A Pilot Study of Lorlatinib for Treatment of Children With Newly Diagnosed High-Grade Glioma With ROS-1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase) or ALK (Anaplastic Lymphoma Kinase) Fusion

The goal of this study is to determine the response of the study drug loratinib in treating children who are newly diagnosed high-grade glioma with a fusion in ALK or ROS1. It will also evaluate the safety of lorlatinib when given with chemotherapy or after radiation therapy.

Start Date01 Sep 2024

Sponsor / Collaborator

Nationwide Children's Hospital

[+1]

NCT06361589 / RecruitingNot ApplicableIIT

Real World Study of Lolatinib for Patients With Advanced/Metastatic Anaplastic Lymphoma Kinase (ALK) - Positive Non-Small Cell Lung Cancer (NSCLC)

This study was a multicenter, prospective, non-interventional clinical study that included first-line and late-line patients with advanced non-small cell lung cancer with ALK fusions treated with the third generation ALK-TKI lorlatinib until disease progression, intolerable toxicity, investigator or subject decision to withdraw, lost to follow-up, initiation of other antineoplastic therapy, or death. Clinical pathology including sex, age, ALK mutation status at diagnosis, and clinical stage at diagnosis were collected from medical records. Physical condition as assessed by ECOG-PS before administration of lorlatinib was also recorded. Treatment information was obtained from the records, including dose and timing of ALK-TKI therapy and tumor response, number of prior systemic lines of therapy, and local treatment modalities such as radiotherapy and surgery. Quality of life based on the EORTC QLQ C30+LC29 scale (plus the EORTC QLQ BN20 scale in patients with brain/meningeal metastases) was performed at baseline and at each follow-up point. This study will use REDCap platform to collect and manage the study data information of multi-center patients.

Start Date01 May 2024

Sponsor / Collaborator

Sichuan Cancer Hospital

NCT06378892 / RecruitingPhase 2IIT

A Multicenter Single-arm Phase II Interventional Study to Evaluate the Activity and Safety of the Combination of Platinum-pemetrexed Based Chemotherapy Plus Lorlatinib in ALK Positive Non-Small Cell Lung Cancer (NSCLC) With Exclusively Extracranial Disease Progression on Lorlatinib.

This study aims to evaluate the activity and safety of the combination of platinum-pemetrexed based chemotherapy plus Lorlatinib in ALK positive Non-Small Cell Lung Cancer (NSCLC) with exclusively extracranial disease progression on Lorlatinib. Platinum-pemetrexed based chemotherapy plus Lorlatinib will be administered for an induction phase of four cycles. Subsequently, patients with response or stability of disease at radiological assessment will start the maintenance phase with pemetrexed-Lorlatinib in 21-day cycles until progression, unacceptable toxicity, death, or withdrawal of consent.

Start Date15 Mar 2024

Sponsor / Collaborator

Centro di Riferimento Oncologico

100 Clinical Results associated with Lorlatinib

100 Translational Medicine associated with Lorlatinib

100 Patents (Medical) associated with Lorlatinib

499

Literatures (Medical) associated with Lorlatinib

01 Feb 2024·Computers in biology and medicine

Dissecting the role of ALK double mutations in drug resistance to lorlatinib with in-depth theoretical modeling and analysis

Article

Author: Pan, Peichen ; Tong, Jianbo ; Hou, Tingjun ; Wang, Tianhao ; Xu, Lei ; Wang, Tianyue ; Wang, Zhe ; Zhang, Xing

Anaplastic lymphoma kinase (ALK) is implicated in the genesis of multiple malignant tumors. Lorlatinib stands out as the most advanced and effective inhibitor currently used in the clinic for the treatment of ALK-positive non-small cell lung cancer. However, resistance to lorlatinib has inevitably manifested over time, with double/triple mutations of G1202, L1196, L1198, C1156 and I1171 frequently observed in clinical practice, and tumors regrow within a short time after treatment with lorlatinib. Therefore, elucidating the mechanism of resistance to lorlatinib is paramount in paving the way for innovative therapeutic strategies and the development of next-generation drugs. In this study, we leveraged multiple computational methodologies to delve into the resistance mechanisms of three specific double mutations of ALK^{G1202R/L1196M}, ALK^{G1202R/L1198F} and ALK^{I1171N/L1198F} to lorlatinib. We analyzed these mechanisms through qualitative (PCA, DCCM) and quantitative (MM/GBSA, US) kinetic analyses. The qualitative analysis shows that these mutations exert minimal perturbations on the conformational dynamics of the structural domains of ALK. The energetic and structural assessments show that the van der Waals interactions, formed by the conserved residue Leu1256 within the ATP-binding site and the residues Glu1197 and Met1199 in the hinge domain with lorlatinib, play integral roles in the occurrence of drug resistance. Furthermore, the US simulation results elucidate that the pathways through which lorlatinib dissociates vary across mutant systems, and the distinct environments during the dissociation process culminate in diverse resistance mechanisms. Collectively, these insights provide important clues for the design of novel inhibitors to combat resistance.

