Lung cancer is the most common type of cancer and the leading cause of cancer death. In 2020 alone, lung cancer killed more than 1.7 million people worldwide. The early symptoms of lung cancer are relatively insidious and lack specificity, and most patients are already in the middle and late stage when diagnosed, which greatly increases the difficulty of lung cancer treatment and leads to poor prognosis of patients. Pathological types of lung cancer can be roughly divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), among which NSCLC is the most common type of lung cancer, accounting for about 80%-85% of lung cancer cases. Over the past few decades, we have made great strides in developing innovative treatments for lung cancer that have improved outcomes and quality of life for many patients. Here, we will introduce the current therapies for NSCLC based on official information from the American Cancer Society.
What Are The Targeted Drug Therapies For NSCLC?
1. Drugs targeting tumor angiogenesis - angiogenesis inhibitors
Tumor growth is inseparable from the generation of new blood vessels to maintain the nutrients needed for its growth. Some drugs that specifically target this process can prevent the formation of new blood vessels in tumors and curb tumor growth. This class of drugs is called angiogenesis inhibitors.
Common angiogenesis inhibitors are Avastin (Bevacizumab) and Cyramza (Ramucirumab), both monoclonal antibodies that target vascular endothelial growth factor (VEGF), a protein that helps new blood vessels form. The two drugs are usually used in combination with chemotherapy agents. Avastin was approved by the FDA in 2006 for the treatment of unresectable locally advanced, relapsed, or metastatic non-squamous NSCLC, and Cyramza was approved by the FDA in 2014 for the treatment of NSCLC in combination with docetaxel. The National Medical Products Administration (NMPA) has also approved the marketing of Avastin in China for the treatment of advanced, metastatic or recurrent non-small cell lung cancer. Although Cyramza is marketed in China, its indication for NSCLC has not yet been approved in China.
2. KRAS-targeted drugs
About a quarter of NSCLC patients carry mutations in the KRAS gene, and the resulting mutant KRAS protein facilitates the growth and spread of cancer cells. The KRAS G12C mutation is a common form of mutation in NSCLC patients (about 13%), and NSCLC patients with this mutation are often resistant to other targeted drugs, such as EGFR inhibitors. Currently, targeted drugs targeting KRAS G12C mutations have been successfully marketed, such as sotorasib, which was approved by the US FDA in 2021 for the treatment of NSCLC patients with KRAS G12C mutation who have received at least one previous systemic therapy. Sotorasib can specifically bind to KRAS G12C mutant protein and inhibit its activity, blocking KRAS G12C protein-related signaling pathways, so as to inhibit tumor growth. Currently, the drug has not been approved for marketing in China.
3. EGFR-targeted drugs
Epidermal growth factor receptor (EGFR) is a protein on the cell surface that helps cells grow and divide. NSCLC cancer cells have higher levels of EGFR protein on their surface, which causes them to grow faster. EGFR-targeted drugs can block EGFR-transmitting cell growth signals, and some of these drugs can be used to treat NSCLC. EGFR-targeted drugs commonly used in the treatment of NSCLC include Tarceva (Erlotinib), Giotrif (Afatinib), Iressa (Gefitinib), Tagrisso (Osimertinib) and VIZIMPRO (Dacomitinib), all of which have been approved by the NMPA for the treatment of non-small cell lung cancer carrying EGFR mutations.
According to drug information published by the American Cancer Society, all of these drugs can be used to treat advanced NSCLC patients with EGFR mutations, and Tagrisso (Osimertinib) can also be used as an adjunctive agent after surgery to treat early lung cancer patients with certain types of EGFR mutations.
EGFR mutation sites are diverse in non-small cell lung cancer. In actual clinical treatment, targeted drug therapy regiments are also different according to different EGFR mutations.
EGFR T790M mutation: In general, EGFR inhibitor drugs can usually shrink tumors for several months or longer, but when the T790M mutation occurs in the EGFR gene of cancer cells, the general EGFR inhibitor drugs no longer work. Tagrisso is clinically used to treat NSCLC patients with EGFR T790M mutation.
