RegulationBreakthrough Therapy (US), Orphan Drug (US), Orphan Drug (AU), Overseas New Drugs Urgently Needed in Clinical Settings (CN), Fast Track (US)

Gene Sequence

Sequence Code 13007203H

Source: *****

Sequence Code 13007633L

Source: *****

Clinical Trials associated with Olaratumab

NCT03437070 / WithdrawnPhase 1IIT

A Phase I Study of Trabectedin in Combination With Fixed Doses of Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma

This study seeks to determine if addition of trabectedin (T) to combination doxorubicin (D) and olaratumab (O), is feasible and tolerable with antitumor activity in metastatic or recurrent Leiomyosarcomas (LMS) patients who have limited therapeutic options.

Start Date01 Jun 2019

Sponsor / Collaborator

University of Miami

[+1]

NCT03698227 / TerminatedPhase 2

Efficacy of Olaratumab and Rechallenge With Doxorubicin in Anthracycline Pretreated, Advanced Soft Tissue Sarcoma Patients. An Exploratory Phase-II Study

This is an exploratory, prospective, open label, single arm, phase II-study for the evaluation of efficacy and feasibility (as determined by safety and tolerability) of olaratumab and doxorubicin rechallenge in anthracycline pretreated locally advanced (unresectable) or metastatic soft tissue sarcoma patients.

Start Date12 Nov 2018

Sponsor / Collaborator-

NCT03985722 / Active, not recruitingPhase 1IIT

Phase I Clinical Trial of Olaratumab Plus Trabectedin in Advanced Soft-tissue Sarcoma Patients

Phase I, multicentre clinical trial of olaratumab plus trabectedin in patients with advanced soft-tissue sarcoma.
Olaratumab plus trabectedin could be synergistic and with a manageable toxicity profile in advanced STS.
The study is a phase I, non-randomised, one-armed, multicenter trial, open-label.
The dose escalation rules include patients in blocks of 3 o 6 patient. Treatment is a combination of unlimited cycles of oralatumab and trabectedin.
Primary clinical study endpoint of phase I:
- Determine the maximum tolerated dose (MTD) or the recommended dose of olaratumab combined with trabectedin in advanced soft tissue sarcoma
Secondary clinical study endpoints:
Objective Response Rate (ORR): ORR is defined as the number of subjects with a Best Overall Response (BOR) according to RECIST 1.1.
Progression free survival (PFS): time to progression or death from treatment initiation.
Overall survival (OS): Time from treatment initiation until death. Efficacy measured through tumor response according to Choi criteria. The evaluation criteria will be based on the identification of target lesions in baseline and their follow-up until tumor progression.
Correlation of clinical outcome with translational biomarkers.
Quality of life (QoL) measured per QLQ-C30 questionnaire of EORTC

Start Date21 Sep 2018

Sponsor / Collaborator

Grupo Español de Investigación en Sarcomas

100 Clinical Results associated with Olaratumab

100 Translational Medicine associated with Olaratumab

100 Patents (Medical) associated with Olaratumab

107

Literatures (Medical) associated with Olaratumab

03 Jun 2024·Clinical cancer research : an official journal of the American Association for Cancer Research

Best Overall Response–Associated Signature to Doxorubicin in Soft Tissue Sarcomas: A Transcriptomic Analysis from ANNOUNCE

Article

Author: Wright, Jennifer ; Wagner, Andrew J ; Jones, Robin L ; Liu, Jiangang ; Moura, David S ; Aggarwal, Amit ; Ebert, Philip J ; Martin-Broto, Javier ; Tap, William D

Abstract:

Purpose::

This exploratory analysis evaluated the tumor samples of the patients treated with doxorubicin (with or without olaratumab) in a negative phase III ANNOUNCE trial to better understand the complexity of advanced soft tissue sarcomas (STS) and to potentially identify its predictive markers.

Experimental Design::

RNA sequencing was performed on pretreatment tumor samples (n = 273) from the ANNOUNCE trial to evaluate response patterns and identify potential predictive treatment markers for doxorubicin. A BOR-associated signature to doxorubicin (REDSARC) was created by evaluating tumors with radiographic response versus progression. An external cohort of doxorubicin-treated patients from the Spanish Group for Research on Sarcomas (GEIS) was used for refinement and validation.

Results::

A total of 259 samples from the trial were considered for analysis. Comparative analyses by the treatment arm did not explain the negative trial. However, there was an association between the BOR signature and histologic subtype (χ2P = 2.0e−7) and grade (P = 0.002). There were no associations between the BOR signature and gender, age, ethnicity, or stage. Applied to survival outcomes, REDSARC was also predictive for progression-free survival (PFS) and overall survival (OS). Using the GEIS cohort, a refined 25-gene signature was identified and applied to the ANNOUNCE cohort, where it was predictive of PFS and OS in leiomyosarcoma, liposarcoma, and other sarcoma subtypes, but not in undifferentiated pleomorphic sarcoma.

