From targeted therapy to a novel way: Immunogenic cell death in lung cancer
WCLC: Biomarker Could Guide Dato-DXd Use In Lung Cancer
News
National Cancer Institute
A biomarker could help identify patients with lung cancer who are most likely to benefit from treatment with AstraZeneca and Daiichi Sankyo's TROP2-directed drug datopotamab deruxtecan (Dato-DXd).
The antibody-drug conjugate (ADC) is currently under review by the FDA as a treatment for advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) in adults who have undergone prior systemic therapy, with a decision due in December.
It was filed on the back of progression-free survival data from the TROPION-Lung01 study, although, there was disappointment for AZ and Daiichi Sankyo after Dato-DXd was unable to show a statistically significant improvement in overall survival (OS) compared to docetaxel, currently a go-to option in patients who have failed prior targeted drugs or immunotherapies.
AZ has developed an artificial intelligence-powered biomarker – known as quantitative continuous scoring (QCS) – to try to guide treatment with the ADC to those most likely to benefit from it. It has also partnered with Roche to turn it into a companion diagnostic that could support the launch of Dato-DXd if approved.
Simply looking for TROP2 on cancer cell surfaces using immunohistochemical (IHC) assays has not proved to be effective in predicting therapeutic response to TROP2 ADCs. The QCS deep learning algorithm was designed to investigate TROP2 in both the membrane and cell interior (cytoplasm) for all individual cells across a digitised image of a biopsy slide.
The ratio of TROP2 in the membrane to the cytoplasm – normalised membrane ratio (NMR) – was used to stratify patients into groups that were then compared for their response to Dato-DXd treatment.
In a nutshell, a retrospective look at the Tropion-Lung01 data found much better efficacy in patients who were deemed positive for the QCS-NMR biomarker than those who were negative.
In the positive group, Dato-DXd reduced the risk of disease progression or death by 43% versus docetaxel – with a median PFS of 6.9 months versus 4.1 months for docetaxel – which compared to a 25% reduction for the overall study population.
For patients without the biomarker, Dato-DXd performed worse than docetaxel, with a median PFS of 2.9 months and 4 months, respectively.
"We have shown with this analysis that the more precise quantitative measurement of TROP2 on and inside tumour cells, enabled by AZ's computational pathology platform, can identify which patients with non-small cell lung cancer are most likely to benefit from treatment," said trial investigator Marina Garassino of the University of Chicago, who presented the data at the World Conference on Lung cancer (WCLC).
Dato-DXd is heading for a decision in December from the FDA based on the Tropion-Lung01 data, with the jury out on its approvability after the OS miss and a lack of efficacy in the squamous population.
A rival TROP2 ADC from Gilead Sciences, Trodelvy (sacituzumab govitecan), also failed to deliver wholly convincing data in NSCLC. The drug achieved a modest 16% OS reduction in the EVOKE-01 study as a second-line treatment for both squamous and non-squamous NSCLC patients after Gilead said earlier it had missed the endpoint.
AZ licensed rights to Dato-DXd in July 2020 for $1 billion upfront, plus up to $5 billion in regulatory and sales milestones, and the company has pinned a peak sales target of $5 billion a year on the drug.
AZ and Daiichi Sankyo have more than 20 trials evaluating the efficacy and safety of Dato-DXd across multiple cancers, including NSCLC, triple-negative breast cancer (TNBC), and HR-positive, HER2-negative breast cancer.
AZ has already suggested that the new algorithm could assist in the development of the ADC. Its head of oncology R&D, Susan Galbraith, said it "has great potential to help more precisely select patients across our broader antibody-drug conjugate portfolio."
Photo by National Cancer Institute on Unsplash
AstraZeneca Shares Hit By Lung Cancer Drug Trial Results
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Libtayo® (cemiplimab) Demonstrates Durable Survival Benefit At Five Years In Advanced Non-small Cell Lung Cancer
Late-breaking data at WCLC show Libtayo monotherapy nearly doubled median overall survival and reduced the risks of death and disease progression by 41% and 50%, respectively, compared to chemotherapy
WCLC presentation also reviews data on overall survival, progression-free survival and response rate among patients who added chemotherapy to Libtayo following disease progression
TARRYTOWN, N.Y., Sept. 09, 2024 (GLOBE NEWSWIRE) -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced five-year results from the final pre-specified overall survival (OS) analysis of the Phase 3 EMPOWER-Lung 1 trial, which evaluated Libtayo® (cemiplimab) monotherapy versus chemotherapy as a first-line treatment for adults with advanced non-small cell lung cancer (NSCLC) with ≥50% PD-L1 expression and no EGFR, ALK or ROS1 aberrations. The late-breaking results will be presented in an oral session at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer.
