Carcinoma of ampulla of Vater

Longest survival follow-up ever reported for immunotherapy treatment in this setting WILMINGTON, Del.--(BUSINESS WIRE)-- Updated exploratory results from the TOPAZ-1 Phase III trial showed AstraZeneca's IMFINZI® (durvalumab) in combination with standard-of-care chemotherapy demonstrated a clinically meaningful long-term overall survival (OS) benefit at three years for patients with advanced biliary tract cancer (BTC). These results from TOPAZ-1, which are the longest survival follow-up ever reported for a global, randomized Phase III trial in this setting, will be presented on April 18 at the 2024 Cholangiocarcinoma Foundation Conference in Salt Lake City, Utah. At more than three years (median follow-up of 41.3 months), results showed IMFINZI plus chemotherapy reduced the risk of death by 26% versus chemotherapy alone (based on a hazard ratio [HR] of 0.74; 95% confidence interval [CI], 0.63-0.87). The median OS was 12.9 months for IMFINZI plus chemotherapy versus 11.3 months for chemotherapy alone. More than twice as many patients on the IMFINZI-based regimen were alive at three years versus chemotherapy alone (14.6% versus 6.9%). The TOPAZ-1 trial met the primary endpoint of OS in October 2021 at a planned interim analysis, showing that the combination reduced the risk of death by 20% versus chemotherapy alone (based on a HR of 0.80; 95% CI, 0.66-0.97; 2-sided p=0.021 at a statistical significance threshold of 0.03). Do-Youn Oh, MD, PhD, Professor, Division of Medical Oncology, Department of Internal Medicine at Seoul National University Hospital and Seoul National University College of Medicine, and principal investigator in the trial, said: “The latest data from TOPAZ-1 show that twice as many patients with advanced biliary tract cancer were still alive at three years with durvalumab and chemotherapy, an especially meaningful advance in a setting where historically the prognosis has been poor. These results reinforce the long-term benefit of this immunotherapy-based combination as a standard of care for patients with this devastating disease.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “TOPAZ-1 raised the bar for the treatment of advanced biliary tract cancer, showing a remarkable survival benefit for IMFINZI added to chemotherapy with a well-tolerated regimen. These data represent the longest survival follow-up reported for immunotherapy in this setting, and the three-year landmark survival improvement underscores our commitment to improving long-term outcomes in gastrointestinal cancers.” Stacie Lindsey, CEO, Cholangiocarcinoma Foundation said: “AstraZeneca’s longer survival data in advanced biliary tract cancer represents a meaningful milestone in that we are seeing three-year survival data for the first time for these patients. The data spurs hope that research will continue to improve outcomes for patients living with these challenging and rare cancers.” Summary of updated survival results: TOPAZ-1i OSi,ii IMFINZI+ chemotherapy (n=341) Chemotherapy (n=344) Median OS (95% CI in months) 12.9 (11.6-14.1) 11.3 (10.1-12.5) HR (95% CI)iii 0.74 (0.63-0.87) OS rate at 36 months (95% CI) (%)iv 14.6 (11.0-18.6) 6.9 (4.5-10.0) i. 26 months of additional follow-up (data cut-off: 23 October 2023) after the primary analysis, with 89% overall OS event maturity ii. At data cut-off for this analysis, median (95% CI) follow-up time in all patients calculated using reverse Kaplan-Meier technique was 42.9 (39.8-44.3) months for IMFINZI plus chemotherapy and 41.8 (36.7-46.2) months for chemotherapy iii. HR and 95% CI calculated using Cox proportional hazards model iv. OS rates calculated using Kaplan-Meier technique IMFINZI plus chemotherapy continued to be well-tolerated, with no new safety signals observed with longer follow-up. Results showed 15.4% of patients experienced treatment-related serious adverse events with IMFINZI plus chemotherapy versus 17.3% with chemotherapy alone. IMPORTANT SAFETY INFORMATION There are no contraindications for IMFINZI® (durvalumab). Immune-Mediated Adverse Reactions Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity. See USPI Dosing and Administration for specific details. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions. In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC or BTC when given in combination with chemotherapy. Immune-Mediated Colitis IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions. Immune-Mediated Hepatitis IMFINZI can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions. Immune-Mediated Endocrinopathies Adrenal Insufficiency: IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Hypophysitis: IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Grade 3 hypophysitis/hypopituitarism occurred in <0.1% (1/1889) of patients who received IMFINZI. Thyroid Disorders: IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Thyroiditis: Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. Hypothyroidism: Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Grade 3 immune-mediated Type 1 diabetes mellitus occurred in <0.1% (1/1889) of patients receiving IMFINZI. Immune-Mediated Nephritis with Renal Dysfunction IMFINZI can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Immune-Mediated Dermatology Reactions IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions. Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or were reported with the use of other PD-1/PD-L1 blocking antibodies. Cardiac/vascular: Myocarditis, pericarditis, vasculitis. Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine: Hypoparathyroidism. Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection. Infusion-Related Reactions IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity. See USPI Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions. Complications of Allogeneic HSCT after IMFINZI Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT. Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and advise them to use effective contraception during treatment with IMFINZI and for 3 months after the last dose of IMFINZI. Lactation There is no information regarding the presence of IMFINZI in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI, advise women not to breastfeed during treatment and for 3 months after the last dose. Adverse Reactions In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), the most common adverse reactions (occurring in ≥20% of patients) were fatigue (42%), nausea (40%), constipation (32%), decreased appetite (26%), abdominal pain (24%), rash (23%), and pyrexia (20%). In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), discontinuation due to adverse reactions occurred in 6% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), and upper gastrointestinal hemorrhage (2 patients). The safety and effectiveness of IMFINZI have not been established in pediatric patients. Indication: IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). Please see Full Prescribing Information including Medication Guide for IMFINZI. Notes Biliary tract cancer Biliary tract cancer (BTC) is a group of rare and aggressive gastrointestinal (GI) cancers that form in the cells of the bile ducts (cholangiocarcinoma), gallbladder or ampulla of Vater (where the bile duct and pancreatic duct connect to the small intestine).1,2 Approximately 50,000 people in the US, Europe and Japan and about 210,000 people worldwide are diagnosed with BTC each year.3-5 These patients historically have a poor prognosis, with approximately 5% to 15% of patients with BTC surviving five years. For patients with metastatic disease, the five-year survival rate drops to less than 5%.6 Cholangiocarcinoma is more common in China and Thailand and is on the rise in Western countries.1,7 Gallbladder cancer is more common in certain regions of South America, India and Japan.8 Early-stage BTC affecting the bile ducts and gallbladder often presents without clear symptoms and most new cases of BTC are therefore diagnosed at an advanced stage, when treatment options are limited and the prognosis is poor.7-9 TOPAZ-1 TOPAZ-1 is a randomized, double-blind, placebo controlled, multicenter, global Phase III trial of IMFINZI in combination with chemotherapy (gemcitabine plus cisplatin) versus placebo in combination with chemotherapy as a 1st-line treatment in 685 adult patients with unresectable, locally advanced or metastatic BTC including intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer. Patients with ampullary carcinoma were excluded. The primary endpoint is overall survival and key secondary endpoints included progression-free survival, objective response rate and safety. The trial was conducted in 105 centers across 17 countries including in the US, Europe, South America and several countries in Asia including South Korea, Thailand, Japan and China. IMFINZI® (durvalumab) IMFINZI® (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor's immune-evading tactics and releasing the inhibition of immune responses. In addition to its indications in unresectable, Stage III NSCLC and ES-SCLC, IMFINZI is currently approved in a number of countries in combination with a short course of tremelimumab-actl and chemotherapy for the treatment of metastatic NSCLC. IMFINZI is also approved in a number of countries in combination with chemotherapy in locally advanced or metastatic biliary tract cancer and in combination with tremelimumab-actl in unresectable hepatocellular carcinoma (HCC). IMFINZI is also approved as a monotherapy in unresectable HCC in Japan and the EU and in previously treated patients with advanced bladder cancer in a small number of countries. Since the first approval in May 2017, more than 220,000 patients have been treated with IMFINZI. As part of a broad development program, IMFINZI is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, breast cancer, several gastrointestinal cancers and other solid tumors. AstraZeneca in GI cancers AstraZeneca has a broad development program for the treatment of GI cancers across several medicines and a variety of tumor types and stages of disease. In 2020, GI cancers collectively represented approximately 5.1 million new cancer cases leading to approximately 3.6 million deaths.10 Within this program, the Company is committed to improving outcomes in gastric, liver, biliary tract, esophageal, pancreatic and colorectal cancers. In