Overview 120 New Therapeutic Drugs For Solid Tumors In The Past 30 Years.pdf

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Overview 120 New Therapeutic Drugs For Solid
Tumors In The Past 30 Years
The US Food and Drug Administration (FDA) has been a pioneer in drug evaluation and
regulation. Over the past 31 years, 1,050 drugs (excluding vaccines, cell therapies, and
gene therapy products) have been approved for marketing. Of these 1,050 drugs, a total
of 228 were identified as cancer treatments or cancer-related drugs, of which 120 were
classified as solid tumor treatments based on their initial indications. These drugs have
evolved from early small molecules with broad-spectrum anti-tumor properties to more
precise targeted monoclonal antibodies (mAbs) and antibody-drug conjugations
(ADCs) in the last decade, forming a single drug or combination cancer therapy system.
However, limited by the available targets are still mainly focused on receptor tyrosine
kinases (RTKS), which largely hinders the development of anti-tumor drugs.
Here, we retrospectively summarize, classify, and analyze the 120 solid tumor drugs
approved by the FDA over the past 31 years based on their initial approved indications,
characteristics, and functions. In addition, the existing challenges and potential
opportunities in drug development were analyzed and prospected, hoping to further
promote the development of solid tumor treatment drugs in the future.
Global Status: Serious Cancer Burden, High
Incidence of Solid Tumors
Cancer remains a major health challenge in most countries around the world. In 2020,
there were approximately 19.3 million new cancer cases and 10 million cancer deaths
worldwide, with solid tumors being the leading cause of death in cancer patients,
accounting for more than 90% of overall deaths. Since the mortality rate of cardiovascular
and cerebrovascular diseases has decreased significantly in many countries compared

with cancer. Therefore, cancer has become the first or second leading cause of death for
people under the age of 70 in 112 out of 183 countries.
Among the tumor types with high incidence in the world, solid tumors account for a higher
proportion. For male and female cancer patients, solid tumors are among the top ten new
and deadly tumors. Among them, the top ten tumor types accounted for more than 60% of
newly diagnosed cancer cases and more than 70% of cancer deaths. Female breast
cancer has surpassed lung cancer to become the most common cancer in the world, with
an estimated 2.3 million newly diagnosed cases in 2020, accounting for 11.7% of the total
cases, followed by lung cancer, colorectal cancer, prostate cancer and gastric cancer.
Globally, lung cancer remains the leading cause of cancer death with an estimated 1.8
million deaths (18%), followed by colorectal, liver, stomach and breast
cancers.
Statistics on new cases and deaths in 2020 from 36 high-incidence tumor species (CA: a cancer journal
for clinicians, 2021, 71:209-249)
Drug therapy has become a mainstream strategy for unresectable locally advanced or
metastatic solid tumors. Over the past 31 years, cancer treatment drugs have undergone
profound changes. During this period, biological agents have become an important

therapeutic strategy and gradually ushered in a prosperous era. For solid tumor drugs, the
number of approvals and their proportion of all FDA-approved drugs have increased,
especially in the last decade (figures a and b). With the development of therapeutic
technology, solid tumor treatment drugs have developed more precise types of drug
therapy, including small molecule targeted drugs, monoclonal antibodies (mAbs)
and antibody-drug conjugates (ADCs).
Statistics of FDA-approved drugs and cancer drugs. a Number of FDA-approved drugs
(NMEs: New molecular entities, BLAs: Biologics license applications) over the past 31
years. b Number of FDA-approved cancer drugs over the past 31 years. c Number of
FDA-approved therapeutic drugs for solid tumors during the past 31 years

FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021
Over the past three decades, FDA has approved 120 new therapeutic drugs for lung,
breast, prostate, gastrointestinal and other cancers with high frequency, and has
gradually become the mainstay of the modern cancer treatment system. In particular, lung
cancer and breast cancer, which have a high incidence in men and women, have also
become the fields with the highest number of new drugs approved by the FDA in 31 years,
reaching about 20% respectively.
Despite remarkable achievements, it is still limited by enormous challenges, including
drug resistance, safety, and hyperprogressive disease of basic immunotherapy PD-1/L1.
FDA-approved Therapeutic Drugs For Solid
Cancers
In the past 31 years, the FDA-approved therapeutic drugs for solid tumors have ranged
from the initial milestone drug paclitaxel to various tumor drugs with new mechanisms and
new concepts, pushing tumor therapy into new eras one after another.
1. Lung Cancer
Although the incidence of breast cancer surpassed that of lung cancer in 2020, the death
rate from lung cancer still far exceeds that of any other cancer. Lung cancer accounted for
11.4% of global cancer cases and 18.0% of cancer-related deaths in 2020. In the past 31
years, the FDA has approved 22 new lung cancer treatments (including 20 small molecule
and two antibody drugs).
Non-small cell lung cancer (NSCLC), which includes adenocarcinoma, squamous cell
carcinoma (SCC) and large cell carcinoma (LCC), accounts for approximately 85% of all
lung cancer cases, with the majority of patients presenting with locally advanced or

metastatic disease at diagnosis. Twenty of the 22 therapeutic agents used NSCLC as an
initial indication, most of which were classified as epidermal growth factor receptor
(EGFR) and anaplastic lymphoma kinase (ALK) inhibitors.
EGFR mutations occur in approximately 50% of Asian and 11% to 16% of European
patients with non-small cell lung cancer. The introduction of EGFR inhibitors brings
NSCLC treatment into a new era. Currently, the FDA has approved six EGFR inhibitors
and has achieved iterative development between drugs. During that time, necitumumab,
an EGFR antibody, was also approved for first-line treatment, but was significantly
overshadowed by small molecules.
Like EGFR inhibitors, the acquired resistance of most patients after treatment with ALK
inhibitors also promoted the iterative development of ALK inhibitors. After the first
generation of Crizotinib, the second generation of Ceritinib, Alectinib, Brigatinib and the
third generation of ALK inhibitors, Lorlatinib were also introduced.
In addition, in the past two years, new drugs in the field of NSCLC have not only created
new peaks in the market over the years, but also achieved milestone progress. RET and
EGFR exon20ins have ushered in the first batch of drugs on the market, and even KRAS,
which was once hailed as "undruggable", has been broken by sotorasib.

However, in the field of small cell lung cancer (SCLC), only two drugs, topotecan and
lurbinectedin, have received FDA approval in the past 31 years as first indications for
second-line treatment in patients with relapsed metastatic SCLC.
2. Breast Cancer
Breast cancer is more common in women (about 1% in men), accounting for 24.5% of
cancer cases and 15.5% of cancer-related deaths in women, and will overtake lung
cancer as the most common type of cancer in 2020. In the past 31 years, the FDA has
approved 24 new breast cancer drugs (18 small molecules, 3 mAbs, and 3 ADCs), more
than any other solid tumor. The three ADCs currently approved as immunotherapy for
breast cancer are trastuzumab emtansine (Kadcyla), trastuzumab deruxtecan (Enhertu),
and sacituzumab govitecan (Trodelvy).
Hormone receptor (HR) positive breast cancers, including estrogen receptor (ER) and/or
progesterone receptor (PR) positive breast cancers, account for more than 70% of all
breast cancer cases and cause approximately 50% of breast cancer-related deaths.
Selective ER modulators (SERMs), such as tamoxifen, have been the standard treatment
for patients with ER-positive breast cancer for more than 40 years. Since then, aromatase
inhibitors, SERMs, and CDK4/6 inhibitors have gradually become the new standard of
care for HR positive and HER2-negative breast cancer patients.
HER2-positive breast cancer accounts for 13% to 15% of all breast cancer cases and is
associated with aggressive and metastatic behavior. As the first monoclonal antibody
approved for the treatment of solid tumors, trastuzumab has become a landmark drug in

