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1991-2021, 120 new drugs for solid tumors

 Last Update: 2022-11-05
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The U.
S.
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 passed through new molecular entities (NME) or biologics license application (BLA) 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 treatment drugs
based on initial indications.
These drugs have evolved from small molecules with broad-spectrum anti-tumor properties in the early stage to more precise targeting of monoclonal antibodies (mAbs) and antibody drug conjugates (ADCs) in the last decade, forming a single-agent or combination cancer treatment system
.
However, limited by the availability of targets, the focus is mainly on receptor tyrosine kinase (RTK), which greatly hinders the development of
anti-tumor drugs.

Recently, Chinese scholars have retrospectively summarized, classified and analyzed the 120 solid tumor drugs approved by the FDA in the past 31 years according to the indications, characteristics and
functions originally approved.
In addition, the existing challenges and potential opportunities in drug development are analyzed and prospected, and it is expected to further promote the development of
solid tumor treatment drugs in the future.
Here, this document is briefly compiled and supplemented for reference
only.

Global status: The cancer burden is serious, and solid tumors are high and frequent

At a macro level, cancer remains a major health challenge
in most countries around the world.
According to the literature, there were an estimated 19.
3 million newly diagnosed cancer cases and nearly 10 million cancer deaths worldwide in 2020
.
Mortality from cardiovascular and cerebrovascular diseases has decreased significantly in many countries compared to cancer; As a result, cancer has become the first or second leading cause of
death for people under 70 in 112 out of 183 countries.

CA: a cancer journal for clinicians, 2021, 71: 209-249）

Among the tumors with a 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 emerging and lethal tumors
.
Among them, the top ten tumor types account for more than 60% of newly diagnosed cancer cases and more than
70% of cancer deaths.
Female breast cancer has overtaken lung cancer to become the world's most common cancer, with an estimated 2.
3 million newly diagnosed cases in 2020, accounting for 11.
7% of the total number of cases, followed by lung, colorectal, prostate and stomach cancers
.
Globally, lung cancer remains the leading cause of cancer death, with an estimated 1.
8 million deaths (18%), followed by colorectal, liver, gastric and breast cancers
.

Statistics on new cases and deaths of 36 high-incidence tumor species worldwide in 2020 (CA: a cancer journal for clinicians, 2021, 71: 209-249）

For unresectable locally advanced or metastatic solid tumors, pharmacotherapy has become a mainstream strategy
.
In the past 31 years, cancer treatment drugs have undergone profound changes
.
During this period, biologics have become an important treatment 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 below
).

Note: a.
The number of new drugs approved by the FDA over the years; b.
FDA approval of cancer therapeutics over the years (Journal of Hematology & Oncology.
2022,15:143; Same below)

In the past three decades, the FDA has approved a total of 120 new therapeutic drugs for high-incidence tumors such as lung cancer, breast cancer, prostate cancer, and gastrointestinal cancer, and has gradually become the mainstay
of the modern cancer treatment system.
In particular, lung cancer and breast cancer, which are highly common in men and women, have also become the areas with the highest number of new drugs approved by the FDA in 31 years, reaching about
20% each.

Despite this remarkable achievement, it is still limited by significant challenges, including drug resistance, safety, and the hyper-progressive disease of PD-1/L1 as a primary immunotherapy
.

Tumor track: each has its own merits, and the strength is uneven

In the past 31 years, FDA-approved innovative drugs for solid tumors have led the "flag" in various tumor species
.
From the initial milestone drug paclitaxel to the current tumor drugs with new mechanisms and concepts, tumor treatment has been promoted into one new era
after another.

1.
Lung cancer has achieved a lot, but challenges remain

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
.
In 2020, lung cancer accounted for 11.
4% of cancer cases worldwide and 18.
0%
of cancer-related deaths.
Over the past 31 years, the FDA has approved 22 new lung cancer treatments (including 20 small molecule and 2 antibody drugs).

Non-small cell lung cancer (NSCLC) includes adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma (LCC), accounting for about 85% of all lung cancer cases Most patients present with locally advanced or metastatic disease
at the time of diagnosis.
20 of the 22 therapeutics have NSCLC as their initial indication, most of which are classified as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors
.

EGFR mutations occur in about 50% of Asian and 11%~16% of European patients with non-small cell lung cancer, and the launch of EGFR inhibitors brings NSCLC treatment into a new era
.
At present, the FDA has approved 6 EGFR inhibitors and realized iterative development
between drugs.
During this period, the EGFR antibody drug netulimumab (necitumumab) was also approved for first-line treatment, but it was significantly
dimmer under the pinching of small molecules.

As with EGFR inhibitors, the acquired resistance of most patients after receiving ALK inhibitors has also driven the iterative development of ALK inhibitors, followed by second-generation ceritinib, eletinib, bugatinib, and third-generation ALK inhibitor lorlatinib
.

