Durvalumab

iStock, Noppharat05081977 The explosion of GLP-1 weight loss drugs is reminiscent of the early days of PD-1 inhibitors, but key market differences suggest history may not repeat itself. If you’ve been around drug development for a while, the rise of GLP-1 therapies might sound familiar to you: a breakthrough emerges after years of hard work in the clinic. A leader captures the market. Billions are made. Copycats follow, hoping for a slice of the pie. It’s the story of PD-1 inhibitors and the immunotherapy boom that redefined how we treat cancer a decade ago. Many industry insiders often call back to this cancer revolution when talking about the meteoric rise of GLP-1s. But within the storied history of PD-1s lies a flashing warning sign for the “fast-follower” approach, experts say. That’s because the harsh reality that was laid bare with PD-1 inhibitors is that many of the companies gambling on being the second or third drug in an indication will not be successful. Despite oncology being the dominant market for R&D over the last decade, “there are a large number of biotech companies, as well as Big Pharma companies, rushing to enter the GLP-1 space at a rate not seen before, even with PD-1s,” Akash Patel, a pharma analyst at GlobalData, told BioSpace . “The race out of the gate to achieve a highly efficacious GLP-1 therapy has been huge.” Winners and Losers in the PD-1 Space Keytruda was the first approved PD-1 therapy, entering the market in September 2014, but the jockeying for supremacy in the space began well before that drug was ever approved. Merck’s immuno-oncology juggernaut was not always the dominant cancer therapeutic. While Bristol Myers Squibb’s PD-1 therapy Opdivo was approved second in December 2014, it quickly established a sales lead. By the end of 2015, Opdivo had generated $942 million in full year sales against Keytruda’s $566 million. “Initially, Bristol Myers Squibb was dominating that race—they had broader approvals and bigger indications,” Matt Phipps, a partner at William Blair, told BioSpace . “And then Merck completely took over based on better trial design and approvals in lung cancer.” Fast forward to 2024, full-year results show the gulf that now exists between the two treatments, with Keytruda generating global sales of $29.4 billion—by far the best-selling drug of the year —while Opdivo brought in just $9.3 billion worldwide. That was, however, still enough to make the number nine slot on the list of the top-10 best selling drugs of 2024 , and is still a healthy earner for BMS. Opdivo’s sales fell away from Keytruda around 2018 and have never made up the gap; sales produced by both treatments show the scale of the market and the opportunity for competitors to carve out a smaller, but substantial, slice. There are other examples of drugs that were developed later but ultimately became more successful, Phipps noted, such as with statins and TNF-alpha inhibitors. This history suggests that subsequent weight loss drug developers could catch up to Eli Lilly and Novo Nordisk, the current market leaders . Beyond the big two PD-1 therapies, there was still space for two other major entrants to carve out a market share, in Roche’s Tecentriq and AstraZeneca’s Imfinzi, both of which inhibit PD-1’s molecular partner, PD-L1, Phipps said. Of the treatments that arrived later to market, the strategy has been to go after smaller indications that were not already targeted by BMS or Merck. Roche’s PD-1 Tecentriq, for example, achieved sales of $4.1 billion worldwide in 2024, becoming the Swiss pharma’s leading oncology seller. AstraZeneca’s PD-1 Imfinzi brought in $4.7 billion the same year, the third-largest drug overall for the U.K. company. Even against such heavyweights, smaller companies are still pushing forward with PD-1s. Incyte Biosciences received approval for its PD-1 inhibitor, Zynyz, in 2023 . The drug brought in sales of $3 million for the full year 2024. When asked about the possibility to differentiate in a competitive space, an Incyte spokesperson told BioSpace the company sees an opportunity to “meet the needs of different patient populations.” Incyte is aiming to make Zynyz the first PD-1–targeting drug to achieve approval against squamous cell anal carcinoma with the POD1UM-303/InterAACT2 trial currently in Phase III. But those are just the successful examples. The clinical record is also littered with failed followers. The PD-1 market witnessed a surge of R&D, but both Big Pharmas and small-scale biotechs struggled to translate this into successful treatments. Pfizer developed Bavencio with Merck KGaA,which was fourth-to-market but struggled to achieve significant sales, leading Pfizer to return the drug’s rights to its partner in 2023. The treatment is still marketed by Merck KGaA but managed only $735 million in full-year 2024 results. The same occurred with Novartis’ PD-1 treatment Tevimbra, developed alongside BeiGene, with the partnership on the drug cancelled in 2023. The treatment is still on the market but had just $621 million in full-year 2024 sales. The relative failure of these treatments shows that even the financial firepower of Big Pharma is not always enough to successfully break into the market as a fast follower. For small-cap companies, Phipps said that many tried to develop combination therapies to improve efficacy over monotherapies and retain ownership of their assets. However, this approach “didn’t really pan out to be as good as they hoped,” due to the failures to show improved efficacy. This resulted in various unsuccessful partnerships, such as Nektar Therapeutics and BMS’ investigational combination therapy . A similar story unfolded with Innate Pharma and AstraZeneca’s Phase III trial of monalizumab. One certainty for those investing in weight loss drugs is that, like PD-1s, there will be failures. Phipps thinks the fallout could be even more severe given the major differences between the two markets. Different Markets, Different Challenges Demand for PD-1 therapies was based on their potential to dramatically improve the survival chances of those with cancer. This was largely driven by physician prescribers. The GLP-1 market, on the other hand, is consumer-led. GLP-1 weight loss treatments have broken out of the traditional medical field and become instilled into the public consciousness, and even pop culture. The lower perceived medical necessity also means there are ongoing discussions between drug developers and payers over discounts to pricing and rebates in weight loss, which will impact revenue for any would-be entrants onto the market. The dynamic in the oncology market is different for PD-1s, with drug developers competing on efficacy and expanding on approved indications rather than on pricing . Another major drawback that Phipps identified is “patient churn,” where within one year most patients will stop taking GLP-1 treatments, with these figures declining even further at the two-year mark. By comparison, PD-1 drugs were initially approved when there were no other treatment options, which meant patients would complete treatment courses because there were no alternative pathways for recovery from cancer. The urgency of treating cancer, for both patients and physicians, therefore does not allow for direct parallels to be drawn between sales growth for PD-1s and GLP-1s. This differing market dynamic led Phipps to caution that some estimates suggesting the weight loss drug market will continue to expand at current rates are likely flawed. Analysts have put potential sales as high as $150 billion by the early 2030s, but Phipps does not think the market will reach that because drug developers have not yet solved the problem of how to keep people on the therapies. Without patient retention, revenues for any potential treatment developed could be limited, with Phipps noting that both Novo Nordisk and Eli Lilly delivered 2025 guidance that was “a little below analysts’ expectations,” though he added that this could also be due to manufacturing issues. One area that could unfold similarly in the journeys of PD-1s and GLP-1s is the gathering of indications. Expanding a drug’s label can help extend its patent exclusivity period and boost revenue. Since Keytruda’s 2014 approval, Merck has gone to work collecting indications to add to its roster. The drug is now approved to treat nearly 50 different types and stages of cancer, from lung to melanoma, breast to non-Hodgkin lymphoma. The drug has also been granted biomarker-based approvals allowing its use with certain genetic mutations regardless of tumor type. Oncology offersa far broader range of potential indications for drug developers than those available to GLP-1 drug developers. But obesity companies could still follow this playbook, Patel said. Indeed, Novo and Lilly are pursuing a similar strategy for their weight loss drugs. Novo’s Wegovy has received a label expansion for reducing cardiovascular risk . Lilly, meanwhile, added an FDA nod for the treatment of obstructive sleep apnea . The companies are also pursuing metabolic dysfunction-associated steatohepatitis (MASH), kidney disease , Alzheimer’s and alcohol use disorder , among other indications. For investors seeking a potential blockbuster weight loss drug that could emerge from a heaping pile of options, Phipps said there are three important considerations: improving efficacy, improving tolerability and being a small molecule formulation. Each could potentially offer advantages over current treatments, with greater weight loss potentially attracting more patient interest, improved tolerability allowing people to take the treatment for longer and small molecules offering significant manufacturing and dosing advantages, such as the ability to be taken orally. This is different from the early stages of the PD-1 market, Phipps noted, where the focus was on quickly developing a “me-too” treatment. As a result, he said, investing in the obesity space is “less enticing” because of the complexity of developing a differentiated product. What is not yet clear is which approach investors will favor, with Phipps describing the market as being in the “early innings” of discovering how to best serve patients.

Approval based on ADRIATIC Phase III trial results which showed a 27% reduction in the risk of death versus placebo LONDON, UK I March 17, 2025 I AstraZeneca’s Imfinzi (durvalumab) has been approved in the European Union (EU) as monotherapy for the treatment of adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following platinum-based chemoradiation therapy (CRT). The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on results from the ADRIATIC Phase III trial, which were published in The New England Journal of Medicine . SCLC is a highly aggressive form of lung cancer, with an estimated 8,000 people treated for LS-SCLC across the five major European countries each year. 1-2 LS-SCLC typically recurs and progresses rapidly, despite initial response to standard-of-care chemotherapy and radiotherapy. 3-4 The prognosis for LS-SCLC is particularly poor, as only 15-30% of patients survive for five years after diagnosis. 5 Suresh Senan, PhD, radiation oncologist at the Amsterdam University Medical Centers, The Netherlands, and principal investigator in the trial, said: “This approval marks a turning point for patients with limited-stage small cell lung cancer in Europe, bringing them an immunotherapy option for the first time. An unprecedented 57% of patients treated with durvalumab were still alive at three years in the ADRIATIC trial. This significant advance establishes a new benchmark in a setting where the standard of care has remained unchanged for decades.” Dave Fredrickson, Executive Vice President, Oncology Haematology Business Unit, AstraZeneca, said: “Imfinzi has the potential to transform how limited-stage small cell lung cancer is treated as the first immunotherapy approved in Europe in this setting. As the only immunotherapy approved for both early and late-stage disease, Imfinzi is poised to become the foundation for transforming outcomes for people with small cell lung cancer.” In the trial, results showed Imfinzi reduced the risk of death by 27% versus placebo (based on an overall survival [OS] hazard ratio [HR] of 0.73; 95% confidence interval [CI] 0.57-0.93; p=0.0104). Estimated median OS was 55.9 months for Imfinzi versus 33.4 months for placebo. An estimated 57% of patients treated with Imfinzi were alive at three years compared to 48% for placebo. Imfinzi also reduced the risk of disease progression or death by 24% (based on a progression-free survival [PFS] HR of 0.76; 95% CI 0.61-0.95; p=0.0161) versus placebo. Median PFS was 16.6 months for Imfinzi versus 9.2 months for placebo. An estimated 46% of patients treated with Imfinzi had not experienced disease progression at two years compared to 34% for placebo. The safety profile for Imfinzi was generally manageable and consistent with the known profile of this medicine. No new safety signals were observed. Imfinzi is approved in the US and several other countries in this setting based on the ADRIATIC results. Regulatory applications are currently under review in Japan and several other countries for this indication. Imfinzi is also approved in combination with chemotherapy for the treatment of extensive-stage SCLC based on the CASPIAN Phase III trial. Notes Small cell lung cancer Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths. 6-7 Lung cancer is broadly split into non-small cell lung cancer (NSCLC) and SCLC, with about 15% of cases classified as SCLC. 8 LS-SCLC (Stage I-III) accounts for approximately 30% of SCLC diagnoses and is classified when the disease is generally only in one lung or one side of the chest. 9 The prognosis for patients with LS-SCLC remains poor despite curative-intent treatment with standard-of-care concurrent CRT (cCRT). 10 ADRIATIC The ADRIATIC trial is a randomised, double-blind, placebo-controlled, multi-centre global Phase III trial evaluating Imfinzi monotherapy and Imfinzi plus Imjudo (tremelimumab) versus placebo in the treatment of 730 patients with LS-SCLC who had not progressed following cCRT. In the experimental arms, patients were randomised to receive a 1500mg fixed dose of Imfinzi with or without Imjudo 75mg every four weeks for up to four doses/cycles each, followed by Imfinzi every four weeks for up to 24 months. The dual primary endpoints were PFS and OS for Imfinzi monotherapy versus placebo. Key secondary endpoints included OS and PFS for Imfinzi plus Imjudo versus placebo, safety and quality of life measures. The trial included 164 centres in 19 countries across North and South America, Europe and Asia. Imfinzi 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 tumour’s immune-evading tactics and releasing the inhibition of immune response s. In addition to its indications in SCLC, Imfinzi is also the global standard of care based on OS in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after CRT. Additionally, Imfinzi is approved as a perioperative treatment in combination with neoadjuvant chemotherapy in resectable NSCLC; and in combination with a short course of Imjudo and chemotherapy for the treatment of metastatic NSCLC. Imfinzi is also approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma (HCC). Imfinzi is also approved as a monotherapy in unresectable HCC in Japan and the EU. In March 2025, perioperative Imfinzi added to standard-of-care chemotherapy met the primary endpoint of event-free survival in the MATTERHORN Phase III trial in resectable gastric and gastroesophageal junction cancers. Imfinzi in combination with chemotherapy followed by Imfinzi monotherapy is approved as a 1 st -line treatment for primary advanced or recurrent endometrial cancer (mismatch repair deficient disease only in US and EU). Imfinzi in combination with chemotherapy followed by Lynparza (olaparib) and Imfinzi is approved for patients with mismatch repair proficient advanced or recurrent endometrial cancer in EU and Japan. Since the first approval in May 2017, more than 374,000 patients have been treated with Imfinzi . As part of a broad development programme, 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 and gynaecologic cancers, and other solid tumours. AstraZeneca in lung cancer AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most. The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi and Imjudo ; Enhertu (trastuzumab deruxtecan) and Datroway (datopotamab deruxtecan) in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action. AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment. 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-tumour immune response and stimulate the body’s immune system to attack tumours. AstraZeneca strives to redefine cancer care and help transform outcomes for patients with Imfinzi as a monotherapy and in combination with Imjudo 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 programme, 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 catalyse 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. AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca . References 1. National Cancer Institute. NCI Dictionary – Small Cell Lung Cancer. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/small-cell-lung-cancer . Accessed March 2025. 2. AstraZeneca PLC. Investor Relations Epidemiology Spreadsheet. Available at: https://www.astrazeneca.com/investor-relations.html . Accessed March 2025. 3. Qin A, Kalemkerian GP. Treatment Options for Relapsed Small-Cell Lung Cancer: What Progress Have We Made? J Oncol Pract . 2018;14(6):369-370. 4. Cheng Y, et al. Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer. N Engl J Med . 2024;391(14):1313-1327. 5. Bebb DG, et al. Symptoms and Experiences with Small Cell Lung Cancer: A Mixed Methods Study of Patients and Caregivers. Pulm Ther . 2023;9:435-450. 6. World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Available at: https://gco-iarc-who-int.libproxy1.nus.edu.sg/media/globocan/factsheets/cancers/15-trachea-bronchus-and-lung-fact-sheet.pdf . Accessed March 2025. 7. World Health Organization. International Agency for Research on Cancer. World Fact Sheet. Available at: https://gco-iarc-who-int.libproxy1.nus.edu.sg/media/globocan/factsheets/populations/900-world-fact-sheet.pdf . Accessed March 2025. 8. LUNGevity Foundation. Types of Lung Cancer. Available at: https://www.lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer . Accessed March 2025. 9. American Cancer Society. Small Cell Lung Cancer Stages. Available at: https://www.cancer.org/cancer/types/lung-cancer/detection-diagnosis-staging/staging-sclc.html . Accessed March 2025. 10. Senan S, et al. ADRIATIC: A phase III trial of durvalumab ± tremelimumab after concurrent chemoradiation for patients with limited stage small cell lung cancer. Ann Oncol . 2019;30(suppl. 2):ii25. SOURCE: AstraZeneca