01 May 2024·Anti-cancer agents in medicinal chemistry

An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021)

Review

Author: Gupta, Ghanshyam Das ; Jain, Ankit ; Vishakha, S ; Verma, Sant Kumar ; Navneesh, N ; Patel, Preeti ; Kurmi, Balak Das

Abstract::

New drugs being established in the market every year produce specified structures for selective biological targeting. With medicinal insights into molecular recognition, these begot molecules open new rooms for designing potential new drug molecules. In this review, we report the compilation and analysis of a total of 56 drugs including 33 organic small molecules (Mobocertinib, Infigratinib, Sotorasib, Trilaciclib, Umbralisib, Tepotinib, Relugolix, Pralsetinib, Decitabine, Ripretinib, Selpercatinib, Capmatinib, Pemigatinib, Tucatinib, Selumetinib, Tazemetostat, Avapritinib, Zanubrutinib, Entrectinib, Pexidartinib, Darolutamide, Selinexor, Alpelisib, Erdafitinib, Gilteritinib, Larotrectinib, Glasdegib, Lorlatinib, Talazoparib, Dacomitinib, Duvelisib, Ivosidenib, Apalutamide), 6 metal complexes (Edotreotide Gallium Ga-68, fluoroestradiol F-18, Cu 64 dotatate, Gallium 68 PSMA-11, Piflufolastat F-18, 177Lu (lutetium)), 16 macromolecules as monoclonal antibody conjugates (Brentuximabvedotin, Amivantamab-vmjw, Loncastuximabtesirine, Dostarlimab, Margetuximab, Naxitamab, Belantamabmafodotin, Tafasitamab, Inebilizumab, SacituzumabGovitecan, Isatuximab, Trastuzumab, Enfortumabvedotin, Polatuzumab, Cemiplimab, Mogamulizumab) and 1 peptide enzyme (Erwiniachrysanthemi-derived asparaginase) approved by the U.S. FDA between 2018 to 2021. These drugs act as anticancer agents against various cancer types, especially non-small cell lung, lymphoma, breast, prostate, multiple myeloma, neuroendocrine tumor, cervical, bladder, cholangiocarcinoma, myeloid leukemia, gastrointestinal, neuroblastoma, thyroid, epithelioid and cutaneous squamous cell carcinoma. The review comprises the key structural features, approval times, target selectivity, mechanisms of action, therapeutic indication, formulations, and possible synthetic approaches of these approved drugs. These crucial details will benefit the scientific community for futuristic new developments in this arena.

27 Jan 2024·The Journal of pharmacy and pharmacology

Potential interactions between triazole antifungal agents and lorlatinib based on ultra-performance liquid chromatography-tandem mass spectrometry in rat plasma

Article

Author: Li, Rongqi ; Chen, Yizhang ; Wang, Chenxiang ; Zhou, Tao ; Zhang, Xiuhua ; Ye, Zhongjiang ; Chen, Chuang ; Yang, Jianhui ; Jin, Mi ; Fu, Jing ; Zhou, Ziye ; Huang, Aifang

Abstract:

Aim:

Our study is to investigate the effects of triazole antifungal drugs on the pharmacokinetics of lorlatinib in rats.

Methods:

The samples were precipitated with methanol. Chromatographic separation was performed on a ultra-performance liquid chromatography (UPLC) system using a BEH C18 column. The mobile phase consisted of 0.1% formic acid water and methanol. Lorlatinib and crizotinib (internal standard) were detected in multiple reaction monitoring mode. The fragment ions were 407.3–228.07 for lorlatinib and m/z 450.3–260.0 for crizotinib. Lorlatinib and different triazole antifungal drugs were given to Sprague Dawley rats by gavage, and blood was collected from the tail vein at a certain time point. The validated UPLC–MS/MS method was applied to a drug interaction study of ketoconazole, voriconazole, itraconazole, and posaconazole with lorlatinib in rats.

Results:

Ketoconazole and voriconazole significantly inhibited lorlatinib metabolism. When administration with ketoconazole and voriconazole, the area under the curve from time zero to infinity of lorlatinib increased by 49.0% and 104.3%, respectively; the clearance decreased by 40.0% and 40.0%, respectively. While itraconazole and posaconazole did not affect lorlatinib pharmacokinetics.