In addition, in the past two years, new drugs in the field of NSCLC have not only created new peaks in the market, but also achieved milestone progress
.
RET、EGFR exon20ins has ushered in the first batch of drugs on the market, and even KRAS, once known as "undruggable", has been broken by sotorasib
.

However, in small cell lung cancer (SCLC) In the past 31 years, only two drugs, topotecan and rubipatidine (lurbinectedin), have been approved by the FDA as the primary indications for the second-line treatment of patients with recurrent metastatic SCLC, which is obviously a sharp gap
with the "bustle" in the field of NSCLC.

2.
Breast cancer is the most prosperous and has entered a new stage

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 surpassed lung cancer as the most common tumor in
2020.
For the past 31 years, the FDA Approved 24 new breast cancer treatments (including 18 small molecules, 3 mAbs, and 3 ADCs), outperforming all other solid tumors
.

Currently, cytotoxic drugs are still widely used in clinical practice of breast cancer, especially in recurrent unresectable (local or regional) human epidermal growth factor receptor 2 (HER2).
Negative breast cancer
.
Docetaxel, carbetapine, etc.
are representative products
of this type of drug.

Hormone receptor (HR)-positive breast cancer, including estrogen receptor (ER) and/or progesterone receptor (PR) Positive breast cancer, which accounts for more than 70% of all breast cancer cases and causes about 50% of breast cancer-related deaths
.
Selective ER modifier (SERM), such as tamoxifen, has been the standard of care
for patients with ER-positive breast cancer for more than 40 years.
Since then, aromatase inhibitors, SERMs and CDK4/6 inhibitors have also gradually become the new standard of
care for patients with HR-positive and HER2-negative breast cancer.

HER2-positive breast cancer accounts for 13%~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 exerts therapeutic efficacy through multiple mechanisms such as ADCC action, inhibition of HER2 shedding, and destruction of ligand-independent downstream cascade reactions, becoming a landmark drug in the field of breast cancer, and few drugs other than pertuzumab can win
head-to-head clinical studies 。 In contrast, HER2 small molecule inhibitors have performed poorly in breast cancer, with three drugs (lapatinib, lenatinib and tucatinib) in combination with trastuzumab and/or capecitabine, respectively, approved as second-line or above treatment
options for HER2-positive breast cancer.

ADC products have also reached milestones
.
Kadcyla is the first ADC drug in the solid tumor field and remains the best-selling ADC product
in 2021.
However, Enhertu has begun to show potential beyond Kadcyla, not only winning 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.
Gosatuzumab (Sacituzumab govitecan) became the first ADC product in the triple-negative breast cancer field and the first trop2-targeted ADC product
on it.

3.
The gap in gynecological cancer is obvious, and new mechanisms are explored

Gynecological cancers include cervical, ovarian, uterine, vaginal, vulvar, and fallopian tube cancers, accounting for 2020 Women worldwide account for 15.
2% of all malignancies and 15.
3%
of cancer-related deaths.
However, since 1991, only 6 treatments have been approved by the FDA for gynecological cancers as initial indications
.
It can be said that the number of drugs for gynecological cancer as the first indication is significantly smaller than that of other solid tumors, but there are also many innovative drugs
with new mechanisms and new concepts.

Ovarian cancer, the third most common gynecologic cancer, accounted for 3.
4% of all female malignancies and 4.
7%
of cancer-related deaths in women worldwide in 2020.
At present, the FDA has approved 4 new ovarian cancer treatment drugs, but paclitaxel is undoubtedly a milestone in the history of anti-cancer drugs, and it is still widely used to treat various malignancies
.

BRCA1 and/or BRCA2 germline mutations are present in approximately 14.
1% of ovarian cancer cases based on homologous recombination defects A new concept of synthetic lethality (HRD), olaparib (olaparib, rucaparib and niraparib) and three other PARP inhibitors are approved as maintenance therapy
for BRCA1/2 mutant ovarian cancer.

Cervical cancer is also one of the most common gynecologic cancers, accounting for 6.
6% of all malignancies and 7.
8%
of cancer-related deaths in women globally in 2020.
Tissue factor (TF) antibody conjugate drug tisotumab Vedon was approved in 2021 for recurrent or metastatic cervical cancer with prior treatments such as bevacizumab plus dual chemotherapy, becoming the first marketed and first ADC product
for this mechanism (TF).

4.
The first onset of gastrointestinal cancer is a choice, and barriers are a strategy

Gastrointestinal cancers include esophageal, gastric, colorectal, pancreatic, gallbladder and liver cancers (including cholangiocarcinoma), accounting for 26.
4% of global cancer cases and 36.
3%
of cancer-related mortality in 2020.
In the last 31 In mid-year, the FDA approved 17 new gastrointestinal cancer therapeutics, including 12 small molecules, 4 mAbs, and 1 recombinant fusion protein.

Gastrointestinal tumors such as esophageal cancer, gastric cancer and liver cancer are all malignant solid tumors
with high incidence in China.
Although 17 new drugs have been approved as the first indication, imatinib, sunitinib, regorafenib, avatinib, pemetinib, etc.
are also generic varieties and innovative drugs
that have attracted much attention.
However, how to build competitive barriers for gastrointestinal cancer after the drug is on the market is a strategic issue that needs to be considered, especially in the face of the expansion of
more advantageous innovative drug indications.

5.
Prostate and urinary system cancer, progress together

In 2020, prostate cancer accounted for 14.
1% of male cancer cases worldwide and 6.
8%
of cancer-related mortality.
For the past 31 years, the FDA Approved 12 new prostate cancer treatment drugs
.
In addition to prostate cancer, kidney cancer and bladder cancer are the most common urological cancers, and the FDA has also approved 12 new urological cancer treatments in 31 years
.

Proliferation of luminal epithelial cells in the prostate due to accumulation of somatic mutations or AR amplification, manifested as progression of prostate cancer usually accompanied by androgen receptors (AR) of overexpression
.
With the translocation of AR from the cytoplasm to the nucleus, including binding to specific DNA sequences, initiates transcription
of target genes including prostate-specific antigen (PSA).
Therefore, AR-based antagonists, prostate-specific antigen therapy, and androgen deprivation (ADT) therapy have all become clinical strategies
for prostate cancer.

IL-2 receptors, TRK inhibitors (RAF1, BRAF, VEGFR, PDGFR-β, FGFR, FLT3, KIT, RAT and RET, etc.
), rapamycin (mTOR) Inhibitors and novel immunotherapies (PD-1/L1) and antibody conjugates (Nectin-4) are successful innovative drug targets and drug forms
for urological tumors.
In particular, atezolizumab, duvalumab, and Padcev have all taken urinary tumors as the primary indications
.

6.
Other solid tumors, transformative therapies are also evolving

Melanoma is a relatively common skin cancer, accounting for about 1.
7%
of cancer cases worldwide.
Over the past 31 years, nine drugs have been approved in the field of melanoma, including the world's first cytotoxic T lymphocyte antigen 4 (CTLA4) antibody ipilimumab, as well as nivolizumab and pembrolizumab
, known as the cornerstone therapy of immunity.

In addition to dermatomas, there is also a well-known number of important products in the field of solid tumors, such as the thyroid cancer treatment drug lenvatinib and TRK class inhibitors
, which have created an umbrella clinical research paradigm in NTRK-positive solid tumors.

Overall, receptor tyrosine kinase (RTK) inhibitors and immune checkpoint blockers (ICBs) Undoubtedly the most successful anti-tumor drug in the past 31 years, 120 drugs have been approved throughout the history of anti-tumor and have influenced the anti-tumor strategy
of solid tumors.

In the first decade, efforts were devoted to the development of antiendocrine drugs, microtubule inhibitors, DNA alkylating agents, and DNA topoisomerase inhibitors
.
The advent of trastuzumab opened a new era of RTK-targeted therapy, and in the second decade, the research ideas of RTK-targeted inhibitors were extended to the downstream signals of RTK, enriching the TKI library and shifting the focus of anti-cancer drugs to targeted drug development
.
In addition, the advent of ipilimumab, leading the shift in immunotherapy from positive stimuli (e.
g.
, IL-2 and INFα) to immune checkpoint blockade, began a true paradigm shift
in metastatic or advanced solid tumors.
As a result, during the third decade, RTK pathway inhibitors and ICB therapies were widely developed, and the treatment of solid tumors also entered the era of
precise targeting.

However, the 31-year history of development is not difficult to make us clearly understand that the drug resistance of tumor treatment and cancer recurrence are always inevitable and continue to occur, and the succession of multiple drugs is also a evidence
.
At the same time, it is currently impossible to predict how an individual tumor will respond
to available treatments.

prospect

With the development of pharmaceutical technology, proteolysis targets chimeras (PROTACs) and similar degradation technologies, such as chaperone-mediated autophagy and lysosome-targeted chimeras (LYTACs), may bring new therapeutic promises
.
New products such as multispecific antibodies, cell therapies, gene therapies, CAR-T cells in solid tumors, and oncolytic viruses and cancer vaccines also have the potential to bring new options
for cancer treatment.

In addition, whether it can pass through the extracellular matrix (ECM) and epigenetic remodeling or more complex metabolic and immune remodeling to control tumor progression and metastasis, systematic manipulation and domestication of cancer cells, and long-term coexistence and even cure between humans and cancer, may also be the direction of
future exploration.

Artificial Intelligence (AI) , improved the ability to process large amounts of tumor genomic information and promoted the ability to
decipher protein structures.
Artificial intelligence technologies such as AlphaFold may significantly shorten the process of
drug development.
At the same time, with the development of artificial intelligence and nanotechnology, existing diagnosis and treatment methods may be replaced by dynamic nanosensors and intelligent nanorobots, thereby promoting the transformation
of precision medicine to intelligent medicine.

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