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Lung cancer has always been one of the malignant tumors with a high mortality rate in the mainland and even in the world. According to the latest global cancer burden data in 2020, the mortality rate of lung cancer is the first in the world, and the incidence and mortality rate are the first in China for malignant tumors, and the number of deaths has reached 710,000.
Since there are no obvious symptoms in early lung cancer, most patients in the clinic have long been in advanced lung cancer when they visit the doctor. Although various treatment techniques are constantly advancing, the overall 5-year survival rate for advanced patients is not high. Patients with advanced diagnosis are mostly unable to undergo surgery, and in the past few decades, only chemoradiation and chemotherapy have been given, with limited treatment. In addition to the killing effect on tumor cells, traditional radiotherapy and chemotherapy is also toxic to some normal tissue cells.
The era of immunotherapy for lung cancer
Immunotherapy, as a new weapon in the era of anti-cancer treatment, does not have the side effects of traditional chemotherapy of "killing a thousand enemies and self-inflicting eight hundred", but brings hope to more patients with advanced lung cancer. According to clinical data, immunotherapy has greatly improved the overall survival of lung cancer patients.
At present, the most commonly used immunotherapy for lung cancer is PD-1/PD-L1 inhibitors, mainly including O drug nivolumab (nivolumab), K drug (pambolizumab) and domestic carellizumab, tirelizumab, etc.; CTLA-4 inhibitor - ipilimumab, RNA polymerase II inhibitor - lubitidine, VEGF receptor 2 antagonist - ramovizumab and so on.
Primary bronchogenic carcinoma, or lung cancer for short. According to histopathological classification, it is mainly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), and non-small cell lung cancer is the most common type of lung cancer, accounting for about 85%. Current etiology and pathogenesis are not well understood and are generally thought to be related to smoking, occupational carcinogens such as asbestos, air pollution, diet, ionizing radiation, genetic and genetic alterations, and other triggers such as tuberculosis.
According to the researchers' research and predictions, immunotherapy will further improve the survival of lung cancer, especially the late NSCLC that drives the gene mutation negative.
1. Immunotherapy drugs
PD-1/PD-L1 inhibitors
PD-1 is an immunosuppressive transmembrane protein expressed on the surface of T cells, and its main ligand is PD-L1. Tumor cells can also express PD-L1, and when it binds to PD-1, it reduces T cell activation and cytokine production. PD-1/PD-L1 inhibitors can block the binding of PD-1 and PD-L1 to restore the immune function of T cells to tumors.
Image source: Chinese Journal of Lung Cancer
(1) Nivolumab
In March and October 2015, NAVUMUMAB was approved for the second-line treatment of squamous and non-squamous metastatic non-small cell lung cancer (NSCLC) with failed platinum-containing chemotherapy; in May 2020, navumab plus ipimumab was approved for the first-line treatment of PD-L1≥1% metastatic non-small cell lung cancer, and navumab plus ipicumab and 2-cycle platinum-containing dual-drug chemotherapy were approved for the first-line treatment of metastatic non-small cell lung cancer.
In June 2018, it was officially approved by the State Drug Administration (NMPA), which is the first immunotherapy drug in China for the treatment of lung cancer (locally advanced/metastatic non-small cell lung cancer that has previously undergone chemotherapy with a platinum-containing regimen of disease progression or intolerance).
In a study of patients with non-small cell lung cancer, the CheckMate227 study, clinical data showed that the first-line double-immunity treatment of nalumab plus ipilimumab was more effective than chemotherapy, which more effectively improved the overall survival of patients with advanced non-small cell lung cancer with PD-L1≥1%, with a 33% survival rate of 33%. 1
(ii) Pembrolizumab
On October 2, 2015, pembrolizumab was approved by the FDA for second-line treatment in patients with PD-L1-positive advanced non-small cell lung cancer; in 2016, the FDA approved it for the first-line treatment of metastatic non-small cell lung cancer with ≥50% PD-L1 TPS and no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene mutation; in March 2019, Pambolizumab combined with pemetrexed and platinum chemotherapy is FDA-approved for first-line treatment of metastatic nonsquamous non-small cell lung cancer without EGFR/ALK mutations.