Conclusion:

The UPLC-MS/MS-based assay is helpful to further understand the pharmacokinetics of lorlatinib in rats, and confirmed the findings that the combination of lorlatinib with CYP3A inhibitors should be avoided as predicted by our pre-clinical studies.

News (Medical) associated with Lorlatinib

19 Jun 2024

·www.prnewswire.com

From Comfort to Cure: 2024 ASCO Meeting Reveals Groundbreaking Oncology Data

USA News Group Commentary Issued on behalf of Oncolytics Biotech Inc. VANCOUVER, BC, June 19, 2024 /PRNewswire/ -- USA News Group – This year's 2024 Annual Meeting of the American Society of Clinical Oncology (ASCO) has now come and gone, but not without increasing hope for cancer patients around the world. This year's ASCO 2024 theme was 'The Art and Science of Cancer Care: From comfort to cure,' with attendees hearing presentations from experts and receiving a wide range of important clinical results for the first time. According to analysts at Spherical Insights, the Global Oncology Drugs Market is projected to be worth $564.5 billion by 2033, growing at a CAGR of 11.5%. Because a new drug typically might take 10-15 years to complete all 3 phases of clinical trials, the developments of today directly impact the results of tomorrow. This is why retail investors are wise to pay attention to the milestones and data shared by this year's ASCO attendees, which included O ncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC), AbbVie Inc. (NYSE: ABBV), AstraZeneca PLC (NASDAQ: AZN), Pfizer Inc. (NYSE: PFE), and Bristol-Myers Squibb Company (NYSE: BMY). Updating the audience for its flagship novel immunotherapy, pelareorep, Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC) presented two abstracts demonstrating further potential for the intravenously delivered immunotherapeutic agent in pancreatic cancer and its immunotherapeutic mechanism of action across multiple cancer indications. Oncolytics' first abstract presented was for a trial-in-progress of cohort 5 of the company's GOBLET study, evaluating the effectiveness of combining pelareorep and modified FOLFIRINOX (mFOLFIRINOX) with and without Roche's atezolizumab (Tecentriq®) in newly diagnosed patients with metastatic pancreatic ductal adenocarcinoma (PDAC). "The first abstract outlines the design of a new GOBLET PDAC cohort that could significantly expand the potential of the company's pancreatic cancer program," said Dr. Matt Coffey, President and CEO of Oncolytics. "The chemotherapy regimens of mFOLFIRINOX and gemcitabine/nab-paclitaxel are the two most common standards of care in metastatic pancreatic cancer. We previously reported that the combination of pelareorep, gemcitabine, nab-paclitaxel, and atezolizumab yielded tumor response rates nearly triple historical results. Should the combination of pelareorep and mFOLFIRINOX produce a similarly positive outcome, an even broader range of metastatic PDAC patients may benefit from pelareorep-based therapy." Funded by a US$5 million Therapeutic Accelerator Award grant from the Pancreatic Cancer Action Network (PanCAN), Oncolytics Biotech plans to start enrolling patients this quarter following regulatory clearance received in May. The GOBLET cohort 5 abstract and poster detail a study assessing innovative treatments for patients newly diagnosed with metastatic PDAC. Utilizing a Simon two-stage design, the study aims to determine if the treatments are promising enough for further investigation. Initially, 15 patients per treatment arm will be randomly assigned to receive either pelareorep with mFOLFIRINOX or pelareorep with mFOLFIRINOX and atezolizumab. The study's primary goals include evaluating the effectiveness and safety of these treatments. Researchers will measure progression-free survival (the length of time patients live without the cancer worsening), overall survival (the total length of time patients live), and biomarkers (biological indicators of treatment response). Should the first stage yield positive results, one or both treatment groups may progress to the second stage, which will involve an additional 17 patients per arm. Throughout the study, blood and tumor samples will be collected for in-depth analysis. This approach aims to provide a comprehensive understanding of how the treatments impact patient outcomes and pave the way for potential future advancements in PDAC therapy. Among the big pharma contenders that presented at ASCO 2024 was AbbVie Inc. (NYSE: ABBV), which took the opportunity at the meeting to showcase its robust solid tumor pipeline, with new data from its innovative antibody-drug conjugate (ADC) platform. AbbVie's ADCs are designed to target unique protein biomarkers such as c-Met (MET protein) and SEZ6 (seizure-related homolog 6 protein), which are over-expressed across various tumor types. The biotech giant states that by utilizing these biomarkers as targets, ADCs are designed to deliver potent cancer cell death-inducing agents called 'payloads' to the tumor. "Building upon our strong commitment to patients and existing leadership in hematological malignancies, we are rapidly advancing a differentiated pipeline in solid tumors," said Daejin Abidoye, M.D., Vice President, Head of Solid Tumors, Oncology Development, for AbbVie. "Our ADC platform allows us to utilize selected biomarkers such as c-Met and SEZ6 to induce targeted cancer cell death by delivering potent anti-cancer agents." At the meeting, Abbvie presented positive Phase I and II trial data for three ADC therapies, Teliso-V, ABBV-400 and ABBV-706, in solid tumour patients—with Teliso-V being the company's most advanced c-Met targeted ADC in development. The LUMINOSITY study enrolled 172 patients with c-Met protein overexpression and epidermal growth factor receptor wild type, advanced/metastatic non-squamous NSCLC. The Teliso-V results showed a mean overall response rate (ORR) of 28.6%, with ORRs of 34.6% in c-Met high patients and 22.9% in c-Met intermediate patients. The therapy demonstrated a median duration of response (DOR) of 9 months in c-Met high patients and 7.2 months in c-Met intermediate patients. Another ADC gaining attention was Enhertu, developed by British multinational AstraZeneca PLC (NASDAQ: AZN) and Japanese multinational Daiichi Sankyo. In a clinical trial, Enhertu