"The five-year results from EMPOWER-Lung 1 showcase the durable survival benefit and impressive efficacy of first-line Libtayo monotherapy compared to chemotherapy in patients with PD-L1 high, advanced NSCLC, including a direct correlation between survival benefits and PD-L1 expression level," says Ana Baramidze, MD, PhD, Head of Clinical Research Department at Todua Clinic, Tbilisi, Georgia. "Furthermore, EMPOWER-Lung 1 continues to offer important new data to help doctors increase their understanding of investigational treatment strategies for patients who progress on PD-1 inhibitor monotherapy. For instance, EMPOWER-Lung 1 was one of the few trials to evaluate survival when adding chemotherapy to a PD-1 inhibitor following progression."
At the five-year follow-up, Libtayo remained superior to chemotherapy in the population of patients confirmed to have ≥50% PD-L1 expression (using an FDA approved assay), demonstrating continued and clinically meaningful benefits consistent with the prior 1-year analysis in this study population (as previously published in The Lancet and also as previously provided in the approved label for the FDA-approved assay):
1-year Analysis 5-year Analysis Libtayo(n=283) Chemotherapy(n=280) Libtayo(n=284) Chemotherapy(n=281) Overall survival (OS) Mediana not reached 14 months 26 months 13 months Hazard ratio (HR)(95% confidenceinterval [CI]; p-value)b 0.57(0.42 to 0.77; p=0.0002) 0.59(0.48 to 0.72; p<0.0001) Progression-free survival (PFS) Mediana 8 months 6 months 8 months 5 months HR (95% CI; p-value)b 0.54(0.43 to 0.68; p<0.0001) 0.50(0.41 to 0.61; p<0.0001) Objective responserate (ORR) 39% 20% 46.5% 21% Median duration ofresponse (DoR) 17 months 6 months 24 months 6 monthsNOTE: The analysis was conducted in a subset of the randomized population that excluded 147 patients whose tumors could not be retested or were later found to have <50% PD-L1 expression.A Based on Kaplan-Meier methodb Based on stratified proportional hazards model
Continued and clinically meaningful benefits were also observed at this five-year follow-up of the overall trial population (in which not all patients were confirmed to have ≥50% PD-L1 expression), as compared to the prior 1-year analysis in this population.
1-year Analysis 5-year Analysis Libtayo(n=356) Chemotherapy(n=354) Libtayo(n=357) Chemotherapy(n=355) OS Mediana 22 months 14 months 23 months 14 months HR (95% CI; p-value)b 0.68(0.53 to 0.87; p=0.0022) 0.64(0.54 to 0.77; p<0.0001) PFS Mediana 6 months 6 months 6 months 5 months HR (95% CI; p-value)b 0.59(0.49 to 0.72; p<0.0001) 0.55(0.46 to 0.66; p<0.0001) ORR 37% 21% 42% 21% Median DoR 21 months 6 months 24 months 6 monthsa Based on Kaplan-Meier methodb Based on stratified proportional hazards model
Importantly, EMPOWER-Lung 1 allowed patients who experienced disease progression to change their therapy, with those assigned to Libtayo having the option to add four cycles of chemotherapy. Among these patients (n=75), the addition of chemotherapy was associated with a 15-month median OS (95% CI: 11 to 18 months), 7-month median PFS (95% CI: 6 to 8 months) and 28% ORR (95% CI: 18% to 40%).
The exploratory subgroup analysis of EMPOWER-Lung 1 also showed direct correlations between survival and disease progression benefits and PD-L1 expression level among Libtayo patients, supporting the direct correlation between tumor response and PD-L1 expression level previously observed. At five years, those with tumor PD-L1 expression of ≥90% (n=99) derived the greatest benefit with a median OS of 39 months (95% CI: 23 months to not evaluable) and a 15-month median PFS (95% CI: 10 to 21 months). These correlations with PD-L1 expression level were not observed with chemotherapy.
No new safety signals were observed at five years among evaluable patients (Libtayo=356; chemotherapy=343), following a median duration of exposure of 36 weeks to Libtayo and 18 weeks to chemotherapy. Adverse events (AEs) of any grade occurred in 93% of Libtayo patients (46% ≥Grade 3) and 96% of chemotherapy patients (52% ≥Grade 3). The most common AEs occurring in at least 10% of Libtayo patients included anemia (20%), decreased appetite (14%), fatigue (14%), pneumonia (12%), arthralgia (12%), back pain (12%), dyspnea (11%), cough (10%) and pruritus (10%). Among Libtayo patients, AEs were serious in 36% and led to permanent discontinuation in 9% and death in 10%, compared to 29%, 5% and 10% in the chemotherapy arm, respectively.
Among the 75 Libtayo patients who received additive chemotherapy after disease progression, AEs of any grade occurred in 89% (36% ≥Grade 3), following a median duration of exposure of 27 weeks to Libtayo. The most common AEs included anemia (35%), alopecia (24%), diarrhea (21%), nausea (20%), neutropenia (15%) and asthenia (11%). AEs were serious in 27% of patients and led to discontinuation of treatment in 5% of patients and death in 4% of patients.
Additional presentations on data from Regeneron's oncology portfolio and pipeline are being shared at WCLC.
The potential use of adding chemotherapy to Libtayo following disease progression as described above is investigational, and the safety and efficacy of this regimen have not been fully evaluated by any regulatory authority.
About Regeneron in Cancer We aspire to turn revolutionary discoveries into medicines that can transform the lives of those impacted by cancer. Our team around the world is driven to solve the needs and challenges of those affected by one of the most serious diseases of our time.
Backed by our legacy of scientific innovation and a deep understanding of biology, genetics and the immune system, we're pursuing potential therapies across more than 30 types of solid tumors and blood cancers. Our cancer strategy is
To complement our extensive in-house capabilities, we collaborate with patients, healthcare providers, governments, biopharma companies and each other to further our shared goals. Together, we are united in the mission to serve as a beacon of transformation in cancer care.
About Libtayo Libtayo is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1 on T cells and was invented using Regeneron's proprietary VelocImmune® technology. By binding to PD-1, Libtayo has been shown to block cancer cells from using the PD-1 pathway to suppress T-cell activation. In the U.S. and other countries Libtayo is indicated in certain patients with advanced basal cell carcinoma (BCC), advanced cutaneous squamous cell carcinoma (CSCC) and advanced NSCLC, as well as in advanced cervical cancer in the European Union, Canada and Brazil. As of July 1, 2022, Libtayo is developed and marketed globally by Regeneron.
In the U.S., the generic name for Libtayo in its approved indications is cemiplimab-rwlc, with rwlc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration (FDA). Outside of the U.S., the generic name of Libtayo in its approved indication is cemiplimab.
The extensive clinical program for Libtayo is focused on difficult-to-treat cancers. Libtayo is currently being investigated in trials as a monotherapy, as well as in combination with either conventional or novel therapeutic approaches for other solid tumors and blood cancers. These potential uses are investigational, and their safety and efficacy have not been evaluated by any regulatory authority.
U.S. FDA-approved Indications Libtayo is a prescription medicine used to treat:
It is not known if Libtayo is safe and effective in children.
IMPORTANT SAFETY INFORMATION FOR U.S. PATIENTS
What is the most important information I should know about LIBTAYO? LIBTAYO is a medicine that may treat certain cancers by working with your immune system. LIBTAYO can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended.
Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including:
Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with LIBTAYO. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with LIBTAYO if you have severe side effects.
Before you receive LIBTAYO, tell your healthcare provider about all your medical conditions, including if you:
Females who are able to become pregnant:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
The most common side effects of LIBTAYO when used alone include tiredness, muscle or bone pain, rash, diarrhea, and low levels of red blood cells (anemia). The most common side effects of LIBTAYO when used in combination with platinum-containing chemotherapy include hair loss, muscle or bone pain, nausea, tiredness, numbness, pain, tingling, or burning in your hands or feet, and decreased appetite. These are not all the possible side effects of LIBTAYO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Regeneron Pharmaceuticals at 1-877-542-8296.
Please see full Prescribing Information, including Medication Guide.
About Regeneron's VelocImmune Technology Regeneron's VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron's co-Founder, President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite® technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create a substantial proportion of all original, FDA-approved or authorized fully human monoclonal antibodies. This includes REGEN-COV® (casirivimab and imdevimab), Dupixent® (dupilumab), Libtayo®, Praluent® (alirocumab), Kevzara® (sarilumab), Evkeeza® (evinacumab-dgnb), Inmazeb® (atoltivimab, maftivimab and odesivimab-ebgn) and Veopoz® (pozelimab-bbfg).
About Regeneron Regeneron is a leading biotechnology company that invents, develops, and commercializes life-transforming medicines for people with serious diseases. Founded and led for 35 years by physician-scientists, Regeneron's unique ability to repeatedly and consistently translate science into medicine has led to numerous FDA-approved treatments and product candidates in development, almost all of which were homegrown in Regeneron's laboratories. Regeneron's medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, hematologic conditions, infectious diseases, and rare diseases.
Regeneron is accelerating and improving the traditional drug development process through its proprietary VelociSuite® technologies, such as VelocImmune®, which uses unique genetically humanized mice to produce optimized fully human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center®, which is conducting one of the largest genetics sequencing efforts in the world.
For additional information about Regeneron, please visit www.Regeneron.Com or follow Regeneron on LinkedIn.
Forward-Looking Statements and Use of Digital MediaThis press release includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals, Inc. ("Regeneron" or the "Company"), and actual events or results may differ materially from these forward-looking statements. Words such as "anticipate," "expect," "intend," "plan," "believe," "seek," "estimate," variations of such words, and similar expressions are intended to identify such forward-looking statements, although not all forward-looking statements contain these identifying words. These statements concern, and these risks and uncertainties include, among others, the nature, timing, and possible success and therapeutic applications of products marketed or otherwise commercialized by Regeneron and/or its collaborators or licensees (collectively, "Regeneron's Products") and product candidates being developed by Regeneron and/or its collaborators or licensees (collectively, "Regeneron's Product Candidates") and research and clinical programs now underway or planned, including without limitation Libtayo®(cemiplimab) as a monotherapy or in combination with chemotherapy for the treatment of advanced non-small cell lung cancer; uncertainty of the utilization, market acceptance, and commercial success of Regeneron's Products and Regeneron's Product Candidates and the impact of studies (whether conducted by Regeneron or others and whether mandated or voluntary), including the studies discussed or referenced in this press release, on any of the foregoing; the likelihood, timing, and scope of possible regulatory approval and commercial launch of Regeneron's Product Candidates and new indications for Regeneron's Products (such as Libtayo as a monotherapy or in combination with either conventional or novel therapeutic approaches for other solid tumors and blood cancers); the ability of Regeneron's collaborators, licensees, suppliers, or other third parties (as applicable) to perform manufacturing, filling, finishing, packaging, labeling, distribution, and other steps related to Regeneron's Products and Regeneron's Product Candidates; the ability of Regeneron to manage supply chains for multiple products and product candidates; safety issues resulting from the administration of Regeneron's Products (such as Libtayo) and Regeneron's Product Candidates in patients, including serious complications or side effects in connection with the use of Regeneron's Products and Regeneron's Product Candidates in clinical trials; determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron's ability to continue to develop or commercialize Regeneron's Products and Regeneron's Product Candidates; ongoing regulatory obligations and oversight impacting Regeneron's Products, research and clinical programs, and business, including those relating to patient privacy; the availability and extent of reimbursement of Regeneron's Products from third-party payers, including private payer healthcare and insurance programs, health maintenance organizations, pharmacy benefit management companies, and government programs such as Medicare and Medicaid; coverage and reimbursement determinations by such payers and new policies and procedures adopted by such payers; competing drugs and product candidates that may be superior to, or more cost effective than, Regeneron's Products and Regeneron's Product Candidates; the extent to which the results from the research and development programs conducted by Regeneron and/or its collaborators or licensees may be replicated in other studies and/or lead to advancement of product candidates to clinical trials, therapeutic applications, or regulatory approval; unanticipated expenses; the costs of developing, producing, and selling products; the ability of Regeneron to meet any of its financial projections or guidance and changes to the assumptions underlying those projections or guidance; the potential for any license, collaboration, or supply agreement, including Regeneron's agreements with Sanofi and Bayer (or their respective affiliated companies, as applicable), to be cancelled or terminated; the impact of public health outbreaks, epidemics, or pandemics (such as the COVID-19 pandemic) on Regeneron's business; and risks associated with intellectual property of other parties and pending or future litigation relating thereto (including without limitation the patent litigation and other related proceedings relating to EYLEA® (aflibercept) Injection), other litigation and other proceedings and government investigations relating to the Company and/or its operations (including the pending civil proceedings initiated or joined by the U.S. Department of Justice and the U.S. Attorney's Office for the District of Massachusetts), the ultimate outcome of any such proceedings and investigations, and the impact any of the foregoing may have on Regeneron's business, prospects, operating results, and financial condition. A more complete description of these and other material risks can be found in Regeneron's filings with the U.S. Securities and Exchange Commission, including its Form 10-K for the year ended December 31, 2023and its Form 10-Q for the quarterly period ended June 30, 2024. Any forward-looking statements are made based on management's current beliefs and judgment, and the reader is cautioned not to rely on any forward-looking statements made by Regeneron. Regeneron does not undertake any obligation to update (publicly or otherwise) any forward-looking statement, including without limitation any financial projection or guidance, whether as a result of new information, future events, or otherwise.
Regeneron uses its media and investor relations website and social media outlets to publish important information about the Company, including information that may be deemed material to investors. Financial and other information about Regeneron is routinely posted and is accessible on Regeneron's media and investor relations website (https://investor.Regeneron.Com) and its LinkedIn page (https://www.Linkedin.Com/company/regeneron-pharmaceuticals).
Contacts: Media RelationsAshley Buford FredericksTel: +1 914-356-2235ashley.Buford@regeneron.Com Investor RelationsVesna TosicTel: +1 914-847-5443vesna.Tosic@regeneron.Com
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