Inhibrx : CTOS 2022- INBRX-109 Phase 2 Chondrosarcoma TiP

106 kDa

DR5, death receptor 5; sdAb, single-domainantibody.

Figure 2. INBRX-109Mechanism of Action

• INBRX-109is based on a single- domain antibody (sdAb) platform

- It consists of 2 identical camelid heavy-chain-only antigen-bindingdomains targeting DR5

- Chondrosarcomas form in the bone cartilage and usually start in the pelvis, scapula, ribs, or the ends of long bones2

• The conventional subtype of chondrosarcoma represents 85% to 90% of cases and is typically treated with surgical resection1

• However, treatment for unresectable or metastatic conventional chondrosarcoma is limited, and prognosis remains poor3

- Unresectable or metastatic conventional chondrosarcoma is generally resistant to chemotherapy and radiation, and standard molecular targeted agents are not available3

- Median progression-freesurvival (PFS) in patients receiving ineffective agents or placebo has historically been <4 months4

• Several agents for unresectable or metastatic conventional chondrosarcoma have been evaluated, but most have been ineffective, and no systemic therapies have been approved5-9

INBRX-109Mechanism of Action

• INBRX-109is a third-generation,tetravalent, agonistic antibody that targets human death receptor 5 (DR5), 1 of 2 proapoptotic receptors for the trimeric tumor necrosis factor-relatedapoptosis- inducing ligand (TRAIL) (Figures 1 and 2)

- TRAIL selectively induces apoptosis in cancer cells while sparing normal tissues and therefore plays an important role in tumor and viral immune surveillance10

- Targeting DR5 may hold great promise in chondrosarcoma, as suggested by the clinical activity previously observed with dulanermin (recombinant TRAIL)11

Figure 1. Structure of INBRX-109

and the third most

INTRODUCTION

• Chondrosarcomas are a heterogeneous group of malignant bone tumors common type of primary bone cancer after myeloma and osteosarcoma1

DR5

(PROAPOPTOTIC RECEPTOR)

DR5: sdAb

DR5: sdAb

P322

A Randomized, Placebo-Controlled, Phase 2 Trial of INBRX-109 in

Unresectable or Metastatic Conventional Chondrosarcoma

Robin Lewis Jones, MD1; Sant P. Chawla, MD2; Dale R. Shepard, MD, PhD3; Elizabeth J. Davis, MD4; Victoria Wang, MD, PhD5; Lara E. Davis, MD6; Garrett Thomas Wasp, MD, MPH7; Ana Sebio, MD8; Javier Martín-Broto, MD, PhD9;

Silvia Stacchiotti, MD10; Jean-Yves Blay, MD, PhD11; Peter Reichardt, MD, PhD12; Hans Gelderblom, MD13; Lane Senne, MS14; Michelle Darling, BS14; Kevin Bayer, BS14; Brendan Eckelman, PhD14; Anthony Paul Conley, MD15

1Royal Marsden Hospital and Institute of Cancer Research, London, UK; 2Sarcoma Oncology Research Center, Santa Monica, CA, USA; 3Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 4Vanderbilt University Medical Center, Nashville, TN, USA;

5University of California, San Francisco, San Francisco, CA, USA; 6Oregon Health & Science University, Portland, OR, USA; 7Dartmouth Cancer Center at Dartmouth-Hitchcock, Lebanon, NH, USA; 8Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;

9Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; 10Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 11Department of Medical Oncology, Center Léon Bérard, Lyon, France; 12Helios Klinikum Berlin-Buch, Berlin, Germany;

13Leiden University Medical Center, Leiden, the Netherlands; 14Inhibrx, Inc, La Jolla, CA, USA; 15The University of Texas MD Anderson Cancer Center, Houston, TX, USA