Conclusions::

The refined REDSARC signature provides a potential tool to direct the application of doxorubicin in sarcomas and other malignancies. Validation and further refinement of the signature in other potentially subtype specific prospective cohorts is recommended.

01 Jun 2024·CURRENT TREATMENT OPTIONS IN ONCOLOGY

What are the Optimal Systemic Treatment Options for Rhabdomyosarcoma?

Review

Author: Demura, Satoru ; Miwa, Shinji ; Asano, Yohei ; Hayashi, Katsuhiro ; Taniguchi, Yuta

OPINION STATEMENT:

Rhabdomyosarcoma, a soft tissue sarcoma commonly observed in childhood, requires multidisciplinary treatment, including surgical tumor resection, chemotherapy, and radiation therapy. Although long-term survival can be expected in patients with localized rhabdomyosarcoma, the clinical outcomes in patients with metastatic or unresectable rhabdomyosarcoma remain unsatisfactory. To improve the outcomes of rhabdomyosarcoma, it is important to explore effective systemic treatments for metastatic rhabdomyosarcoma. Currently, multiagent chemotherapy comprising vincristine, actinomycin D, and ifosfamide/cyclophosphamide remains standard systemic treatment for rhabdomyosarcoma. On the other hand, new treatment, such as immune checkpoint inhibitors and molecular targeted drugs, have demonstrated superior clinical outcomes compared to those of standard treatments in various type of malignancies. Therefore, it is necessary to assess the efficacies of these treatments in patients with rhabdomyosarcoma. Recent clinical studies have shown efficacies and safeties of temozolomide combined with vincristine/irinotecan, olaratumab combined with doxorubicin or vincristine/irinotecan, and long-term maintenance therapy. Furthermore, basic researches demonstrated new therapeutic targets. Future studies using these approaches are required to assess their clinical significances.

06 Oct 2023·Cancers

Randomized Phase 2 Clinical Trial of Olaratumab in Combination with Gemcitabine and Docetaxel in Advanced Soft Tissue Sarcomas.

Article

Author: Dickson, Mark A ; Jones, Robin L ; Ceccarelli, Matteo ; Peterson, Patrick M ; Wagner, Andrew J ; Chmielowski, Bartosz ; Hindi, Nadia ; Villalobos, Victor ; Attia, Steven ; Oakley, Gerard J

Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Adults with unresectable locally advanced/metastatic STS, ≤2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. In Phase 2, patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab (20 mg/kg Cycle 1 and 15 mg/kg other cycles, Days 1 and 8), gemcitabine (900 mg/m², Days 1 and 8), and docetaxel (75 mg/m², Day 8). The primary objective was overall survival (OS) in the O-naïve population (α level = 0.20). Secondary endpoints included OS (O-pretreated), other efficacy parameters, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. Baseline patient characteristics were well balanced. No statistically significant difference in OS was observed between the investigational vs. control arm for either cohort (O-naïve cohort: HR = 0.95 (95% CI: 0.64-1.40), p = 0.78, median OS, 16.8 vs. 18.0 months; O-pretreated cohort: HR = 0.67 (95% CI: 0.39-1.16), p = 0.15, median OS 19.8 vs. 17.3 months). Safety was manageable across treatment arms. There was no statistically significant difference in the primary endpoint of OS between the two arms in the O-naïve population, and therefore based on hierarchical evaluation no other outcomes in this study can be considered statistically significant. No new safety signals were observed.

News (Medical) associated with Olaratumab

14 Sep 2024

·www.globenewswire.com

Avacta Reports Updated Phase 1 Clinical Data of AVA6000 at the European Society for Medical Oncology (ESMO) Congress Demonstrating Multiple Ongoing, Durable Responses in Solid Tumors

