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: Solid Tumors Dominate The Anticancer Market

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.

FDA-approved therapeutic drugs for lung cancers

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).

FDA-approved therapeutic drugs for breast cancers

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.

FDA-approved therapeutic drugs for gynecologic cancers

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).

FDA-approved therapeutic drugs for gastrointestinal cancers

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 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. 

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.

FDA-approved therapeutic drugs for prostate cancers

6. Other Solid Tumors

FDA-approved therapeutic drugs for urologic cancers

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.

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FDA-approved therapeutic drugs for melanoma and other skin cancers

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.

Future Prospects of Therapeutic Drugs For Solid Tumors

In the past few decades, the identification of targets and drug design for tumors have always been the core of the development of anti-tumor drugs throughout history.

During the first decade, pharmacologists focused on the development of drugs such as antiendocrine drugs, microtubule inhibitors, DNA alkylating agents, and DNA topoisomerase inhibitors. During this period, people did not pay much attention to targeting Drugs, although the advent of trastuzumab has opened a new era of RTK targeted therapy.

In the second decade, targeted therapy drugs formally stepped on the stage of history. People extended RTK targeted inhibitors to downstream related inhibitors including RTK, and promoted the development of targeted drugs, which made RTK targeted therapy drugs become the treatment drugs for solid tumors and the most approved drugs in recent decades. Notably, the approval of Ipilimumab also heralds another therapeutic era in which immunotherapy shifts from active stimulation to immune checkpoint suppression, ushering in a new paradigm for the treatment of metastatic or advanced solid tumors.

In the third decade, inhibitors of RTK-related pathways have been widely developed and several immune checkpoint inhibitors have been approved for marketing. Solid tumor therapy has entered a new era, that is, an era of more precise targeting.

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.  
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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

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