reduced the risk of breast cancer progression by 37% compared to chemotherapy in patients who are HER2-positive, HER2-low, and HER2-ultralow. "DESTINY-Breast06 represents another potential paradigm shift in how we treat patients across the spectrum of HR-positive metastatic breast cancer," said Susan Galbraith, Executive Vice President, Oncology R&D, of AstraZeneca. "The results reinforce the potential for Enhertu to improve outcomes earlier in the treatment landscape and in a broader population of patients with HER2-expressing breast cancer who have never before been eligible for a HER2-directed therapy." AstraZeneca achieved multiple successes at ASCO this year. Among the highlights was the impressive performance of Tagrisso in a phase 3 lung cancer trial. The kinase inhibitor significantly reduced the risk of disease progression by 84% compared to the placebo. "Tagrisso extended progression-free survival by more than three years in this potentially curative setting, reinforcing the need to test and diagnose patients early," said Galbraith. "These practice-changing data cement the powerful impact Tagrisso can make as backbone therapy in EGFR-mutated lung cancer, especially in the lives of these patients who have historically experienced early progression following chemoradiotherapy." Another highlight at ASCO 2024 came from Pfizer Inc.'s (NYSE: PFE) phase 3 clinical trial results for Lorbrena, a drug approved by the U.S. Food and Drug Administration (FDA) for non-small cell lung cancer (NSCLC) in 2021. The five-year follow-up of patients with the ALK mutation showed that Lorbrena reduced the risk of disease progression by 81% compared to Xalkori, a recognized first-line treatment for NSCLC. Lorbrena's readout was among the most impressive at ASCO as 60% of the patients showed a five-year progression-free survival. "These results from the CROWN trial are unprecedented, as the majority of patients on LORBRENA are living beyond five years without disease progression," said Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer. "These results are an excellent example of Pfizer's long-standing commitment to discovering and developing scientific breakthroughs for patients, and support LORBRENA as a standard of care for the first-line treatment of people with ALK-positive advanced NSCLC." Another class of drugs that garnered attention at ASCO 2024 was KRAS inhibitors. However, the trial results from Bristol-Myers Squibb Company (BMS) (NYSE: BMY) and Amgen each experienced challenges. Although KRAS mutations are common in non-small cell lung cancer (NSCLC), and despite the drug being granted accelerated approval by the FDA in 2022, BMS's Krazati underperformed when looking at median progression-free survival, even though it reduced tumor progression risk by 42%. Krazati's median progression-free survival (PFS) – the period during which a patient's condition remains stable after treatment – extended beyond chemotherapy by 1.7 months in a confirmatory study. "The accelerated approval of KRAZATI from the FDA in 2022 was welcome news for patients with KRASG12C-mutated locally advanced or metastatic NSCLC," said Abderrahim Oukessou, M.D., Vice President, Global Program Lead, KRAZATI, Bristol Myers Squibb. "These confirmatory results further support KRAZATI as an efficacious, targeted treatment option for these patients. We look forward to further sharing these results, while also continuing to evaluate KRAZATI in other advanced KRASG12C-mutated solid tumors." Article Source: USA NEWS GROUP [email protected] (604) 265-2873 DISCLAIMER: Nothing in this publication should be considered as personalized financial advice. We are not licensed under securities laws to address your particular financial situation. No communication by our employees to you should be deemed as personalized financial advice. Please consult a licensed financial advisor before making any investment decision. This is a paid advertisement and is neither an offer nor recommendation to buy or sell any security. We hold no investment licenses and are thus neither licensed nor qualified to provide investment advice. The content in this report or email is not provided to any individual with a view toward their individual circumstances. USA News Group is a wholly-owned subsidiary of Market IQ Media Group, Inc. ("MIQ"). MIQ has been paid a fee for Oncolytics Biotech Inc. advertising and digital media from the company directly. There may be 3rd parties who may have shares of Oncolytics Biotech Inc., and may liquidate their shares which could have a negative effect on the price of the stock. This compensation constitutes a conflict of interest as to our ability to remain objective in our communication regarding the profiled company. Because of this conflict, individuals are strongly encouraged to not use this publication as the basis for any investment decision. The owner/operator of MIQ own shares of Oncolytics Biotech Inc. which were purchased in the open market, and reserve the right to buy and sell, and will buy and sell shares of Oncolytics Biotech Inc. at any time without any further notice commencing immediately and ongoing. We also expect further compensation as an ongoing digital media effort to increase visibility for the company, no further notice will be given, but let this disclaimer serve as notice that all material, including this article, which is disseminated by MIQ has been approved by Oncolytics Biotech Inc.; this is a paid advertisement, we currently own shares of Oncolytics Biotech Inc. and will buy and sell shares of the company in the open market, or through private placements, and/or other investment vehicles. While all information is believed to be reliable, it is not guaranteed by us to be accurate. Individuals should assume that all information contained in our newsletter is not trustworthy unless verified by their own independent research. Also, because events and circumstances frequently do not occur as expected, there will likely be differences between the any predictions and actual results. Always consult a licensed investment professional before making any investment decision. Be extremely careful, investing in securities carries a high degree of risk; you may likely lose some or all of the investment. SOURCE USA News Group