the field of breast cancer through multiple mechanisms such as ADCC action, inhibition of
HER2 shedding, and disruption of ligand-independent downstream cascade reactions.
Few drugs other than pertuzumab have been successful in head-to-head clinical studies.
In contrast, HER2 small molecule inhibitors have not performed well in breast cancer,
where three drugs (Lapatinib, Neratinib, and Tucatinib) have been approved in
combination with trastuzumab and/or capecitabine, respectively, for the treatment of
HER2-positive breast cancer as second-line and beyond.
ADC products also ushered in a milestone development. Kadcyla (trastuzumab
emtansine) is the first ADC drug in the field of solid tumors and will remain the
best-selling ADC product in 2021. However, Enhertu (trastuzumab deruxtecan) has
begun to show the potential to surpass Kadcyla, not only winning in head-to-head studies,
but also later redefining the classification criteria for HER2-negative breast cancer, and
becoming the first ADC drug approved for low HER2 expression. Trodelvy (Sacituzumab
govitecan) became the first ADC product in the field of triple-negative breast cancer, and
also the first trop2-targeted ADC product.
3. Gynecological Cancer
Gynaecological cancers, which include cervical, ovarian, uterine, vaginal, vulvar and
fallopian tube cancers, accounted for 15.2% of all malignancies and 15.3% of
cancer-related deaths among women worldwide in 2020. However, since 1991, only six
drugs have been approved by the FDA for gynecological cancer as an initial indication. It
can be said that the number of drugs for gynecological cancer as the first indication is
significantly less than that for other solid tumors, but there are also many innovative drugs
with new mechanisms and new concepts.

Ovarian cancer is the third most common gynaecological cancer, accounting for 3.4% of
all female malignancies and 4.7% of cancer-related deaths among women worldwide in
2020. Currently, the FDA has approved four new drugs for ovarian cancer, paclitaxel is
certainly a milestone in the history of cancer drugs and is still widely used to treat a variety
of malignancies.
BRCA1 and/or BRCA2 line mutations are present in approximately 14.1% of ovarian
cancer cases. Based on the new concept of synthetic lethal results from homologous
recombination deficiency (HRD), three PARP inhibitors, including olaparib, rucaparib, and
niraparib, are approved as maintenance therapy for BRCA1/2 mutated ovarian cancer.
Cervical cancer is also one of the most common gynecological cancers, accounting for
6.6% of all malignancies and 7.8% of cancer-related deaths in women worldwide in
2020. The Tissue factor (TF) antibody-drug conjugate (ADC) drug tisotumab vedotin was
approved in 2021 for recurrent or metastatic cervical cancer on prior therapy (e.g.,
bevacizumab plus doublet chemotherapy), making it the first launch and first ADC product
for this mechanism (TF).
4. Gastrointestinal Cancer
Gastrointestinal cancers, which include cancers of the oesophagus, stomach, colorectal,
pancreatic, gallbladder and liver (including cholangiocarcinoma), account for 26.4% of
cancer cases and 36.3% of cancer-related deaths worldwide in 2020. In the past 31 years,
the FDA has approved 17 new drugs for gastrointestinal cancer (including 12 small
molecules, 4 mAbs, and 1 recombinant fusion protein).

Gastrointestinal tumors such as esophageal cancer, gastric cancer and liver cancer are
the most common malignant solid tumors in China. Although 17 new drugs have been
approved as initial indications, Imatinib, Sunitinib, Regorafenib, Afatinib and Pemigatinib
are all generic and innovative drugs that have attracted much attention. However, how to
build competitive barriers for gastrointestinal cancer after the drug is marketed is a
strategic issue that needs to be considered, especially under the impact of more
advantageous innovative drug indication expansion.
5. Prostate And Urinary System Cancer
In 2020, prostate cancer accounted for 14.1% of cancer cases and 6.8% of cancer-related
deaths among men worldwide. In the past 31 years, the FDA has approved 12 new
prostate cancer drugs. After prostate cancer, kidney and bladder cancer are the most
common cancers of the urinary system, and the FDA has approved 12 new drugs for
urinary cancers in 31 years.

Progression of prostate cancer is usually accompanied by overexpression of androgen
receptors (AR) due to accumulation of somatic mutations or AR amplification leading to
proliferation of prostate luminal epithelial cells. As AR translocates from the cytoplasm to
the nucleus, including binding to specific DNA sequences, it initiates transcription of target
genes including prostate-specific antigen (PSA). Thus, AR-based antagonists,
prostate-specific antigen therapy, and androgen deprivation therapy (ADT) have all
become clinical strategies for prostate cancer.
IL-2 receptor, TRK inhibitors (RAF1, BRAF, VEGFR, PDGFR-β, FGFR, FLT3, KIT and
RET, etc.), rapamycin (mTOR) inhibitors and novel immunotherapy (PD-1/L1 )
and antibody-drug conjugates (Nectin-4) are successively successful innovative drug
targets and drug forms for urinary system tumors. In particular, Tecentriq

