New Drugs for Cancer

The long development process of lab screening and animal tests is expensive and weeds out most compounds. Only about 0.1% of potential medicines eventually make it to clinical trials in human subjects. Nevertheless, the pharmaceutical industry continues to produce new compounds. Hundreds are in the drug development pipeline.

In recent years the FDA has approved on average 11 new molecular entities per year for cancer treatment. Additional new therapies include combinations of existing drugs and new delivery methods for existing drugs.

The reasons medicines are screened out are many. Some drugs kill malignant cells but are not specific enough for the targets the scientists set for them or are poisonous. Others are unstable and would break down in any serious clinical use. Others may work at the cellular level but there is no way to get the medicine to the cells through administration to the body (e.g. oral, IV).

Once medicines make it to clinical trials, most of those are screened out too. For one reason or another the backers drop development and do not seek to advance the medicine to the next phase. Reasons include overly severe side effects or too many side effects or ineffectiveness of the medicine.

Dead ends

Antisense drugs generated quite a bit of excitement in the early 21st Century, but that excitement has faded. A targeted therapy, antisense agents switch off specific genes. The idea is that by inserting an oligonucleotide that essentially blocks the gene transcription process, the disease cannot proceed. There was hope they would be used for genetic disorders, including cancer. And although some antisense therapies are used in treatment of some genetic diseases, none have been approved for cancer yet.

Notch inhibitors have been investigated with the idea that they may be a way to stop proliferation of cancer.

Stem cells are an area of research in rehabilitative therapy. Although they have generated excitement among scientists, few practical solutions have come out of the lab. A type of cell called Cancer Stem Cells (CSC) might be important in growth and metastasis of some types of cancers, but this idea has not been proven yet.

Some of the clinical trials have not focused on the disease of cancer but on the effect of new drugs on CSCs. Stem cells are a difficult enemy; scientists suspect combination therapy might be required in order to prevent crosstalk among signaling pathways.

Future of Chemotherapy

The drug discovery industry today divides potential new therapeutic compounds into two categories: small molecule and biologics. Remember when you were in chemistry class and you drew out the structure of molecules? Any molecule you can draw on a piece of paper is a “small molecule”. Most medicine are small molecule drugs, also called low molecular weight (LMW) drugs. They are often made by chemical synthesis or some are made by fermentation.  The signal transduction inhibitors are small molecule drugs.

Biologics, also called biopharmaceuticals, are enormous molecules. If you know anything about proteins you know they can have thousands of atoms in a molecule. Biologics are often, but not always proteins. They are often referred to as biotech drugs. They are produced by living cells. As therapeutics biologics first appeared in oncology medicine in the 1990s. Under the categories immunotherapy and monoclonal antibodies, they offer greater specificity and fewer side effects.

A larger share of new oncology drugs are biologic than drugs for other diseases. Going forward, industry observers anticipate new combinations of existing therapeutic products and new solutions such as cancer vaccines, nucleic-acid therapies, and new antibodies.

A 2018 review stated 150 kinase-targeted drugs are in clinical trials, with many more in laboratory research.  Indeed, kinase inhibitors are the focus of a quarter of all new pharmaceutical research. Synthetic lethality is another area of interest to scientists and PARP inhibitors work that way.

Another interesting and exciting trend is the development of tumor-agnostic medicines.

Small interfering RNAs have attracted the attention of researchers. Also called short interfering RNAs (siRNAs) or silencing RNAs, these compounds can switch off expression of genes, and they have thus proven valuable in figuring out which genes regulate what biochemistry. Could we find siRNAs that turn cancer off – stop the genetic drivers of tumor growth? That is the idea, and some laboratory and animal experiments have shown promise. But there has been no success in developing treatments for human cancer patients.

Targeted protein degradation has been proposed as a therapeutic strategy specifically for proteins that are not amenable to conventional pharmacological methods. Proteolysis-targeting chimeras (PROTACs) are the first class of drug developed with this approach in mind.

Anti-evolution therapies

Cancer cells continue to mutate in a tumor.  This is partly why cancer is so hard to defeat. It continues to change inside the body – microevolution in action. Scientists are trying to approach with “anti-evolution” therapies. None have reached the trial phase yet; the development is a high-tech affair employing “big data” and feedback from imaging systems that show cancer spread in the body during treatment. Scientists involved are talking about a triple-drug attack and speak of blocking APOBEC proteins, which other therapies do not do.

How New are the New Drugs?

Most new drugs approved by the FDA aren’t totally new. They are variations or combinations of old drugs – new methods of delivery, etc. A survey of new drugs approved from 1989 to 2000 found only 35% were new molecular entities (NMEs). The rest were combinations with other drugs or differed from previously approved medicines in method of administration or dosage. The 1984 Hatch-Waxman Act allows the FDA to give market exclusivity to new medicines which are not NMEs and therefore cannot be patented.

New Immunotherapy

In recent years, development of new immunotherapy agents has revolutionized cancer treatment. These drugs induce or potentiate the anti-tumor activity of the immune system.

The immune system identifies tumors and triggers an anti-tumor response. Such response, however, is modulated by stimulating and inhibiting factors. The new immunomodulating agents work by slowing down the action of natural immune system inhibitors and by speeding up natural stimulatory factors. The novelty of this approach stems from the fact that the drug targets the host immune cells and not the tumor itself. Antibody-drug conjugates are related avenue of research that is yielding promising results. Following therapeutic and commercial successes, a lot of efforts are being put in the development of new ADCs. With milder side effects, ADCs promise to substantially expand the medical oncologist’s toolkit for fighting cancer.

More on immnotherapy.

Gene Therapy

Gene therapy has been talked about by futurists for years. The idea is that by changing the DNA in the body’s cells, the genetic cause of illness can be addressed. Strategies include inactivating a bad gene, changing a mutated gene to a healthy gene, and putting a new gene in the body to fight disease. Researchers are making progress in employing gene therapy against sickle cell anemia, connective tissue disorders, and retinal disease. Some gene therapy for cancer is have entered clinical use. The most advanced area in anti-cancer gene therapy is CAR-T therapies, chimeric antigen receptor T-cell, which involves genetic modification of T-cells removed from the patient and then re-introduced to the body. In 2017 the FDA approved tisagenlecleucel and axicabtagene ciloleucel which are CAR-T processes, and in 2020 brexucabtagene autoleucel was approved.

See more on notch inhibitors.

A Shortage of Test Patients

There is so much interest from pharmaceutical companies in developing new immunotherapy treatments and personalized therapy that experts worry there aren’t enough cancer patients to fill up the openings in clinical trials needed to test the new therapies.

Newly Approved Oncology Drugs

Here is a list of oncology drugs approved in recent years:

Medicine Trade Name Category Target Manufacturer
Tisotumab vedotin-tftv Tivdak Monoclonal Antibody cervical cancer Seagen
Mobocertinib Exkivity kinase inhibitor lung cancer Takeda
Infigratinib Truseltiq kinase inhibitor cholangiocarcinoma QED Therapeutics
Amivantamab-vmjw Rybrevant Monoclonal Antibody non-small cell lung cancer Janssen Pharmaceutical
Sotorasib Lumakras Kinase Inhibitor non-small cell lung cancer Amgen
Loncastuximab tesirine-lpyl Zynlonta Antibody Conjugate lymphoma ADC Therapeutics
Dostarlimab-gxly Jemperli Monoclonal Antibody endometrial cancer Glaxo SmithKline
Tivozanib Fotivda kinase inhibitor renal cell carcinoma Aveo Pharmaceuticals
Melphalan flufenamide Pepaxto alkylating agent myeloma Oncopeptides AB
Umbralisib Ukoniq kinase inhibitor lymphoma TG Therapeurtics
Tepotinib Tepmetko kinase inhibitor non-small cell lung cancer EMD Serono (Merck)
Avapritinib Ayvakit kinase inhibitor gastrointestinal stromal tumor Blueprint Medicines
Tazemetostat Tazverik enzyme inhibitor epithelioid sarcoma Epizyme
Isatuximab Sarclisa Monoclonal Antibody multiple myeloma Sanofi
Tucatinib Tukysa kinase inhibitor breast cancer Cascadian Therapeutics
Pemigatinib Pemazyre kinase inhibitor cholangiocarcinoma Incyte
Sacituzumab govitecan-hziy Trodelvy Topoisomerase inhibitor breast cancer Immunomedics
Capmatinib Tabrecta kinase inhibitor non small-cell lung cancer Novartis
Selpercatinib Retevmo kinase inhibitor thyroid cancer, lung cancer Loco Oncology (Eli Lilly)
Ripretinib Qinlock kinase inhibitor gastrointestinal-stromal tumors Deciphera Pharmaceuticals
Lurbinectedin Zepzelca oncogenic transcription inhibitor small-cell lung cancer Jazz and PharmaMar
Pralsetinib Gavreto kinase inhibitor non small-cell lung cancer Blueprint Medicines
Belantamab mafodotin-blmf Blenrep monoclonal antibody multiple myeloma GlaxoSmith Kline
Tafasitamab-cxix Monjuvi monoclonal antibody diffuse large B-cell lymphoma Morphosus US
Naxitamab Danyelza monoclonal antibody neuroblastoma Y-mAbs Therapeutics
Brexucabtagene autoleucel Tecartus CAR-T therapy mantle cell lymphoma Kite Pharma
Margetuximab Margenza Monoclonal Antibody HER2+ breast cancer Macrogenics
Relugolix Orgovyx hormone suppressant prostate cancer Myovant Sciences
Medicine Trade Name Category Target Manufacturer
Erdafitinib Balversa kinase inhibitor bladder cancer Janssen Biotech
Alpelisib Piqray PI3K inhibitor breast cancer Novartis
Polatuzumab vedotin Polivy antibody conjugate diffuse large B-cell lymphoma Genentech
Selinexor Xpovio selective inhibitor of nuclear export multiple myeloma Karyopharm Therapeutics
Darolutamide Nubeq androgen receptor antagonist castration resistant prostate cancer Bayer
Entrectinib Rozlytrek kinase inhibitor NTRK-defect tumors; tissue-agnostic oncology drug Genentech
Zanubrutinib Brukinsa BTK inhibitor mantle cell lymphoma Beigene
Enfortumab vedotin-ejfv Padcev Antibody-drug conjugate bladder cancer Astellas
Fam-trastuzumab deruxtecan-nxki Enhertu Antibody-drug conjugate breast cancer Daiichi Sankyo
Lutetium Lu 177 dotatate Lutathera radioimmunotherapy conjugate gastroenteropancreatic neuroendocrine tumors AAA USA, Inc
Binimetinib Mektovi kinase inhibitor metastatic melanoma Array Biopharma
Encorafenib Braftovi kinase inhibitor metastatic melanoma Array Biopharma
Ivosidenib Tibsovo IDH1 inhibitor acute myeloid leukemia Agios Pharmaceuticals
Mogamulizumab Poteligeo Monoclonal Antibody non-Hodgkin lymphoma Kyowa Kirin
Moxetumomab pasudotox-tdfk Lumoxiti Monoclonal Antibody hairy cell leukemia Innate Pharma
Duvelisib Copiktra PI3K inhibitor leukemia and lymphoma Secura
Dacomitinib Vizimpro kinase inhibitor non-small-cell lung cancer Pfizer
Cemiplimab-rwlc Libtayo Monoclonal antibody squamous cell carcinoma Regeneron Pharmaceuticals
Talazoparib Talzenna PARP Inhibitor breast cancer Pfizer
Lorlatinib Lorbrena kinase inhibitor non-small cell lung cancer Pfizer
Glasdegib Daurismo Hedgehog pathway inhibitor acute myeloid leukemia Pfizer
Larotrectinib Vitrakvi kinase inhibitor solid tumors (only the second tissue-agnostic oncology drug approved by FDA) Pfizer
Gilteritinib Xospata kinase inhibitor acute myeloid leukemia Astellas
Calaspargase pegol-mkn Asparlas enzyme acute lymphoblastic leukemia Servier Pharmaceuticals
Tagraxofusp-erzs Elzonris conjugate of interferon and toxin blastic plasmacytoid dendritic cell neoplasm Stemline Therapeutics
Avelumab Bavencio monoclonal antibody metastatic Merkel cell carcinoma EMD Serono (Merck)
Niraparib Zejula PARP inhibitor epithelial ovarian, fallopian tube or primary peritoneal cancers Glaxo Smith Kline
Durvalumab Imfinzi Monoclonal Antibody urothelial carcinoma AstraZeneca
Neratinib maleate Idhifa Kinase inhibitor acute myeloid leukemia Puma Biotech
Inotuzumab ozogamicin Besponsa Antibody drug conjugate acute lymphoblastic leukemia Wyeth Pharmaceuticals
Copanlisib Aliqopa PI3K inhibitor follicular lymphoma Bayer Healthcare
Enasidenib Idhifa IDH2 inhibitor acute myeloid leukemia Celgene
Abemaciclib Verzenio kinase inhibitor metastatic breast cancers Eli Lilly
Acalabrutinib Calquence kinase inhibitor mantle cell lymphoma AstraZeneca
Venetoclax Venclexta BCL-2 Inhibitor chronic lymphocytic leukemia AbbVie
Atezolizumab Tecentriq monoclonal antibody urothelial carcinoma Genentech
Olaratumab Lartruvo monoclonal antibody soft tissue sarcoma Eli Lilly
Rucaparib Rubraca PARP inhibitor ovarian cancer Clovis Oncology
Medicine Trade Name Category Target Manufacturer
Palbociclib Ibrance kinase inhibitor metastatic breast cancer Pfizer
Lenvatinib Lenvima kinase inhibitor differentiated thyroid cancer Eisai
Panobinostat Farydak HDAC inhibitor multiple myeloma Secura
Dinutuximab Unituxin Monoclonal antibody neuroblastoma United Therapeutics
Sonidegib Odomzo Hedgehog pathway inhibitor locally advanced basal cell carcinoma Sun Pharma
Trifluridine and tipiracil Lonsurf thymidine phosphorylase inhibitor (antimetabolite colorectal cancer Taiho Oncology
Trabectedin Yondelis alkylating agent liposarcoma and leiomyosarcoma Janssen Pharmaceuticals
Cobimetinib Cotellic kinase inhibitor advanced melanoma Genentech
Osimertinib Tagrisso kinase inhibitor non-small cell lung cancer AstraZeneca
Daratumumab Darzalex monoclonal antibody multiple myeloma Janssen Biotech
Ixazomib Ninlaro Proteasome inhibitor multiple myeloma Millenium Pharmaceuticals
Necitumumab Portrazza monoclonal antibody squamous non-small cell lung cancer Eli Lilly
Elotuzumab Empliciti monoclonal antibody multiple myeloma Bristol Myers Squibb
Alectinib Alecensa kinase inhibitor ALK-positive lung cancer Hoffman LaRoche