addition to its indications in BTC and HCC, IMFINZI is being assessed in combinations, including with tremelimumab-actl, in liver, esophageal and gastric cancers in an extensive development program spanning early to late-stage disease across settings. The Company is also assessing rilvegostomig (AZD2936), a PD-1/TIGIT bispecific antibody, in combination with chemotherapy as an adjuvant therapy in biliary tract cancer. Fam-trastuzumab deruxtecan-nxki, a HER2-directed antibody drug conjugate, is approved in the US and several other countries for HER2-positive advanced gastric cancer and is being assessed in colorectal cancer. It also has been assessed in multiple GI settings including biliary tract cancer in the DESTINY-PanTumor02 Phase II trial, and it was recently approved in the US for the treatment of unresectable or metastatic HER2-positive solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. Fam-trastuzumab deruxtecan-nxki is jointly developed and commercialized by AstraZeneca and Daiichi Sankyo. Olaparib, a first-in-class PARP inhibitor, is approved in the US and several other countries for the treatment of BRCA-mutated metastatic pancreatic cancer. Olaparib is developed and commercialized in collaboration with Merck & Co., Inc., known as MSD outside the US and Canada. AstraZeneca is advancing multiple modalities that provide complementary mechanisms for targeting Claudin 18.2, a promising therapeutic target in gastric cancer. These include AZD0901, a potential first-in-class antibody drug conjugate licensed from KYM Biosciences Inc., currently in Phase II development, AZD5863, a novel Claudin 18.2/CD3 T-cell engager bispecific antibody licensed from Harbour Biomed in Phase I development, and AZD6422, an armored autologous chimeric antigen receptor T-cell (CAR-T) therapy, currently being evaluated in an Investigator Initiated Trial (IIT) in collaboration with AbelZeta in China. In early development, AstraZeneca is developing two Glypican 3 (GPC3) armored CAR-Ts in HCC. AZD5851, currently in Phase I development, is being developed globally, and C-CAR031 / AZD7003 is being co-developed with AbelZeta in China where it is under evaluation in an IIT. AstraZeneca in immuno-oncology (IO) AstraZeneca is a pioneer in introducing the concept of immunotherapy into dedicated clinical areas of high unmet medical need. The Company has a comprehensive and diverse IO portfolio and pipeline anchored in immunotherapies designed to overcome evasion of the anti-tumor immune response and stimulate the body’s immune system to attack tumors. AstraZeneca strives to redefine cancer care and help transform outcomes for patients with IMFINZI as a monotherapy and in combination with tremelimumab-actl as well as other novel immunotherapies and modalities. The Company is also investigating next-generation immunotherapies like bispecific antibodies and therapeutics that harness different aspects of immunity to target cancer, including cell therapy and T cell engagers. AstraZeneca is pursuing an innovative clinical strategy to bring IO-based therapies that deliver long-term survival to new settings across a wide range of cancer types. The Company is focused on exploring novel combination approaches to help prevent treatment resistance and drive longer immune responses. With an extensive clinical program, the Company also champions the use of IO treatment in earlier disease stages, where there is the greatest potential for cure. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit and follow us on social media @AstraZeneca. References Marcano-Bonilla L, et al. Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations. CCO. 2016;5(5). ESMO. What is Biliary Tract Cancer. Available at: . Accessed March 2024. Siegel RL. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7-30.​ ECIS - European Cancer Information System. Available: Accessed March 2024.​ Kohei Nakachi, et al. Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group, A randomized Phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1202, ASCOT), Japanese Journal of Clinical Oncology. 2018,48:392-395.​ American Cancer Society. Survival Rates for Bile Duct Cancer. Available at: . Accessed March 2024. Turkes F, et al. Contemporary Tailored Oncology Treatment of Biliary Tract Cancers. Gastroenterol Res Pract. 2019;2019:7698786. Rawla P, et al. Epidemiology of gallbladder cancer. Clin Exp Hepatol. 2019;5(2):93-102. Banales JM, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nature Reviews Gastroenterology & Hepatology. 2020; 17: 557-588. WHO. World Cancer Fact Sheet. Available at: . Accessed September 2022. US-88271 Last Updated 04/24

