This article details molecularly targeted therapy for advanced non-small cell lung cancer in terms of driver gene testing, EGFR-TKI, ALK and ROS-1 fusion gene inhibitors, and angiogenesis inhibitors, ultimately concluding that.
(a) For patients with advanced non-squamous NSCLC with functional status score 0 to 1, in the absence of significant hemoptysis and tumor invasion of large blood vessels, combining bevacizumab on top of first-line chemotherapy (carboplatin/paclitaxel or cisplatin/gemcitabine) is recommended (bevacizumab has no indication for lung cancer in China at the moment, but is expected to be approved by CFDA soon).
For patients with advanced NSCLC, vincristine/cis-molybdenum in combination with recombinant human vascular endothelial inhibitor may be used.
Lung cancer is one of the most common malignant tumors in the world, and the mortality rate is the highest among cancers, among which non-small cell lung cancer (NSCLC) accounts for more than 85% of lung cancers, and most of them are already in advanced stages when diagnosed.
In recent years, although the status of chemotherapy in the treatment of NSCLC has not been fundamentally shaken, its efficacy has reached a plateau, and toxicity and adverse effects have limited its clinical application. Targeted therapy has become one of the most popular and promising treatments due to its reliable efficacy and mild toxicity and adverse effects.
The Lung Cancer Group of the Chinese Medical Association Respiratory Disease Branch and the China Lung Cancer Prevention and Control Alliance have organized relevant experts to discuss issues related to molecular targeted therapy for advanced NSCLC, and formed an expert consensus on molecular targeted therapy for advanced NSCLC suitable for China’s national conditions.
1. Driver gene testing
1.1. Mutation of epidermalgrowthfactorreceptor (EGFR) gene
The results of numerous studies have shown that EGFR mutation status is the most important predictor of efficacy for EGFR tyrosine kinase inhibitors (EGFR-TKI) in the treatment of advanced NSCLC. Mutations usually occur in exons 18-21, with exon 19 deletions and exon 21 L858R point mutations being the most common mutations sensitive to EGFR-TKI therapy (EGFR-sensitive mutations).
The results of several studies have confirmed that the total EGFR mutation rate is about 30% in non-selective Chinese NSCLC patients, the mutation rate is about 50% in adenocarcinoma patients, and can be as high as 60%-70% in nonsmoking adenocarcinoma, while squamous carcinoma patients still have about 10% EGFR-sensitive mutation rate [1-2], therefore, there is a need to raise awareness among clinicians to routinely perform EGFR mutation testing.
Surgical resection specimens from tumor sites, tissue biopsy specimens and cytology specimens can all be used for EGFR gene mutation detection. Regardless of which specimen is used, it should be ensured that the specimen contains at least 200-400 tumor cells. The method of blood specimen for EGFR mutation detection is still immature and less sensitive than tissue specimen, so it is recommended not to be used as a routine test for the time being. The test specimens need to be quality controlled by experienced pathologists [2].
There are many methods for the detection of EGFR mutations, including direct sequencing, real-time fluorescent quantitative polymerase chain reaction (PCR)-based methods such as the scorpionamplificationrefractorymutationsystem (scorpionARMS), fragment length analysis and denaturing high performance liquid chromatography techniques, each with its own advantages and disadvantages, and there is no consensus on which method is more advantageous.
DNA direct sequencing method is widely used and can detect known mutations and unknown mutations, but it requires a high content of tumor cells in the specimen, generally requiring the proportion of tumor cells in the specimen to be above 50%, at least not less than 30%. Methods based on real-time fluorescence quantitative PCR (e.g. ARMS method) are more sensitive than direct sequencing methods and can detect 1.0%~0.1% of mutated genes in the sample, which is more suitable for detection of small specimens with low tumor cell content.
The ARMS method is simple to operate and is one of the more commonly used methods in clinical practice, but it can only detect known mutations, and the specimens need to be pretreated, which makes the test more expensive.