This announcement contains inside information for the purposes of Article 7 of the UK version of Regulation (EU) No 596/2014 which is part of UK law by virtue of the European Union (Withdrawal) Act 2018, as amended ("MAR"). Upon the publication of this announcement via a Regulatory Information Service, this inside information is now considered to be in the public domain. 14 September 2024 Avacta Group plc (“Avacta” or “the Group” or “the Company”) Avacta Reports Updated Phase 1 Clinical Data of AVA6000 at the European Society for Medical Oncology (ESMO) Congress Demonstrating Multiple Ongoing, Durable Responses in Solid Tumors AVA6000 is safe and well-tolerated in both study arms: every three weeks (Q3W) and every two weeks (Q2W) dosing, with an early lack of serious cardiac safety signal and preliminary evidence of efficacy Multiple ongoing and durable RECIST responses observed in patients with FAPhigh and doxorubicin sensitive diseases including in patients with stroma-only expression of FAP pre|CISION-enabled doxorubicin (AVA6000) results in multiple fundamental changes in the pharmacokinetics of released doxorubicin in plasma and tumor versus conventional doxorubicin Avacta Group plc (AIM: AVCT), a life sciences company developing innovative, targeted cancer treatments and powerful diagnostics, is today presenting updated data from the ongoing Phase 1a trial of AVA6000 in patients with FAP-positive solid tumors at the 2024 European Society for Medical Oncology (ESMO) Congress, in Barcelona, Spain. The results demonstrate that AVA6000 is well-tolerated across the every 2 weeks and every 3 weeks dosing schedules with early evidence of efficacy supported by ongoing and durable RECIST responses in patients with FAPhigh disease. AVA6000 is the first peptide drug conjugate (PDC) in the Avacta pipeline and consists of doxorubicin conjugated with a peptide moiety that is specifically cleaved by Fibroblast Activation Protein (FAP) in the tumor microenvironment (TME). Professor Chris Twelves, Lead Investigator and Professor of Medicine, University of Leeds, commented: "The AVA6000 data presented at ESMO continue to demonstrate encouraging efficacy with several ongoing, durable responses. The observed efficacy aligns with a highly favorable safety profile including a lack of the significant cardiac toxicity that is often seen with doxorubicin treatment. “The mechanism of action of the pre|CISION™ peptide drug conjugates with the observed warhead release in tumors with lower FAP activity together speak to the potential of this platform to treat a broad range of solid tumor patient populations with clinical needs that are not being met. I am looking forward to working with the Company, colleagues and patients on the continued development of AVA6000." Christina Coughlin MD, PhD, Chief Executive Officer of Avacta, added: “With nearly six months of added follow-up, these compelling data strengthen the clinical validation for AVA6000 and the pre|CISIONTM drug delivery platform to challenge current drug delivery methods and expand the reach of highly potent therapeutics using peptide drug conjugates. “We believe our platform has the potential to revolutionize cancer treatment by enabling patients to achieve improved outcomes with fewer side effects by leveraging the tumor specific enzyme FAP to protect normal tissues from toxic drugs. The observation of warhead release in the tumor even in the setting of lower FAP activity is highly encouraging for our pipeline. We are excited to move our Company into the next stage of development, implementing these findings of this drug release mechanism across our innovative pipeline.” Trial Results Summary As at the latest data cut-off date, ten dose cohorts (n=57) have completed the Phase 1a trial under the Arm 1 dosing schedule of every three weeks (“Q3W”) and the Arm 2 dosing schedule of every two weeks (“Q2W”). In total, 57 patients were enrolled and are evaluable for safety (primary outcome measure) and 49 patients formed the efficacy evaluable dataset (secondary outcome measure). Efficacy data Cancer indications were categorized based on published data regarding both immunohistochemistry and FAPI-PET studies as FAPhigh (soft tissue sarcoma and salivary gland cancer) or FAPmid (pancreatic cancer, colorectal cancer, lung cancer and other malignancies). Patients with indications considered FAPlow were excluded from the trial. Patients had a median of two prior systemic cancer therapies (range 0-7) with 65% including cytotoxic exposure. Reduction in the sum of longest diameters (SLD) is used to measure response per RECIST 1.1 with partial responses of >30% reduction and minor responses of between >10% and <30% reduction. Among patients with FAPhigh cancers (n=23), three partial responses and four minor responses were observed, including: A durable, confirmed partial response at 12 weeks in a 79-year-old male patient with progressive salivary gland cancer (SGC). After an initial minor response (22% reduction in SLD), the observed durable PR is ongoing despite patient discontinuation due to lifetime maximum dosing (duration of response >18 weeks, with 46.2% reduction in SLD). Tumor histology demonstrates no expression of FAP in tumor cells with only stromal cell expression noted.A minor response (14.6% reduction in SLD at first 8-week scan) in a 65-year-old female patient with SGC who remains on the trial. This patient was dosed in the 250 mg/m2 Q2W cohort of the trial and had progression on a prior line of therapy. This patient continues on study. Similarly, the histology shows FAP-negative tumor cells and FAP expression only in the stromal compartment.A partial response (40.5% reduction in SLD) in a 55-year-old male patient with dedifferentiated liposarcoma who had progressed on two prior lines of therapy in the metastatic setting. After