EGFR exon 20 mutation: When exon 20 of the EGFR gene is mutated in cancer cells of NSCLC patients, the efficacy of the above-mentioned EGFR-targeted drugs on these patients becomes very limited. Targeted drugs targeting EGFR exon 20 mutations have been successfully developed, such as amivantamab and mobocertinib, which were approved by the US FDA in May and September 2021, respectively, for the treatment of adult NSCLC patients with EGFR exon 20 mutations. At present, these two drugs have not yet been approved for marketing in China.
4. ALK-targeted drugs
About 5% of NSCLC patients have ALK gene rearrangement, which is more common in the adenocarcinoma subtype of NSCLC. Patients in this category usually have no smoking history (or light smoking) and are younger. The mutant ALK protein produced by ALK gene rearrangement can promote the growth and spread of cancer cells. Therefore, ALK-targeted drugs can inhibit tumor growth and promote apoptosis of cancer cells by selectively inhibiting the activity of the mutant ALK protein and blocking its downstream signal. Common targeted drugs for ALK mutations include Xalkori (Crizotinib), Zykadia (Ceritinib), Alecensa (Alectinib), Alunbrig (Brigatinib) and Lorbrena (Lorlatinib), these drugs have been approved by the US FDA and the NMPA for the treatment of ALK-positive locally advanced or metastatic NSCLC patients.
5. ROS1-targeted drugs
Approximately 1% to 2% of patients with NSCLC carry the ROS1 gene rearrangement. This mutated form of ROS1 is often found in the adenocarcinoma subtype of NSCLC. Tumors in these patients are negative for ALK, KRAS, and EGFR mutations. ROS1 gene rearrangement is similar to ALK gene rearrangement, so some NSCLC drugs targeting ALK gene rearrangement mutations can also be used to treat ROS1 gene rearrangement in non-small cell lung cancer patients. Current drugs targeting the ROS1 mutated protein include Xalkori (Crizotinib), Zykadia (Ceritinib), Lorbrena (Lorlatinib), and Rozlytrek (Entrectinib). Among them, Xalkori and Rozlytrek were approved by the US FDA and the NMPA for the treatment of ROS1 positive non-small cell lung cancer, while the related indications of Zykadia and Lorbrena for ROS1 gene mutant non-small cell lung cancer were not approved by the US FDA and the NMPA for the time being.
6. BRAF-targeted drugs
In some NSCLC patients, cancer cells have a mutation in the BRAF gene and produce a corresponding mutant version of the BRAF protein, which helps cancer cells grow. Several targeted drugs for BRAF mutations are already available, including Tafinlar (Dabrafenib) and Mekinist (Trametinib), which were approved by the FDA in 2017 in combination with metastatic NSCLC patients carrying the BRAF V600E mutation. This year, Dabrafenib combined with Trametinib for BRAF V600E mutation-positive NSCLC patients was approved by the NMPA, which is the first approved dual-target combination therapy for BRAF mutation-positive lung cancer in China.
7. RET-targeted drugs
RET-targeted drugs play an anti-tumor role by inhibiting the activity of RET protein in cancer cells. Selpercatinib and Gavreto (Pralsetinib), commonly used in the treatment of NSCLC, were approved by the US FDA in May and September 2020 respectively for the treatment of RET fusion positive metastatic NSCLC patients. In March 2021, the NMPA conditionally approved the marketing of Pralsetinib for the treatment of adult patients with locally advanced or metastatic NSCLC who have received platinum-containing chemotherapy in the past and are positive for RET gene fusion. Selpercatinib has not yet been launched in China.
8. MET-targeted drugs
In the treatment of NSCLC, the main targeted drugs for MET mutations are capmatinib and tepotinib, both of which target jump mutations occurring in MET exon 14. The former was approved by FDA in May 2020 for the treatment of advanced NSCLC patients carrying this mutation. The latter was approved by the FDA in February 2021 for patients with metastatic NSCLC with MET mutations. Neither has yet been approved for listing in China.
9. HER2-targeted drugs
At present, for NSCLC patients with HER2 mutations, available drugs include Enhertu, which is an ADC (Antibody-drug conjugate) drug. In August 2022, the drug’s new indication for lung cancer has just been approved by the US FDA for the treatment of patients with HER2 mutations. Patients with mutated unresectable or metastatic NSCLC who have previously received one systemic therapy.
Enhertu may cause hematological adverse reactions such as decreased blood cell counts, leading to an increased risk of infection and bleeding. Other common side effects include nausea, vomiting, diarrhea or constipation, loss of appetite, fever, tiredness, and hair loss. In rare cases, this drug may cause heart damage.
10. NTRK-targeted drugs
Mutations in the NTRK gene are uncommon in non-small cell lung cancer, and only a small number of NSCLC patients carry the mutation, which causes abnormal cell growth. At present, there are two drugs that can target NSCLC patients with this gene mutation in clinical practice—Vitrakvi (Larotrectinib) and Rozlytrek (Entrectinib). Both drugs are indicated for solid tumors carrying NTRK gene fusion mutations (including NSCLC), and both drugs received accelerated FDA approval in 2018 and 2019, respectively. Both drugs have been approved for sale in China.
What Are The Available Immunotherapies For NSCLC?
Immunotherapy refers to treatments that use a person's immune system to fight diseases such as cancer. Generally speaking, immunotherapy exerts its anti-cancer effect by activating and enhancing the ability of the human immune system to recognize and kill cancer cells. In the clinical treatment of NSCLC, available immunotherapy is mainly immune checkpoint inhibitors.
1. PD-1 and PD-L1 inhibitors
PD-1 is a checkpoint protein on immune cells, mainly in T cells. When PD-1 on T cells binds to a protein produced by cancer cells called PD-L1, their immune function is suppressed. Therefore, drugs targeting either PD-1 or PD-L1 can block the binding between the two and boost the immune response of the body to cancer cells.
There are various types of PD-1/PD-L1 inhibitors commonly used in the treatment of NSCLC. Among them, the drugs targeting PD-1 mainly include Opdivo (Nivolumab), Keytruda (Pembrolizumab) and Libtayo (Cemiplimab). The drugs targeted at PD-L1 are Tecentriq (Atezolizumab) and Imfinzi (Durvalumab), which have been approved by the US FDA and NMPA for relevant indications of NSCLC.
2. CTLA-4 inhibitor
CTLA-4 inhibitors include Yervoy (Ipilimumab), which enhances the immune activity of human T cells and stimulates the anti-tumor response of the immune system by targeting the inhibition of CTLA-4. Ipilimumab was approved by the US FDA in 2020 for first-line treatment in combination with Nivolumab in patients with metastatic NSCLC whose tumors have PD-L1 expression of ≥1% and do not carry EGFR or ALK mutations. Moreover, the combination of ipilimumab and Nivolumab with two cycles of platinum-containing chemotherapy has also been approved by the FDA for the first-line treatment of adult patients with metastatic/relapsed NSCLC without EGFR or ALK mutations. PD-L1 expression is not restricted in patients receiving this treatment regimen, and it is applicable to all patients with squamous and non-squamous carcinoma. Ipilimumab is currently available for sale in China, but has not yet been approved by the NMPA for indications related to non-small cell lung cancer.
In recent years, the rapid development of targeted therapies and immune checkpoint inhibitors has greatly changed the treatment pattern of NSCLC. The maturity of these therapies has brought new hope for the majority of patients. Here, we only introduce a part of NSCLC therapies , not all treatments are listed. For the majority of patients with advanced NSCLC, drug resistance has always been a bottleneck restricting the therapeutic effect. With the further research on lung cancer and the discovery of more drug targets and biomarkers, we look forward to solving this puzzle one day and providing more options for the treatment of NSCLC.
Huateng Pharma is a worldwide API pharmaceutical intermediates & PEG derivatives supplier that dedicated to supplying a variety of pharmaceutical intermediates for anti-cancer drugs and high-quality PEG linkers for ADC drugs. We can supply key intermediates of Entrectinib, which is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. We can also supply some intermediates of Larotrectinib. We have our own factory and make scale-up production with capacities varying from gram to kilograms and multi tons.
 CANCER FACT SHEETS, Retrieved Sep 22nd, 2022
 Chemotherapy for Non-Small Cell Lung Cancer，Retrieved Sep 22nd, 2022
 Targeted Drug Therapy for Non-Small Cell Lung Cancer，Retrieved Sep 22nd, 2022
 Immunotherapy for Non-Small Cell Lung Cancer，Retrieved Sep 22ndth, 2022
5 ADC Targets And Representative Drugs For Non-Small Cell Lung Cancer (NSCLC)