LEXINGTON, Mass.--(BUSINESS WIRE)--Agenus Inc. (“Agenus”) (Nasdaq: AGEN), a leader in developing novel immunological agents to treat various cancers, today announced results for the second quarter 2023. Key accomplishments and highlights include: Botensilimab Update: Botensilimab/balstilimab combination data presented at ESMO-GI demonstrated median overall survival (mOS) of 20.9 months and a 23% overall response rate (ORR), both surpassing data reported for standard of care in 3L+ Non-MSI-H colorectal cancer (CRC) in patients without active liver metastases. Regulatory: The U.S. FDA granted Fast Track designation for the botensilimab/balstilimab combination in 3L+ Non-MSI-H CRC in patients without active liver metastases. Agenus is exploring global accelerated approval strategies for CRC. Clinical Trial Progress: Ongoing Phase 2 ACTIVATE trials in CRC and melanoma expected to fully enroll by end of year. AGEN2373 Update: AGEN2373 Phase 1 dose escalation data presented at ASCO demonstrated promising monotherapy clinical responses in patients with advanced solid tumors. “Botensilimab, alone or in combination with balstilimab, continues to display remarkable clinical activity in over 600 patients treated across nine late-stage, treatment resistant solid tumor cancers, demonstrating great potential to revolutionize the role of immunotherapy in cancer treatment,” said Chief Executive Officer, Garo Armen, Ph.D. “Agenus is committed to advancing our diverse clinical pipeline with a focus on expediting our first regulatory submission for the botensilimab/balstilimab combination in colorectal cancer. Our data has demonstrated an unprecedented survival benefit over what has been reported for standard of care, underscoring this combination as an important potential treatment option for patients with non-MSI-high colorectal cancer, which represents 85% of the population of patients with colorectal cancer1.” Botensilimab/Balstilimab (“Bot/Bal”) Combination in 3L+ Non-MSI-H Metastatic CRC Data Presented at the ESMO-GI World Congress on Gastrointestinal Cancer in June 2023: In 69 evaluable patients with non-MSI-High CRC without active liver metastases, results demonstrated a meaningful improvement over standard of care in both overall response rate (ORR%) and median overall survival (mOS): mOS of 20.9 months as compared to the recently reported 12.9-month benchmark with standard care.2 ORR of 23% as compared to the recently reported 2.8%1 benchmark with standard care. In April 2023, the U.S. FDA granted Fast Track designation to the bot/bal combination for patients with non-MSI-H/dMMR metastatic CRC without active liver metastases. The ACTIVATE Phase 2 trial in this patient population is on target to conclude enrollment by year-end. Planning is underway for a Phase 3 CRC study; with Fast Track designation from the FDA, study design and timing will be determined as we discuss our filing approach with the agency. A Biologics License Application to the FDA is planned in 2024. Botensilimab in Other Advanced Solid Tumor Cancers: Lung: Enrollment continues for a Phase 1b trial targeting PD-(L)1 +/- chemotherapy relapsed/refractory non-small-cell lung cancer (NSCLC); data update planned by year-end. Melanoma: Ongoing global enrollment in Phase 2 ACTIVATE trial with data update planned in 2024. Ovarian: Phase 1b trial in patients with platinum-resistant ovarian cancer (PROC) demonstrated a 33% ORR and 67% disease control rate among primarily high-grade, heavily pretreated patients (presented at SGO in March 2023). Sarcomas: Updated data for a Phase 1b cohort with advanced sarcomas to be presented at ESMO on October 21st 2023. AGEN2373 Data Presented at the ASCO 2023 Annual Meeting: Complete results from the first-in-human monotherapy dose escalation study of AGEN2373, a CD137 agonist, in patients with advanced solid tumors: Reported responses in metastatic prostate cancer, ampullary carcinoma, and vulvar squamous cell carcinoma highlight the potential impact of AGEN2373. AGEN2373 is the first CD137 agonist antibody to report single-agent responses with no major toxicities. Clinical data are consistent with mechanistic design intent of AGEN2373 to avoid hepatic toxicity, a typical constraint of CD137-targeted agonists. Leadership Appointments: In alignment with Agenus' next phase of growth and anticipated commercialization of the bot/bal combination, the company announced the following key executive appointments: Robin Taylor, Ph.D., Chief Commercial Officer. Homa Yeganegi, Chief Product Strategy and Global Medical Affairs Officer. Stephanie Fagan, Chief Communications Officer. Second Quarter 2023 Financial Results: We ended our second quarter 2023 with a cash, cash equivalent and short-term investment balance of $157.6 million, compared to $193.4 million at December 31, 2022. In addition, we have raised $20.3 million through sales of our common stock under our at market issuance sales agreement since the end of Q2 2023. For the three and six months ended June 30, 2023, we recognized revenue of $25.3 million and $48.2 million and incurred a net loss of $73.4 million and $144.3 million, respectively. Our net loss includes non-cash expenses of $28.9 million for the three months ended, and $53.8 million for the six months ended, June 30, 2023. Select Financial Information (in thousands, except per share data) (unaudited) June 30, 2023 December 31, 2022 Cash, cash equivalents and short-term investments $ 157,852 $ 193,358 Cash raised since quarter end $ 20,281 Three months ended June 30, Six months ended June 30, 2023 2022 2023 2022 Revenues, royalty sales milestone $ - $ 17,316 $ - $ 17,316 Revenues, non-cash royalty 22,068 144 41,174 17,778 Revenues, research and development 