Elikya Therapeutics’ Post

Advances in Antibody-Drug Conjugates (ADCs) for treatment of Breast Cancer Lifescience Dynamics’ oncology experts explored this years’ #ESMO23 to glean insights that are driving strategies of our clients. Exciting advances in Antibody-Drug Conjugates (ADCs) are reshaping the landscape of breast cancer treatment, offering new hope to patients and medical professionals alike. To this end, AstraZeneca and Daiichi Sankyo presented data from the Phase 3 TROPION-Breast01 trial of their TROP2-targeting ADC, Dato-DXd (datopotamab deruxtecan) in patients with HR+/HER2- metastatic breast cancer (mBC). This data demonstrated that Dato-DXd offers a significant benefit in progression-free survival (PFS) when compared to traditional chemotherapy in HR+/HER2- mBC patients who have undergone endocrine therapy and received prior chemotherapy.   This development follows the 2022 data from Gilead’s Phase 3 TROPiCS-02 trial, which showcased the meaningful advantage of Trodelvy (sacituzumab govitecan) over chemotherapy in heavily pretreated HR+/HER2- mBC in terms of PFS. As a result, Trodelvy received regulatory approval for HR+/HER2- mBC in both the US and EU. Notably, unlike Dato-DXd, Trodelvy has demonstrated improved overall survival (OS) when compared to chemotherapy. We are eagerly awaiting additional OS analyses from TROPION-Breast01 to deepen our understanding of the efficacy differences between these two ADCs.   Looking beyond TROP2-targeting ADCs, the HR+/HER2- mBC market also includes AstraZeneca’s and Daiichi Sankyo’s Enhertu, an ADC designed to target HER2. Enhertu transformed the breast cancer treatment paradigm through its approval in HER2-low mBC. This extended the percentage of patients with a level of HER2 expression treatable by certain HER2-ADCs from 15% to 65%.  With the potential availability of three ADCs for HR+/HER2- mBC, questions regarding ADC sequencing have arisen. How effective is one ADC after the failure of another? What is the correct order to sequence ADCs? How does altering the payload, linker and target influence the development of ADC resistance? The medical community eagerly anticipates answers to these questions in order to determine the most effective treatment practices for breast cancer patients moving forward.  #oncology #lifescience #ESMO23 #ESMO #breastcancer  #ADC #cancertreatment #cancerresearch #cancer    Gilead Sciences, AstraZeneca, Daiichi Sankyo, Inc. Merck Group, MSD  For more information contact: Miranda Carleton, Ph.D.

📃Scientific paper: Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: a study protocol for an open-label phase I/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma Abstract: BACKGROUND: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer. METHODS: The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, ad... Continued on ES/IODE ➡️ https://etcse.fr/OAqn ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.

<!-- Content start --> Basel, 04 July 2024 – Roche announced today that the phase II/III SKYSCRAPER-06 study, evaluating tiragolumab plus Tecentriq (atezolizumab) and chemotherapy versus pembrolizumab and chemotherapy as an initial (first-line) treatment for people with previously untreated, locally advanced unresectable or metastatic non-squamous non-small cell lung cancer, did not meet its primary endpoints of progression-free survival (PFS) at its primary analysis with a hazard ratio (HR) of 1.27 [95% CI: 1.02,1.57] and overall survival (OS) at its first interim analysis with a HR of 1.33 [95% CI: 1.02, 1.73], which was immature. The combination of tiragolumab plus Tecentriq and chemotherapy showed reduced efficacy in both PFS and OS compared to the comparator arm in the intent-to-treat population, which includes the phase II and phase III cohorts. The overall safety profile remains consistent with the safety profile previously observed for the combination of tiragolumab plus Tecentriq and chemotherapy, and no new or unexpected findings were identified. Based on these results, patients and investigators will be unblinded and we intend to halt the study. A communication will be sent to the investigators and results will be shared with health authorities and subsequently presented at an upcoming medical meeting. “These results are disappointing as it was our hope that this combination might yield improved outcomes for people living with metastatic non-squamous lung cancer,” said Levi Garraway, M.D., Ph.D., Chief Medical Officer and Head of Global Product Development. “We are thankful to all of the patients and healthcare professionals involved in the study, and we will leverage the learnings to inform our scientific understanding of the anti-TIGIT pathway and new avenues in cancer research.” Ongoing phase III studies are investigating treatment settings and indications distinct from SKYSCRAPER-06. Based on today’s results, we will evaluate any relevant changes needed to the ongoing tiragolumab programme. About SKYSCRAPER-06 studySKYSCRAPER-06 is a global phase II/III, randomised, placebo-controlled and double-blinded study evaluating tiragolumab plus Tecentriq (atezolizumab) and chemotherapy as an initial (first-line) treatment versus pembrolizumab and chemotherapy in 542 people with non-squamous non- small cell lung cancer. Primary endpoints are overall survival (OS) and progression-free survival (PFS). About tiragolumabTiragolumab is an investigational novel immune checkpoint inhibitor with an intact Fc region. Tiragolumab selectively binds to TIGIT, a novel inhibitory immune checkpoint which suppresses the immune response to cancer. Based on preclinical research, tiragolumab is thought to work as an immune amplifier with other cancer immunotherapies such as Tecentriq (atezolizumab). The TIGIT pathway is distinct but complementary to the PD-L1/PD-1 pathway. Dual blockade with tiragolumab and Tecentriq may help overcome

