On September 26, 2023 Starpharma (ASX: SPL, OTCQX: SPHRY) reported the presentation of data that demonstrate the benefits of combining DEP irinotecan with other important classes of anti-cancer therapies, including immuno-oncology (IO) agents, in models of human colorectal cancer (Press release, Starpharma, SEP 26, 2023, View Source;mc_eid=bf52dd3418 [SID1234635420]). The data will be presented in Boston, US, at the AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), co-hosted by the American Association For Cancer Research (AACR) (Free AACR Whitepaper), the National Cancer Institute (NCI) and the European Organisation for Research and Treatment of Cancer (EORTC) from 11 to 15 October 2023. This poster presentation is one of three by Starpharma at the AACR (Free AACR Whitepaper)-NTI-EORTC conference showcasing multiple DEP programs, including DEP irinotecan and Starpharma’s radiotheranostic, DEP HER2-zirconium.
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This DEP irinotecan combination poster builds on Starpharma’s recently released positive clinical data on DEP irinotecan in advanced colorectal cancer (CRC) and advanced platinum-resistant ovarian cancer2.
The DEP irinotecan combination data to be presented show DEP irinotecan improves the anti-tumour activity of an IO agent3 in the same class as the highly successful Merck product, Keytruda (pembrolizumab), including in models of CRC that respond poorly to IO agents.
DEP irinotecan in combination with the IO agent enhanced anti-tumour responses compared to the IO agent alone in a CRC model that is only moderately responsive to the IO agent. The combination also resulted in complete tumour regression and prolonged survival compared to the IO agent alone in this CRC model. In another model of CRC that was not responsive to the IO agent alone, the anti-tumour effects of the combination of DEP irinotecan and the IO agent were enhanced when compared with either agent alone.
DEP irinotecan’s ability to elicit an anti-cancer response to an IO agent in an otherwise non-responsive CRC tumour is significant. These improved results in CRC models provide a rationale for a potentially important new application of DEP irinotecan in combination with IO agents, which are a leading and growing class of anticancer therapies.
Importantly, 85% to 95% of CRC patients do not respond to IO agents, such as Keytruda, and this cancer remains a significant unmet medical need. These CRC patients do not respond to IO agents because their cancer is classified as microsatellite stable (MSS). These MSS cancers are more difficult to treat, more likely to recur, and typically less responsive to IO therapies than cancers that are not MSS. This DEP irinotecan poster includes new clinical data from Starpharma’s Phase 1/2 trial of the product showing that all CRC patients who responded to DEP irinotecan were MSS and, therefore, in the category that is more difficult to treat.
IO agents have changed the landscape of cancer treatment, demonstrating impressive results in treating a number of cancers, including lung cancer and melanoma, and generating over USD $60.3 billion in sales in 2021, with sales predicted to grow 14 to 17% per year to 20264.
IO anti-cancer drugs are designed to disrupt normal immune processes, allowing the body’s immune cells to effectively target and destroy cancer cells. Currently marketed IO drugs include Keytruda (Merck), Opdivo (BMS), Yervoy (BMS), Tecentriq (Genentech), and Imfinzi (AstraZeneca). The global colorectal cancer drugs market was valued at ~US$14 billion in 2023 and is forecast to reach more than US$16 billion by 20275. Immunotherapies, such as Keytruda, had approximately 25% market share in 20186.
Despite their impressive efficacy, IO agents can cause serious immune-mediated adverse events that are challenging to manage. Treatment with DEP irinotecan resulted in no immune-mediated adverse events in CRC and ovarian patients, and therefore, there was no overlap of adverse events with those reported for IO agents – another benefit for this combination application.
In addition to the promising data for DEP irinotecan in combination with the IO agent, Starpharma’s poster also includes data on DEP irinotecan in combination with AstraZeneca’s Lynparza (olaparib). Olaparib is from a class of drugs called PARP inhibitors. DEP irinotecan also showed a synergistic effect in combination with olaparib in a model of CRC. The CRC model used was resistant to olaparib alone, but the combination of DEP irinotecan and olaparib achieved increased anti-tumour effects compared to DEP irinotecan alone, and also prolonged survival.