an initial minor response this patient experienced a partial response with SLD change of -40.6%. The patient experienced new lesions at their latest follow-up scan. Eight patients remain on study in the Phase 1a cohorts with a diagnosis of FAPhigh cancers Among patients with FAPmid cancers (n=26), two minor responses were observed. Safety and Pharmacokinetics Data Treatment with AVA6000 continues to be well-tolerated with the addition of the Q2W dosing regimen (Arm 2) with a favorable safety profile and reduction in severe and mild-to-moderate treatment-emergent toxicities as compared with conventional dose doxorubicin. A maximum tolerated dose has not been identified in either arm of the trial. Severe (CTCAE grade 3 or 4) neutropenia was observed in 14% of AVA6000 patients vs 49% treated with conventional dose doxorubicin (comparison made to a Ph III trial where doxorubicin monotherapy is the comparator arm in a similar patient population).1 There were no cases of febrile neutropenia in the AVA6000 trial compared to 16.5% of patients receiving conventional doxorubicin alone in a similar patient population1 The observed cardiac safety profile of AVA6000 compares favorably to conventional dose doxorubicin, with low incidence of left ventricular ejection fraction (LVEF) changes (LVEF dysfunction 12.3% v. 48.4% with conventional doxorubicin1,2) and no grade 3 or 4 severe cardiac events reportedReductions were observed in toxicities that impact quality of life including nausea, mouth sores, decreased appetite, constipation and vomiting and similar reductions were observed with both the Q3W and Q2W dosing schedules.as compared to conventional doxorubicin dosing1No new dose limiting toxicities were observed and neither arm has determined an MTD Treatment with AVA6000 results in multiple fundamental changes in the PK of released doxorubicin (compared to conventional doxorubicin administration3) including: Extension of the plasma half-life by ~40% Reduction of approximately 40-50% in both Cmax and the peripheral volume of distribution, suggesting AVA6000-released doxorubicin demonstrates a more limited distribution into normal tissues versus conventional doxorubicin4,5 Tumor biopsies taken 24 hours after the first dose of AVA6000 reveal additional insights regarding the role of FAP, in that the level of FAP positivity in the tumor appears not to correlate with the level of released doxorubicin in the TME (n=9). This lack of correlation indicates that lower levels of FAP activity are sufficient for warhead release. These data provide evidence for targeting of the FAPmid tumor types with novel warheads. pre|CISIONTM technology Many solid tumors have higher levels of FAP compared with healthy tissues. Avacta’s pre|CISIONTM technology is designed to leverage the tumor-specificity of FAP expression by rendering a therapeutic warhead inert with the bound peptide moiety attached to the warhead, until it encounters FAP and is cleaved, releasing active warhead into the TME. FAP targeted release of the warhead specifically in the TME aims to reduce damage to healthy tissues and systemic side effects, improving the tolerability for patients and allowing optimization of the dosing schedule to improve efficacy. References1Tap WD, et al. Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial. JAMA. 2020;323(13):1266-1276. doi: 10.1001/jama.2020.17072Jones, RL et al. Prospective evaluation of doxorubicin cardiotoxicity in patients with advanced soft tissue sarcoma in the ANNOUNCE Phase III randomized trial. Clin Ca Res 2021;27:3751-66. doi: 0.1158/1078-0432.CCR-20-4592 3Villalobos VM, et al. Pharmacokinetics of doxorubicin following concomitant intravenous administration of olaratumab (IMC-3G3) to patients with advanced soft tissue sarcoma. Cancer Med. 2020;9(3):882-893. doi: 10.1002/cam4.27284Kontny N et al, Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years, Cancer Chemother Pharmacol 2013;71(3):749-63. doi: 10.1007/s00280-013-2069-15Pérez‐Blanco JS et al, Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non‐Hodgkin's lymphoma, Br J Clin Pharmacol. 2016; 82(6): 1517–1527 -Ends- For further information from Avacta Group plc, please contact: Avacta Group plcChristina Coughlin, CEOMichael Vinegrad, Group CommunicationsDirector Tel: +44 (0) 1904 21 7070www.avacta.com Peel Hunt (Nomad and Broker)James Steel / Chris Golden / Patrick Birkholm www.peelhunt.com ICR ConsiliumMary-Jane Elliott / Jessica Hodgson / Sukaina Virji avacta@consilium-comms.com About Avacta Group plc - www.avacta.com Avacta Group is a UK-based life sciences company focused on improving healthcare outcomes through targeted cancer treatments and diagnostics. Avacta Therapeutics: a clinical stage oncology biotech division harnessing proprietary therapeutic platforms to develop novel, highly targeted cancer drugs. Avacta Diagnostics focuses on supporting healthcare professionals and broadening access to diagnostics. Avacta has two proprietary platforms, pre|CISION™ and Affimer®. The pre|CISION™ platform is a highly specific substrate for fibroblast activation protein (FAP) which is upregulated in most solid tumors compared with healthy tissues. The pre|CISION™ platform harnesses this tumor specific protease to activate pre|CISION™ peptide drug conjugates and pre|CISION™ antibody/Affimer® drug conjugates in the tumor microenvironment, reducing systemic exposure and toxicity, allowing dosing to be optimised to deliver the best outcomes for patients. The lead pre|CISION™ program AVA6000, a peptide drug conjugate form of doxorubicin, is in Phase 1 studies. It has shown an improvement in safety and tolerability in clinical trials to date compared with standard doxorubicin and preliminary signs of clinical activity in multiple patients. To register for news alerts by email go to www.avacta.com/investor-news-email-alerts