2,489 1,907 5,101 8,647 Revenues, other 739 1,559 1,923 3,126 Total Revenue 25,296 20,926 48,198 46,867 Research and development expenses 59,285 44,960 116,402 87,404 General and administrative expenses 20,415 18,914 38,653 37,866 Cost of service revenue 254 2,024 2,548 2,567 Other income (883 ) (8,966 ) (1,604 ) (8,776 ) Non-cash interest expense 19,647 13,636 36,920 28,588 Non-cash contingent consideration fair value adjustment 8 (407 ) (398 ) (943 ) Net loss* $ (73,430 ) $ (49,235 ) $ (144,323 ) $ (99,839 ) Net loss per share attributable to Agenus Inc. common stockholders: $ (0.20 ) $ (0.17 ) $ (0.41 ) $ (0.35 ) *Includes non-cash expenses Adjusted Net loss for non-cash expenses: Net loss as reported $ (73,430 ) $ (49,235 ) $ (144,323 ) $ (99,839 ) Non-cash expenses Depreciation and amortization 2,973 1,690 5,535 3,350 Share based compensation 6,042 4,634 11,527 9,625 Non-cash interest expense 19,647 13,636 36,920 28,588 Other 285 (409 ) (100 ) (943 ) Total non-cash expenses 28,947 19,551 53,882 40,620 Net loss excluding non-cash expenses $ (44,483 ) $ (29,684 ) $ (90,441 ) $ (59,219 ) References 1 2 Cohen et al. ASCO Annual Meeting 2023 About Botensilimab Botensilimab, an investigational multifunctional CTLA-4 antibody, is designed to extend immunotherapy benefits to “cold” tumors, which have not historically responded to standard of care or other investigational therapies. Besides binding to the CTLA-4 receptor, its Fc-enhanced structure induces a memory immune response, downregulates regulatory T cells, and activates T cells, thereby enhancing immune responses. Approximately 600 patients have been treated with botensilimab in phase 1 and phase 2 clinical trials. Botensilimab alone, or in combination with Agenus’ PD-1 antibody, balstilimab, has shown clinical responses across nine metastatic, late-line cancers. For more information about botensilimab trials, visit with the identifiers NCT03860272, NCT05608044, NCT05630183, and NCT05529316. About AGEN2373 AGEN2373 is a novel anti-CD137 agonist that has been designed to activate T and NK cells while mitigating liver toxicities common to the CD137 target class. CD137 (4-1BB) is an activating receptor expressed on T and NK cells. Upon binding to CD137, AGEN2373 is designed to stimulate the growth and activation of cytotoxic T and NK cells, triggering a lasting memory response to cancer. AGEN2373 binds to a unique epitope designed to achieve this response specifically within the tumor microenvironment. This selective binding is designed to avoid serious side effects associated with CD137 activation in the liver that have been reported by competitor molecules. AGEN2373 has demonstrated preliminary clinical activity and has been well tolerated by patients without signs of liver toxicity (Barve et al. ASCO 2023). About Agenus Agenus is a leading immuno-oncology company targeting cancer and infectious diseases with a comprehensive pipeline of immunological agents. The company’s mission is to expand patient populations benefiting from cancer immunotherapy through combination approaches, using a broad repertoire of antibody therapeutics, adoptive cell therapies (through MiNK Therapeutics) and adjuvants (through SaponiQx). Agenus is headquartered in Lexington, MA. For more information, visit or follow us on LinkedIn and Twitter @agenus_bio. Non-GAAP Financial Measures To supplement our financial disclosures that are prepared and presented in accordance with generally accepted accounting principles in the United States (“GAAP”), this press release includes Adjusted Net Loss, which is a non-GAAP financial measure that we believe is helpful to our investors. We use these non-GAAP financial measures for financial and operational decision-making purposes. We believe these measures provide investors with meaningful period-to-period comparisons of our underlying performance. Adjusted Net Loss is a supplemental measure of our operating performance and excludes the impacts of certain costs required to be recorded under GAAP. We calculate Adjusted Net Loss as net loss adjusted to exclude non-cash expenses of depreciation and amortization, share based compensation, non-cash interest expense and certain other non-cash expenses. Accordingly, Adjusted Net Loss should not be considered in isolation or as a substitute for net loss, which is the most directly comparable financial measure presented in accordance with GAAP. Forward-Looking Statements This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements relating to our technologies, therapeutic candidates, and capabilities, for instance, statements regarding therapeutic benefit and efficacy, mechanism of action, potency, durability, and safety and tolerability pro our therapeutic candidates, both alone and in combination with each other and/or other agents; statements regarding future plans, including research, clinical, regulatory, and commercialization plans; and any other statements containing the words "may," "believes," "expects," "anticipates," "hopes," "intends," "plans," "will" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission and available on our website: . Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement.