Clinical ResultASCOImmunotherapyPhase 3Phase 1

13 Jun 2024

·www.fiercepharma.com

Pfizer expects 8 blockbuster cancer drugs to come from each of 4 focus areas: exec

Pfizer’s internal calculation suggests that “on paper” more than eight cancer drugs could become blockbusters, even though the company is only publicly targeting eight for now, Suneet Varma, Pfizer Oncology’s commercial president, said. During a recent investor event dedicated to the newly expanded oncology business, Pfizer unveiled a goal to have eight blockbuster cancer drugs by 2030 but fell short of naming specific products. That contribution of blockbusters will come from each of Pfizer Oncology’s four focused therapeutic areas, Suneet Varma, the division’s commercial president, told Fierce Pharma in an interview on the sidelines of American Society of Clinical Oncology annual meeting in Chicago. The four fields are breast, genitourinary, hematology and thoracic cancers. Pfizer’s internal calculation suggests that “on paper” more than eight cancer drugs could become blockbusters, but the New York pharma decided that eight is what it can stand by now, Varma added. Pfizer is betting big on oncology with the $43 billion acquisition of antibody-drug conjugate specialist Seagen last year. The heavy investment runs in parallel with some multiyear, multi-billion-dollar cost-cutting schemes as once high-flying sales from COVID products fell back to earth. Like many Big Pharma deals, the Seagen tie up came with its own consolidation, including a round of proposed layoffs in Switzerland and scrapping of a manufacturing facility in Washington. The oncology department won’t be affected by Pfizer’s latest multiyear cost reduction, or, as Varma put it: “there’s nothing more to be done in oncology.” The unit has already finished its organizational shuffles and cost containment efforts, including as part of the integration between Pfizer and Seagen, he said. Pfizer in December made oncology a separate division within the group and named then-oncology R&D head Chris Boshoff, M.D., Ph.D., as chief oncology officer. As to whether Pfizer Oncology might expand its commercial infrastructure further, Varma said, “We’re at the scale that we think we need to be.” Lung cancer reaching 'critical mass' Among the four focus areas, thoracic cancer, or mainly lung cancer, is currently the weakest link in Pfizer’s portfolio. But Varma argued that “lung will become its own franchise when it has that sufficient critical mass, which I think is upon us.” At the ASCO meeting a few days ago, Pfizer unveiled updated phase 3 results for the next-generation ALK inhibitor Lorbrena in newly diagnosed advanced ALK-positive non-small cell lung cancer. After five years, 60% of patients who got Lorbrena in the CROWN trial remained alive without disease progression, compared with just 8% for those who got Pfizer’s old ALK drug Xalkori. By investigators’ analysis, Lorbrena led to an 81% reduction in the risk of disease progression or death, or a 94% reduction in progression of brain metastases, over Xalkori. The progression-free survival results were compelling, and they compare well across trials with Roche’s current first-line standard of care, Alecensa, which reported a five-year overall survival rate of 62.5% in a phase 3 Xalkori head-to-head trial, Leerink Partners analysts said in a May 31 note. Since its first-line approval in March 2021, Lorbrena hasn’t really threatened Alecensa’s leading position in the ALK space. In 2023, Alecensa brought Roche 1.5 billion ($1.7 billion) Swiss francs in sales, while Lorbrena ginned up $539 million for Pfizer. An FDA approval in April also just moved Alecensa into postsurgical treatment of early-stage cancers, whereas Pfizer currently doesn’t have any studies geared toward that indication. One problem that has stopped more doctors from using Lorbrena in the first-line setting has to do with the drug’s neuro toxicities, including such side effects as seizures, changes in cognitive functions or mood, mental status, among others. Lorbrena’s best-in-class tumor progression results could persuade some doctors and patients to use it upfront, “although we do not expect it to rapidly become standard of care given the toxicity and tolerability profile, especially with no approved drugs to treat patients failing [Lorbrena],” the Leerink analysts noted. But Varma said Pfizer remains “very bullish” on Lorbrena. “Yes, there’s extra therapy management required,” Varma acknowledged. “But it’s worth it because years of life are being added to the patients.” “When we look at the data of people who