In the study on KEYNOTE-010/024/042 of pembolizumab, the results showed a significant improvement in overall and progression-free survival in patients treated with pambolizumab compared with standard platinum-containing chemotherapy. 5-year survival was 31.9% in 50% of patients with driver gene-negative advanced NSCLC in PD-L1≥ and 25% in PD-L1≥1% of patients3.
(3) Carellizumab, tirelizumab
In June 2020, carrelizumab combined with the chemotherapy drugs pemetrexed and carboplatin was approved by NMPA as a first-line treatment for advanced or metastatic nonsquamous non-small cell lung cancer. Carellizumab is the first domestic PD-1 immune drug approved in mainland China for the treatment of lung cancer.
On June 22, 2021, terelizumab combined with pemetrexed and platinum chemotherapy was approved by NMPA for the first-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer without EGFR/ALK mutations.
In a multicenter, randomized controlled phase III study of first-line immunotherapy for lung squamous cell carcinoma, RATIONALE 307, 360 patients with advanced pulmonary squamous, including terelizumab + paclitaxel + carboplatin group and tirelizumab + albumin paclitaxel + carboplatin group, the patients had a progression-free survival of 7.6 months.
PD-1 inhibitor, is a humanized monoclonal antibody, for the treatment of advanced non-small cell lung cancer patients, its biggest feature is that it can stimulate the patient's own immune system function, thereby increasing the level of T lymphocytes to fight tumors, it is not for the tumor cells themselves to produce effects.
All four drugs have different effects on the treatment of lung cancer patients, especially those with advanced non-small cell lung cancer, especially in combination with other standard chemotherapy drugs, and their survival can be greatly improved.
CTLA-4 inhibitor ipilimumab
CTLA-4 inhibitors are different from PD-1 inhibitors, and their biggest feature is to improve the killing effect of their own immune cells, so its toxic side effects may be greater.
CTLA-4, also known as CD152, is a glycoprotein expressed on the surface of activated clusters of differentiated CD4 and CD8T lymphocytes. Generally in the initial stage of cell activation, it has a very important regulatory effect. It blocks secondary activation signals from antigen-presenting cells, thereby inhibiting T cell activation.
On June 10, 2021, ipilimumab was approved as the first CTLA-4 inhibitor to be marketed in China. It is mainly combined with navulamumab for the first-line treatment of PD-L1≥1% of metastatic non-small cell lung cancer, and the combination of navulamumab and 2-cycle platinum-containing dual-drug chemotherapy is used for the first-line treatment of metastatic non-small cell lung cancer.
In a clinical trial of stage III non-small cell lung cancer, the data showed a median overall survival of about 13.4 months. In a clinical trial of first-line treatment for multicenter stage II small cell lung cancer, the data showed that the progression-free survival of patients with combination chemotherapy was significantly improved.
Although ipilimumab has certain advantages in the treatment of lung cancer, lung cancer is an important problem faced by the entire medical community, and ipilimumab still has many problems to be solved in the treatment of lung cancer.
Inhibitor of RNA polymerase II - lurbinectedin
In 2018, lubitidine was approved by the FDA for orphans in the second-line treatment of small cell lung cancer. It is mainly an inhibitor of RNA polymerase II, which can make tumor cells aberrant and apoptosis during mitosis, reducing cell proliferation.
In a phase II clinical trial on rubitidine, the results showed an overall objective response rate (ORR) of 35.2% in patients treated with small cell lung cancer, and about 65% of patients had tumor reductions, although the median progression-free survival was 3.9 months, but the median overall survival reached 9.3 months.
Although the short-term effect of rubitidine is not as effective as that of PD-1 inhibitors such as navulamab, its long-term effect is comparable to that of navulamab.
VEGF receptor 2 antagonist - ramucirumab
Ramosumab, an antagonist of VEGF receptor 2, can specifically bind to VEGF receptor 2 to block the coordination of VEGF-A, VEGF-C and VEGF-D. This inhibits the activation of the LIgand-excited VEGF receptor 2, which ultimately inhibits ligand-induced proliferation and migration of human endothelial cells.