Clinical ResultPhase 1Phase 3Phase 2

20 Aug 2024

·www.echemi.com

Osimertinib Faces Patent Crisis, $100 Million Compensation Remains Unsettled, Lung Cancer Treatment Market Faces Uncertainty!

In recent days, the long-standing patent dispute between Pfizer and AZ has finally come to an end. According to Reuters, US District Judge Matthew Kennelly dismissed the jury's decision that AZ's lung cancer drug Tagrisso (osimertinib) had infringed Pfizer's anti-cancer drug Nerlynx (neratinib) patent and should pay $107.5 million in damages. The judge ruled that Pfizer's two patents were invalid. In the reversal of this patent lawsuit, neratinib, as a human epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), can irreversibly bind to EGFR (HER1), HER2, and HER4, inhibiting the phosphorylation of the receptor and blocking downstream signal transduction, thereby inhibiting the proliferation, survival, and migration of cancer cells and improving the tumor microenvironment. Pfizer acquired Wyeth for $68 billion in 2009 and included neratinib in its product line. In 2011, Puma Biotechnology obtained a license from Pfizer for neratinib and took full responsibility for the global development and commercialization of the drug. In July 2017, the US Food and Drug Administration (FDA) approved neratinib for reducing the risk of recurrence in early-stage HER2-positive breast cancer. In 2020, the FDA further approved neratinib in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who had received two or more prior therapies. With this indication's approval, neratinib's application range has expanded from early-stage breast cancer patients to patients with advanced or metastatic breast cancer. Osimertinib is the third-generation EGFR-TKI developed by AstraZeneca, which was approved by the FDA in November 2015 for the treatment of non-small cell lung cancer (NSCLC) patients with the T790M gene mutation as a second-line treatment. Currently, osimertinib has been approved for several indications in the NSCLC field. As the market leader of the third-generation EGFR-TKI, osimertinib's sales have continued to rise, reaching $5.799 billion in 2023 and becoming AstraZeneca's flagship product. In 2021, Pfizer's subsidiary Wyeth and Puma Biotechnology filed a lawsuit against AstraZeneca, accusing osimertinib of infringing on their two key patents. One of the patents, "Patent 314," involves a method for treating NSCLC patients who are resistant to gefitinib and/or erlotinib with an EGFR inhibitor that covalently binds to cysteine 773 of the protein. The other is Wyeth's "Patent 162," which protects the use of these irreversible inhibitors to treat NSCLC patients who are resistant to gefitinib or erlotinib and carry a specific T790M mutation in the EGFR protein. In May 2023, a federal jury in Delaware ruled that AstraZeneca had indeed infringed on Pfizer's patent and awarded $107.5 million in damages. Despite AstraZeneca's argument that Pfizer's patent was invalid, the jury did not adopt it. In response to this result, AstraZeneca filed an "additional defense." In the latest ruling, the judge pointed out that two of Pfizer's patents were invalid because they lacked an effective written description of their invention, and that ordinary scientists in the field could not reproduce them based on these descriptions. Therefore, AstraZeneca has won the patent lawsuit. However, there are still many challenges ahead for Osimertinib. At present, lung cancer has become the second most common type of cancer globally, according to statistics from the World Health Organization's International Agency for Research on Cancer (IARC), with lung cancer accounting for 11.1% of all cancer cases worldwide in 2020. Among lung cancer patients, non-small cell lung cancer (NSCLC) accounts for 85% of the total, while small cell lung cancer (SCLC) accounts for the remaining 15%. Epidermal growth factor receptor (EGFR) is one of the most important oncogenic driver genes in NSCLC, and studies have shown that the incidence rate of EGFR mutations in metastatic NSCLC patients is about 30%. In China, the proportion of EGFR mutations among NSCLC patients is about 51%. To date, three generations of EGFR tyrosine kinase inhibitors (EGFR-TKI) have been approved for marketing worldwide. The first and second generation EGFR-TKIs mainly target patients with the EGFR ex19del mutation and the EGFR 21L858R mutation. However, the third-generation drugs are not only effective against these sensitive mutations, but also against the T790M resistance mutation that arises after treatment with the first and second-generation TKIs. Osimertinib, an EGFR-TKI that is already on the market, has seen consistent sales growth since its launch, becoming an important revenue driver for AstraZeneca. However, despite the huge market potential of the third-generation EGFR-TKIs, the competition is extremely fierce, with seven similar products approved globally and six approved in the domestic market. Moreover, the compound patent for Osimertinib in China (CN103702990) will expire in July 2032. Given the huge potential of Osimertinib in the domestic market for imported anti-cancer drugs, Jiangsu Wanbangshenghua Pharmaceutical Group has submitted an application for the approval of a biosimilar and successfully obtained approval. In the field of innovative drugs, Jiangsu Haosen Pharmaceutical's Ametinib and Aileris Pharmaceutical's Fumetinib have been approved for marketing by the National Medical Products Administration (NMPA). Meanwhile, Oseacon's Limertinib, Johnson & Johnson's Lanresertinib, Tongyuan Pharmaceutical's TY-9591, and Aisen Pharmaceutical's Aivetinib have also submitted marketing applications or have entered the III phase clinical trial stage in China. In addition to the competition from similar products, osimertinib is also facing the challenge of dual antibody drugs. Recently, Johnson & Johnson's EGFR/C-MET dual antibody Amivantamab, combined with the third-generation EGFR-TKI Lartruvo (A+L), achieved the primary endpoint of progression-free survival (PFS) in a direct comparison clinical trial with osimertinib monotherapy for the first-line treatment of EGFR-mutated advanced NSCLC. The study results showed that compared with osimertinib, the A+L group significantly reduced the risk of PFS by 30% (HR, 0.70; 95% CI, 0.58-0.85; P<0.001), with a median PFS of 23.7 months (compared with 16.6 months), and an objective response rate (ORR) of 86% (compared with 85%). In terms of overall survival (OS), the median OS for the A+L group could not be estimated (HR, 0.77), while the OS for the osimertinib group was 37.3 months (HR, 0.77). The OS reached a statistically significant endpoint, indicating that A+L may become a new standard for the first-line treatment of EGFR-mutated NSCLC. Faced with the dual pressure of generic drugs and innovative drugs, AstraZeneca's osimertinib is facing a severe competitive situation. Nevertheless, the victory in the patent lawsuit has saved AstraZeneca up to $107 million in potential compensation.