switched [to Lorbrena], the outcomes are not as good,” Varma said. “So we believe firmly in your first chance is your best chance with Lorbrena.” Pfizer is applying to Lobrena some therapy management know-how brought over by the Seagen team, Varma noted. ADCs often come with complex side-effect profiles, and Seagen’s advice there could be helpful. Genitourinary franchise to surpass breast cancer portfolio The addition of Seagen and its ADC portfolio also allows Pfizer to expand commercial capabilities in biologics as the pharma giant’s cancer portfolio has historically been dominated by small molecules. The Pfizer-Seagen cross-boosting goes in both ways, Varma said. Pfizer has its large scale and sophistication in commercialization. Pfizer Oncology’s commercial and medical sales team was already double the size of Seagen’s before the combination, and the large pharma company is now applying its digital and publicist tools to all Seagen products. Legacy Seagen’s Astellas-partnered bladder cancer drug Padcev is among the top 10 brands that Pfizer Oncology is granting “disproportionate attention” for investment and resources, sales force prioritization and agency assistance, Varma said. Thanks to some impressive first-line bladder cancer data in a combination with Merck & Co.’s Keytruda, Padcev has swept the oncology community off its feet. And Pfizer has put the Nectin-4 ADC’s peak sales at more than $3 billion from around $700 million last year, Varma said. The Pfizer exec has divided up the genitourinary cancer team into two franchises reporting directly to him: one for prostate cancer that’s built around Astellas-partnered blockbuster drug Xtandi, and the other for bladder and kidney cancers. “By separating prostate from bladder and having two GU teams, they get tremendous focus,” Varma said. Because of Padcev’s great commercial prospect, Pfizer sees GU as becoming the oncology unit’s largest franchise supplanting breast cancer between now and 2030 despite Xtandi’s expected U.S. patent cliff in 2027. Besides Padcev and Xtandi, Pfizer also has the PARP inhibitor Talzenna, which is approved alongside Xtandi in certain prostate cancer patients. In the pipeline, the company has the EZH2 inhibitor mevrometostat, which is being moved into phase 3 trials in prostate cancer; and the subcutaneous PD-1 inhibitor sasanlimab, which is initially being angled toward bladder cancer. In addition, the HER2 ADC, disitamab vedotin, also has FDA breakthrough therapy designation in HER2-positive advanced bladder cancer. As to breast cancer, the fall of Pfizer’s largest oncology asset, Ibrance, is already on full display ahead of a 2027 patent cliff. Sales from the CDK4/6 inhibitor dropped 7% year over year in 2023 to $4.75 billion as the first-in-class med faces intense competition from rival drugs by Novartis and Eli Lilly. Still, Varma suggested that Ibrance has reached “stabilization.” The aging product for now owns about half of the CDK4/6 market share and about a third of new patient starts, he said. Ibrance still plays a “foundational role” that allows other Pfizer franchises to grow and launch, Varma said. But he declined to offer a projection on where and when Ibrance might eventually bottom out. Down the pipeline, Pfizer has highlighted the selective CDK4 inhibitor atirmociclib, which it believes could become a next-generation backbone in HR-positive breast cancer. There’s also vepdegestrant, an estrogen receptor protein degrader. What’s more, disitamab vedotin could have a place behind AstraZeneca and Daiichi Sankyo’s much-touted ADC Enhertu in the HER2 breast cancer space. And Seagen’s former CEO David Epstein has touted that Enhertu-relapsed setting as a blockbuster opportunity as well. Elsewhere in blood cancer, Pfizer is going toe-to-toe with Johnson & Johnson with their BCMA-directed T-cell engager for multiple myeloma. As J&J’s myeloma franchise is unrivaled for its modality breadth and commercial scale, Pfizer will face a tough fight even for a company of its size. Varma suggested that J&J’s franchise effect in myeloma won’t stop doctors from using Pfizer’s Elrexfio. And Seagen is here to help again, as Takeda-partnered Hodgkin lymphoma ADC Adcetris was the Seattle biotech’s biggest product before the merger. Despite his expressed confidence in Pfizer’s ability to reach eight cancer blockbusters by 2030, Varma again wouldn’t specify which drugs could reach that threshold. In a March note, Guggenheim analysts figured Padcev, Elrexfio, atirmociclib, vepdegestrant, mevrometostat, disitamab vedotin and sigvotatug vedotin (IB6 ADC) could make the cut.

