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    Home > Active Ingredient News > Antitumor Therapy > Nature Summary: Highlights and Setbacks of Oncology Drugs in 2021

    Nature Summary: Highlights and Setbacks of Oncology Drugs in 2021

    • Last Update: 2022-01-09
    • Source: Internet
    • Author: User
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    The research and development of oncology drugs has always been very hot.
    In 2021, the U.
    S.
    Food and Drug Administration (FDA) has approved more than a dozen new cancer drugs this year, and hundreds of drugs have entered clinical trials
    .

    The key to the kingdom of KRAS With the accelerated approval of Amgen’s sotorasib by the FDA in May for non-small cell lung cancer (NSCLC) with KRASG12C mutations, the non-drugability of KRAS proto-oncogene has been officially overcome! Since KRAS was first reported to be related to cancer in the 1980s, evidence of its carcinogenic effect has been accumulating: Activating KRAS mutations is the most common carcinogenic change in human cancers and is usually associated with poor disease prognosis
    .

    However, due to the relatively smooth three-dimensional structure of this GTPase—except for a GTP binding pocket that tightly binds to its substrate, KRAS medicine becomes a problem
    .

    In 2013, with the discovery of the drug pocket on the protein KRASG12C variant, a number of KRAS target inhibitors began to be developed, including Amgen/BeiGene’s AMG 510, Mirati Therapeutics Inc.
    ’s MRTX849, and Boehringer Ingelheim’s research and development.
    BI 1701963, etc.
    The research indications include colorectal cancer, NSCLC, pancreatic cancer, advanced solid tumors and many other tumors
    .

    Amgen’s Sotorasib was the first drug approved for marketing.
    It was approved by the FDA based on a single-arm, open-label, phase i/ii trial that included patients with locally advanced or metastatic NSCLC with KRASG12C mutations
    .

    Among 124 patients who had disease progression during or after at least one previous systemic treatment, Sotorasib had an overall response rate of 36%
    .

    The median duration of remission was 10 months
    .

    The drug has not yet achieved higher hopes in other cancer settings, but trials are ongoing
    .

    Amgen is testing Sotorasib in a variety of combination treatment options to find a suitable combination of drugs
    .

    The impact of CAR-T cells on BCMA, the key to the kingdom, Bristol-Myers Squibb and Bluebird’s idecabtagene vicleucel were approved for multiple myeloma in March, which is aimed at BCMA targeting chimeric antigen receptor (CAR) T cells An important milestone in therapy
    .

    BCMA was first discovered in 1992 and named after its connection with B cell maturation
    .

    But it is gradually becoming clear that it is overexpressed on multiple myeloma cells and is not necessary for overall B cell health
    .

    The development of the first-generation BCMA targeting antibody was stopped due to insufficient efficacy
    .

    Using idecabtagene vicleucel, T cells harvested from patients were modified in vitro to express in tandem an anti-BCMA single-chain variable fragment connected to the CD8α hinge and the T cytoplasmic signaling domain of CD137 (4-1BB) and CD3-ζ
    .

    These cells are reinfused into the patient's body, looking for and destroying cells expressing BCMA
    .

    The FDA approval relies on a single-arm Phase II trial in 127 treated patients with multiple myeloma
    .

    The overall response rate was 72%, the complete response rate was 28%, and the overall median response duration was 11 months
    .

    CAR-T therapy has gradually become hot.
    The FDA approved GlaxoSmithKline’s BCMA targeting antibody-drug conjugate belantamab mafodotin in 2020.

    .

    Johnson & Johnson and Legend Biotech's CAR-T ciltacabtagene autoleucel is undergoing FDA review, and dozens of other BCMA targeted cell therapies, bispecifics, and antibody-drug conjugates are under development
    .

    U.
    S.
    regulatory agencies have approved four other CAR-T therapies, all targeting CD19 to treat blood system cancers
    .

    More than 2,000 cell therapies are being tested in nearly 1,400 trials
    .

    CD19, BCMA and CD22 are the most popular targets for hematological tumors
    .

    HIF-2α inhibitor opens up a new way.
    In July of this year, the FDA approved the Belzutifan of Merck & Co.
    , Ltd.
    to provide the first treatment for cancers related to von Hippel–Lindau (VHL) disease.
    VHL is a rare genetic disease with multiple characteristics.
    Well-vascularized cysts and tumors in organs
    .

    HIF-2α is a driving factor of oncogenic angiogenesis in VHL diseases and some cancers, but it is difficult to be a transcription factor to be a drug
    .

    In 2009, researchers discovered an allosteric pocket that provided key evidence for its medicine
    .

    The FDA approved belzutifan based on an open phase 2 trial in 61 patients with VHL-related renal cell carcinoma (RCC)
    .

    Among them, 49% of patients achieved partial or complete remission
    .

    Merck&Co.
    is testing anti-angiogenic drugs in indications, including RCC, paraganglioma, and pancreatic neuroendocrine tumors
    .

    Arrowhead Pharmaceuticals is conducting a phase 1 trial of ARO-HIF2 (an RNA interference drug that blocks the production of HIF-2α), and Arcus will start a phase 1 trial of its small molecule AB521 in 2021
    .

    Is the accelerated approval speeding up? The FDA’s accelerated approval pathway has opened up a green drug line with the support of Phase 2 clinical data
    .

    In April 2021, the FDA called on the Oncology Drug Advisory Committee (ODAC) to discuss 6 such cases, targeting 3 PD-1/PD-L1 blockers
    .

    Within 3 days, the team members discussed these projects and how to deal with them, and voted for 4 of the 6 pending approvals
    .

    FDA officials emphasized that the failure of the Phase 3 trial does not necessarily mean that a drug is ineffective
    .

    The trial design may complicate the interpretation of negative results
    .

    However, the mismatch between the Phase 2 trial and the confirmatory trial still has problems
    .

    Although some oncologists hope regulators will extend the benefits of questioning to potentially transformative drug candidates, others urge them to adhere to the basic principles of clinical trial design and reliable statistical analysis
    .

    Within a few months after the meeting, the FDA will suspend an accelerated approval under discussion and turn it into a full approval
    .

    The drug sponsor has voluntarily withdrawn 4 of them
    .

    In October 2020, Oncopeptides withdrew its alkylating agent melphalan flufinamide from the market a few days before ODAC was about to discuss it.
    Prior to this, the drug had accelerated approval in February 2021
    .

    Currently, the policy of accelerating approval is still in the exploratory stage
    .

    TGF-β inhibitors are stuck in the quagmire Merck's dual-target broad-spectrum anti-cancer drug M7824 (Bintrafusp alfa) is the most advanced anti-cancer drug candidate in the TGF-β pipeline - it has struggled in multiple trials
    .

    TGF-β is a secreted cytokine with background-dependent activity
    .

    In healthy cells, its signal can inhibit proliferation
    .

    But as cancer progresses, they can inhibit cytokines and thereby inhibit adaptive and innate immunity
    .

    The first pivotal trial tested bintrafusp α as a first-line NSCLC treatment compared with pembrolizumab, and it ended in failure
    .

    Subsequently, bintrafusp α combined with gemcitabine and cisplatin was used in the first-line treatment of locally advanced or metastatic biliary tract cancer (BTC) patients.
    After it is unlikely to reach the primary end point of overall survival (OS), Merck said that it will stop the therapy.
    Phase INTR@PID BTC 055 trial
    .

    Other anti-TGF-β targeted drug candidates are also in the clinic
    .

    In September, Novartis started its Phase 3 trial of antibody-based TGF-β trap NIS793 in pancreatic cancer
    .

    Sanofi’s antibody SAR-439459 is in phase 1, and Bristol-Myers Squibb acquired Forbius’ trap fusion protein AVID200 in 2020
    .

    Agonist antibody failure In 2021, the agonist antibody that activates T cell costimulatory receptors, GlaxoSmithKline’s feladilimab, also experienced a critical failure
    .

    In 2019, GlaxoSmithKline’s ICOS targeting feladilimab became the first agonist antibody to enter a key trial
    .

    In April of this year, the company stopped a joint trial of head and neck squamous cell carcinoma
    .

    In July of this year, it announced that a Feladilimab regimen had also failed in the Phase 2 trial of NSCLC
    .

    GlaxoSmithKline is still testing feladilimab plus belantamab mafodotin in a phase 1 multiple myeloma trial, but the prospects for this agonist antibody are bleak
    .

    Among other drug candidates, Jounce's ICOS agonist vopratelimab is still in the phase 2 study of NSCLC and other cancers
    .

    Sanofi has two trispecific agonist antibodies, phase 1 targets CD28xCD3xCD38 and CD28xCD3xHER2, and regeneron has 3 phase 1 bispecific antibodies that target CD28xMUC-16, CD28xEGFR and CD28xPSMA
    .

    Various OX40-, 4-1BB- and GITR-agonist antibodies are under development
    .

    Reference: Mullard, A.
    Cancer drug approvals and setbacks in 2021.
    Nat Cancer 2, 1246–1247 (2021).
    https://doi.
    org/10.
    1038/s43018-021-00303-8
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