS1, ALK mutations or ALK fusions or any other mutations for which there are TKIs available

• Prior therapies: Immunotherapies not previously specified including anti-CTLA-4,

anti-OX40, and anti-CD137 Combination therapy with checkpoint inhibitor and cancer therapy

having same mechanism of action as sitravatinib

• Unacceptable toxicity on prior CIT

• Active or prior documented autoimmune disease

• Active or prior immunocompromising conditions

• Unstable angina pectoris, CHF ≥ NYHA Class 3, QTc ≥ 480 msec

RESULTSPATIENT CHARACTERISTICS AND DISPOSITION• As of 26 June 2017, patient data were entered in the clinical trial database

for 10 patients (2 men/8 women; median age 69.5 years range 49-76 years) with advanced or metastatic NSCLC.

RECOMMENDED PHASE 2 DOSE (RP2D)• The starting dose of the lead-in cohort was 120 mg QD of sitravatinib in

combination with nivolumab. No protocol defined dose limiting toxicities (DLTs) were reported in the first 6 evaluable patients. Based on the experience of patients enrolled into the study, 120 mg dose was selected as the RP2D and all patients have been enrolled at this dose.

• 120 mg of sitravatinib achieves plasma exposure required for inhibition of VEGF and TAM receptors necessary to achieve antitumor efficacy in the combination setting.

SAFETY• As of 26 June 2017, among the 10 patients with available safety data,

10 patients (100%) had experienced at least one treatment emergent AE and 6 patients (60%) had experienced AEs considered related to sitravatinib.

• Most frequent (≥20%) treatment related AEs of any grade are reported in Table 1

• There have been no Grade 5 events reported.

RESULTS RESULTS

Evidence of Clinical Activity of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitor Therapy

CONCLUSIONS• The combination of sitravatinib with nivolumab is a rational approach to restoring or

enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC.

• The combination has an acceptable toxicity profile with manageable AEs.

• Early signs of clinical activity have been observed in patients who have progressed following prior CIT.

• The study is ongoing and actively accruing patients. (Clinical Trial: NCT02954991)

REFERENCES 1. Akalu, Y. T., et al. Immunological Rev 276, 165 – 177 (2017). 2. Kwilas, A.R., et al. Cancer Cell Microenviron. 2(1) (2015).

T. Leal1, L. Horn2, K. Velastegui3, J. Christensen3, I. Chen3, A. Spira4 1University of Wisconsin Carbone Cancer Center, Madison, WI, USA, 2Vanderbilt-Ingram Cancer Center, Nashville, TN, USA, 3Mirati Therapeutics, Inc., San Diego, CA, USA, 4Virginia Cancer Specialists, Fairfax, VA, USA

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Study Trial Information: www.mirati.com

Abstract # 4795

• Targeting VEGFR2 reduces Tregs & MDSCs

• Targeting KIT also depletes MDSCs

• Releases brakes for expansion of CD8+ T cells via PD-1 inhibition

Both TAM & Split RTKs cooperate to:• Increase dendritic cell

maturity & antigen presentation capacity

• Increase NK cell response

• Increase T cell expansion & trafficking into tumors

• Targeting MERTK & Axl shifts tumor associated macrophage (TAM) type to M1

• M1 macrophages secrete cytokines that enhance immune response (IL-12, TNF)

MDSC

MDSC

iDC mDC

MDSC

M2 TAM

M2 TAM

M2 TAM

M1 TAM

Treg

CD8

CD4

Treg

Treg

CD4

Split (VEGFR2 and KIT)

Immunosuppressive tumor microenvironment

TAMs (MERTK and Axl)

Non-Squamous NSCLC

Stage 1

Expand if ≥ 1 Response

Stage 2

Result of interest if ≥ 3

Responses in a Stratum

n=9 n=8Prior Clinical Benefit

n=9 n=8No Prior Clinical Benefit

Disease progression on or after prior

checkpoint inhibitor

Sitravatinib + Nivolumab

Baseline CT Post Treatment Confirmed PR (58% decrease)

Baseline CT Post Treatment Confirmed PR (49% decrease)

Baseline CT Post Treatment Confirmed PR (34% decrease)

Table 1. Safety table shows most frequent (≥20%) treatment related AEs of any grade:

PREFERRED TERM FREQUENCY (N=10)

Fatigue 5 (50%)

Diarrhea 4 (40%)

Aspartate aminotransferase increase 3 (30%)

Dysphonia 3 (30%)

Palmar-plantar erythrodysaesthesia 3 (30%)

Lipase increase 2 (20%)

Weight decrease 2 (20%)

Nausea 2 (20%)

Vomiting 2 (20%)

Decreased appetite 2 (20%)

Hyponatremia 2 (20%)

Hypertension 2 (20%)

Hypothyroidism 2 (20%)

ANTITUMOR ACTIVITY• Evidence of clinical activity has been seen in both treatment groups. As of

10 August 2017, 11 patients have had at least one on-study tumor assessment.

In the Prior Clinical Benefit arm, of the 6 evaluable patients, one patient has achieved a confirmed partial response (PR).

In the No Prior Clinical Benefit arm, of the 5 evaluable patients, two patients have achieved a confirmed PR.

• The study continues to enroll and efficacy data are maturing.

Fig. 1. Patient #1 NSCLC with left hilar and mediastinal adenopathy, and left adrenal disease; stable brain metastases

• 71 year old female with stage IIIA adenocarcinoma of the right lower lobe of the lung, diagnosed in 5/13.• Prior treatment included cisplatin/etoposide, paclitaxel, carboplatin, pemetrexed, docetaxel, and pembrolizumab (prior clinical benefit).• Patient continues on study in Cycle 5.

Sitravatinib