1.2 Mesenchymal lymphoma kinase (ALK) fusion gene
ALK fusion genes are newly identified driver genes in NSCLC, of which fusion of the echinoderm microtubule-associated class 4 (EML4) gene with ALK (EML4-ALK) is the most common type. ALK fusion genes are mainly found in non-smoking or oligometastatic lung adenocarcinoma patients and are usually not present in the same patient simultaneously with EGFR gene mutations.
The incidence of ALK fusion genes in NSCLC patients is about 5%, while in NSCLC patients without mutations in EGFR, KRAS, HER2 or TP53, the positive rate of ALK fusion genes reaches 25%; the positive rate of ALK fusion genes in our adenocarcinoma patients with both EGFR and KRAS wild type is as high as 30%-42% [4]. Currently, the common methods for detecting ALK fusion genes are fluorescence in situ hybridization (FISH), PCR amplification-based techniques and immunohistochemical methods (IHC).
FISH is still the reference standard method for determining ALK fusion genes, but it is expensive, requires high operational specifications, and is not yet suitable for screening of ALK-positive patients. Real-time fluorescence quantitative PCR is easy to operate and highly sensitive, but requires specific kits and instruments. There are already commercial kits for real-time fluorescence quantitative PCR that have been approved by the Food and Drug Administration (CFDA) in China for clinical testing.
IHC is easy to perform, inexpensive, and has a mature operation method. The specificity and sensitivity of D5F3 (cellsignaling) and 5A4 (Abeam) antibodies with high affinity have reached 100% and 95%~99% respectively. With reproducibility of 99.7%, it has been approved by CFDA for diagnosing ALK-positive NSCLC patients.
Laboratory testing should be based on the type of tissue specimen and laboratory conditions to select the appropriate testing technique, and quality control of the specimen should be the responsibility of an experienced pathologist, and when the reliability of one technique is suspected, another technique can be used to verify it [4].
1.3. ROS-1 fusion gene
R0S1, another fusion form of tyrosine kinase receptor gene, is a newly identified driver gene in NSCLC, with CD74-ROS-1 as its common type, with an incidence of about 1% in NSCLC patients [5], higher in young, non-smoking or lightly smoking lung adenocarcinoma patients, and often without overlap with other driver genes.
The clinical features of ROS-1 fusion genes and ALK fusion genes are very similar, suggesting that these two mutant subtypes may share a common pathogenic mechanism. There are several methods used to detect the ROS-1 fusion gene, but the most commonly used assay is currently the FISH method [5].
Conclusion.
Specimens should be obtained for EGFR gene mutation testing as much as possible before treatment of NSCLC patients.
EGFR test specimens need to be quality-controlled by pathologists, and appropriate testing methods should be selected for testing, with high sensitivity recommended, such as the ARMS method.
ALK and ROS-1 fusion gene testing is recommended for patients without EGFR gene mutations.
It is recommended that EGFR gene mutation, ALK and ROS-1 fusion gene testing be performed simultaneously in units that have the conditions.
2. EGFR-TKI
2.1. First-line treatment
The IPASS study reported in 2009 was a large international multicenter randomized controlled phase III clinical study [6] with the primary endpoint of progression-free survival (PFS). The results showed that for patients with NSCLC with EGFR gene sensitive mutations, PFS was significantly better with first-line gefitinib than with first-line carmolybdenum combined with vincristine, with PFS of 9.8 and 6.4 months in the two groups, respectively, and objective remission rate (ORR) was also significantly higher in the gefitinib group, with good tolerability and significant improvement in quality of life.
However, there was no difference in overall survival between the two groups, which may be related to the higher proportion of patients receiving subsequent crossover therapy or other effective treatments. This is a landmark study of targeted therapy, opening the door to truly individualized lung cancer treatment.
The WJTOG3405 study, an open, multicenter, randomized controlled phase III clinical trial comparing the efficacy of first-line application of gefitinib or cisplatin/doxorubicin in 177 patients with advanced NSCLC with EGFR gene sensitive mutations, showed that the PFS of the two groups was 9.2 and 6.3 months, respectively, and the gefitinib group was significantly better than the cisplatin/doxorubicin group [7].
