Botensilimab (BOT) plus balstilimab (BAL) in microsatellite stable metastatic colorectal cancer: Assessing efficacy in non-liver metastatic sites

Poster #

219

Botensilimab (BOT) plus balstilimab (BAL) in microsatellite stable metastatic colorectal cancer: Assessing efficacy in non-liver metastatic sites

Marwan G. Fakih, MD1, Andrea J. Bullock, MD, MPH2, Benjamin L. Schlechter, MD3, Apostolia M. Tsimberidou, MD, PhD4, Wells Messersmith, MD5, Agustin Pimentel, MD6, Ani S. Balmanoukian, MD7, Rachel E. Sanborn, MD8, Neil H. Segal, MD, PhD9,10, Bruno Bockorny, MD2, Sunil Sharma, MD, FACP, MBA11, Brian Henick, MD12, Ian Chau, MD, FRCP13, Joseph E. Grossman, MD14, Jaymin M. Patel, MD14, Wei Wu, MS14, Benny Johnson, DO14, Heinz-Josef Lenz, MD, FACP15, Steven J. O'Day, MD14,16, Anthony B. El-Khoueiry, MD15

1City of Hope Comprehensive Cancer Center, Duarte, CA, USA, 2Beth Israel Deaconess Medical Center, Boston, MA, USA, 3Dana-Farber Cancer Institute, Boston, MA, USA, 4The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 5University of Colorado Cancer Center, Aurora, CO, USA, 6Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA, 7The Angeles Clinic and Research Institute, Los Angeles, CA, USA, 8Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA, 9Memorial Sloan Kettering Cancer Center, New York, NY, USA,10Weill Medical College at Cornell University, New York, USA, 11HonorHealth Research Institute, Scottsdale, AZ, USA,

12Columbia University Irving Medical Center, New York, NY, USA, 13Royal Marsden Hospital, London, UK, 14Agenus Inc., Lexington, MA, USA, 15University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA,16Providence Saint John's Cancer Institute, Santa Monica, CA, USA

BACKGROUND

• Botensilimab (BOT) is an Fc-enhanced, multifunctional anti-CTLA-4 antibody

with differentiated mechanisms of action, designed to extend therapy to

cold/poorly immunogenic solid tumors including microsatellite stable

metastatic colorectal cancer (MSS mCRC; Figure 1)1,2

• Responses to novel immunotherapy (I-O) combinations in MSS mCRC have

typically been restricted to non-liver metastatic (NLM) populations. Within

RESULTS

Baseline Characteristics

	N=77
Median Age, years (range)	56 (36-82)
Sex, n (%)
Male	37 (48%)
Female	40 (52%)

	N=77
TMB >10, Mut/Mb, n/N (%)a	2/39 (5%)
RAS mutation, n/N (%)	47/72	(65%)
BRAF mutation, n/N (%)	2/39	(5%)

Time from metastatic disease to first dose of study drug, months

Case Study: Radiologic Growth of an Occult Brain Metastasis With a Pathologic Response and No Recurrence

AD

this subgroup, responses outside of metastatic sites such as the lungs and

lymph nodes are rare3,4

• We sought to determine whether BOT and balstilimab (BAL; anti-PD-1) could

confer responses in NLM sites outside of the lungs and lymph nodes

Botensilimab Mechanism of Action

Botensilimab

Multifunctional Fc-enhancedAnti-CTLA-4

Race, n (%)
White	59	(77%)
Black	1	(1%)
Asian	10	(13%)
Other or not specified	7	(9%)
Ethnicity, n (%)
Hispanic or Latino	13	(17%)
Not Hispanic or Latino	61	(79%)
Not specified	3	(4%)
ECOG PS, n (%)
0	32	(42%)
1	45	(58%)
Prior Lines of Therapy, n (%)
Median (range)	4 (2-6)
≥3	56	(73%)

Median (range)	36.7 (0.2-179.4)
≥18 months, n (%)	59	(77%)
<18 months, n (%)	18	(23%)
Location of metastases, n (%)
Lungs	62	(81%)
Peritoneal disease	33	(43%)
Lymph nodes	32	(42%)
Soft tissue	15	(19%)
Otherb	18	(23%)
Bone	3	(4%)
Brain	2	(3%)
Metastatic sites, n (%)
1 organ	28	(36%)
Lung only	22	(29%)
Lymph nodes only	2	(3%)

12/202203/2023

B

12/202203/2024

C

12/202203/2024

Figure 2. Patient scans at baseline and follow-up in a patient with an occult brain metastasis.

1. Screening (left, 12/2022) and an urgent MRI showing growth of an occult brain metastasis ~3 months later (right, 03/2023). (B-C) Chest CT at screening (left, 12/2022) versus follow-up 2 years later (right, 03/2024) showing resolution of target lesions in the lung. (D) H&E stain of the resected brain metastasis showing necrosis and lymphocytic infiltration consistent with an immune response, alongside scant residual cancer cells. As of 4/2024, this patient was still under observation, with an ongoing PR in lung lesions.

Figure 1. A novel innate and adaptive immune activator. BOT promotes enhanced T cell priming and expansion, T cell activation and memory formation, activation of antigen presenting cells, and reduction of intratumoral regulatory T cells, while improving safety through a reduction in complement-mediatedtoxicities1,2

Prior PD-(L)1/CTLA-4, n (%)	16 (21%)
Prior regorafenib, n (%)	17 (22%)
Prior trifluridine/tipiracil, n (%)	12 (16%)
Prior bevacizumab, n (%)	65 (84%)

Table 1. Baseline demographics and patient characteristics.

Peritoneal disease only	4	(5%)
≥2 organs	49	(64%)

Data cutoff: 01-MAR-2024

aOnly two patients had a TMB >10 Mut/Mb and <13.

bOther organ involvement includes adrenal glands, bone, brain, kidney, pleura, retroperitoneum, and spleen.

Safety Overview

• No new safety signals
• Safety in CRC consistent across tumor types in study
• No treatment-related deaths

C-800-01 Study Design: NLM MSS mCRC Cohort (N=77)

NCT0386027: First-in-human trial of BOT ± BAL in patients with advanced cancer5

Efficacy

Number of

ORR, %

DCR, %

Median OS, months

CONCLUSIONS

Key Eligibility

• Relapsed/refractory mCRC
• MSS by local assessment
• Prior I-O allowed

Study Endpoints

• Efficacy: ORR, DCR, DOR, PFS, OS
• Safety: AEs

Treatment (up to 2 years)

BOT +	BAL		Combination therapy
[Fc-enhanced	[PD-1]
CTLA-4]
1 or 2 mg/kg	3 mg/kg
0	2	4	6	8 10 12
Q6W	Q2W

Week

	patients	(n/nn)	(n/nn)	(95% CI)
NLM MSS mCRC (efficacy evaluable population)	70	26% (18/70)	80% (56/70)	NR (20.7-NR)
NLM MSS mCRC (safety analysis population)	77	23% (18/77)	73% (56/77)	21.2 (16.5-NR)
Any lung involvement	62	26% (16/62)	74% (46/62)	21.2 (20.7-NR)
Lung only	22	18% (4/22)	82% (18/22)	NR (13.3-NR)
Any peritoneal involvement	33	18% (6/33)	67% (22/33)	20.7 (6.3-NR)
Any soft tissue involvement	15	27% (4/15)	73% (11/15)	20.7 (3.6-NR)
Any other organ involvement	18	33% (6/18)	72% (13/18)	20.9 (6.3-NR)

• In patients with NLM MSS mCRC, response rates were comparable across different sites of metastatic disease, including historically poor prognostic sites such as the peritoneum, soft tissue, pleura and brain
• This broader clinical activity outside the lungs and lymph nodes has not previously been reported with other IO and IO/non-IO combinations
• A global randomized phase 2 trial of BOT ± BAL (versus standard of care) in MSS mCRC is fully enrolled (NCT05608044) and a global phase 3 trial is planned

Patient Population

• Safety Analysis Population - 77 patients with NLM MSS mCRC treated with 1 or 2 mg/kg BOT Q6W plus 3 mg/kg BAL Q2W
• Efficacy Evaluable Population - 70 of these patients with ≥1 post-baseline6-week imaging scan

References: 1. Chand et al. Submitted manuscript. 2. Bullock A et al. Ann Oncol 2023;34:S178-9. 3. Fakih M et al. EClinicalMedicine 2023; 58:101917.

4. Fakih M et al. JAMA Oncol 2023; 9: 627-634. 5. https://clinicaltrials.gov/ct2/show/NCT03860272.

Abbreviations: AE, adverse event; APC, antigen presenting cell; bal, balstilimab; bot, botensilimab; CR, complete response; CT, computed tomography; CTLA-4, cytotoxic T-lymphocyte associated protein 4; DCR, disease control rate (CR, PR, or SD ≥6 weeks); DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; Fc, fragment crystallizable; FcγR, fragment crystallizable gamma receptor; H&E, hematoxylin and eosin; I-O, immunotherapy; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; MRI, magnetic resonance imaging; NK, natural killer; NLM, no active liver metastases; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression free survival; PD, progressive disease; PD- 1, programmed cell death protein 1 ; PR, partial response; PS, performance status; Q[X]W, every X weeks ; SD, stable disease; TMB, tumor mutational burden; Treg, regulatory T cell. Correspondence: [e-mail]

Data cutoff: 01-MAR-2024

Median follow-up for NLM MSS mCRC (safety analysis population) patients (N=77) was 13.6 months (range, 0.6-41.8 months), with 11/18 responses ongoing/censored.

Table 2. Efficacy outcomes by sites of metastatic disease in patients with NLM MSS mCRC.

• Across different NLM sites:
• • Response rates ranged from 18-33%
  • Disease control rate ranged from 67-82%
  • Median OS remained consistent and ranged from 20.7 months to not reached (NR)

Acknowledgments

• Agenus Inc. funded and is the sponsor of this study.
• The authors would like to thank the patients and their families for participating in the C-800-01 study, as well as the trial coordinators and investigators for their contributions.

Disclosures

MGF: consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Incyte, Mirati, Pfizer, and Taiho, and data safety monitoring/advisory board for Bayer Corp, Eisai, Entos, Janssen, Merck, Mirati Therapeutics, Nouscom, Seattle Genetics, and Xenthera. AJB:

research funding from Agenus Inc., AstraZeneca, Geistlich Pharma, Oncomatryx Biopharma , and Panavance Therapeutics, travel support from Agenus Inc., and consulting/advisory fees from Exelixis, Merck, and Oncolytics. WM: consulting/advisory Role at

QED Therapeutics. RES: research funding from AstraZeneca and Merck, consulting fees from Amgen, AstraZeneca, Daiichi Sankyo, GE HealthCare, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, Janssen, Regeneron, and Sanofi Aventis, honoraria from

Binay Foundation, EMD Serono, GameOn!, Illumina, OncLive, and Targeted Oncology. NHS: consulting fees from ABL Bio, Agenus Inc., AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Numab, Puretech, Revitope, and Roche/Genentech, support for attending

meetings and/or travel from AstraZeneca and Regeneron, and research funding from Agenus Inc., AstraZeneca, Bristol-Myers Squibb, Immunocore, Merck, Pfizer, Puretech, Regeneron, and Roche/Genentech. BB: research funding from Agenus Inc, and

NanoView Biosciences, consulting fees from BioLineRx, received support for attending meetings and/or travel from Agenus Inc. and Erytech Pharma; data safety monitoring board for Blueprint Medicines and Enlivex Therapeutics. SS: honoraria from Array BioPharma, consulting/advisory role for Barricade Therapeutics, Celularity, Dracen Pharmaceuticals, and Elevar Therapeutics, research funding from Aadi Bioscience Inc., Amal Therapeutics, Celgene, Dracen Pharmaceuticals, HonorHealth, Inhibrx, Merck, Nektar Therapuetics, Novartis, Plexxikon, Sirnaomics, Syndax Pharmaceuticals, Takeda, Tesaro, Toray Industries, and Zai Lab, stock and other ownership interests with Barricade Therapeutics, Beta Cat Pharmaceuticals, ConverGene, Elevar Therapeutics, HLB, Salarius Pharmaceuticals, and Stingray Therapeutics. BH: honoraria from OncLive/MJH Life Sciences, DAVA Oncology, consulting/advisory role for AstraZeneca, IDEAYA Biosciences, Jazz Pharmaceuticals, Sorrento Therapeutics, Genentech/Roche, and Regeneron. IC: Honoria from Bristol-Myers Squibb, Eisai, Lilly, Novartis, Roche/Genentech, SERVIER, consulting/advisory role for Astellas Pharma, AstraZeneca, BioNTech SE, Bristol-Myers Squibb, Daiichi Sankyo/Astra Zeneca, Eisai, GlaxoSmithKline, Lilly, Merck Serono, MSD Oncology, OncXerna Therapeutics, Roche/Genentech, Seagen, SERVIER, Sotio, Taiho Oncology, Turning Point Therapeutics, travel and expenses from Bristol-Myers Squibb, and SERVIER. H-JL: consulting fees from Janssen and Pfizer, honoraria from AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Mirati, and Regeneron. ABE: honoraria/consulting/advisory role for Agenus Inc., AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck, QED Therapeutics, Qurient, Roche/Genentech, Senti Biosciences, Servier Laboratories, and Tallac Therapeutics, research funding from Astex Pharmaceuticals, AstraZeneca, and Fulgent Genetics. JEG, JP, WW, BJ, and SJO: Employees of Agenus Inc. with stock/stock options. JP and JEG: Leadership position at Agenus Inc. SJO: Officer at Agenus Inc. The other authors declare no competing interests (AP, ASB, and BLS).