Drug ApprovalAcquisitionLicense out/inPatent InfringementClinical Result

08 Aug 2024

·www.echemi.com

Regulatory Challenges of Gene Therapy and Cancer Drugs: Industry Trends Behind the Withdrawal of Zydelig and FDA's Response

In 2022, Gilead announced that it would voluntarily withdraw Zydelig from the U.S. market for two lymphoma treatments, a full six years after it suspended the trial due to patient deaths. A Gilead spokesperson clarified that the withdrawal was not due to safety concerns, but rather because of insurmountable obstacles to recruiting subjects for additional research trials required by the FDA. Nevertheless, Zydelig retains its eligibility for the treatment of chronic lymphocytic leukemia and remains on the market for patients. Notably, the withdrawal of Zydelig coincides with the withdrawal of several other PI3K inhibitors used to treat follicular lymphoma: Secura Bio's duvelisib (trade name Copiktra) withdrawn in December 2021, TG's umbralisib (trade name Ukoniq) withdrawn in 2022 (here may be a clerical error, read "February" or adjusted to another month), Bayer's copanlisib (trade name Aliqopa) also withdrew from the market in November 2023. Together, these events outline an industry trend. A study published in JAMA Internal Medicine reveals an interesting data point: Before Gilead decided to withdraw some uses of Zydelig from the U.S. market, its global sales had reached a staggering $842 million. This reflects the wide application and high recognition of the drug in the market, although it ultimately failed to fully meet all expectations for various reasons. Interestingly, the pharmaceutical industry sometimes employs a series of ingenious strategies to speed up the process of bringing a product to market. Eli Lilly, for example, successfully used all four avenues of acceleration to bring oncology product Lartruvo to market in 2016. The key clinical data for the product is based only on the results of a trial involving 133 patients, and while the results showed a possible positive impact on survival outcomes for sarcoma, a cancer that affects muscles and other soft tissues, the specific effect on slowing cancer growth is unclear. However, just over two years later, a larger study revealed that Lartruvo had no significant impact on patient survival, and Eli Lilly had to withdraw it from the market. Despite this, Lartruvo still managed to achieve a whopping $500 million in sales during its short market life. Among the many drugs approved for accelerated marketing, oncology products have become the hardest hit by ineffective drugs. However, as the development of therapies continues to deepen and progress, new questions continue to emerge and are presented to the FDA. In particular, advanced therapies represented by cell and gene therapies, when they meet with the accelerated approval system, have brought unprecedented challenges to this "old revolution". Given the complexity of cell and gene therapies and the relative lack of understanding of their safety, once ineffective advanced therapies are released to the market, the consequences and impacts will be far beyond the scope of small molecule ineffective drugs. For example, the tragic death of a three-year-old boy in a clinical trial of Pfizer's fordadistrogene movaparvovec, a gene therapy for Duchenne muscular dystrophy, highlights the shortcomings and limitations of researchers in predicting the potential for serious adverse events. As vectors of ssRNA (single stranded RNA), viruses (such as AAV) play a critical role in gene therapy, but can also cause a series of serious adverse events including cardiopulmonary failure, myocarditis, thrombotic microangiopathy, and acute liver failure. These potential risks have forced the FDA to be more cautious and rigorous in approving gene therapies. Speaking at the annual meeting of the American Society for Gene and Cell Therapy, CBER director Peter Marks said speeding up the withdrawal of approved gene therapies could be easier and faster than for small-molecule therapies. At the same time, he stressed that "accelerated approval of gene therapy is not a get-out-of-jail-free ticket." The FDA will not hesitate to withdraw accelerated approval of rare disease gene therapies if they fail subsequent confirmatory trials." Marks further points out that the "one-size-fits-all" nature of gene therapy makes confirmatory studies easier to follow and monitor patients over time. It also makes for greater clarity and clarity on the question of whether to withdraw gene therapy. In contrast, there may be more controversy and disagreement in the decision process of withdrawing cancer therapy. Marks, however, said the FDA would only withdraw gene therapy if it was clear that the patient benefit was likely to be "minimal" but the side effects were significant. He cited a case in which Bluebird Bio's sickle cell gene therapy Lyfgenia (lovotibeglogene autotemcel) caused patients to develop myelodysplastic syndrome and leukemia during treatment. The product was approved by the FDA in December 2023 with a boxed warning about hematologic malignancies. Marks said it is unclear whether these malignancies are related to the preconditioning regimen associated with Lyfgenia treatment, the underlying disease, or the gene therapy itself. In addition, the case of drug manufacturers refusing to voluntarily withdraw the market is not unique in the history of FDA accelerated approval. Everything from the withdrawal of Makena, a drug that reduced the risk of preterm birth, after 12 years on the market, to the legal battle between Pepaxto and the FDA highlights the complexity and seriousness of the issue. In the face of these challenges, FDA has to seek the support of legislation to strengthen its regulatory power and capability. Fortunately, the introduction of the FDORA (Comprehensive Food and Drug Reform Act) bill provides the FDA with greater flexibility and autonomy to act without public hearings.