The NEJ002 study compared the efficacy of first-line application of gefitinib or carboplatin/paclitaxel in 230 patients with advanced NSCLC with EGFR gene sensitive mutations and showed that the PFS was significantly better in the gefitinib group than in the carboplatin/paclitaxel group (10.8 and 5.4 months) [8].
OPTIMAL, a randomized, phase DI clinical study initiated by the Chinese Thoracic Oncology Research Group (CTONG), compared the efficacy of first-line receipt of erlotinib with gemcitabine/carboplatin in 165 patients with advanced NSCLC with EGFR gene sensitive mutations. The results showed PFS of 13.1 and 4.6 months in the two groups, respectively, with the erlotinib group significantly better than the gemcitabine/carboplatin group by 0.16, and quality of life significantly better in the erlotinib group than in the chemotherapy group, while there was no difference in overall survival between the two groups [9].
However, subgroup analysis showed a short survival of 11.7 months (21 patients) for patients receiving chemotherapy only, a median overall survival of 20.6 months (33 patients) for patients receiving EGFR-TKI only, and a median overall survival of up to 30.4 months (94 patients) for patients receiving chemotherapy after EGFR-TKI treatment, suggesting that EGFR-TKI for EGFR gene sensitive mutations made an important contribution to the improvement of survival in patients with EGFR genes [10].
The EURTAC study, which is equivalent to the OPTIMAL study in the Caucasian population, compared the efficacy of first-line erlotinib with chemotherapy in patients with EGFR gene-sensitive mutations. 174 patients were randomized to erlotinib treatment or chemotherapy, and the primary study endpoint was PFS, which showed that PFS in the two groups was 9.7 and 5.2 months, respectively, with the erlotinib group significantly outperforming the chemotherapy group [1].
Recently, the results of a randomized phase III clinical study (FASTACT-II) suggested that in patients with non-selective advanced NSCLC, PFS was 7.6 and 6.0 months and overall survival was 18.3 and 15.2 months in the two-agent chemotherapy combined with interspersed erlotinib first-line treatment followed by erlotinib maintenance therapy versus the control group (two-agent chemotherapy plus placebo), respectively.
A subgroup analysis of EGFR gene mutation status showed that only patients with EGFR gene sensitive mutations benefited, while EGFR wild-type patients did not benefit from this treatment modality [12].
The results of an international multicenter randomized controlled phase III clinical study, LUX-LUNG3, showed that for patients with advanced EGFR gene-sensitive mutations in lung adenocarcinoma, PFS after first-line treatment with the irreversible ErbB family inhibitor afatinib was significantly better than cis-molybdenum/pemetrexed, with PFS of 11.1 and 6.9 months in the two groups, respectively, and 0RR was also significantly improved in the afatinib group, with 56% and 23%, respectively [13].
The results of another randomized controlled phase III clinical study LUX-LUNG6 in an Asian population showed that for patients with advanced EGFR mutated lung adenocarcinoma, the primary endpoint PFS afatinib first-line treatment was significantly better than gemcitabine/cisplatin, 11.0 and 5.6 months in the two groups, respectively, and ORR also significantly benefited, 66.9% and 23.0% in the two groups, respectively [14].
Adverse effects of EGFR-TKI were mild, with the most common adverse reactions being skin reactions (rash, pruritus, dry skin and acne) and diarrhea.
The incidence of first-generation EGFR-TKI adverse reactions is more than 50%, but they are usually mild, and the incidence of grade 3 or higher adverse reactions is about 2% to 10%. A less common and serious adverse reaction is interstitial pneumonia, the incidence of which is about 1% and should be given special attention because interstitial pneumonia can lead to patient death if it is not treated properly or actively; second-generation EGFR-TKI ( afatinib) has a higher and more serious incidence of adverse reactions than the first-generation EGFR-TKI.
Conclusion.
