Preliminary Biomarker Analysis of Sitravatinib in ... · 2. Akalu YT, Rothlin CV, Ghosh S, TAM...

PRIOR TESTING

CENTRAL LAB

BEST PD-L1 RESULT RESPONSE

High PD-L1 High CR

High PD-L1 No/Low PD-L1 High PR

High PD-L1 High PR

High PD-L1 High PR

High PD-L1 High SD + 14

No/Low PD-L1 High PD-L1 High SD + 14

High PD-L1 High SD + 14

High PD-L1 High SD + 14

High PD-L1 High SD + 14

High PD-L1 High SD + 14

High PD-L1 High PD-L1 High SD + 14

High PD-L1 High SD + 14

No/Low PD-L1 No/Low PR

No/Low PD-L1 No/Low PR

No/Low PD-L1 No/Low PR

No/Low PD-L1 No/Low SD + 14

No/Low PD-L1 No/Low SD + 14

No/Low PD-L1 No/Low SD + 14

High PD-L1 High PD

High PD-L1 High PD

High PD-L1 High SD - 14

No/Low PD-L1 No/Low PD No/Low PD-L1 No/Low PD

No/Low PD-L1 No/Low PD

No/Low PD-L1 No/Low PD-L1 No/Low SD - 14

No/Low PD-L1 No/Low SD - 14

No/Low PD-L1 No/Low SD - 14

No/Low PD-L1 No/Low SD - 14

RESULTMRTX-500 Safety: Most Frequent (≥10%)

Treatment-Related (Sitravatinib and/or Nivolumab)* PD-L1 IHC vs ResponseClinical Benefit - Best PD-L1 Staining

STUDY OBJECTIVESMRTX-500 STUDY DESIGN • 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 240/480 mg intravenously every 2/4 weeks, as continuous 28 day cycles.

METHODSKEY OBJECTIVES:• Objective Response Rate (ORR) by RECIST 1.1.

• Safety, tolerability, pharmacokinetics

• Investigate baseline biomarkers for correlation with clinical outcome parameters including comparing clinical benefit (CR, PR, stable disease > 14 wks) and no clinical benefit (SD < 14 week, PD)

KEY ELIGIBILITY CRITERIA:• Non-squamous NSCLC, metastatic or unresectable, locally advanced

• Treatment with at least one prior therapy

CIT-experienced patients: Most recent treatment must have included a checkpoint inhibitor with the result of progression of disease on or after treatment.

CIT-naïve patients: Receipt of prior platinum-based doublet chemotherapy

• No active brain metastases

• No history of tumors positive for EGFR, ROS1, ALK mutations

• No prior immunotherapies or combo therapies with similar mechanism of action

BASELINE AND PHARMACODYNAMIC BIOMARKERS:• PD-L1 IHC (28-8 assay (nivolumab); prior PD-L1 assay data)

• Total mutation burden (TMB) – Guardant Omni plasma ctDNA assay

• Flow cytometry for key circulating immune cell populations including CD8+ effector cells, Tregs, myeloid cells, including MDSCs, and cytokines

• Gene expression (HTG EdgeSeq) and multi-plex immunofluorescence for selected cell populations in the tumor microenvironment

RESULTS

Preliminary Biomarker Analysis of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitor

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• Early signs of clinical activity have been observed in patients who have progressed

following prior CIT• Preliminary analysis of PD-L1 status at baseline indicates a nonsignificant trend

towards high PD-L1 staining and clinical benefit • CD8+ T effector cell response evident in patients achieving clinical benefit from

the combination

• The study is ongoing and actively accruing patients

MHC I EXPRESSION IN CIRCULATING TUMOR CELLS • In an exploratory, longitudinal analysis of HLA I expression of CTCs in one patient, up

regulation of HLA I corresponding to a radiographic detection of 13% reduction in tumor size was observed between the two time points that were analyzed while the patient received sitravatinib/nivolumab combination therapy.

• Off treatment time point displayed down regulation of HLA I expression and progression. Pt developed pancreatitis, possible pneumonitis versus lymphagitic carcinomatosis and progression of intrathoracic disease.

• No correlation between total mutation burden and clinical benefit.

• Four patients with clinical benefit harbored alterations hypothesized to be sensitive to single agent sitravatinib (MET or CBL mutation, RET fusion); All 3 STK11 mutant pts experienced no clinical benefit.

Cell-free DNA (cfDNA) from baseline patient blood samples was sequenced using the Guardant OMNI assay to estimate total mutation burden (TMB) and detect sitravatinib-sensitizing mutations. TMB was calculated for 33 patients.

• An increase in the fold change of circulating T effector cells (CD3+CD4-CD8+CD45RA+CD62L-) between C1D15 and C1D1 was observed in PRs and patients with clinical benefit vs the rest of the cohort. Clinical benefit vs no clinical benefit p-value = 0.003 and PR vs Non-PRs p-value = 0.012; Kruskal-Wallis test.

Blood was collected before and after treatment and immune cell populations were analyzed by flow cytometry using multi-marker panels at a central lab.

REFERENCES1. Du W, Huang H, Sorrelle N, Brekken RA, MERTK inhibition potentiates immune checkpoint blockade in refractory cancer models. JCI Insight (in press).

2. Akalu YT, Rothlin CV, Ghosh S, TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev, 2017. 276(1): p. 165-177.

3. Kwilas AR, Donahue RN, Tsang KY, Hodge JW, Immune consequences of tyrosine kinase inhibitors that synergize with cancer immunotherapy. Cancer Cell Microenviron, 2015. 2(1).