OBJECTIVE

• INBRX-109is currently in clinical development in an ongoing phase 1 dose-escalation study (NCT03715933) with dedicated single-agent expansion cohorts in chondrosarcoma, nonconventional chondrosarcoma, synovial sarcoma, malignant pleural mesothelioma, gastric adenocarcinoma, and colorectal adenocarcinoma as well as chemotherapy combination cohorts in malignant pleural mesothelioma, pancreatic adenocarcinoma, and Ewing sarcoma
• In an early assessment of the phase 1 study (October 1, 2021), INBRX-109 demonstrated clinical activity with a manageable safety profile in 20 patients with chondrosarcoma13
• • The disease control rate (complete response + partial response [PR] + stable disease [SD]) was 89% (16/18); 2 patients (11%) achieved a PR and 14 patients (78%) had SD
  • Notably, 11 of the 18 patients (61%) had a reduction in the sum of target lesions as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; 6 patients (33%) had a decrease of ≥10%
  • Median PFS among patients with chondrosarcoma was 7.4 months (historical PFS, <4 months)4
  • Among all 116 patients treated with INBRX-109 in the phase 1 study, any-grade hepatotoxicity was observed in 13 patients (11%); grade ≥3 liver-related adverse events occurred in 5.2% of patients
• Updated results as of May 26, 2022 confirmed these results and indicated activity in conventional chondrosarcoma (see CTOS 2022 presentation P043 for updated information)
• Given the early clinical activity observed in the phase 1 study and the unmet need in conventional chondrosarcoma, a phase 2 study (ChonDRAgon; NCT04950075) of INBRX-109 in unresectable or metastatic conventional chondrosarcoma has been initiated

Endpoints

Primary Endpoint

• PFS per RECIST 1.1 assessed by central real-time IRR in the ITT population
• • PFS is defined as the time from randomization to disease progression or death due to any cause, whichever occurs first

Secondary Endpoints

• Overall survival in the ITT population
• PFS per RECIST 1.1 by investigator assessment
• Overall response rate, duration of response, and disease control rate per RECIST 1.1 by real-time IRR
• QOL (European Organisation for Research and Treatment of Cancer QLQ-C30)
  - QOL will also be measured using the EQ-5D-5L,PGI-C, and PGI-S questionnaires (exploratory endpoint)
• Safety (treatment-emergent adverse events, including serious adverse events, graded by Common Terminology Criteria for Adverse Events version 5.0)
• Immunogenicity of INBRX-109
• Pharmacokinetic characterization

IRR, independent radiology review; ITT, intent-to-treat; PFS, progression-free survival; PGI-C, Patient Global Impression of Change; PGI-S, Patient Global Impression of Severity; QOL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors.

DR5: sdAb

DR5: sdAb

Fc: effector function disabled

• • These domains are joined end to end with an effector-silenced Fc constant domain based on human immunoglobulin G1
• By way of our sdAb platform, INBRX-109 eliminates recognition by preexisting antidrug antibodies (ADAs), lessening the potential for hyperclustering
• • Previous tetravalent DR5 agonists failed in the clinic due to hepatotoxicity, likely due to hyperclustering
    by ADAs12

METHODS

• ChonDRAgon is a multicenter, randomized, blinded, placebo-controlled phase 2 study of INBRX-109 in patients with unresectable or metastatic conventional chondrosarcoma (Figure 3)
• Eligible patients will be randomized 2:1 to receive either INBRX-109 at a dose of 3 mg/kg every 3 weeks (Q3W; n=134) or placebo (n=67)
• • Patients will be stratified by grade, isocitrate dehydrogenase 1/2 [IDH1/IDH2] mutation status, and line of therapy
• Treatment with INBRX-109 or placebo will continue until disease progression, death, or study withdrawal for other reasons
• Patients in the placebo arm who experience documented disease progression verified by central real-time independent radiology review (IRR) will have their treatment assignment unblinded and will be able to cross over to open-labelINBRX-109
• • Patients will receive INBRX-109 until subsequent disease progression; tumor assessments will not be submitted for central IRR
  • Assessments for the crossover population will be analyzed separately
• The primary efficacy endpoint is PFS assessed by real-time IRR, using RECIST 1.1
• • PFS is defined as the time from randomization to the first observation of documented disease progression or death due to any cause, whichever occurs first

Planned Enrollment

If interested in participating in this clinical trial, please contact Michelle Darling or Kevin Bayer at [e-mail]