First-line EGFR-TKI is recommended for patients with advanced NSCLC with EGFR gene-sensitive mutations (many countries have approved gefitinib and erlotinib as first-line therapeutic agents, but only gefitinib is approved in China, and afatinib has been approved as first-line therapeutic agent in the United States and Taiwan).
For patients with advanced NSCLC with EGFR gene-sensitive mutations, first-line chemotherapy combined with interpolation of erlotinib for 6 cycles followed by maintenance therapy with erlotinib can be considered.
2.2 Maintenance therapy
The INFORM study conducted in China compared the efficacy of gefitinib with placebo for maintenance therapy in advanced NSCLC. The results showed that PFS was significantly prolonged in the gefitinib group compared to the placebo group, with 4.8 and 2.6 months in the two groups, respectively, with a more significant prolongation in the EGFR gene sensitive mutation subgroup treated with gefitinib, with PFS of 16.6 and 2.8 months in the two groups, respectively (HR=0.17), indicating that patients with advanced NSCLC, especially those with EGFR gene sensitive mutations, can benefit from gefitinib maintenance therapy [5].
In another phase III trial (WJTOG0203), 604 patients with stage IIIb or IV NSCLC were randomized to 2 groups, one receiving 3 cycles of standard first-line chemotherapy followed by maintenance treatment with gefitinib and the other receiving 6 cycles of platinum-containing regimen chemotherapy. PFS was 4.3 months in the chemotherapy alone group and 4.6 months in the chemotherapy followed by gefitinib maintenance treatment group.
Although the difference in overall survival between the two groups was not statistically significant, in the adenocarcinoma subgroup, overall survival was 14.3 months in the chemotherapy alone group compared with a significantly better overall survival of 15.4 months in the gefitinib maintenance treatment group [16].
The results of a meta-analysis of erlotinib for maintenance therapy (included in the SATURN, ATLAS and IFCT-GFPC0502 studies) showed that erlotinib prolonged PFS and overall survival in patients with advanced NSCLC with disease control after first-line chemotherapy.
All subgroups of patients benefited from erlotinib maintenance therapy, but the greatest benefit was seen in female, non-smoking, non-squamous patients, which may be related to the higher rate of EGFR mutations in these populations [17].The results of the subgroup analysis of the SATURN study found that patients with EGFR gene-sensitive mutations had significantly longer PFS with erlotinib maintenance therapy compared to the placebo group [18-19]
CONCLUSION: Gefitinib or erlotinib maintenance therapy may be considered for patients with advanced NSCLC who have achieved disease control (PR/CR/SD) with first-line chemotherapy.
2.3. Second-line and follow-up treatment
The results of a meta-analysis including four phase II/III clinical studies showed that for unselected Asian patients with relapsed advanced NSCLC, gefitinib treatment reduced the risk of progression by 19% and increased the objective remission rate by 117% compared with docetaxel [20]. analysis of the Chinese subgroup of the INTEREST study showed that the objective remission rates of gefitinib and docetaxel were 21.9% and 9.1%, with a median PFS of 5.4 and 3.9 months in the adenocarcinoma subgroup [21].
The results of the Korean phase III KCSG-LU-801 study showed objective remission rates of 58.8% and 22.4% with a median PFS of 9.0 and 3.0 months for second-line gefitinib versus pemetrexed, respectively, in Asian nonsmoking patients with advanced adenocarcinoma [22].The results of the BR.21 study showed that in unselected patients with relapsed advanced MSCLC, the erlotinib and placebo groups had an overall survival of 6.7 and 4.7 months, respectively, with a statistically significant difference [23].
Two studies by TITAN and HORG comparing the efficacy of erlotinib with docetaxel and pemetrexed showed that erlotinib was comparable to standard second-line monotherapy docetaxel or pemetrexed, but was better tolerated [24-25].
In the phase III non-inferiority ICOGEN study comparing the efficacy of erlotinib with gefitinib conducted in China [26], the PFS of unselected relapsed advanced NSCLC patients with erlotinib versus gefitinib was 4.6 and 3.4 months, respectively, indicating that the efficacy of erlotinib in unselected relapsed advanced NSCLC patients was not inferior to that of gefitinib.
The results of the study comparing the efficacy of gefitinib with erlotinib [27-28] and the study comparing the efficacy of gefitinib with erlotinib [26] suggest that the efficacy of the three EGFR-TKIs as second-line therapy in patients with advanced NSCLC is similar.
The results of the international multicenter TAILOR phase III clinical study showed that PFS and overall survival were significantly shorter with erlotinib than docetaxel in second line in patients with EGFR wild-type advanced NSCLC [29]. The PFS was 2.9 and 2.4 months for docetaxel and erlotinib, respectively, and the 6-month progression-free survival rates were 27.3% and 16.5%, respectively.
Similarly, the results of the DELTA study confirmed that the PFS and ORR of second-line erlotinib in patients with EGFR wild-type advanced NSCLC were worse than those of docetaxel, with PFS of 1.3 and 2.9 months and ORR of 5.6% and 20.0% for both, respectively [30].
The results of the CTONG0806 study showed that second-line treatment with pemetrexed or gefitinib in advanced NSCLC patients with EGFR wild-type nonsquamous carcinoma resulted in PFS of 4.8 and 1.6 months and disease control rate (DCR) of 61.3% and 32.0%, respectively [31].
The results of all three studies mentioned above suggest that chemotherapy should be preferred as second-line treatment for patients with EGFR wild-type advanced NSCLC.
Conclusion.
EGFR-TKIs (gefitinib, erlotinib or erlotinib) can be used as second- or third-line treatment for patients with advanced NSCLC, while EGFR-TKIs are recommended in preference for patients with EGFR gene-sensitive mutations.
Patients with EGFR wild type are not recommended for second-line treatment with EGFR-TKI in preference to EGFR-TKI.
2.4. Treatment of elderly and low functional status score patients
Elderly (over 70 years of age) lung cancer patients often have difficulty receiving platinum-containing two-drug chemotherapy due to poor organ function and comorbidities, while EGFR-TKI may be considered for first-line use because it is well tolerated.
In an analysis combining three NEJ studies (001, 002, 003), the results of first-line gefitinib versus chemotherapy for elderly patients with advanced NSCLC with EGFR gene-sensitive mutations showed significant differences in ORR of 73.2% and 26.5% and PFS of 14.3 and 5.7 months [32], with NEJ002 showing that elderly versus young and middle-aged patients There was no difference in toxicity and quality of life for first-line gefitinib treatment.
The results of this study suggest a better efficacy of first-line gefitinib in elderly patients with EGFR-sensitive mutations, whose toxicity is tolerable. Results from another randomized phase III clinical study (TOPICAL) of erlotinib versus placebo in patients with advanced NSCLC who were intolerant to first-line chemotherapy showed a 17% reduction in the risk of disease progression with erlotinib compared with placebo [33].
A pooled analysis of the efficacy of gefitinib or erlotinib versus single-agent chemotherapy in patients who were elderly or had poor functional status scores, pooling 5 studies with 330 patients in the EGFR-TKI group and 10 studies with 1095 patients in the single-agent chemotherapy group, showed a 0RR of 18% and a DCR of 50% in the EGFR-TKI group, compared with an ORR of 12% in the single-agent chemotherapy group and DCR of 36% [34].
The results of the WJTOG0402 study showed an ORR of 20% and a DCR of 47%, a median PFS of 2.7 months, and a median overall survival of 11.9 months for first-line gefitinib in elderly patients with adenocarcinoma. The most common toxic reaction was rash; others included diarrhea, loss of appetite, hepatic dysfunction, and anemia, but all were mild and easily managed.
The ORR in nonsmoking patients was 43%, DCR was 57%, median PFS was 7.1 months, and median overall survival was 13 months, suggesting better efficacy and good tolerability of first-line use of gefitinib in older patients or patients with poor functional status scores in the dominant population [35].
Conclusion.