AKT-1 E17K, a validated oncogenic driver with clinical significance, manifests in approximately 1-2% of cancer cases. It demonstrates notable prevalence in various solid tumors, notably breast cancer (around 5%), endometrial cancer (approximately 3%), and prostate cancer (about 1.5%). Intriguingly, a striking observation emerges: over half of the AKT-1 E17K mutated breast and gynecologic cancers exhibit homozygosity of the mutated oncogene. This phenomenon, suggestive of oncogene addiction through copy-neutral loss of heterozygosity (CN-LOH), underscores the robust oncogenic drive inherent in these tumor subtypes. Navigating the landscape of current therapies presents its own set of challenges. While inhibitors targeting wild-type (WT) PI3K or AKT have demonstrated clinical efficacy in HR+/HER2 metastatic breast cancer with PI3K/AKT pathway mutations, they are not without drawbacks. Common adverse events such as hyperglycemia, diarrhea, and rash pose potential hurdles to treatment tolerability and longevity. Yet, strides have been made in validating clinical efficacy targeting AKT-1 E17K. The phase 2 clinical outcomes of capivasertib, the first approved pan-AKT inhibitor, reveal an objective response rate (ORR) of 28.6% in 35 patients with AKT1 E17K mutated metastatic tumors. These patients experienced a median progression-free survival of 5.5 months and a 6-month survival rate of 50%, with a median overall survival of 14.5 months. Researchers are now focused on the development of a covalent, highly selective inhibitor utilizing the mutated lysine of the E17K variant. Employing structure-guided design informed by proprietary co-crystal structures, lead molecules were meticulously identified based on their inhibition of pAKT S473 and selectivity against WT AKT-1 and AKT-2. Among these, ALTA-2618 emerges as a potent inhibitor of AKT-1 E17K, boasting an EC50 of 7 nM and exhibiting 22-fold selectivity against WT AKT-1 and 140-fold selectivity against WT AKT-2. Importantly, ALTA-2618 has been conclusively demonstrated to covalently bind to the AKT-1 E17K protein through thorough mass spectrometry analysis. In the realm of preclinical efficacy, ALTA-2618 has undergone rigorous testing in patient-derived xenograft (PDX) models derived from individuals with AKT-1 E17K-driven breast and endometrial cancer. Administered orally once daily, ALTA-2618 induced tumor regression even at low doses of 10 mg/kg/day, exhibiting efficacy across HR+/HER2 low breast cancer, triple-negative breast cancer (TNBC), and endometrial cancer PDX models. Particularly noteworthy is the observation of complete remission in the HR+/HER2 low breast PDX model at a dose of 30 mg/kg/day, administered for 60 days, without significant occurrences of weight loss or hyperglycemia.