In December 2014, ramovizumab combined with docetaxel, approved by the FDA for the treatment of metastatic non-small cell lung cancer that progressed during or after platinum-containing chemotherapy, or patients with mutations in the EGFR or ALK gene whose disease progressed after receiving other therapies.
In May 2020, the FDA approved ramosumab plus erlotinib for the first-line treatment of patients with metastatic non-small cell lung cancer with exon EGFR19 deletion or exon 21 L858R mutation.
According to its clinical study data, with ramosumab treatment, patient median PFS can reach 19.4 months. Its disease progression and mortality rates have been significantly reduced.
2. Adverse drug reactions
For the above-mentioned PD-1 inhibitors, CTLA-4 inhibitors, RNA polymerase II inhibitors, and VEGF receptor 2 antagonists - ramosumab, different drugs have different side effects.
For example, PD-1 inhibitors, their adverse reactions are mainly in hypothyroidism, vitiligo, joint pain, etc.; while the side effects of CTLA-4 inhibitors may lead to immune-mediated overdistrainment, with different levels of enteritis, pitinitis and rashes; for rubitidine, fever, nausea and vomiting, loss of appetite, anemia, etc. are common adverse reactions; the most common adverse reactions of ramorimumab are hypertension.
Third, the dosage
Since each drug is used in combination with other chemotherapy drugs, it is important to pay attention to whether it is used in advance or at the same time.
1. PD inhibitors: navumab is mainly 3mg/kg every 2 weeks, 60 minutes intravenous injection; while pambolizumab is less frequent, every 3 weeks 2mg/kg, intravenous infusion for more than 30 minutes; carrelizumab and tirelizumab are the same intravenous injection of 200mg / time every 3 weeks, but it should be noted that when carellid beads are treated with other chemotherapy drugs, it is necessary to give carellizulizumab intravenous injection first, and then give other chemotherapy drugs after at least 30 minutes apart.
2. Ipilimumab is still injected intravenously every 3 weeks, but the dosage becomes 1mg/kg, and the time is also longer -90 minutes.
3. Rubitidine, there is a premise when using it for treatment, which requires an absolute neutrophil count (ANC) ≥ 1500 cells / mm, a platelet count of ≥ 100000 / mm. The frequency of intravenous injection every 3 weeks is also maintained, and the dosage is 3.2mg/㎡.
4. Ramorimumab, injected once every 3 weeks, but it should be noted that the first intravenous injection is greater than 60 minutes. 10 mg/kg each time. In the case of combination therapy, it should be used before doceta.
Each treatment has different specific requirements, not all drugs are effective for every patient, and it is hoped that patients can rationally view the efficacy of the drug. When using the injectable drug, it is necessary to follow the doctor's advice and avoid self-use.
Fourth, the future outlook
Now for the treatment of lung cancer, especially the treatment of advanced lung cancer, it has developed from radiotherapy and chemotherapy in the traditional sense to precision molecular targeted therapy, and has developed into the current era of immunotherapy. After decades of efforts, there are more and more immune drugs to treat lung cancer, and many drugs have been listed in China. Although different immune drugs still have different side effects, they are within the controllable range. This is gratifying for most patients. Immunotherapy for lung cancer will also become more and more widespread, and it is believed that the survival period of lung cancer patients in the future may be more than 5 years or even longer.
bibliography:
1Ramalingam SS, Ciuleanu TE, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as f irst-line treatment for advanced non-small cell lung cancer: Three-year update from CheckMate 227 Part 1. J Clin Oncol, 2020, 38(Suppl_15): 9500. doi: 10.1200/JCO.2020.38.15_suppl.9500
2Brahmer JR, Rodriguez-Abreu D, Robinson AG, et al. L BA 51 K EY NOTE-024 5-year OS update: First-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%. A nn Oncol, 2020, 31(Suppl 4): S1181-S1182. doi: 10.1016/ j.annonc.2020.08.2284
3Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for prev iously untreated, PD-L1-ex pressing , locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, control led, phase 3 tria l. Lancet, 2019, 393(10183): 1819-1830. doi: 10.1016/S0140-6736(18)32409-7