(Atezolizumab), Imfinzi (Durvalumab) and Padcev (enfortumab vedotin-ejfv) were all
first indications for urinary tumors.
6. Other Solid Tumors
Melanoma is a relatively common skin cancer, accounting for approximately 1.7% of
cancer cases worldwide. In the past 31 years, 9 drugs have been approved in the field of
melanoma, including Ipilimumab, the world's first cytotoxic T-lymphocyte-associated
protein 4 (CTLA4) antibody, and Nivolumab (Opdivo) and Pembrolizumab (Keytruda),
both known as cornerstone therapies of immunity.
In addition to skin tumors, there are also important and well-known products in the field of
other solid tumors, such as lenvatinib, a thyroid cancer treatment drug, and TRK inhibitors,
which have created umbrella clinical research paradigms in NTRK-positive solid tumors.
In general, receptor tyrosine kinase (RTK) inhibitors and immune checkpoint blockers
(ICB) are undoubtedly the most successful anti-tumor drugs in the past 31 years, with 120
drugs successively approved in the entire anti-tumor history , and affect the anti-tumor
strategy of solid tumors.

During the first decade, efforts were made to develop antiendocrine drugs, microtubule
inhibitors, DNA alkylating agents, and DNA topoisomerase inhibitors. The advent of
trastuzumab opened a new era of RTK targeted therapy. In the second decade, the
research idea of RTK targeted inhibitors was extended to the downstream signal of RTK,
enriching the TKI library and shifting the focus of anticancer drugs to the development of
targeted drugs. In addition, the advent of ipilimumab led immunotherapy to shift from
positive stimuli (e.g., IL-2 and INFα) to immune checkpoint blocking, initiating a true
paradigm shift in metastatic or advanced solid tumors. Therefore, during the third decade,
RTK pathway inhibitors and ICB therapy were widely developed, and solid tumor therapy
entered the era of precise targeting.

However, 31 years of development history also makes us clearly realize that drug
resistance and cancer recurrence are inevitable and continue to occur, and the
succession of multiple drugs is also a kind of evidence. At the same time, it is currently
impossible to predict how individual tumors will respond to available treatments.
Prospect
With the development of pharmaceutical technology, proteolysis-targeting chimeras
(PROTACs) and similar degradation techniques, such as Chaperone-mediated
autophagy (CMA) and lysosome targeting chimeras (LYTACs), may bring new
therapeutic hopes. New products such as multi-specific antibodies, cell therapies, gene
therapies, the exploration of CAR T cells in solid tumors, and oncolytic viruses and cancer
vaccines also have the potential to bring new options to cancer treatment.
In addition, whether it is possible to control tumor progression and metastasis through
extracellular matrix (ECM) and epigenetic remodeling or more complex metabolic and
immune remodeling, to systematically manipulate and domesticate cancer cells, and to
realize long-term coexistence and even cure of human and cancer, may also be the
direction of future exploration.
Advanced drug delivery systems using poly(ethylene glycol) (PEG) is an important
development in anti-cancer therapy. PEGylation is being used as a universal therapeutic
technique to provide diverse conjugation with peptides, proteins, antibody fragments,
aptamers, enzymes, and small molecules. Biopharma PEG is a leading PEG supplier
that dedicated to manufacturing and supplying PEG derivatives with high purity. We can
also supply a variety of high purity PEG linkers, ADC linkers and other click
chemistry reagents to empower ADC drug research & development.

Reference:
Wu, Q., Qian, W., Sun, X. et al. Small-molecule inhibitors, immune checkpoint inhibitors,
and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021. J
Hematol Oncol 15, 143 (2022). https://doi.org/10.1186/s13045-022-01362-9
Related articles:
[1].EGFR-Directed ADCs for Cancer Treatment
[2].ADC Drugs For Non-small Cell Lung Cancer
[3].Antibody-drug Conjugates (ADCs) - Approvals & Clinical Trails
[4].FDA Approved Antibody-Drug Conjugates (ADCs) Up To 2023

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