Drug ApprovalGene Therapy

100 Deals associated with Olaratumab

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KEGG	Wiki	ATC	Drug Bank
D09939	Olaratumab	L01XC27	DB06043

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Ichthyosis, X-Linked	US	Eli Lilly & Co.	19 Oct 2016
Soft Tissue Sarcoma	US	Eli Lilly & Co.	19 Oct 2016

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Soft Tissue Sarcoma	Phase 3	US	Eli Lilly & Co.	14 Sep 2015
Metastatic Soft Tissue Sarcoma	Phase 3	JP	Eli Lilly & Co.	14 Sep 2015
Metastatic Soft Tissue Sarcoma	Phase 3	AR	Eli Lilly & Co.	14 Sep 2015
Metastatic Soft Tissue Sarcoma	Phase 3	AU	Eli Lilly & Co.	14 Sep 2015
Metastatic Soft Tissue Sarcoma	Phase 3	AT	Eli Lilly & Co.	14 Sep 2015
Metastatic Soft Tissue Sarcoma	Phase 3	BE	Eli Lilly & Co.	14 Sep 2015
Metastatic Soft Tissue Sarcoma	Phase 3	BR	Eli Lilly & Co.	14 Sep 2015
Metastatic Soft Tissue Sarcoma	Phase 3	CA	Eli Lilly & Co.	14 Sep 2015
Metastatic Soft Tissue Sarcoma	Phase 3	DK	Eli Lilly & Co.	14 Sep 2015
Metastatic Soft Tissue Sarcoma	Phase 3	FI	Eli Lilly & Co.	14 Sep 2015

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03126591 (CTgov)	Phase 1	Metastatic Soft Tissue Sarcoma	41	Olaratumab+pembrolizumab (20 mg/kg Olaratumab + 200 mg Pembrolizumab - Dose Escalation)	cjtievgnmy(mdeyyfwsns) = fxjewwmbym tvwbtmeeuo (ysibqoexsa, kwtyhnhjfg - grxepctrms) View more	-	23 Oct 2024
				Olaratumab+pembrolizumab (20 mg/kg Olaratumab + 200 mg Pembrolizumab - Dose Expansion)	cjtievgnmy(mdeyyfwsns) = iushkmzrsd tvwbtmeeuo (ysibqoexsa, olfntaalzw - qfyicmiqot) View more
NCT03086369 (CTgov)	Phase 1/2	Secondary malignant neoplasm of pancreas	184	Olaratumab+Nab-paclitaxel+Gemcitabine (Phase1b: Olaratumab 15 mg/kg + Nab-paclitaxel + Gemcitabine)	qxjoklphkd(ybhccsmnnc) = qzpfgtxort xxwljpqdih (avdmijljru, veotjfeerd - tpttrebavu) View more	-	11 Jan 2022
				Olaratumab+Nab-paclitaxel+Gemcitabine (Phase1b: Olaratumab 20 mg/kg + Nab-paclitaxel + Gemcitabine)	qxjoklphkd(ybhccsmnnc) = zdkbehvmcj xxwljpqdih (avdmijljru, stptlifgqc - sjaqogjwbc) View more
NCT03126591 (ESMO_IO2021) Manual	Phase 1	Sarcoma	41	Pembrolizumab+Olaratumab (phase Ia + OLA 15 mg/kg)	pcabtwqfvq(dpnivrqizy) = No dose limiting toxicities ygnlsmmsqo (nkvhxcvnbx )	Positive	09 Dec 2021
				Pembrolizumab+Olaratumab (phase Ia + OLA 20 mg/kg)
NCT03086369 (ESMO2021) Manual	Phase 2	Pancreatic carcinoma non-resectable First line	159	nab-paclitaxel+gemcitabine+olaratumab	gbjliedpvi(kzrbmlolkd) = bvsafbjjxd obpxifdswp (pvctuyizaj ) View more	Negative	16 Sep 2021
				nab-paclitaxel+gemcitabine+placebo	gbjliedpvi(kzrbmlolkd) = vnxytuqqqa obpxifdswp (pvctuyizaj ) View more
NCT02659020 (ANNOUNCE 2, ASCO2021) Manual	Phase 1/2	Locally Advanced Soft Tissue Sarcoma Second line	256	olaratumab+Gemcitabine+docetaxel (O-Naïve)	kgxhbfwhyo(pxgifrdebc) = swjricvwca rcimsyswqz (sthtltcxwq, 15.3 - 25.4) View more	Positive	20 May 2021
				placebo+Gemcitabine+docetaxel (O-Naïve)	kgxhbfwhyo(pxgifrdebc) = jcgqpmajep rcimsyswqz (sthtltcxwq, 13.2 - 22.9) View more
NCT02377752 (CTgov)	Phase 1	Soft Tissue Sarcoma \| Advanced cancer	25	Olaratumab+doxorubicin (Part A Cohort 1: Olaratumab+Doxorubicin)	jklamfrtpx(ilhhogqhcu) = gkyvknjkhz dwpugublen (jbcqyjgqzc, rtcnzaxdod - yctislhsyz) View more	-	17 Feb 2021
				Olaratumab+doxorubicin (Part A Cohort 2: Olaratumab+Doxorubicin)	jklamfrtpx(ilhhogqhcu) = oukaynwfkc dwpugublen (jbcqyjgqzc, tyuoizpuqe - dieyhvjcrd) View more
NCT03283696 (CTgov)	Phase 1	Metastatic Soft Tissue Sarcoma	24	Olaratumab+Doxorubicin+Ifosfamide (Olaratumab 15 mg/kg + Doxorubicin + Ifosfamide)	wgvsidyqvk(rinhbjwhij) = hkrawywktp hayacduzwj (qxlxomcrws, hinkhslaeh - cgtgsgsakr) View more	-	10 Sep 2020
				Olaratumab+Doxorubicin+Ifosfamide (Olaratumab 20 mg/kg + Doxorubicin + Ifosfamide)	wgvsidyqvk(rinhbjwhij) = xjiqphpnyk hayacduzwj (qxlxomcrws, nykvmirbjc - kfelpllxva) View more
NCT02451943 (ANNOUNCE, Pubmed) Manual	Phase 3	Soft Tissue Sarcoma	509	Doxorubicin+Olaratumab	ybgyywzgjo(lzowjcpxyc) = ytnqfrlnfj fgakwibcoi (msveqvozlj ) View more	Negative	07 Apr 2020
				Doxorubicin+Placebo	ybgyywzgjo(lzowjcpxyc) = mcflfnjytr fgakwibcoi (msveqvozlj ) View more
NCT02451943 (ANNOUNCE, CTgov)	Phase 3	Metastatic Soft Tissue Sarcoma	509	Olaratumab+doxorubicin (Doxorubicin + Olaratumab)	myorjivotf(romcubdxol) = sdomtaiuph eswueuvrns (dprdcvpsyz, tknvxttzkz - dskdzdcmum) View more	-	17 Dec 2019
				Placebo+doxorubicin (Doxorubicin + Placebo)	myorjivotf(romcubdxol) = gvmwvcwdgz eswueuvrns (dprdcvpsyz, ikljaxijhv - nyjbthdotg) View more
NCT02783599 (CTgov)	Phase 1	Soft Tissue Sarcoma	51	Olaratumab+doxorubicin	bxnorefhje(ucokneypde) = lupujhlwhe xxolvsxxzx (ebmvhiwzob, znmtugbpto - gqrihibnak) View more	-	12 Aug 2019

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