Kai He1, Ticiana A. Leal2, Alexander Spira3, Collin Blakely4, David Berz5, Donald A. Richards6, James Uyeki7, Robert Jotte8, Alison Savage9, Erminia Massarelli10, Tammy Roque11, Igor Rybkin12, Manish R. Patel13, Ryan Ramaekers14, Timothy Larson15, Anthony Pham16, Abhinav Chandra17, Wangjian Zhong18, David Hong19, Isan Chen20, James Christensen20, Peter Olson20, Vanessa Tassell20, Adam Pavlicek21, Leora Horn22 1The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA, 2University of Wisconsin Carbone Cancer Center, Madison, WI, USA, 3Virginia Cancer Specialists, Fairfax, VA, USA, 4UC San Francisco, CA, USA, 5Beverly Hills Cancer Center, CA, USA, 6Texas Oncology - Longview Cancer Center, Tyler, TX, USA, 7Texas Oncology - South Austin, TX, USA, 8Rocky Mountain Cancer Centers - Denver - Midtown, CO, USA, 9Hematology Oncology Associates - Barnett Office, Medford, OR, USA, 10City of Hope National Medical Center, Duarte, CA, USA, 11USOR - Texas Oncology - Sherman, TX, USA, 12Henry Ford Health System, Detroit, MI, USA, 13University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA, 14St Francis Cancer Treatment Center, Grand Island, NE, USA, 15Minnesota Oncology Hematology-Coons Rapids, Minneapolis, MN, USA, 16Northwest Cancer Specialists, P.C., Tualatin, OR, 17Yuma Regional Cancer Center, AZ, USA, 18Baptist Health, Louisville, KY, USA, 19MD Anderson Cancer Center, Houston, TX, USA, 20Mirati Therapeutics, San Diego, CA, USA, 21Monoceros Biosystems, San Diego, CA, USA, 22Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

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Table 1. MRTX-500 Safety * As of 26 June 2018 (Investigators Brochure) – all patients including CIT-Experienced and CIT-Naive ** Grade 4 treatment-related events were seen in 1 patient each (1.4%) included: hypertensive crisis, gastric ulcer perforation, and hypomagnesaemia. Grade 5 treatment-related cardiac arrest was reported in one patient. -12 patients (17%) discontinued study treatment due to treatment toxicity

BACKGROUNDMRTX-500 • Sitravatinib (MGCD516) is an orally available, small molecule inhibitor of a spectrum

of related receptor tyrosine kinases (RTKs) including:

TAM family (AXL and MER): - Target cellular IC50: 1nM.

Split family RTKs (VEGFR2, PDGFRA and KIT): - Target cellular IC50: 5-10 nM.

RET, MET, DDR2, TrkA: - Target cellular IC50: 10-25 nM.

• 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).

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

ADVERSE EVENT (Preferred Term)N=70

All Grades n (%) Grade ≥3n (%)**

Diarrhea 31 (44) 8 (11)

Nausea 28 (40) 0

Fatigue 27 (39) 2 (3)

Decreased appetite 18 (26) 0

Vomiting 18 (26) 1 (1)

Dysphonia 17 (24) 0

Weight decrease 16 (23) 1 (1)

Hypertension 16 (23) 9 (13)

Alanine aminotransferase increase 12 (17) 0

Aspartate aminotransferase increase 10 (14) 0

Stomatitis 10 (14) 1 (1)

Palmar-plantar erythrodysaesthesia 10 (14) 1 (1)

Hypothyroidism 10 (14) 0

Mucosal Inflammation 8 (11) 3 (4)

Lipase increase 4 (6) 2 (3)

Hyponatremia 5 (7) 2 (3)

NO

CLI

NIC

AL

BEN

EFIT

CLI

NIC

AL

BEN

EFIT

PERC

ENT

• Highest PD-L1 result from previous testing (any test) or from the central lab (DAKO 28-8) was compared to response.

• A non-significant trend between PD-L1 high staining and clinical benefit was observed (p-value = 0.45).

• Clinical benefit, including PRs, still observed in PD-L1 low pts and some PD-L1 high pts did not respond.

CB

High

Clinical Benefit

BEST PD-L1 IHCLow

NCB

Figure 1. Sitravatinib in the Tumor Microenvironment Sitravatinib is hypothesized to sensitize tumors to immune checkpoint inhibitor therapy

MRTX-500 Clinical Activity Preliminary maximum response in NSCLC patients

who failed prior checkpoint therapy by best response (CIT-Experienced Cohorts – Clinical Activity Evaluable Patients, N=56)

MRTX-500 Clinical Activity Duration on Treatment Preliminary maximum response in NSCLC patients

who failed prior checkpoint therapy by best response (CIT-Experienced Cohorts - Clinical Activity Evaluable Patients, N=56)

MRTX-500 Circulating Biomarkers

MRTX-500 PD-L1

Total Mutation Burden Circulating Effector T Cells

On study as of 27-Aug-18

Complete response (1 target lymph node)

Study cycles of 28 days, with disease assessment scans every 2 cycles Data as of 27-Aug-2018

Confirmed Response Unconfirmed Response uCR/PR will never confirm Stable Disease Progressive Disease

45/56 Tumor Regression 18/56 Tumor Regression >30% 16/56 CR/PR 9 confirmed 2 yet to be confirmed and on study 5 will not be confirmed

Confirmed Response Unconfirmed Response uCR/PR will never confirm (BOR=SD) Stable Disease Progressive Disease Response first archieved on study Off study On study as of 27-Aug-18 Complete response (1 target lymph node)

Study cycles of 28 days, with disease assessment scans every 2 cycles

Weeks