PD-1 x TIGIT

Objective response rate of 34% (2 responses pending confirmation) and 25% (confirmed) in the 100mg daily dose expansion cohort (n=32) of ARC-20, a Phase 1/1b study of casdatifan in metastatic clear cell renal cell carcinoma (ccRCC) Low rate of primary progression (19%) and high rate of disease control (81%) was observed in the 100mg expansion cohort with many of those patients still on treatment Arcus will host a conference call to discuss these results, including results from the 50mg expansion cohort, at 5:00 AM PT / 8:00 AM ET today HAYWARD, Calif.--(BUSINESS WIRE)--Arcus Biosciences, Inc. (NYSE:RCUS), a clinical-stage, global biopharmaceutical company focused on developing differentiated molecules and combination therapies for patients with cancer, today presented the first clinical activity data for casdatifan, a HIF-2a inhibitor with best-in-class potential, in an oral plenary session by Dr. Toni K. Choueiri, Dana-Farber Cancer Institute at the 2024 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. “Based on our experience in the ARC-20 study, we have seen casdatifan’s ability to quickly bring tumor growth under control and its high response and disease control rates,” said Toni K. Choueiri, M.D., director of the Lank Center for Genitourinary (GU) Oncology at Dana-Farber, the Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School and lead investigator of ARC-20. “Based on these data, casdatifan has the potential to be a future treatment option for kidney cancer. I am particularly interested in planned research into novel combinations for casdatifan in both first- and second-line ccRCC.” “In the 100mg daily dose-expansion cohort of ARC-20, casdatifan showed encouraging results, particularly a low primary progressive disease rate and very durable responses. This was accomplished with a manageable safety profile,” said Dimitry Nuyten, M.D., Ph.D., chief medical officer of Arcus. “These data support the potential for casdatifan to be a best-in-class HIF-2a inhibitor for the treatment of ccRCC. We look forward to initiating our first Phase 3 study for casdatifan, PEAK-1, in the first half of 2025, and expanding our development program into the first-line setting with a novel combination, as well as into other ccRCC subpopulations.” ARC-20 is a Phase 1/1b dose-escalation and -expansion study. In the dose escalation (20mg to 200mg) portion of the study, the safety pro comparable across the doses; there were no dose-limiting toxicities, and the maximum tolerated dose was not reached at daily doses of up to 150 mg (200 mg portion of the study is currently ongoing). The 100 mg daily dose (50 mg BID [twice daily]) was selected for dose expansion, and casdatifan was evaluated in patients with metastatic ccRCC who had progressed on at least two prior lines of therapy, including both an anti-PD-1 and a tyrosine kinase inhibitor (TKI) therapy (n=33). The patient population was heavily pre-treated: 52% had received at least three prior lines of therapy; 26% had received at least four prior lines of therapy; and 61% had an International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor of intermediate. At the time of data cut off (DCO, Aug. 30, 2024), median follow-up was 11 months. Casdatifan showed a rapid time to response, and only 19% of patients had primary progressive disease (progressed at or before their first disease assessment). The majority of patients (81%) experienced disease control with either a partial response or stable disease. At the time of the DCO, the median progression-free survival had not been reached. 34% of patients experienced an objective response, meaning their tumor shrank by at least 30%. A summary of initial results is below. Objective Response Rate (ORR) per RECIST v1.1 100mg Efficacy-Evaluable* Population (n=32) ORR [95% CI] 34% (11)** [16,50] Responses Pending Confirmation 2** Confirmed ORR [95% CI] 25% (8) [12,43] Progressive Disease 19% (6) Disease Control Rate [95% CI] 81% [64,93] Median Progression-Free Survival Not Reached CI=confidence interval *100mg daily dose is 50mg BID (twice daily); efficacy-evaluable population for this expansion cohort is defined as all eligible participants who have measurable disease at baseline, receive at least one dose of casdatifan, and have at least one post-baseline efficacy assessment, or who discontinue study treatment due to progressive disease or death. One participant was enrolled but deemed not eligible for the study and was not evaluated for efficacy. **One patient achieved a response after DCO and nearly a year on treatment, which increased the ORR from 31% (10) to 34%. In the 100mg dose-expansion cohort, no unexpected safety signals were observed at the time of DCO, and casdatifan had an acceptable and manageable safety profile. Grade 3 treatment-emergent adverse events (TEAEs) related to casdatifan were 42%, including anemia (36%) and hypoxia (9%). No patients discontinued treatment from anemia. No TEAEs were life-threatening or led to death. Arcus is pursuing a broad development program in both the first-line and post-anti-PD-1 settings with differentiated combinations to maximize the opportunity for casdatifan in ccRCC. In addition to the monotherapy cohorts of ARC-20, the study is also enrolling a cohort to evaluate casdatifan in combination with cabozantinib, a VEGFR TKI which is intended to support the initiation of Arcus’s planned first Phase 3 study, PEAK-1, evaluating casdatifan in combination with cabozantinib versus cabozantinib monotherapy in patients with metastatic ccRCC who have previously received anti-PD-1 therapy. The primary endpoint will be progression-free survival with a key secondary endpoint of overall survival. Arcus also recently announced a clinical collaboration as part of its first-line strategy in advanced ccRCC to evaluate casdatifan in combination with volrustomig, an investigational anti-PD-1/CTLA-4 bispecific antibody. Investors may dial in to the conference call at +1 (404) 975- 4839 (local) or +1 (833) 470-1428 (toll-free), using Conference ID: 595409 on Thursday, October 24, 2024 at 5:00 AM PT / 8:00 AM ET. Participants may also register for the call online using the following link: . In addition to the ARC-20 data, the conference call will address the development strategy and market potential for casdatifan. Arcus will also be joined by Dr. Rana McKay of the University of California San Diego. To access the live webcast and accompanying slide presentation, please visit the “Investors & Media” section of the Arcus Biosciences website at . A replay will be available following the live event. About Casdatifan (AB521) Casdatifan is a small-molecule inhibitor of HIF-2a, a tumorigenic transcription factor involved in oxygen sensing in multiple organs as well as in tumors. Clear cell RCC is almost universally associated with HIF-2a dysregulation as a result of genetic abnormalities in the VHL pathway. This creates a situation of pseudohypoxia and the abnormal increase in HIF-2a-mediated expression of a broad range of oncogenic proteins. By selectively inhibiting HIF-2a, casdatifan is designed to disable a wide array of pathways involved in tumor proliferation and survival, treatment resistance and angiogenesis, leading to cancer cell death. Casdatifan is being evaluated in ARC-20, a Phase 1/1b study in cancer patients, and STELLAR-009, a Phase 1b/2 study in combination with zanzalintinib in patients with advanced solid tumors, including ccRCC. Under the Gilead and Arcus collaboration agreement, Gilead has the right to opt-in to development and commercialization for casdatifan after Arcus’s delivery of a qualifying data package. Casdatifan is an investigational molecule. Approval from any regulatory authority for its use has not been received, and its safety and efficacy have not been established. About RCC According to the American Cancer Society, kidney cancer is among the top 10 most commonly diagnosed forms of cancer among both men and women in the U.S., and an estimated 81,600 Americans will be diagnosed with kidney cancer in 2024. Clear cell RCC is the most common type of kidney cancer in adults. If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 15%. In 2022, approximately 32,200 patients with advanced kidney cancer required systemic therapy in the U.S., with over 20,000 patients receiving first-line treatment. About Arcus Biosciences Arcus Biosciences is a clinical-stage, global biopharmaceutical company developing differentiated molecules and combination medicines for people with cancer. In partnership with industry collaborators, patients and physicians around the world, Arcus is expediting the development of first- or best-in-class medicines against well-characterized biological targets and pathways and studying novel, biology-driven combinations that have the potential to help people with cancer live longer. Founded in 2015, the company has expedited the development of multiple investigational medicines into clinical studies, including new combination approaches that target TIGIT, PD-1, HIF-2a, CD73, dual A2a/A2b receptor, CD39, and AXL. For more information about Arcus Biosciences’ clinical and preclinical programs, please visit . Forward Looking Statements This press release contains forward-looking statements. All statements regarding events or results to occur in the future contained herein are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, the statements in Dr. Nuyten’s and Dr. Choueiri’s quotes and statements regarding: the potency, efficacy or safety of casdatifan, including its potential for a best-in-class profile; casdatifan’s safety profile; ability for casdatifan to be used in first-line therapy; how data from ARC-20 will support or advance Arcus’s development program for casdatifan, including plans for future development; plans to initiate a new Phase 3 study with casdatifan, including timing for initiating any such study; and combinations that Arcus plans to explore in future studies. All forward-looking statements involve known and unknown risks and uncertainties and other important factors that may cause Arcus’s actual results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to risks associated with: interim data not being replicated in future studies evaluating the same investigational molecules or regimen; the unexpected emergence of adverse events or other undesirable side effects in Arcus’s investigational products; risks associated with manufacturing or supplying product for such clinical trials; uncertainties in timelines associated with the conduct of clinical studies and with respect to the regulatory application process; difficulties associated with the management of the collaboration activities with our strategic partners or expanded clinical programs; changes in the competitive landscape for Arcus’s programs; and the inherent uncertainty associated with pharmaceutical product development and clinical trials. Risks and uncertainties facing Arcus are described more fully in the “Risk Factors” section of Arcus’s most recent periodic report filed with the U.S. Securities and Exchange Commission. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date of this press release. Arcus disclaims any obligation or undertaking to update, supplement or revise any forward-looking statements contained in this press release except to the extent required by law. The Arcus name and logo are trademarks of Arcus Biosciences, Inc. All other trademarks belong to their respective owners. Contacts Investor Inquiries: Pia Eaves VP of Investor Relations & Strategy (617) 459-2006 peaves@arcusbio.com Media Inquiries: Holli Kolkey VP of Corporate Communications (650) 922-1269 hkolkey@arcusbio.com

HAYWARD, Calif.--(BUSINESS WIRE)--Arcus Biosciences (NYSE:RCUS), a clinical-stage, global biopharmaceutical company focused on developing differentiated molecules and combination therapies for patients with cancer, announced that its management team will host a conference call and webcast on Wednesday, November 6 th , 2024 at 2 PM PT / 5 PM ET to discuss details of the Company’s financial results and pipeline update for the quarter ended September 30 th , 2024. Investors interested in listening to the conference call may do so by dialing +1 (404) 975-4839 (local) or +1 (833) 470-1428 (toll-free), using Access Code: 940081. Participants may also register for the call online using the following link: . To access the live webcast and accompanying slide presentation, please visit the “Investors & Media” section of the Arcus Biosciences website at . A replay of the webcast will be available following the live event. About Arcus Biosciences Arcus Biosciences is a clinical-stage, global biopharmaceutical company developing differentiated molecules and combination medicines for patients with cancer. In partnership with industry collaborators, patients and physicians around the world, Arcus is expediting the development of first- or best-in-class medicines against well-characterized biological targets and pathways and studying novel, biology-driven combinations that have the potential to help people with cancer live longer. Founded in 2015, the company has expedited the development of multiple investigational medicines into clinical studies, including new combination approaches that target TIGIT, PD-1, HIF-2a, CD73, dual A2a/A2b receptor, CD39, and AXL. For more information about Arcus Biosciences’ clinical and preclinical programs, please visit . Contacts Investor Inquiries Pia Eaves VP of Investor Relations & Strategy (617) 459-2006 peaves@arcusbio.com Media Inquiries Holli Kolkey VP of Corporate Communications (650) 922-1269 hkolkey@arcusbio.com

iStock/ 111chemodan111 As companies roll out data showing the power and improved safety pro antibodies that target two antigens, analysts say the class could overtake monoclonal antibody Keytruda as the “immunotherapy backbone” of solid tumor treatment. With Merck’s mega-blockbuster monoclonal antibody Keytruda set to lose exclusivity in 2028, another class of immunotherapy is waiting in the wings to take center stage in cancer treatment: bispecific antibodies with two separate targets. “I think bispecifics are making a big comeback,” Mayank Mamtani, head of healthcare research at B.Riley Securities, told BioSpace prior to the 2024 European Society for Medical Oncology Congress, adding that the modality could supplant Keytruda as the “immunotherapy backbone of choice across many solid tumors.” Bispecifics have drawn immense interest since the discovery of monoclonal antibodies (mAbs) in 1975. Development turned out to be challenging , however, and the first bispecific antibody (bsAb)—catumaxomab—was pulled from the U.S. market four years after its approval in 2013 for commercial reasons. A recent paper published in mAbs suggested this may have been due to administration restrictions—catumaxomab could only be administered intraperitoneally due to severe infusion reactions—and high immunogenicity. Only two more bispecific antibodies were approved between 2009 to 2020, but the pace has since picked up significantly. The FDA has green-lit nine bispecifics for cancer over the past three years. With over 100 bispecifics in clinical development, several biopharma companies—including AstraZeneca, BioNTech and Summit Therapeutics—are hoping to jump on the comeback train. Why a Bispecific Is Better Than a Drug Combo Traditionally, combination drugs have meant giving “drug A” plus “drug B” to a patient at the same time. With a bispecific, A and B are part of the same molecule, offering benefits that stretch beyond manufacturing and patient convenience. It is proving safer and more powerful to pack them in together, said Ryan Schoenfeld, CEO of The Mark Foundation for Cancer Research. One key feature, Schoenfeld told BioSpace , is specificity. “The drug only works when it meets both its targets, so you can fine-tune the selectivity.” He estimated that around a third of cancer bispecifics are designed to bring immune cells into an environment they may otherwise not be trafficking. One side of the antibody anchors into the tumor while the other side attracts an immune cell to attack. This is particularly important in cold tumors, which are characterized by a lack of T cells and are often unresponsive to immunotherapy, Schoenfeld said. While it’s relatively easy with immune stimulators to “turn up” a patient’s immunity, “that will lead to terrible side effects that won’t be tolerated,” Schoenfeld said. “Bispecific antibodies offer a very elegant solution to combination therapy . . . You’re ramping up immunity in a very specific region.” In addition to the beneficial specificity, bispecifics also offer cooperative binding, John Heymach, chair of thoracic/head and neck oncology at MD Anderson Cancer Center, told BioSpace . The structure of these drugs promotes clustering, which leads to potent signaling for increased efficacy, he said. AstraZeneca has been advancing a number of bispecific antibodies to overcome the challenges associated with the co-administration of drugs, such as dose-limiting toxicities. The company has also seen an efficacy benefit from the bispecific therapeutic design. “The bispecifics’ nature allows for this cooperative, coordinated receptor binding,” Sunil Verma, SVP and global head of oncology, medical at AstraZeneca, told BioSpace . “As a result, we’re seeing greater T cell engagement and activation.” With a Wealth of Targets, Bispecifics Are Poised for Growth Bispecific antibodies currently in clinical trials for solid tumors have a wide variety of targets. AstraZeneca has two lead bispecific candidates, targeting PD-1 (Keytruda’s target) plus either CTLA-4 or TIGIT. Volrustomig is a PD-1/CTLA-4 bispecific the company is studying in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Verma explained that the antibody only binds to CTLA-4, a protein found on T cells, in the presence of PD-1 for a coordinated mechanism of action. In the past, magnitude of benefit was limited because CTLA-4 inhibitors were not as combinable with chemotherapy, he said. Recent data presented at the 2024 World Conference on Lung Cancer (WCLC) showed volrustomig plus chemo to be effective even in patients with PD-L-1 expression less than 1%, a population where traditionally, immune therapy has not been effective. Patients with non-squamous disease saw a response rate of 43%, while 50% of those with squamous disease achieved a response. Verma said this activity pro much better than what would be seen with chemo alone. A Phase III study is currently underway. AstraZeneca is also developing rilvegostomig, a PD-1/TIGIT bispecific, which elicited a durable response with favorable tolerability in patients with metastatic NSCLC in a Phase I/II trial . In the group of patients with a PD-L-1 tumor proportion score of 50% or higher, treatment at the 750 mg dose produced an overall response rate of 61.8%. A key factor for the value of bispecifics comes from their combinability with other cancer therapies, Verma said. To this end, AstraZeneca is also testing rilvegostomig in combination with its approved antibody-drug conjugate (ADC) Enhertu in a Phase III study as a first-line treatment for advanced or metastatic HER2-expressing biliary tract cancer. The two together could really pack a punch, Verma said, with the bispecific engaging and enhancing the immune response while the ADC attacks and kills the cancer cells. The company’s goal is to “beat out the current first generation of PD-1, PD-L-1 [therapies],” but also “improve outcomes for patients and establish [its bispecifics] as the new standard of care.” Meanwhile, Summit’s ivonescimab is targeting PD-1 and VEGF. At the WCLC, the biotech presented late-phase data showing that ivonescimab outperformed Keytruda as a first-line treatment option in patients with advanced NSCLC. In the Phase III HARMONi-2 trial, treatment with the candidate cut the risk of disease progression or death by nearly 50% compared to Keytruda. While promising, analysts noted that the trial was run entirely in China and said Summit would likely require U.S. data for an FDA approval. A follow-up Phase III in a more diverse population is already planned . BioNTech is also in the game, developing acasunlimab, an investigational bispecific targeting PD-L-1 and 4-1BB. The candidate uses Genmab’s proprietary DuoBody technology and BioNTech’s antibodies. 4-1BB has emerged as a crucial receptor on both cytotoxic and helper T cells, but clinical development has been historically hindered by toxic adverse events. Simultaneous binding to the secondary site—in acasunlimab’s case, PD-L-1—helps to overcome off-target effects as the drug only activates when present at both binding sites. Amgen and Johnson & Johnson also have a considerable footprint in this space, with both companies securing approvals this year. The global market for bispecific antibodies was $8.65 billion in 2023 and could balloon to around $485 billion in the next 10 years, according to Precedence Research . The market potential is huge, Verma said, as is the breadth of patients who could benefit. With the level of interest in this space, Schoenfeld said one thing is certain: “This therapeutic modality has definitely arrived.”