8 countries

51 sites

Country	No. of sites
United States	30
France	3
Germany	2
Ireland	1
Italy	4
The Netherlands	2
Spain	5
United Kingdom	4

Figure 3. ChonDRAgon (NCT04950075) Study Design

Blinded

Open label

IRR discontinued

Off treatment

REFERENCES

1.	Dorfman HD, et al. Cancer. 1995;75(1 suppl):203-210.	8.	Bovée JV, et al. Nat Rev Cancer. 2010;10(7):481-488.
2.	Brown HK, et al. Calcif Tissue Int. 2018;102(2):174-195.	9.	Speetjens FM, et al. Curr Opin Oncol. 2016;28(4):314-322.
3.	Biermann JS, et al. J Natl Compr Canc Netw. 2017;15(2):155-167.	10.	Ashkenazi A, et al. J Clin Invest. 1999;104(2):155-162.

INBRX-109

(TETRAVALENT DR5 AGONIST)

1. Tetramerization of DR5 upon INBRX-109 binding

2. Activation of extrinsic apoptosis pathway and recruitment of DISC

DISC

N=201 (expected)			INBRX-109
		3 mg/kg IV Q3W
•	Age ≥18 years			Until PD,
		(n=134)	Primary endpoint:
•	Conventional chondrosarcoma	R			death, or
	- Unresectable or metastatic			study	PFS by IRR
	2:1			withdrawal
	- Grade 2 or 3			Interim analysis
			Placebo Q3W	for other
	- Any line of therapy,	Stratified by:		reasons
	excluding DR5 agonists		(n=67)
	• Grade

• IDH1/IDH2 mutation status

• Line of therapy			Placebo → INBRX-109

Placebo crossover to INBRX-109 allowed if PD observed

DR5, death receptor 5; IDH, isocitrate dehydrogenase; IRR, independent radiology review; IV, intravenous; PD, progressive disease; PFS, progression-free survival; Q3W, every 3 weeks; R, randomized.

Inclusion/Exclusion Criteria

Key Inclusion Criteria	Key Exclusion Criteria

4.	van Maldegem A, et al. Oncologist. 2019;24(1):110-116.	11.	Subbiah V, et al. Mol Cancer Ther. 2012;11(11):2541-2546.
5.	Tawbi HA, et al. Lancet Oncol. 2017;18(11):1493-1501.	12.	Papadopoulos KP, et al. Cancer Chemother Pharmacol.
6.	Chow W, et al. Cancer. 2020;126(1):105-111.		2015;75(5):887-895.
7.	Kostine M, et al. Mod Pathol. 2016;29(9):1028-1037.	13.	Subbiah V, et al. CTOS 2021. Abstract 1818756.

ACKNOWLEDGMENTS

• We thank our patients and participating clinical sites and teams
• This study is sponsored by Inhibrx, Inc
• Medical editorial assistance with this presentation was provided by Prasanthi Mandalay, PhD, of ArticulateScience, LLC, and funded by Inhibrx, Inc

DISCLOSURES

R. L. Jones received grant support from MSD and GSK and consulting fees from Adaptimmune, Astex, Athenex, Bayer, Boehringer Ingelheim, Blueprint Medicines, Clinigen, Eisai, Epizyme, Daiichi Sankyo, Deciphera, Immune Design, Immunicum, Karma Oncology, Lilly, Merck, Mundipharma,

3. Activation of initiator caspases-8 and -10 and executioner caspases-3

and -7	Higher valency of
4. Tumor	INBRX-109 leads to
Cell Death
robust antitumor activity

INBRX-109: tetravalent DR5 agonist

• INBRX-109 is a tetravalent, agonistic antibody against DR5, a proapoptotic receptor widely

expressed on tumor cells

• The tetravalent format of INBRX-109 was selected as an optimal balance of DR5 agonism on

tumor vs normal cells, enabling robust cancer-biased cell death while avoiding hyperclustering

and concomitant hepatotoxicity observed with previous multivalent DR5 candidates

• Age ≥18 years
• Conventional chondrosarcoma
• • Unresectable or metastatic
  • Grade 2 or 3 per AJCC 8th edition
• Any number of prior lines of therapy
• Measurable disease by RECIST 1.1
• Radiological progression of disease per RECIST 1.1 within 6 months prior to screening
• Adequate hematologic, coagulation, hepatic, and renal function as defined per protocol
• ECOG performance status of 0 or 1
• Availability of archival tissue or fresh cancer biopsy

• Any prior exposure to DR5 agonists
• Nonconventional chondrosarcoma (eg, clear cell, mesenchymal, extraskeletal myxoid, myxoid, and dedifferentiated chondrosarcoma)
• Symptomatic active CNS metastases or leptomeningeal disease
• • Patients with controlled asymptomatic CNS metastases are eligible
• Chronic liver diseases, including NASH, NAFLD, alcohol-related liver disease, and cirrhosis
• • Patients aged <64 years with NAFLD are eligible if adequate hepatic function is confirmed
• Patients aged ≥65 years with BMI >30 kg/m2
• Acute viral or toxic liver disease within 4 weeks prior to first dose of study treatment
• Evidence or history of HBV, HCV, or HIV infection

PharmaMar, SpringWorks, SynOx, TRACON, and UpToDate. S. P. Chawla received grant support, consulting fees, and/or honoraria from Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration, Janssen, Advenchen Laboratories, Bayer, Inhibrx, NKMAX, and TYME and holds stocks or stock options in Aadi Bioscience, Cellestia Biotech, CounterPoint, and Immix Biopharma. E. J. Davis received consulting fees from Deciphera, Aadi Bioscience, and MJH Life Sciences and research support from Top Alliance, Cornerstone, Bristol Myers Squibb, Actuate, BioAtla, Cogent, and Inhibrx. L. E. Davis received research funding from BTG, GSK, Novartis, Eisai, Epizyme, Cornerstone, Salarius, Ayala, BioAtla, SpringWorks, and Inhibrx paid to her institution and consulting fees from Daiichi Sankyo and SpringWorks. A. Sebio received honoraria for participation in advisory boards from PharmaMar and GSK and invited speaker fees from PharmaMar, Boehringer Ingelheim, and Boston Scientific. J. Martín-Broto has financial interests in Asofarma, Bayer, Eisai, Lilly, PharmaMar, Tecnofarma, Adaptimmune, Amgen, AROG, Bayer, Blueprint Medicines, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Deciphera, Forma, GSK, Immix Biopharma, Karyopharm Therapeutics, Lixte, Nektar, Novartis, and Pfizer. S. Stacchiotti has received institutional funding for clinical trials. P. Reichardt has received honoraria for participation in advisory boards from Bayer, Novartis, Roche, Deciphera, Mundipharma, PharmaMar, Blueprint Medicines, GSK, and Boehringer Ingelheim and invited speaker fees from Clinigen, Deciphera, PharmaMar, and Boehringer Ingelheim. L. Senne, M. Darling, and K. Bayer are employees of and own stock in Inhibrx. B. Eckelman is an employee and shareholder of Inhibrx and holds patents and/or is on patent applications for INBRX-109, a compound from Inhibrx. A. P. Conley received grant support from the Chordoma Foundation, Chordoma Foundation/ CRI, Lilly, National Cancer Institute, EpicentRx, Inhibrx, and Roche paid to his institution; received consulting fees from Deciphera and Inhibrx; and participated in a data safety monitoring board or advisory board for Applied Clinical Intelligence, Inhibrx, and Aadi Bioscience. D. R. Shepard, V. Wang, G. T. Wasp, J.-Y.Blay, and H. Gelderblom have nothing to disclose.

DISC, death-inducing signaling complex; DR5, death receptor 5.

AJCC, American Joint Committee on Cancer; BMI, body mass index; CNS, central nervous system; DR5, death receptor 5; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; RECIST, Response Evaluation Criteria in Solid Tumors.

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Presented at the Connective Tissue Oncology Society 2022 Annual Meeting; November 16-19, 2022; Vancouver, BC, Canada

Sponsored by Inhibrx, Inc