Lynparza had global sales of more than US$2.6 billion in 20227 and is approved for use in ovarian, breast, pancreatic and prostate cancers.
The data showing DEP irinotecan enhances anti-tumour responses of the IO agent and PARP inhibitor in models of cancer, together with the promising clinical efficacy and safety profile of DEP irinotecan in CRC and ovarian cancer, provide a strong rationale for clinical evaluation of DEP irinotecan in combination with IO agents and PARP inhibitors. These combination regimens are commercially important because they increase the potential market opportunities for DEP irinotecan and illustrate synergies with successful product categories. Given these findings, Starpharma is engaging in discussions with potential commercial partners, including companies that currently market IO agents.
The above-mentioned poster is one of three posters Starpharma is presenting at the AACR (Free AACR Whitepaper)-NCI-EORTC conference in October 2023.
Thursday, 12 October (Poster Session A): A147: A HER2 targeted polylysine dendrimer nanoparticle radiotheranostic demonstrates excellent tumor accumulation, rapid clearance from circulation, and promising performance in PET-CT imaging.
Friday, 13 October (Poster Session B): B039: A phase 1/2 study of dendrimer-enhanced (DEP) SN38 (SN38-SPL9111 / DEP irinotecan) in patients with advanced solid tumours.
Saturday, 14 October (Poster Session C): C167: An SN38 dendrimer nanoparticle, DEP irinotecan (SN38-SPL9111), demonstrates efficacy in mouse models of gastrointestinal cancer and augments anti-tumor effects of immune checkpoint blockade and PARP inhibition.
Abstracts, which include a summary of the data, will be published on the conference website ahead of the conference, and the full posters will be made available by Starpharma following publication.
About DEP irinotecan
DEP irinotecan is a novel, patented, nanoparticle formulation of SN38, the active metabolite of the widely used anti-cancer drug, irinotecan (marketed as Camptosar), delivered using Starpharma’s proprietary DEP technology. Camptosar and all generic forms of conventional irinotecan carry ‘black box’ warnings mandated by the US Food and Drug Administration (FDA) for both neutropenia and severe diarrhoea, which can be dose-limiting and life-threatening. DEP irinotecan has not resulted in severe diarrhoea in Phase 2 studies. DEP irinotecan has patent filings to 2039 and up to an additional five years.
The severe diarrhoea caused by conventional irinotecan results from the production of toxic metabolites during the liver metabolism of irinotecan to SN38. DEP irinotecan was designed to eliminate the need for liver metabolism, thereby avoiding the production of toxic metabolites.
About Starpharma’s DEP irinotecan Phase 2 clinical trial
Starpharma is evaluating DEP irinotecan as both a monotherapy and in combination with 5-fluorouracil (5-FU) and leucovorin (LV), which is a standard irinotecan combination regimen used in the treatment of CRC known as "FOLFIRI". The Phase 2 DEP irinotecan trial is being conducted at multiple sites, including Guy’s Hospital in London, Beatson Cancer Centre in Glasgow, Imperial College London, and the Kinghorn Cancer Centre in Sydney.
Clinical and commercial opportunity for DEP irinotecan
The global colorectal cancer drugs market was valued at ~US$14 billion in 2023 and is forecast to reach more than US$16 billion by 20278.
Camptosar and generic forms of conventional irinotecan are standard-of-care treatments for advanced CRC, with Pfizer’s Camptosar achieving peak sales of ~US$1.1 billion. CRC accounts for approximately 10% of all new cancer diagnoses and is the second leading cause of cancer, affecting more than 1 million people annually, and is the fourth leading cause of cancer-related death.
CRC incidence is increasing markedly among younger age groups, with rates of colon cancer more than doubling in adults aged 20 to 54 since the 1990s. Studies have shown that, compared with adults born around 1950, those born around 1990 have double the risk of colon cancer and quadruple the risk of rectal cancer.