LEXINGTON, Mass.--( BUSINESS WIRE )--Agenus (Nasdaq: AGEN), a leading immuno-oncology company with a pipeline of immunological agents targeting cancer and infectious disease, presented complete results from the monotherapy arm of the first-in-human dose escalation study of AGEN2373 (CD137 agonist) at the American Society of Clinical Oncology (ASCO) Annual Meeting. AGEN2373 demonstrated objective responses, clinical benefit, and was well tolerated in heavily pre-treated patients with solid tumors. “AGEN2373 has shown meaningful single agent activity and a favorable safety profile without evidence of liver toxicity in patients with heavily pretreated cold and immunotherapy resistant tumors,” said Dr. Steven O’Day, MD, Chief Medical Officer at Agenus. “AGEN2373 is designed to selectively boost tumor immunity while limiting hepatotoxicity and off-target effects associated with systemic CD137 activation. These encouraging monotherapy results support further clinical trials for AGEN2373 alone and in combination with our novel immunotherapy programs.” Study Design: AGEN2373 was administered intravenously at doses ranging from 0.03 mg/kg to 10 mg/kg in a cohort of 46 patients with advanced solid tumors and a median of 4 prior lines of therapy. Objective responses: Notable responses in the dose escalation study include: Confirmed partial response in a patient with vulvar squamous cell carcinoma who progressed on prior pembrolizumab Confirmed partial response with complete resolution of the pancreatic lesion in a patient with ampullary carcinoma Confirmed 38% reduction in target liver lesions in a castrate-resistant prostate cancer that was non-evaluable by RECIST due to palliative radiation for bone metastases Tolerability: No hepatic toxicities, grade ≥3 treatment-related adverse events, or dose-limiting toxicities were observed, consistent with the molecule’s design. Presently, AGEN2373 is being evaluated in combination with botensilimab (multi-functional anti-CTLA-4) at a dose of 10 mg/kg in patients with PD-(L)1 refractory melanoma. Presentation Details: Abstract Title: A Phase 1 Study of AGEN2373, a Novel CD137 Agonist Antibody Designed to Avoid Hepatoxicity, in Patients with Advanced Solid Tumors (NCT04121676) Abstract Number: 2524 Poster Number : 366 Presenting Author: Dr. Minal Barve, MD, Executive Director and Chief Medical Officer, Mary Crowley Research The poster presentation can be accessed in the publications section of our website at https://agenusbio.com/publications/ . About AGEN2373 AGEN2373 is a novel anti-CD137 agonist designed to stimulate T and NK cells for a durable memory response to cancer. AGEN2373’s selective binding to a unique epitope is designed to prevent serious side effects associated with CD137 activation in the liver, as reported by competitor molecules. About Agenus Agenus is a clinical-stage immuno-oncology company focused on developing therapies that engage the body's immune system in fighting cancer and infections. The Company's mission is to broaden the patient populations benefiting from cancer immunotherapy through combination approaches, leveraging a broad repertoire of antibody therapeutics, adoptive cell therapies (through its subsidiary MiNK Therapeutics), and adjuvants (through its subsidiary SaponiQx). Agenus is headquartered in Lexington, MA. For more information, please visit www.agenusbio.com and our Twitter handle @agenus_bio. Forward-Looking Statements This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements relating to the use of AGEN2373, for instance, statements regarding therapeutic benefit and efficacy, mechanism of action (including validation of mechanism of action), potency, durability, and safety profile (including the absence of specific toxicities) of the Company’s therapeutic candidates; and any other statements containing the words "may," "believes," "expects," "anticipates," "hopes," "intends," "plans," "forecasts," "estimates," "will," “establish,” “potential,” “superiority,” “best in class,” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement.