PD-1 x VEGF-A

FDA Grants Fast Track Designation for Ivonescimab in 2L+ EGFRm NSCLC HARMONi Completed Enrollment for Summit’s First Sponsored Study Evaluating Ivonescimab Topline data from the HARMONi Trial Is Expected in Mid-2025 MIAMI--(BUSINESS WIRE)-- $SMMT --Summit Therapeutics Inc. (NASDAQ: SMMT) (“Summit,” “we,” or the “Company”) today announced that we have completed enrollment in our HARMONi clinical trial, a multi-regional Phase III study sponsored by Summit evaluating ivonescimab plus platinum-doublet chemotherapy vs. placebo plus platinum-doublet chemotherapy with epidermal growth factor receptor (EGFR)-mutated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have progressed after treatment with a 3 rd generation EGFR tyrosine kinase inhibitor (TKI). HARMONi completed enrolling patients from sites in North America, Europe, and China. This is a clinical setting with a patient population where PD-1 monoclonal antibodies have previously been unsuccessful in Phase III global clinical trials. “I would like to sincerely thank the investigators, site coordinators, Team Summit, and, most importantly, the patients around the world who are participating in the HARMONi study,” said Dr. Maky Zanganeh, Chief Executive Officer and President of Summit. “Completing enrollment in the first global study for ivonescimab is a credit to the growing belief in the potential for ivonescimab to make a significant difference in the lives of patients around the world.” In addition, the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the proposed use of ivonescimab in combination with platinum-based chemotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR mutation, who have experienced disease progression following EGFR-TKI therapy. The FDA’s Fast Track designation is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. According to the FDA, the purpose is to get important new drugs to patients earlier. A drug that receives Fast Track designation is eligible for some of the following: more frequent meetings with the FDA to discuss the drug’s development plan, more frequent written communication from the FDA, and a rolling review process, allowing the sponsor to submit completed sections of its Biologic License Application (BLA) for review rather than every section at once, though the review by FDA typically begins when the entire application has been submitted. Per the FDA, once a drug receives Fast Track designation, early and frequent communication with the FDA is encouraged throughout the entire drug development and review process; the frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients. “Completing enrollment in the HARMONi study represents another step towards our goal of bringing to patients a drug that is intended to improve the quality and potential duration of life for those facing serious unmet medical needs,” stated Robert W. Duggan, Chairman & Chief Executive Officer of Summit. “As our belief in the potential for ivonescimab to make a meaningful, positive difference continues to grow, we are pleased that the FDA has granted Fast Track designation for ivonescimab.” As a reminder, the HARMONi analysis will include all patients from the HARMONi-A trial who previously received a 3 rd generation TKI. HARMONi-A was a single-region, multi-center Phase III clinical trial evaluating ivonescimab plus platinum-doublet chemotherapy vs. placebo plus platinum-doublet chemotherapy with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with an EGFR TKI. HARMONi-A was sponsored by our collaboration partner, Akeso, Inc. (Akeso, HKEX Code: 9926.HK), with data generated and analyzed by Akeso. On May 24, 2024, our partner, Akeso, received marketing authorization in China from the National Medical Products Administration (NMPA) based on the positive dataset associated with HARMONi-A. HARMONi-A was designed with a primary endpoint of progression-free survival. HARMONi is designed with dual primary endpoints of progression-free survival and overall survival. About Ivonescimab Ivonescimab, known as SMT112 in Summit’s license territories, the United States, Canada, Europe, Japan, Latin America, including Mexico and all countries in Central America, South America, and the Caribbean, the Middle East, and Africa, and as AK112 in China and Australia, is a novel, potential first-in-class investigational bispecific antibody combining the effects of immunotherapy via a blockade of PD-1 with the anti-angiogenesis effects associated with blocking VEGF into a single molecule. Ivonescimab displays unique cooperative binding to each of its intended targets with multifold higher affinity when in the presence of both PD-1 and VEGF. This could differentiate ivonescimab as there is potentially higher expression (presence) of both PD-1 and VEGF in tumor tissue and the tumor microenvironment (TME) as compared to normal tissue in the body. Ivonescimab’s tetravalent structure (four binding sites) enables higher avidity (accumulated strength of multiple binding interactions) in the TME with over 18-fold increased binding affinity to PD-1 in the presence of VEGF in vitro , and over 4-times increased binding affinity to VEGF in the presence of PD-1 in vitro (Zhong, et al , SITC, 2023). This tetravalent structure, the intentional novel design of the molecule, and bringing these two targets into a single bispecific antibody with cooperative binding qualities have the potential to direct ivonescimab to the tumor tissue versus healthy tissue. The intent of this design, together with a half-life of 6 to 7 days (Zhong, et al , SITC, 2023), is to improve upon previously established efficacy thresholds, in addition to side effects and safety profiles associated with these targets. Ivonescimab was engineered by Akeso Inc. (HKEX Code: 9926.HK) and is currently engaged in multiple Phase III clinical trials. Over 1,800 patients have been treated with ivonescimab in clinical studies globally. Summit has begun its clinical development of ivonescimab in non-small cell lung cancer (NSCLC), commencing enrollment in 2023 in two multi-regional Phase III clinical trials, HARMONi and HARMONi-3, with a plan to initiate HARMONi-7 in early 2025. HARMONi is a Phase III clinical trial which intends to evaluate ivonescimab combined with chemotherapy compared to placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with a 3 rd generation EGFR TKI (e.g., osimertinib). HARMONi-3 is a Phase III clinical trial which is designed to evaluate ivonescimab combined with chemotherapy compared to pembrolizumab combined with chemotherapy in patients with first-line metastatic squamous NSCLC. HARMONi-7 is a planned Phase III clinical trial which is intended to evaluate ivonescimab monotherapy compared to pembrolizumab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 TPS > 50%). In addition, Akeso has recently had positive read-outs in two single-region (China), randomized Phase III clinical trials for ivonescimab in NSCLC, HARMONi-A and HARMONi-2. HARMONi-A was a Phase III clinical trial which evaluated ivonescimab combined with chemotherapy compared to placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with an EGFR TKI. HARMONi-2 is a Phase III clinical trial evaluating monotherapy ivonescimab against monotherapy pembrolizumab in patients with locally advanced or metastatic NSCLC whose tumors have positive PD-L1 expression (PD-L1 TPS > 1%). Ivonescimab is an investigational therapy that is not approved by any regulatory authority in Summit’s license territories, including the United States and Europe. Ivonescimab was approved for marketing authorization in China in May 2024. Ivonescimab was granted Fast Track designation by the US Food & Drug Administration (FDA) for the HARMONi clinical trial setting. About Summit Therapeutics Summit Therapeutics Inc. is a biopharmaceutical oncology company focused on the discovery, development, and commercialization of patient-, physician-, caregiver- and societal-friendly medicinal therapies intended to improve quality of life, increase potential duration of life, and resolve serious unmet medical needs. Summit was founded in 2003 and our shares are listed on the Nasdaq Global Market (symbol “SMMT”). We are headquartered in Miami, Florida, and we have additional offices in Menlo Park, California, and Oxford, UK. For more information, please visit and follow us on X @SMMT_TX . Summit Forward-looking Statements Any statements in this press release about the Company’s future expectations, plans and prospects, including but not limited to, statements about the clinical and preclinical development of the Company’s product candidates, entry into and actions related to the Company’s partnership with Akeso Inc., the intended use of the net proceeds from the private placements, the Company’s anticipated spending and cash runway, the therapeutic potential of the Company’s product candidates, the potential commercialization of the Company’s product candidates, the timing of initiation, completion and availability of data from clinical trials, the potential submission of applications for marketing approvals, potential acquisitions, statements about the previously disclosed At-The-Market equity offering program (“ATM Program”), the expected proceeds and uses thereof, and other statements containing the words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “would,” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including the Company’s ability to sell shares of our common stock under the ATM Program, the conditions affecting the capital markets, general economic, industry, or political conditions, including the results of our evaluation of the underlying data in connection with the development and commercialization activities for ivonescimab, the outcome of discussions with regulatory authorities, including the Food and Drug Administration, the uncertainties inherent in the initiation of future clinical trials, availability and timing of data from ongoing and future clinical trials, the results of such trials, and their success, and global public health crises, that may affect timing and status of our clinical trials and operations, whether preliminary results from a clinical trial will be predictive of the final results of that trial or whether results of early clinical trials or preclinical studies will be indicative of the results of later clinical trials, whether business development opportunities to expand the Company’s pipeline of drug candidates, including without limitation, through potential acquisitions of, and/or collaborations with, other entities occur, expectations for regulatory approvals, laws and regulations affecting government contracts and funding awards, availability of funding sufficient for the Company’s foreseeable and unforeseeable operating expenses and capital expenditure requirements and other factors discussed in the “Risk Factors” section of filings that the Company makes with the Securities and Exchange Commission. Any change to our ongoing trials could cause delays, affect our future expenses, and add uncertainty to our commercialization efforts, as well as to affect the likelihood of the successful completion of clinical development of ivonescimab. Accordingly, readers should not place undue reliance on forward-looking statements or information. In addition, any forward-looking statements included in this press release represent the Company’s views only as of the date of this release and should not be relied upon as representing the Company’s views as of any subsequent date. The Company specifically disclaims any obligation to update any forward-looking statements included in this press release. Appendix: Glossary of Critical Terms Contained Herein Affinity – Affinity is the strength of binding of a molecule, such as a protein or antibody, to another molecule, such as a ligand. Avidity – Avidity is the accumulated strength of multiple binding interactions. Angiogenesis – Angiogenesis is the development, formation, and maintenance of blood vessel structures. Without sufficient blood flow, tissue may experience hypoxia (insufficient oxygen) or lack of nutrition, which may cause cell death. 1 Cooperative binding – Cooperative binding occurs when the number of binding sites on the molecule that can be occupied by a specific ligand (e.g., protein) is impacted by the ligand’s concentration. For example, this can be due to an affinity for the ligand that depends on the amount of ligand bound or the binding strength of the molecule to one ligand based on the concentration of another ligand, increasing the chance of another ligand binding to the compound. 2 Immunotherapy – Immunotherapy is a type of treatment, including cancer treatments, that help a person’s immune system fight cancer. Examples include anti-PD-1 therapies. 3 Intracranial - Within the cranium or skull. PD-1 – Programmed cell Death protein 1 is a protein on the surface of T cells and other cells. PD-1 plays a key role in reducing the regulation of ineffective or harmful immune responses and maintaining immune tolerance. However, with respect to cancer tumor cells, PD-1 can act as a stopping mechanism (a brake or checkpoint) by binding to PD-L1 ligands that exist on tumor cells and preventing the T cells from targeting cancerous tumor cells. 4 PD-L1 – Programmed cell Death Ligand 1 is expressed by cancerous tumor cells as an adaptive immune mechanism to escape anti-tumor responses, thus believed to suppress the immune system’s response to the presence of cancer cells. 5 PD-L1 TPS – PD-L1 Tumor Proportion Score represents the percentage of tumor cells that express PD-L1 proteins. PFS – Progression-Free Survival. RANO – R esponse A ssessment in N euro- O ncology, the standard for assessing the response of a brain or spinal cord tumor to therapy. SQ-NSCLC – Non-small cell lung cancer tumors of squamous histology. T Cells – T cells are a type of white blood cell that is a component of the immune system that, in general, fights against infection and harmful cells like tumor cells. 6 Tetravalent – A tetravalent molecule has four binding sites or regions. Tumor Microenvironment – The tumor microenvironment is the ecosystem that surrounds a tumor inside the body. It includes immune cells, the extracellular matrix, blood vessels and other cells, like fibroblasts. A tumor and its microenvironment constantly interact and influence each other, either positively or negatively. 7 VEGF – Vascular Endothelial Growth Factor is a signaling protein that promotes angiogenesis. 8 Summit Therapeutics and the Summit Therapeutics logo are trademarks of Summit Therapeutics Inc. Copyright 2024, Summit Therapeutics Inc. All Rights Reserved. __________________ 1 Shibuya M. Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer. 2011 Dec;2(12):1097-105 2 Stefan MI, Le Novère N. Cooperative binding. PLoS Comput Biol. 2013;9(6) 3 US National Cancer Institute, a part of the National Institute of Health (NIH). . Accessed April 2024. 4 Han Y, et al. PD-1/PD-L1 Pathway: Current Researches in Cancer. Am J Cancer Res. 2020 Mar 1;10(3):727-742. 5 Han Y, et al. PD-1/PD-L1 Pathway: Current Researches in Cancer. Am J Cancer Res. 2020 Mar 1;10(3):727-742. 6 Cleveland Clinic. . Accessed April 2024. 7 MD Anderson Cancer Center. . Accessed April 2024. 8 Shibuya M. Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer. 2011 Dec;2(12):1097-105. Contacts Contact Summit Investor Relations: Dave Gancarz Chief Business & Strategy Officer Nathan LiaBraaten Senior Director, Investor Relations investors@smmttx.com

iStock, Naeblys Summit Therapeutics’ ivonescimab has the potential to challenge Merck’s blockbuster checkpoint inhibitor in non-small cell lung cancer, but experts stress the need for diverse and overall survival data. Summit Therapeutics wowed attendees at the World Conference on Lung Cancer with late-stage data for its in-licensed bispecific ivonescimab, declaring victory over Merck’s blockbuster Keytruda, which has historically led the non-small cell lung cancer treatment space. Since Summit’s Sept. 9 presentation , eager investors have sent Summit’s stock skyrocketing as much as 140%. Still, some analysts urged caution, as the data was from a trial run only in China. “Results may or may not be generalizable beyond the China-focused patient population initially assessed,” BMO Capital Markets analyst Evan Seigerman wrote in a note to investors, adding that FDA consideration will likely require U.S. data. Summit has already announced it will take its bispecific into a multi-regional study of non-small cell lung cancer (NSCLC) in early 2025. And at the 2024 European Society for Medical Oncology (ESMO) annual meeting this week, Summit reported that ivonescimab also showed promising anti-tumor activity in small trials for colorectal cancer, triple negative breast cancer and head and neck squamous cell carcinoma—all indications where Keytruda is also approved. Ryan Schoenfeld, CEO of The Mark Foundation for Cancer Research, said it’s not too early to get excited about the NSCLC data. Despite checkpoint inhibitors shifting the curve for lung cancer patients, there are still patients with a lot of unmet need, so “this is a really big deal,” he told BioSpace . It’s reasonable to think that ivonescimab might be competitive with Keytruda plus chemo, Schoenfeld added, potentially sparing patients from chemotherapy treatments, which come with a host of side effects including fatigue, nausea and low blood cell counts. John Heymach, head of the Heymach Laboratory at MD Anderson Cancer Center, which specializes in NSCLC research, agreed. “By any measure, the data is impressive,” he told BioSpace . Still to Prove: Overall Survival Heymach noted that Summit’s HARMONi-2 trial is one of the few instances of a candidate successfully taking on Keytruda head-to-head in a population where the latter is approved. He said that he and other investigators had previously believed Summit to be overly optimistic in in how it powered its HARMONi-2 trial , but that the latest results have largely put those concerns to bed. The trial was run by Summit’s development partner Akeso and pitted ivonescimab, a bispecific antibody combining the powers of anti-PD-1 and anti-VEGF, against Keytruda, itself an anti-PD-1 checkpoint inhibitor, as a first-line treatment for patients withadvanced NSCLC. Median progression free survival after nine months of follow-up was 11.14 months in the treatment arm vs. 5.82 months in the Keytruda group. Summit’s bispecific cut the risk of disease progression or death by nearly 50% compared to Keytruda. HARMONi-2 included a variety of patient subgroups, including high and low PD-L1, and squamous and non-squamous cancer. Ivonescimab was effective across all groups, with no obvious outlier driving results, Heymach said. An earlier study echoed this efficacy in a different setting of NSCLC patients with EGFR mutations on platinum chemotherapy. HARMONi-A compared patients receiving chemo alone to patients on chemo plus ivonescimab, with the latter showing significantly improved progression-free survival (PFS). Heymach noted that this is a subgroup in which Keytruda had been tested and did not show benefit. “That’s two consecutive, randomized Phase III [trials] where [ivonescimab] overperformed compared to expectations,” he told BioSpace . After a string of attempted checkpoint combo attempts were “horribly unsuccessful,” Christiana Bardon, co-managing partner at MPM BioImpact, said, “this is really the first data of something that’s worked beyond that first crop. And it’s pretty shocking that it works.” While Bardon called Summit’s data “definitive,” she said they are lacking the holy grail of trial results—overall survival (OS). Summit stated in its press release that OS data was not yet mature and would be evaluated in the future. Heymach said that although improvements to PFS have sometimes not translated into OS improvement, given the magnitude of PFS benefit, it would be surprising if it was not reflected in this outcome measure. Summit will also likely need to demonstrate an improvement on the therapeutic index, which could be achieved from combining an anti-VEGF with an anti-PD-1 as separate agents for treatment, Schoenfeld said. According to Summit, ivonescimab does more than just combine two treatments into one. The bispecific antibody has a unique cooperative binding that results in a higher affinity in the presence of both PD-1 and VEGF. Diverse Data Needed With the current results coming from China-only trials, all three experts who spoke with BioSpace agree that the FDA will need to see more data from a diverse population in order to consider approval. The use of China-only data can be skewed by factors such as variation in genetics, less patient follow up and cultural differences in reporting side effects. Bardon emphasized that safety/side effects in particular could be a concern for the FDA when reviewing China-only data. For example, in HARMONI-2, there were very few grade 3 adverse events. “[Adverse events] are probably underestimated compared to what we would see in a Western-based population,” Bardon said. If the data indeed hold up in a broader population, Summit could tap into a portion of Keytruda’s $25 billion in overall annual sales. While Akeso has already garnered approval for ivonescimab in China where it holds the rights, Summit’s license extends to the U.S., Canada, Europe, Japan, Central, South America and a handful of other markets. Of course, Summit is not the only bispecific developer to announce impressive results of late. On Saturday, BioNTech reported at ESMO 2024 that its own bispecific targeting both PD-L1 and VEGF-A, BNT327, elicited a 57.8% confirmed objective response in a Phase II trial of 64 Chinese patients with EGFR-mutant NSCLC, according to Endpoints News . Meanwhile, Instil Bio, and its China-based partner ImmuneOnco Biopharmaceuticals, are gearing up to begin a Phase II trial of their own bispecific antibody SYN-2510/IMM2510 in NSCLC and triple-negative breast cancer. “This [bispecific] therapeutic modality has definitely arrived,” Schoenfeld said.

BARCELONA — Last week, Summit and Akeso set the industry abuzz after their bispecific antibody beat Merck’s Keytruda in a Phase 3 lung cancer trial. Now, BioNTech is touting mid-stage data for its own lung cancer asset with a similar mechanism. The German drugmaker on Saturday presented data for the PD-L1xVEGF bispecific that it licensed from Biotheus at Europe’s biggest cancer conference in Barcelona. BioNTech said BNT327 achieved a 57.8% confirmed objective response rate in a single-arm Phase 2 trial of 64 patients with EGFR-mutant non-small cell lung cancer (NSCLC) in China who were first given standard treatment. In 13 patients with high PD-L1 expression, the confirmed ORR stood higher, at 92.3%. For BioNTech, it’s good news on two fronts. The company’s $BNTX share price gained about 37% in the week after Summit announced the full data for its PD-1/VEGF bispecific ivonescimab. And the data from the Biotheus-sponsored trial presented at ESMO warrant further study of BNT327, the drugmaker said, although details about what’s next have yet to be confirmed. Both readouts are fueling newly high expectations for this approach, which wasn’t widely hyped prior to Summit’s readout. Bigger drugmakers are still observing from the sidelines, while a smaller biotech company is touting its own development plans amid rocketing interest in its stock. According to TD Cowen analysts on Monday, BNT327 showed “solid efficacy on par” with Summit’s PD-1xVEGF bispecific, ivonescimab, and fewer anti-VEGF-related toxicities compared with bevacizumab, an anti-VEGF antibody. After BioNTech’s presentation, Adrianus Johannes de Langen, a pulmonary medicine doctor at Amsterdam University Medical Center who was not involved with the study, told delegates that the ORR is “impressive” but said it remains to be seen how those results could translate to key survival outcomes. He also said it’s unclear which patients could benefit from adding a PD-L1xVEGF bispecific antibody to chemo in the second line given a recent first-line approval for lung cancer. The FDA last month approved Johnson & Johnson’s EGFRxMET bispecific Rybrevant combined with EGFR tyrosine kinase inhibitor Lazcluze for certain patients with first-line EGFR-mutated NSCLC. But the combo comes with a lot of toxicities, meaning there’s room for the bispecific approach, Dana Farber Cancer Institute oncologist Pasi Jänne told Endpoints News . Meanwhile, a third bispecific maker called Instil Bio $TIL saw its stock jump a whopping 493% in the week after Summit’s data readout. On Monday, Instil spelled out its own plans for a PD-L1xVEGF bispecific antibody that it licensed from Shanghai-based ImmuneOnco. The biotech expects to file an application in the US later this year to start mid-stage studies of IMM2510 as a monotherapy in second-line NSCLC. If these studies are successful, the partners may start global Phase 3 studies in first-line non-small cell lung cancer, where they could potentially also go head-to-head with Keytruda, and/or in triple-negative breast cancer, according to the company release , which did not provide timelines. The flurry of data comes around a week after Summit said ivonescimab cut the risk of progression or death by up to 49% in certain lung cancer patients in China versus Keytruda. If the results can be replicated in a study with US patients and then approved, ivonescimab could be used in the first-line NSCLC setting in place of Keytruda, the world’s top-selling cancer drug. Going head-to-head against Keytruda was “a bold move, and it’s paid off for Summit,” Jänne said. Merck, Keytruda’s maker, this week pointed to safety concerns with Summit’s drug. The results are “really exciting” but VEGF inhibitors are known to come with a lot of safety issues, Merck Chief Medical Officer Eliav Barr said in an interview . The goal is to “create a molecule that provides the VEGF effect but doesn’t end up with toxicity that causes more harm than good,” he added. In Summit’s Phase 3 trial, around 29% of patients treated with ivonescimab had grade 3 or higher adverse events versus around 16% in the Keytruda arm. In BioNTech’s Phase 2 study, 31% of patients had adverse events that disrupted the dosing of BNT327. However, Jänne said that the side effects of this drug class weren’t “off the charts” and seemed to be manageable. Summit’s market value more than doubled to $23.5 billion in the span of about a week, though the company had a tiny, austere booth at the medical meeting. It’s unclear whether these efficacy results can be replicated in larger, global studies, and other companies are paying close attention to what happens next with bispecific VEGFs. Izzy Lowy, Regeneron’s SVP of translational and clinical sciences in oncology, told Endpoints at ESMO that he found the ivonescimab data “provocative.” When asked whether such an approach would be something Regeneron would consider, Lowy said, “These are more complicated, multi-specific antibodies. If it really makes sense to do that, then I imagine that we will engage.” When asked, AstraZeneca head of oncology R&D Susan Galbraith didn’t say whether the company was looking to pursue this particular approach. She did say, however, that AstraZeneca is developing several PD-1 bispecifics, including rilvegostomig, which also targets TIGIT, and volrustomig, which also targets CTLA4. The company is studying these candidates as monotherapies and in combination with its anti-VEGF bevacizumab as part of the GEMINI clinical trial program in various cancers. Combining separate VEGF and PD-L1 agents has led to mixed results in the past, Jänne said. The combo of bevacizumab, Roche’s PD-L1 Tecentriq and chemo is approved in the US for metastatic non-squamous NSCLC, However, Phase 3 trials in Japan and China in certain lung cancer patients failed. There may be an advantage to having a two-pronged “all-in-one molecule” compared with two separate drugs “where you don’t know that both of them will make it in the same way to where you want them to act,” Jänne said. In general, the science behind bispecifics targeting both VEGF and PD-1 or PD-L1 is murky and more data are needed on how they work, he added. “When we’ve thought about bispecifics, we’ve generally thought about them as bridging cells of interest,” Regeneron’s Lowy said. “Targeting different molecules on the same cell — we thought was a little complicated because you don’t know what the optimum engagement affinity for one target is versus another.” “But at the end of the day, if it works, it works,” he said.