Phase 3Drug ApprovalClinical ResultASCOBreakthrough Therapy

03 Jun 2024

·pmlive.com

Pfizer shares positive five-year results for Lorbrena in advanced lung cancer

Pfizer has shared positive longer-term follow-up results from a late-stage study of its anaplastic lymphoma kinase (ALK) inhibitor Lorbrena (lorlatinib) in advanced non-small cell lung cancer (NSCLC). The phase 3 CROWN trial has been comparing the drug to Pfizer’s tyrosine kinase inhibitor Xalkori (crizotinib) in patients with previously untreated ALK-positive disease. Results, presented at this year’s American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the Journal of Clinical Oncology , showed that 60% of patients treated with Lorbrena were alive without disease progression after five years compared to 8% of those in the Xalkori cohort. The updated results also demonstrated an 81% reduction in the rate of disease progression or death and a 94% reduction in the risk of developing intracranial progression in the Lorbrena treatment arm compared to the Xalkori group. The safety profiles of both drugs in the five-year follow-up were consistent with previous findings, with no new safety signals reported for Lorbrena. Roger Dansey, chief development officer of oncology at Pfizer, said: “These results from the CROWN trial are unprecedented… and support Lorbrena as a standard of care for the first-line treatment of people with ALK-positive advanced NSCLC.” Lung cancer is the number one cause of cancer-related death globally and NSCLC accounts for up to 85% of all diagnoses. ALK-positive tumours occur in 3% to 5% of NSCLC cases, translating to approximately 72,000 people who are diagnosed worldwide every year. Lorlatinib, which already holds approvals to treat certain adults with ALK-positive NSCLC, is designed to inhibit tumour mutations that drive resistance to other ALK inhibitors and to penetrate the blood-brain barrier. Principal investigator of CROWN, Benjamin Solomon, Peter MacCallum Cancer Centre, said: “This updated analysis shows that Lorbrena helped patients live longer without disease progression, with the majority of patients experiencing sustained benefit for over five years, including nearly all patients having protection from progression of disease in the brain. “These improvements in outcomes for patients with ALK-positive NSCLC represent a remarkable advancement in lung cancer.” The company also presented at ASCO overall survival results from a phase 3 study evaluating Adcetris (brentuximab vedotin) in combination with lenalidomide and rituximab as a treatment for patients with relapsed/refractory diffuse large B-cell lymphoma.

Clinical ResultASCOPhase 3

100 Deals associated with Lorlatinib

External Link

KEGG	Wiki	ATC	Drug Bank
D11012	Lorlatinib	L01XE44	DB12130

R&D Status

Approved

10 top approved records.

to view more data

Indication	Country/Location	Organization	Date
ALK positive Non-Small Cell Lung Cancer	US	Pfizer Inc.	02 Nov 2018
Non-Small Cell Lung Cancer	JP	Pfizer Inc.	21 Sep 2018

Developing

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Ganglioneuroblastoma	Phase 3	US	National Cancer Institute	14 May 2018
Ganglioneuroblastoma	Phase 3	CA	National Cancer Institute	14 May 2018
Ganglioneuroblastoma	Phase 3	PR	National Cancer Institute	14 May 2018
metastatic non-small cell lung cancer	Phase 2	US	Pfizer Inc.	18 Dec 2015
metastatic non-small cell lung cancer	Phase 2	JP	Pfizer Inc.	18 Dec 2015
metastatic non-small cell lung cancer	Phase 2	AU	Pfizer Inc.	18 Dec 2015
metastatic non-small cell lung cancer	Phase 2	KR	Pfizer Inc.	18 Dec 2015
metastatic non-small cell lung cancer	Phase 2	ES	Pfizer Inc.	18 Dec 2015
Advanced Lung Non-Small Cell Carcinoma	Phase 2	US	Pfizer Inc.	08 Jan 2014
Advanced Lung Non-Small Cell Carcinoma	Phase 2	JP	Pfizer Inc.	08 Jan 2014

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03726333 (CTgov)	Phase 1	Hepatic Insufficiency \| Advanced cancer	1	lorlatinib	cdapyfsbfa(mnddmdjbsm) = fqgfsautwo abgqvezqxd (yyyagqhokx, dxtkkclxwn - rfbiwhurbx) View more	-	21 Jun 2024
NCT03052608 (CROWN, ASCO2024) Manual	Phase 3	ALK positive Non-Small Cell Lung Cancer First line	296	Lorlatinib 100 mg (With Baseline Brain Metastases)	pgxsvuoxql(ndgyhxphki) = zaxbvywqsm mvonjmmdlx (gjhvjvuszj, 32.9 - NR) View more	Positive	02 Jun 2024
				Crizotinib 250 mg (With Baseline Brain Metastases)	pgxsvuoxql(ndgyhxphki) = vnbmufzojh mvonjmmdlx (gjhvjvuszj, 3.7 - 7.6) View more
NCT03612154 (ASCO2024) Manual	Phase 2	Reactive oxygen species 1 positive non-small cell lung cancer First line ROS1 Positive	32	Lorlatinib 100mg	djczvoqflo(sgdaqiwynr) = hklwhedkmo izgcmozcgn (lxbbxnneil, 52 - 83) View more	Positive	24 May 2024
				Lorlatinib 100mg (treatment naïve)	djczvoqflo(sgdaqiwynr) = pnfrblxpte izgcmozcgn (lxbbxnneil ) View more
ESMO_ELCC2024	Not Applicable	Dyslipidemias \| Weight Gain ALK+ \| ROS1+	43	Lorlatinib	fbasairaxy(wurlwjatsk) = qoaimpyzjo flpifegvxj (qhtxdhosoe ) View more	Positive	22 Mar 2024
ASH2023	Phase 2	Recurrent Lymphoma \| Refractory Lymphoma	6	Lorlatinib	zgagsehwnk(uwgbzvqncu) = dxxcrwdzwv tdnmakzkmv (sokmpvykbc, 0.6 - 1.0)	-	11 Dec 2023
ESMO2023 Manual	Not Applicable	Non-Small Cell Lung Cancer	1,147	Lorlatinib	zhaqenzdth(fngwnvmolk) = hvgjoomsgd cubdcpddid (ygwfylhams, 8.40 - 22.73) View more	Positive	23 Oct 2023
				Lorlatinib (clinical trials)	zhaqenzdth(fngwnvmolk) = puzzfrxjlr cubdcpddid (ygwfylhams ) View more
NCT03909971 (WCLC2023) Manual	Phase 2	ALK positive Non-Small Cell Lung Cancer ALK Positive	109	Lorlatinib 100 mg	kozbomkakb(gmodhtqbwl) = glcbsbbgow fxbqmoftau (ezktttgakt ) View more	Positive	10 Sep 2023
				Lorlatinib 100 mg (cohort 1 + ALK-positive locally advanced or metastatic NSCLC and disease progression after crizotinib as the only ALK inhibitor)	shtmwqnhpv(lbrnqgqglx) = klysnbjelb eqagsugkut (wnizfkamon, 46.9 - 77.9) View more
NCT03052608 (CROWN study, Pubmed)	Phase 3	Advanced Lung Non-Small Cell Carcinoma	296	Lorlatinib	gbwxqtgebf(dloiwufztz) = glhzngzpja gxhqatpzvc (hvdfnkvuxi ) View more	-	12 Jun 2023
				Crizotinib	gbwxqtgebf(dloiwufztz) = gwwkpasnce gxhqatpzvc (hvdfnkvuxi ) View more
NCT03052608 (CROWN study, Pubmed)	Phase 3	ALK positive Non-Small Cell Lung Cancer	296	Lorlatinib	ufyykmjupp(ginxoqeeok): HR = 0.5 (95% CI, 0.23 - 1.12) View more	-	07 Jun 2023
				Crizotinib
NCT03107988 (Pubmed \| Nat Med)	Phase 1	Refractory Neuroblastoma	65	Lorlatinib as a single agent in children	kgkjkbvkwu(mxgezfatsh) = kseuqnxwqk lcvhfowfjl (mramjbhauo ) View more	-	03 Apr 2023
				Lorlatinib as a single agent in adults	kgkjkbvkwu(mxgezfatsh) = ysfuqhxzgl lcvhfowfjl (mramjbhauo ) View more

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Leverages most recent intelligence information, enabling fullest potential.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis