ALK inhibitors are
anti-cancer drug
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothera ...
s that act on tumours with variations of
anaplastic lymphoma kinase
Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ''ALK'' gene.
Identification
Anaplastic lymphoma kinase (ALK) was originally dis ...
(ALK) such as an
EML4
Echinoderm microtubule-associated protein-like 4 is a protein that in humans is encoded by the ''EML4'' gene.
This protein is involved in cancers when spliced with the anaplastic lymphoma kinase
Anaplastic lymphoma kinase (ALK) also known as A ...
-
ALK translocation. They fall under the category of
tyrosine kinase inhibitors
A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...
, which work by inhibiting proteins involved in the abnormal growth of tumour cells. All the current approved ALK inhibitors function by binding to the
ATP pocket of the abnormal ALK protein, blocking its access to energy and deactivating it.
A majority of ALK-rearranged NSCLC harbour the EML4-ALK fusion,
[ although as of 2020, over 92 fusion partners have been discovered in ALK+ NSCLC.][ For each fusion partner, there can be several fusion variants depending on the position the two genes were fused at, and this may have implications on the response of the tumour and prognosis of the patient.][
]
Approved inhibitors
First generation
Crizotinib
Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). It acts as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor.
Med ...
(also a ROS1 and c-MET inhibitor) was approved in Aug 2011 by the US FDA for ALK-positive NSCLC. At the time of the discovery of ALK translocations as a molecular driver in NSCLC, crizotinib was being investigated by Pfizer as a potential c-MET inhibitor. Its activity against ALK being known, Pfizer shifted its investigations to focus on this indication, and obtained a full approval 4 years later. Crizotinib's efficacy was proven in phase III trial, PROFILE 1007, when it was compared to then-standard second-line pemetrexed
Pemetrexed, sold under the brand name Alimta among others, is a chemotherapy medication for the treatment of pleural mesothelioma and non-small cell lung cancer (NSCLC)..
It is available as a generic medication.
Medical use
In February 2004, t ...
or docetaxel
Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-ce ...
chemotherapy.[ It induced tumour stabilisation or shrinkage in 90% of patients. Its lack of penetrance in the brain and non-optimal specificity for ALK meant resistance mostly arose within a year, with the brain being a common site of progression. Blockade of ALKAL2 with crizotinib has been shown to produce ]analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
effects in animal models.
Second generation
Despite the excitement of crizotinib's therapeutic success, there was a need to conceive new drugs with better brain penetrance, higher specificity and targeting a broader set of resistance mutations.
As such, Novartis' ceritinib
Ceritinib (INN, trade name Zykadia , from Novartis) is a prescription-only drug used for the treatment of non-small cell lung cancer (NSCLC). It was developed by Novartis and received FDA approval for use in April 2014..Ceritinib is also sold un ...
was approved by the FDA in April 2014 for treatment of NSCLC. It provided good brain penetrance and a significant progression-free survival benefit against chemotherapy in the first line as demonstrated in the ASCEND-4 trial.
Roche's alectinib
Alectinib (INN, marketed as Alecensa) is an oral drug that blocks the activity of anaplastic lymphoma kinase (ALK) and is used to treat non-small-cell lung cancer (NSCLC). It was developed by Chugai Pharmaceutical Co. Japan, which is part of th ...
was FDA approved Dec 2015 (accelerated) for patients who had progressed on crizotinib, with full approval in 2017 as a first-line treatment for ALK-positive NSCLC. Like ceritinib, it provided excellent brain penetrance and high response rates. It demonstrated a clear benefit against both first-line chemotherapy and first-line crizotinib.[''FDA approves Alecensa for ALK-positive metastatic non-small cell lung cancer'' Nov 2017]
/ref> This was based on the phase 3 ALEX trial comparing it with crizotinib
Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). It acts as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor.
Med ...
.[
Ariad's and Takeda's ]brigatinib
Brigatinib, sold under the brand name Alunbrig among others, is a small-molecule targeted cancer therapy being developed by Ariad Pharmaceuticals, Inc. Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor re ...
(also an inhibitor of mutated EGFR) was the latest second-generation inhibitor and was approved in April 2017 by the US FDA for ALK-positive NSCLC. It is very similar to alectinib in efficacy, while being active against some resistant mutations such as the common G1202R mutation that provides resistance to alectinib.
Third generation
Pfizer's lorlatinib
Lorlatinib, sold under the brand name Lorbrena in the United States, Canada, and Japan, and Lorviqua in the European Union, is an anti-cancer drug developed by Pfizer. It is an orally administered inhibitor of ALK and ROS1, two enzymes that play ...
was the first third-generation inhibitor and was approved in 2018 by the US FDA for ALK-positive NSCLC after progression on a first or second-generation inhibitor. Its macrocyclic structure was designed specifically to address some of the most recalcitrant resistance mutations. Still, most tumours eventually develop resistance through various mechanisms, namely compound-mutations (two or three mutations simultaneously) or activation of alternative pathways, such as the c-MET pathway.
Clinical trials
Additional ALK inhibitors currently (or soon to be) undergoing clinical trials include:
* Ensartinib (Xcovery's X-396, undergoing the eXalt3 Phase III multicenter clinical trial against crizotinib in ALK-TKI naïve patients who received up to one prior chemotherapy)
* Entrectinib
Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin r ...
(Nerviano's NMS-E628, licensed by Ignyta and renamed RXDX-101, in the U.S. orphan drug designation and rare pediatric disease designation for the treatment of neuroblastoma and orphan drug designation for treatment of TrkA-, TrkB-, TrkC-, ROS1- and ALK-positive NSCLC)
* Repotrectinib (TPX-0005, Turning Point Therapeutics)
* Belizatinib (TSR-011, Tesaro
Tesaro Inc. is a pharmaceutical company based in Waltham, Massachusetts. They focus on drug development for cancer.
History
Tesaro was founded in 2010. The company's first commercial product, Varubi, was approved by the FDA in October 2015. A ...
)
* Alkotinib (ZG-0418, a dual ALK/ROS1 inhibitor, Suzhou Zelgen Biopharmaceuticals)
* Foritinib (SAF-189, a dual ALK/ROS1 inhibitor undergoing a phase I/II trial as of 2020, Fochon Pharmaceuticals)
* CEP-37440 ( Teva)
* TQ-B3139 (dual ALK/c-MET inhibitor by Chia Tai Tianqing Pharmaceuticals, undergoing a phase III clinical trial against crizotinib in TKI-naïve patients)
* PLB1003 (Beijing Pearl Biotechnology)
* TPX-0131 (Turning Point Therapeutic's next generation ALK inhibitor, shown to work even against compound mutations resistant to lorlatinib)
Discontinued
* ASP-3026 (Astellas
is a Japanese multinational pharmaceutical company, formed on 1 April 2005 from the merger of and . On February 5, 2020, the company announced management changes effective from April 1, 2020.
Astellas is a member of the Mitsubishi UFJ Fina ...
)
Investigational combinations
While the response to ALK inhibitors is often very encouraging in patients with ALK+ NSCLC and lasts for a relatively long time, most of them eventually develop resistance, either through mutations in the ATP binding pocket or activation of alternative oncogenic pathways. Much research is being carried out on understanding the ways the cancer adapts and on how to reverse or delay resistance.
MEK pathway
The MEK pathway (short for MAPK/ERK-Kinase) has been extensively shown to be critical for the survival of tumour cells subjected to ALK inhibition. Inhibition of this pathway was shown to enhance response and delay the onset of resistance in preclinical models. As of 2020, three clinical trials are running to test the following combinations of ALK inhibitors with MEK inhibitor A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2.
They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers. (See MAPK/ERK pathway#Clinical sign ...
s: brigatinib+binimetinib
Binimetinib, also known as Mektovi and ARRY-162, is an anti-cancer small molecule that was developed by Array Biopharma to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. ...
,[ ceritinib+]trametinib
Trametinib, sold under the brand name Mekinist among others, is an anticancer medication used for the treatment of melanoma. It is a MEK inhibitor drug with anti-cancer activity. It inhibits MEK1 and MEK2.
Trametinib had good results for metast ...
,[ and alectinib+]cobimetinib
Cobimetinib, sold under the brand name Cotellic, is an anti-cancer medication used in combination with vemurafenib (Zelboraf) alone or with both vemurafenib and atezolizumab (Tecentriq) to treat melanoma. Cobimetinib is a MEK inhibitor. Cotell ...
.[ Results for the last two are expected around 2020-2021.
]
EGFR/HER2 pathway
The EGFR and HER2
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
pathways are commonly abnormally activated in a large proportion of cancers. This was shown to be the case in preclinical models of ALK+ NSCLC subjected to ALK inhibition, both ''in vitro'' and ''in vivo''. Surprisingly, cells were only sensitive to EGFR/HER2 inhibition when in the process of adapting to ALK inhibitors: both naïve cells and fully-adapted cells showed no measurable response to EGFR/HER2 inhibition alone. Currently, solid preclinical studies have been carried out with second-generation inhibitors combined with afatinib
Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.
It is mainly used to treat ...
, erlotinib
Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) â ...
and lapatinib
Lapatinib ( INN), used in the form of lapatinib ditosylate (USAN) (trade names Tykerb and Tyverb marketed by Novartis) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts ...
. In all cases, the responses were enhanced by the combination with respect to monotherapy, but seemed more pronounced in afatinib and lapatinib (dual EGFR/HER2 inhibitors) than in erlotinib (which only inhibits EGFR).
Anti-VEGF therapies
Several trials are investigating the combination of anti-VEGF antibody bevacizumab
Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, l ...
with ALK inhibitors such as alectinib and brigatinib. Bevacizumab is an antiangiogenic antibody, which normalizes the complex blood vessel structures around cancer and prevents new blood vessels from forming, thus starving the tumour and preventing its proliferation.
Local consolidation therapy
The use of either radiotherapy or surgery in addition to an ALK inhibitor is known as local consolidation therapy, and as of 2020, it is being investigated by three clinical trials. Their goal is to determine whether it delays resistance to the drugs compared with monotherapy.[ Some make use of ]SBRT
Radiosurgery is surgery using radiation, that is, the destruction of precisely selected areas of tissue using ionizing radiation rather than excision with a blade. Like other forms of radiation therapy (also called radiotherapy), it is usually u ...
(stereotactic body radiation therapy), a very precise radiation technique able to provide high doses with minimal side effects. Most trials of LCT in NSCLC focus on oligometastatic disease (under 3-5 lesions, depending on the definitions), but preliminary results of the BRIGHTSTAR trial [ indicate this method may be safe and well tolerated irrespective of the number of lesions.
]
NPM-ALK
NPM-ALK is a different variation/fusion of ALK that drives anaplastic large-cell lymphoma
Anaplastic large cell lymphoma (ALCL) refers to a group of non-Hodgkin lymphomas in which aberrant T cells proliferate uncontrollably. Considered as a single entity, ALCL is the most common type of peripheral lymphoma and represents ~10% of all per ...
s (ALCLs) and is the target of other ALK inhibitors such as TAE-684.
References
{{reflist, refs=
[{{ClinicalTrialsGov, NCT00932451, An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene]
[{{ClinicalTrialsGov, NCT04005144, Brigatinib and Binimetinib in Treating Patients With Stage IIIB-IV ALK or ROS1-Rearranged Non-small Cell Lung Cancer]
[{{ClinicalTrialsGov, NCT03087448, Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC)]
[{{ClinicalTrialsGov, NCT03202940, A Phase IB/II Study of Alectinib Combined With Cobimetinib in Advanced ALK-Rearranged (ALK+) NSCLC]
[{{ClinicalTrialsGov, NCT03707938, Local Consolidative Therapy and Brigatinib in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer]
[{{cite press release , title = Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types , url = http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf , publisher = Pfizer Oncology , date = 2010-05-20 , access-date = 2010-06-07 , url-status = dead , archive-url = https://web.archive.org/web/20100612203421/http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf , archive-date = 2010-06-12 ]
[{{ClinicalTrialsGov, NCT00932893, An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene]
[{{cite journal , vauthors = Ou SI, Zhu VW, Nagasaka M , title = Catalog of 5' Fusion Partners in ''ALK''-positive NSCLC Circa 2020 , journal = JTO Clinical and Research Reports , volume = 1 , issue = 1 , pages = 100015 , date = March 2020 , pmid = 34589917 , doi = 10.1016/j.jtocrr.2020.100015 , doi-access = free ]
[{{cite journal , vauthors = Christopoulos P , title=EML4-ALK fusion variant V3 confers early treatment failure with first and second generation ALK TKI , journal=Pneumologie , date=2018 , volume=72 , issue=S 01 , page=402 , doi=10.1055/s-0037-1619261 ]
External links
alkinhibitors.com
ALK inhibitor discussion forum
Receptor tyrosine kinase inhibitors