Treatment with an EGFR-TKI (gefitinib or erlotinib) is recommended for elderly patients with EGFR-sensitive mutations.
For elderly or NSCLC patients who cannot tolerate chemotherapy and whose EGFR mutation status is unknown, EGFR-TKI (gefitinib or erlotinib) treatment can be tried due to the high EGFR gene mutation rate in Chinese patients and the absence of other effective treatment modalities, and the efficacy and toxicity and adverse effects should be closely observed.
2.5. Treatment after EGFR-TKI resistance
Patients with NSCLC with EGFR gene-sensitive mutations treated with EGFR-TKI in first line usually experience disease progression after 9? 10 months, suggesting the development of secondary EGFR-TKI resistance [6-11]. A retrospective study included 227 patients with secondary drug resistance and explored the treatment patterns after disease progression on EGFR-TKI therapy.
Patients were classified according to time to disease control, tumor load evolution and clinical symptoms6 as rapidly progressive (≥3 months of disease control, rapid increase in tumor load compared to previous assessments, and symptom score of 2), slowly progressive (≥6 months of disease control, slight increase in tumor load compared to previous assessments, and symptom score ≥1) and locally progressive (≥3 months of disease control, isolated extracranial progression or intracranial progression with symptom score ≤1), the results showed median PFS of 9.3, 12.9 and 9.2 months and median survival times of 17.1, 39.4 and 23.1 months for the three modalities, respectively.
Survival times for rapidly progressing patients treated with continuous TKI were shorter than those who switched to chemotherapy, so it is recommended that rapidly progressing patients discontinue EGFR-TKI and switch to chemotherapy. The median overall survival for patients with slow progression who continued with TKI and those who changed to chemotherapy was 39.4 and 17.8 months, respectively = 0.02), so continued TKI therapy was recommended.
Patients with local progression had similar overall survival with continued TKI or chemotherapy, but considering the quality of life of the patients and the limitations of locally progressive lesions, continued TKI plus local treatment is recommended [36].
A retrospective study included 78 patients with acquired resistance to EGFR-TKI (70 with EGFR gene sensitivity mutations), 34 treated with chemotherapy in combination with erlotinib and 44 with chemotherapy only. The results showed that the ORR in the combination erlotinib-treated group and the chemotherapy-only group were 41% and 18%, respectively, with PFS of 4.4 and 4.2 months, respectively [37].
The 2013 edition of the National Comprehensive Cancer Network guidelines recommends continuing EGFR-TKI in patients with EGFR-sensitive mutations after first-line progression with EGFR-TKI if the patient is asymptomatic, and switching to chemotherapy in combination with EGFR-TKI for symptomatic patients.
There is less high-level evidence-based medical evidence on treatment after EGFR-TKI resistance, but there are a series of relevant studies in progress, such as the IMPRESS study of TKI combined with chemotherapy versus chemotherapy alone after EGFR-TKI resistance for treatment modality and the ASPIRATION study of continued use of TKI after resistance, the study of TKI combined with other drugs and the study of EGFR-TKI-resistant new drug studies, etc. We expect the results of these studies to provide more evidence-based medical evidence.
Conclusion.
For patients with slow progression, continuation of the original EGFR-TKI therapy or EGFR-TKI in combination with chemotherapy is recommended.
For patients with rapid progression, discontinuation of EGFR-TKI and switch to chemotherapy is recommended.
In patients with local progression and well-controlled original lesions, it is recommended to continue EGFR-TKI and combine with local therapy.
3.ALK and ROS-1 fusion gene inhibitors
The results of two multicenter clinical trials showed that the ALK inhibitor crizotinib had a significant therapeutic effect in patients with EML4-ALK fusion gene-positive advanced NSCLC. in the A8081001 study, patients in the crizotinib group had an ORR of 60.8%, a median duration of remission of 49.1 weeks, and a median PFS of 9.7 months [38].
In the A8081005 study, the ORR of patients with advanced ALK-positive NSCLC treated with crizotinib in second line was 50%, with a median duration of remission of 41.9 weeks. Common adverse effects (incidence ≥25%) included visual impairment, nausea, diarrhea, edema, and constipation [39].
Phase III clinical study A8081007 compared the efficacy and safety of crizotinib with pemetrexed or docetaxel in ALK-positive advanced NSCLC patients who had received prior chemotherapy. 347 ALK-positive patients treated with platinum-containing chemotherapy prior to enrollment were randomized to receive crizotinib or chemotherapy, with the primary study endpoint of PFS.
The results showed FPS of 7.7 and 3.0 months and ORR of 65% and 20% in the crizotinib and chemotherapy groups, respectively [40]. crizotinib was approved by the CFDA in January 2013 for the treatment of Chinese patients with ALK-positive locally advanced or metastatic NSCLC.
The preliminary efficacy of crizotinib in treating patients with ROS-1 positive NSCLC was reported at the American Society of Clinical Oncology (ASCO) annual meeting in 2012. A total of 13 patients in the human group had a well-tolerated ORR of 54% and an 8-week DCR of 85%.
The efficacy of crizotinib in treating patients with ROS-1-positive advanced NSCLC was also reported at the 2013 ASCO Annual Meeting. The evaluable 25 patients had an ORR of 56% and DCRs of 76% and 60% at 8 and 16 weeks, respectively, with a median PFS yet to be achieved. This study reconfirmed the effectiveness of crizotinib in the treatment of ROS-1-positive advanced NSCLC [42].
CONCLUSION: Crizotinib treatment is recommended for patients with advanced NSCLC positive for ALK and ROS-1 fusion genes.
4. Angiogenesis inhibitors
The results of two phase III randomized studies confirmed the efficacy of the angiogenesis inhibitor bevacizumab in combination with chemotherapy when applied in first line in nonsquamous NSCLC [43-44], and the trial group continued to maintain bevacizumab treatment after the end of chemotherapy until disease progression or the development of intolerable drug toxicity.
In the E4599 study, a regimen of carboplatin/paclitaxel combined with bevacizumab at 15 mg/kg every 3 weeks significantly improved overall survival, PFS, and ORR in patients with overall survival of 12.3 and 10.3 months, PFS of 6.2 and 4.5 months, and ORR of 35% and 15%, respectively [43].
The results of the AVAIL study confirmed that bevacizumab combined with cisplatin/gemcitabine regimen at 7.5 or 15 mg/kg every 3 weeks significantly improved PFS and ORR in patients with no significant prolongation of overall survival compared to placebo combined with cisplatin/gemcitabine [44]. Common adverse effects of bevacizumab include hypertension, proteinuria, and bleeding, but the incidence of grade 3 hypertension is less than 4%, grade 4 hypertension is less than 0.5%, grade 4 proteinuria is less than 0.5%, and the incidence of bleeding is less than 2%.
Bevacizumab is not recommended for the following conditions.
Squamous or mixed type of lung cancer with predominantly squamous cancer.
Tumor invasion of large blood vessels.
A history of hemoptysis (1 hemoptysis > 2.5 ml).
Uncontrollable cardiovascular disease such as primary hypertension.
The results of a phase III randomized clinical study in China confirmed that recombinant human vascular endothelial inhibitor combined with vincristine/cisplatin significantly improved ORR compared with placebo combined with vincristine/cisplatin in patients with advanced NSCLC, 35.4% and 19.5%, respectively, and time to tumor progression, 6.3 and 3.6 months, respectively, and there was no statistical difference in the incidence of adverse events between the two groups [45].
Conclusion.
For patients with advanced non-squamous NSCLC with a functional status score of 0 to 1, in the absence of significant hemoptysis and tumor invasion of large vessels, combining bevacizumab with first-line chemotherapy (carboplatin/paclitaxel or cisplatin/gemcitabine) is recommended (bevacizumab has no indication for lung cancer in China at this time, but is expected to be approved by CFDA soon).
For patients with advanced NSCLC, vincristine/cis-molybdenum in combination with recombinant human vascular endothelial inhibitor may be used.