🌟 Breakthrough in Cancer Treatment: 100% Success in Clinical Trial 🌟 Thrilled to share some groundbreaking news in the field of oncology! A recent clinical trial has shown that a new immunotherapy drug, dostarlimab-gxly, achieved a 100% success rate in treating patients with a specific type of rectal cancer. This trial, conducted by the Memorial Sloan Kettering Cancer Center (MSK) and GSK, marks a significant milestone in cancer treatment. 🎉 📊 Key Highlights: ✅ 100% Success Rate: All 42 patients with dMMR rectal cancer experienced complete disappearance of tumors. 💯 ✅ Immunotherapy Innovation: Dostarlimab works by reactivating the immune system to recognize and destroy cancer cells. 🦠🔬 ✅ Quality of Life: This treatment offers a potential alternative to conventional therapies, which often have debilitating side effects. 🌟 🔍 In-Depth Analysis: This remarkable result stems from a targeted approach to treating mismatch repair deficient (dMMR) rectal cancer, which accounts for about 5% of rectal cancer cases. The conventional treatment options—radiotherapy, chemotherapy, and surgery—often result in significant side effects such as bowel incontinence and sexual dysfunction. Dostarlimab-gxly, however, harnesses the body's immune system to attack cancer cells, potentially sparing patients from these harsh side effects. 🌟 Dr. Andrea Cercek, the study's principal investigator, emphasized the transformative potential of this treatment. As these hypermutated tumors are highly visible to the immune system, the drug effectively reactivates the body's natural defenses to target and eliminate cancer cells. 💪 🔮 Future Aspects: While the initial results are promising, further research is necessary. The global Azur-1 study aims to validate these findings and explore the drug's efficacy as a standalone treatment. Should these studies confirm the current results, dostarlimab-gxly could revolutionize the standard of care for dMMR rectal cancer patients. 🌍🔬 This development underscores the incredible potential of precision medicine and immunotherapy in transforming cancer treatment. As we continue to push the boundaries of medical science, the future holds immense promise for patients worldwide. 🚀 ---------------------- https://lnkd.in/dJ86znKd #healthcareinnovation #oncology #immunotherapy #cancerresearch #medicalbreakthrough #dostarlimab #precisionmedicine #clinicaltrials #cancertreatment

Promising study in Lancet Oncology: Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial https://lnkd.in/esw5he4R Background Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into 4 subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. Methods FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial. Eligible participants were females aged 18–70 years, with an ECOG performance status of 0–1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug (NCT04395989). Findings Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2–29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6–15·2]) than in the control group (5·8 months [4·0–6·7]; hazard ratio 0·44 [95% CI 0·30–0·65]; p<0·0001). The most common grade 3–4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group.

Very excited to see a decade long journey of biomarker development for the multitarget FIT (mtFIT) for improved colorectal cancer screening recognised with our recent publication in The Lancet Oncology.   This paper titled “The multitarget faecal immunochemical test for improving stool-based colorectal cancer screening programmes: a Dutch population-based, paired-design, intervention study" shows that programmatic colorectal cancer screening could further reduce the incidence and associated mortality of this disease by using mtFIT instead of FIT. Many thanks to all study participants, funders, collaborators and the fantastic multicenter multidisciplinary research team over the years. Large interventional head-to-head studies that test the clinical utility of new tests versus existing screening tests are necessary to generate evidence for implementation. To this end, in the present study mtFIT was compared with FIT in a paired-design intervention study that was conducted in the real world setting of the Dutch population-based colorectal cancer screening programme. Detection rates for advanced neoplasia, and especially advanced adenomas, were higher for mtFIT than for FIT in three different scenarios, focusing on different test positivity rates . Long-term modelling revealed that mtFIT could be cost-effective at a realistic price level and further reduce colorectal cancer incidence and associated mortality. The next step, coordinated by the NKI spin-off company #CRCbioscreen, will be to develop a clinical grade test suitable for large scale use in population based colorectal cancer screening. 

Emerging treatments in HER2-positive advanced breast cancer: Keep raising the bar. https://lnkd.in/g_kqVzN7 HER2-positive breast cancer accounts for approximately 15% of breast cancer diagnoses and can be further divided into  four molecular subtypes based on gene expression profiling (eg, HER2-enriched (47%), luminal A (24%), luminal B (20%), and basal-like (9%)). Promisingly, the life expectancy of patients with HER2-positive metastatic breast cancer has consistently improved over the last few decades thanks to advancements in treatment strategies and the emergence of new modalities like antibody drug conjugates (ADCs). This new review by Elisa Agostinetto, Giuseppe Curigliano and @Martine Piccart provides a great overview of current and future treatment strategies for this breast cancer subtype. Current treatment landscape: In first line, the standard of care is dual HER2 blockade with trastuzumab and pertuzumab plus a taxane, based on the CLEOPATRA trial which demonstrated a median progression-free survival of 18.7 months and median overall survival of 56.5 months. In second line, trastuzumab deruxtecan is now the preferred treatment after demonstrating superiority to T-DM1 in the DESTINY-Breast03 trial, with a median PFS of 28.8 vs. 6.8 months. In second/third line, especially for patients with progressive brain metastases, the combination of tucatinib, trastuzumab and capecitabine (based on the HER2Climb-01 trial) is an option, demonstrating improved PFS and OS compared to trastuzumab and capecitabine alone. Future treatment landscape: The current treatment algorithm is likely to be challenged by ongoing clinical trials. Trastuzumab deruxtecan is being compared to the CLEOPATRA regimen in first line in the DestinyBreast-09 trial and may become the new first-line standard of care if positive. In second line, trastuzumab deruxtecan plus tucatinib is being compared to trastuzumab deruxtecan alone in the HER2Climb-04 trial. New agents likely to join the treatment landscape: New strategies aim to tackle HER2-positive disease by acting on various targets including HER2 (extra- and intracellular), HER3, PD-(L)1, CTLA4, NKG2A, AKT, PI3K, estrogen receptors, and CDK4/6. The most promising new agents are antibody-drug conjugates (ADCs) like trastuzumab deruxtecan and bispecific antibodies. Immune checkpoint inhibitors have shown disappointing efficacy so far but investigation is ongoing. Therapeutic cancer vaccines represent another promising strategy, especially in early-stage disease. For triple-positive disease, new strategies are evaluating combinations of endocrine therapy, CDK4/6 inhibitors, PI3K inhibitors, and oral SERDs with anti-HER2 agents.

+++ 𝐎𝐧𝐜𝐨𝐥𝐨𝐠𝐲 𝐩𝐨𝐫𝐭𝐟𝐨𝐥𝐢𝐨 𝐮𝐩𝐝𝐚𝐭𝐞: 𝐒𝐭𝐚𝐫𝐭 𝐨𝐟 𝐭𝐡𝐢𝐫𝐝 𝐥𝐚𝐭𝐞𝐫-𝐬𝐭𝐚𝐠𝐞 𝐭𝐫𝐢𝐚𝐥 𝐰𝐢𝐭𝐡 𝐢𝐧𝐝𝐢𝐯𝐢𝐝𝐮𝐚𝐥𝐢𝐳𝐞𝐝 𝐦𝐑𝐍𝐀 𝐜𝐚𝐧𝐜𝐞𝐫 𝐢𝐦𝐦𝐮𝐧𝐨𝐭𝐡𝐞𝐫𝐚𝐩𝐲 +++   We announced today that the first patient has been treated in a Phase 2 clinical trial with our individualized cancer immunotherapy candidate autogene cevumeran (also known as BNT122, RO7198457), which is being jointly developed with our partner Genentech, in resected pancreatic ductal adenocarcinoma (#PDAC). The study is expected to enroll 260 patients with PDAC at clinical trial sites initially in the United States, followed by Europe and Asia Pacific region.     𝐌𝐞𝐝𝐢𝐜𝐚𝐥 𝐧𝐞𝐞𝐝: PDACs are solid tumors with a poor prognosis reflected in a 5-year overall survival rate of only 8-10%, extremely high recurrence rates after surgery, and limited treatment options.    𝐀𝐛𝐨𝐮𝐭 𝐭𝐡𝐞 𝐜𝐚𝐧𝐝𝐢𝐝𝐚𝐭𝐞: Autogene cevumeran is based on our proprietary mRNA-based individualized neoantigen-specific immunotherapy (#iNeST) platform. Autogene cevumeran is encoding up to 20 patient-specific cancer mutations selected for their proficiency to serve as neoantigens. Neoantigens are proteins that are produced by cancer cells that differ from the proteins produced by healthy cells and are recognized by immune cells. The investigational treatment aims to induce a neoantigen-directed immune response against the patient’s individual tumor.    We have been evaluating neoepitopes since the start of the first clinical trial based on our #mRNA technology in 2014 with the hypothesis that they could be suitable targets for individualized cancer vaccines. Our aim is to prevent relapses and thus ensure that the disease is managed at the earliest possible stage in these high unmet medical need indications.  𝑹𝒆𝒂𝒅 𝒎𝒐𝒓𝒆: https://lnkd.in/e_k3Q4PU

Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study Background The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer. Findings Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0–68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0–67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was –75% (95% CI –80 to –70) with giredestrant and –67% (–73 to –59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3–4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction). Interpretation Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials.