Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy covers second- and third-line therapy, first-line therapy and even maintenance therapy in advanced NSCLC, so an increasing number of patients are bound to develop resistance to TKI or TKI failure at some point in their treatment course. However, there is no high-level, credible clinical research evidence to guide treatment after EGFR-TKI failure.
Two levels of consideration are currently available.
1. Based on some preliminary results and experience, subsequent treatment is selected based on the stage of TKI treatment.
2. Targeted selection of follow-up therapy based on the molecular mechanism of TKI treatment failure or resistance.
In recent years, there has been a growing body of research and evidence involving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI, gefitinib and erlotinib) for the treatment of advanced non-small cell lung cancer (NSCLC). The range of TKI therapy recommended by various guidelines covers second- and third-line therapy, first-line therapy, and even maintenance therapy in advanced NSCLC, so it is inferred that a large proportion of patients with advanced NSCLC will receive EGFR-TKI therapy at some point in their treatment course. However, regardless of the recent efficacy, eventually patients will inevitably develop resistance to TKI or TKI failure, so how should follow-up treatment proceed?
To date, there is still no high-level, credible clinical research evidence to support this. However, in the face of the increasing number of patients who still need or want to be treated after TKI failure, physicians should not sit idly by without guideline recommendations. A few years of exploration and practice have been documented, and although the level of evidence is not high, the experience is valuable and worth learning from. In addition, based on the depth of basic research, the molecular mechanism of EGFR-TKI drug resistance is gradually clear, and more and more targeted drugs targeting tumor resistance mechanism or acting on other related signaling pathways are gradually entering the clinic.
Therefore, the choice after TKI treatment failure in the current situation can be considered at two levels.
1.Choose the follow-up treatment according to the treatment stage of TKI.
2.Select follow-up therapy according to the molecular mechanism of TKI treatment failure.
1. Selection of follow-up therapy according to the stage of TKI treatment
Treatment after failure of first-line EGFR-TKI
For patients with EGFR mutation-positive advanced NSCLC, NCCN guidelines recommend EGFR-TKI as one of their first-line treatment options. There is no high-level evidence-based evidence on how to choose second-line therapy for these patients after first-line TKI therapy has failed or acquired drug resistance has developed. The panel considered a two-drug combination regimen containing platinum as an option after progression of first-line erlotinib therapy (Class 2B recommendation).
Wu et al. retrospectively analyzed 195 patients with intermediate to advanced NSCLC after failure of first-line gefitinib treatment and their subsequent treatment and prognosis at the Third Medical Center in Taiwan, and the results showed that patients receiving platinum-based or paclitaxel-containing regimens in second line had better outcomes; 61 patients with EGFR mutation-positive genes survived better than those receiving erlotinib after receiving gemcitabine combined with platinum-based chemotherapy. Therefore, when patients failed first-line targeted therapy with a physical status (PS) score of 0-2, patients benefited more from platinum-containing regimens than from other treatments (including switching to another TKI). Given these guideline recommendations and the results of the literature, platinum in combination with gemcitabine or paclitaxel is preferred after first-line TKI failure.
Treatment after second-line EGFR-TKI failure
The NCCN guidelines clearly recommend EGFR-TKI for second- and third-line treatment of patients with advanced NSCLC after failure of first-line chemotherapy, and the follow-up treatment of such patients after failure of second- and third-line treatment is only recommended by the NCCN guidelines to choose a different treatment strategy according to the general condition of the patient. If the patient has a PS score of 0-2, experimental therapy or best supportive care may be given; if the patient has a PS score of 3-4, only best supportive care will be given. Follow-up therapy for this patient population with the highest percentage of EGFR-TKI failure or resistance is also the most actively explored and studied target population.
The choice of follow-up therapy after failure of second-line EGFR-TKI therapy is not yet supported by evidence from higher-grade clinical studies and is mostly empirical. The analysis of 32 patients with advanced NSCLC who failed second/third-line TKI treatment with follow-up chemotherapy (triple-generation chemotherapy drug alone, pemetrexed or platinum-containing two-drug combination regimen) at Shanghai Chest Hospital showed that 15.6% had partial remission, 53.1% had disease control, and patients with >6 months of prior TKI treatment or PS score 0-1 had better chemotherapy outcomes and PFS than other patients.
The results of the efficacy and safety analysis of 110 patients with advanced NSCLC treated with pemetrexed monotherapy in third/fourth line at Samsung Medical Center in Korea showed that 16.3% of patients had PR, 53.6% disease control, and 3.2 months PFS, with male being the only negative predictor associated with PFS. 11.6 months OS, poor physical status score and smoking were negative predictors associated with OS [2 negative predictor [2]. The results of these two retrospective analyses suggest that patients with advanced NSCLC with a PS score of 0-2 after second-line TKI failure may be considered for third-line administration of docetaxel, pemetrexed or platinum-containing doublet chemotherapy based on the efficacy and toxic side effects of their first-line chemotherapy regimen, especially for patients treated with EGFR-TKI for >6 months.
Treatment after third-line TKI failure
Compared to patients with advanced NSCLC who have failed second-line TKI therapy, patients who have failed third-line TKI therapy have undergone multiple treatments, have progressed through several episodes of disease, and have decreased PS scores; not only are their conditions complex, but their willingness to treat varies widely among individual patients; and the variety of prior treatments they have received has led to a mountain of options for follow-up.
The patients have received a variety of previous treatments, resulting in the embarrassing dilemma of running out of drugs and technologies to choose from. As can be seen, the above-mentioned factors and disadvantages bring more challenges and uncertainties to the standardization and standardization of follow-up treatment for these patients. On the contrary, this complex situation also gives us more opportunities to think, try and practice.
Continuation of original TKI therapy
The results of continuation of original TKI therapy after EGFR-TKI treatment failure have been reported in recent years, but they are limited to selected populations and there is a lack of results from large-scale clinical studies to verify their effectiveness. yano et al. reported the results of three patients with non-smoking lung adenocarcinoma who were given gefitinib again after at least 7 months of gefitinib failure. All three patients were treated with their first TKI for more than 12 months, and two of them had tumor control and maintenance for >7 months after re-dosing, while the other patient failed again after 4 months due to the development of a malignant pleural effusion. Thus, the authors suggested that some patients may still benefit from reapplication of targeted drugs after the first targeted therapy was effective and discontinued for more than a certain period of time.
Oh et al. reported the results of a single-arm, open phase II clinical study of gefitinib re-treatment after gefitinib failure in patients with intermediate to advanced NSCLC. 18 patients enrolled in the study had a median duration of 264 days on the first dose, received at least one chemotherapy regimen after disease progression, and had a median duration of 86 days on gefitinib re-treatment after chemotherapy, with 27% in partial remission, 53% with stable disease Oh concluded that the re-response of patients to gefitinib treatment may be related to tumor heterogeneity and that a small proportion of EGFR-TKI-dependent tumor cells may remain after the initial response to targeted drug therapy, but over time the tumor may reoccupy these cells and reappear with TKI benefit.
Pro-TKI in combination with monoclonal antibody or chemotherapy
In vitro studies have shown a significant synergistic effect of TKI in combination with monoclonal antibodies, which may act to further downregulate the expression of key enzymes of the activated EGFR signaling pathway. riely reported the results of a study in which erlotinib was continued after erlotinib failure and combined with cetuximab for advanced lung adenocarcinoma, with a median duration of 19 months for patients initially treated with erlotinib The median treatment period was 2 cycles without objective remission and PFS of 3.0 months with continued treatment with erlotinib 100 mg combined with cetuximab (500 mg/m2 given every 2 weeks) after treatment failure, and the authors concluded that the administration of TKI combined with cetuximab after TKI failure was not effective in the treatment of advanced lung adenocarcinoma.
Shukuya et al. reported the results of 16 patients with NSCLC treated with gefitinib in combination with paclitaxel monotherapy after failure of gefitinib therapy, with an efficiency and disease control rate of 13% and 75%, PFS and OS of 4.3 and 8.1 months, respectively, and mild toxic effects that were tolerated by patients. However, it is difficult to say whether this study is the effect of chemotherapy or the synergistic effect of TKI and chemotherapy. Therefore, the effect of continuing TKI in combination with monotherapy and chemotherapy after TKI failure remains to be investigated.
TKI dosing after failure due to brain metastases
Jackman et al. reported one patient with multiple brain metastases after 6 months of gefitinib treatment, with the remaining lesions stable. Oral gefitinib was continued in conjunction with whole brain radiotherapy, and new meningeal metastases developed after 3 months. Gefitinib was gradually increased to 1000 mg/d, and oral temozolomide and intrathecal cytarabine were given at the same time, and the patient’s clinical symptoms were significantly relieved.
After the above treatment was maintained for 4 months, the patient’s disease progressively worsened despite the increase of gefitinib dose to 1250 mg/d, with significant progression of pulmonary and hepatic lesions. The authors concluded that increasing the dose of gefitinib treatment could increase the concentration of the drug in the cerebrospinal fluid accordingly, thus achieving control of intracranial lesions. However, increased drug concentrations in pulmonary and hepatic lesions may induce the development of T790M mutations, which may lead to extracranial lesions resistant to gefitinib. Therefore, we first consider local treatment for brain metastases or apply chemotherapeutic drugs that cross the blood-brain barrier in such patients; if it is ineffective or progresses again, then consider increasing the TKI dose, and closely observe and promptly manage the side effects of the drugs.
Replacement of another TKI after the failure of one TKI
The literature on replacement of another TKI after failure of one TKI is the most extensive, but almost all were retrospective analyses, and the vast majority were studies of switching to erlotinib after failure of gefitinib. kaira et al. performed a pooled analysis of studies related to switching to erlotinib after failure of gefitinib treatment, and included 11 studies with a total of 106 patients. The results of the analysis showed 71.7% disease control with gefitinib and 29.2% with subsequent erlotinib; PFS 6.3-17.0 months with gefitinib and 1.7-5.9 months with erlotinib; patients with stable disease and PFS >6 months after gefitinib treated with erlotinib had better outcomes than other patients; patients with EGFR mutation-positive and wild-type patients who received subsequent erlotinib had better outcomes. There was no significant difference in disease control rate and efficiency when patients received erlotinib (37.5% vs. 21.7%, p=0.1503; 6.3% vs. 8.7%, p=1.000).
Combining the results reported in the literature in recent years, it can be broadly concluded that some patients can still benefit from treatment with erlotinib after gefitinib failure, with an overall effective rate (ORR) of approximately 10%, stable disease (SD) of approximately 20%, and disease progression (PD) of approximately 70%. Favorable factors include adenocarcinoma, never having smoked, previous gefitinib efficacy of SD or partial remission with stable disease for more than 6 months, or discontinuation of gefitinib after failure for more than 3 months. Despite this, erlotinib after gefitinib failure is not a positive recommendation if more options are available.
Multi-target TKI therapy
Since EGFR-TKI blocks only one signaling pathway, other pathways can become remediation or escape mechanisms for cancer cells. In contrast, multi-target tyrosine kinase inhibitors inhibit tumor cell growth and the formation of tumor microenvironment from different links, which has the advantage of multiple anti-tumor activities in a single agent and can directly target binding to tumors and blood vessels. Although there is no single multi-targeted molecular targeting agent approved for NSCLC, many phase II and III clinics are underway.
Sorafenib (BAY4329006, Sorafenib) is an oral multi-targeted antitumor agent that inhibits multiple kinases present both intracellularly and on the cell surface, including RAF kinase, vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor receptor-3 (VEGFR-3), platelet-derived growth factor receptor-β ( It inhibits tumor growth directly by inhibiting the RAF/MEK/ERK signaling pathway on the one hand, and indirectly by blocking tumor neovascularization through inhibition of VEGFR and PDGFR on the other. e2501 is a randomized, terminated, double-blind, placebo-controlled, third-line treatment of NSCLC patients with sorafenib monotherapy. In the double-blind, placebo-controlled phase II clinical study, 51 of the 83 patients enrolled were treated with sorafenib and 32 with placebo, and >50% of patients in both groups had received TKI therapy.
The results showed that sorafenib significantly improved patient PFS over placebo (3.6 months vs. 2.0 months, P=0.009) and there was a trend toward longer OS (11.9 months vs. 9.0 months, P=0.18). In light of the results of this phase II clinical study, a global multicenter (MISSION study) phase III clinical study of sorafenib versus placebo in third/fourth line for the treatment of advanced, recurrent NSCLC with the primary study endpoint of OS is currently underway with promising results.
Vandetanib is a synthetic anilinoquinazoline compound that is an orally administered small molecule multi-targeted tyrosine kinase inhibitor that acts on EGFR, VEGFR, and RET tyrosine kinases, as well as selectively inhibiting other tyrosine kinases and serine/threonine kinases. vandetanib is a vandetanib-controlled placebo treatment for advanced TKI-naïve NSCLC. As of the time of data analysis, 90% of patients had tumor progression and 76% had death. There was no significant difference in overall survival between the two groups, but PFS was longer in the vandetanib group than in the placebo group.
Sunitinib malate is an oral, selective, multi-targeted tyrosine kinase inhibitor that inhibits the activity of vascular endothelial growth factor receptor-1,2,3 and platelet-derived growth factor receptor-alpha,beta, as well as several other related tyrosine kinase activities, with anti-angiogenic and anti-tumor activity Dual action. Sunitinib has been shown in preclinical studies to effectively inhibit growth in human NSCLC xenograft models. Sunitinib has also been shown to be effective in NSCLC in phase I and II clinical trials. To date, several phase II clinics have evaluated the efficacy and safety of sunitinib monotherapy in NSCLC.
In an open, single-arm, multicenter, phase II study in previously treated patients with advanced NSCLC, the ORR was 11.1%, median duration of remission was 21.2 weeks, PFS was 12 weeks, and OS was 23.4 weeks when sunitinib 50 mg was administered according to a 4/2 regimen (4 weeks on and 2 weeks off the drug). In another open, single-arm, multicenter phase II study in previously treated patients with advanced NSCLC, 4 weeks of continuous sunitinib resulted in an ORR of 2.1%, median PFS of 12.3 weeks and median OS of 38.1 weeks. sunitinib was also tried in our center for advanced NSCLC that had failed multiple chemotherapy and EGFR-TKI, and the results showed that sunitinib may also be a treatment option for advanced NSCLC in which multiple chemotherapy and EGFR-TKI have failed [ 11 ]. However, more and more in-depth clinical observations are needed on how to screen and predict patients who benefit from sunitinib treatment, the dose, usage and placement of sunitinib in several lines of treatment are more appropriate, and the safety of sunitinib for advanced NSCLC in China.
2. Selection of subsequent treatment according to the molecular mechanism of TKI treatment failure
TKI primary drug resistance
Several clinical studies have shown that Asian population with female, no smoking history and pathological type of adenocarcinoma show better efficacy for EGFR-TKI and are the best population to benefit from this type of targeted drugs. For the highly selected population with EGFR mutation, clinical studies such as IPASS, SLCG, NEJGSG002, and WJTOG3405 showed that the efficiency of patients receiving TKI in first line ranged from 70.6% to 74.5%, and the PFS ranged from 10.6 months to 14.0 months. Compared with first-line chemotherapy, the efficacy is surprising but some patients are still insensitive to EGFR-TKI therapy, i.e., primary resistance to TKI drugs, and the possible resistance mechanisms are as follows.
K-ras gene mutation-related
The K-ras gene exists in wild-type or mutant form and is an effector downstream of the EGFR pathway. The mutant K-ras gene encodes an abnormal protein that promotes the growth and spread of tumor cells independent of the upstream EGFR signal. Studies have shown that about 5%-30% of lung adenocarcinomas have K-ras gene mutations, EGFR and K-ras mutations are mutually exclusive in lung cancer patients, and K-ras gene mutations are important predictors of primary resistance to targeted drugs and are negative predictors of EGFR-TKI therapy. The results of related studies and Meta-analysis showed that K-ras mutations in NSCLC patients ranged from 16.4% to 21%, were much higher in patients with a history of smoking than in patients with no or little smoking (25% vs 6%), and higher in adenocarcinoma than in other histological types (26% vs 16%), with no significant difference between men and women (22% vs 20%). the efficiency of patients with K-ras mutations treated with TKI Patients with K-ras mutations had an efficiency rate of about 3%, while K-ras wild-type patients had an efficiency rate of nearly 26%. As a result, the 2009 edition of the NCCN guidelines recommended that patients with K-ras mutations should be treated with something other than trospium, with a recommendation of Class 2B.
Preliminary results from BATTLE, a phase II clinical study integrating relevant biological markers to guide targeted lung cancer therapy, were reported at the 2010 ASCO Annual Meeting: the disease control rate was 58% in the sorafenib-treated group, including 61% in patients with positive K-ras mutations, and lower in patients with positive EGFR mutations than in wild-type patients. (23% vs. 64%, P=0.012), and EGFR copy number amplification (27% vs. 62%, P=0.048), thus the investigators concluded that patients with positive K-ras mutations and/or EGFR wild-type may benefit from sorafenib treatment, while patients with positive EGFR mutations and EGFR patients with positive EGFR mutations and EGFR copy number amplification may have a poor outcome with sorafenib treatment. This result provides a treatment opportunity for patients with K-ras mutations and wild-type and EGFR wild-type. However, this study is only a small phase II clinical study and will need to be validated in a large clinical study.
EML4-ALK fusion gene related
The N-terminus of the protein encoding microtubule-associated protein-like 4 (EML4) was partially fused to the intracellular i-tyrosine kinase structural domain of mesenchymal lymphoma kinase (ALK) and rearranged to EML4-ALK, resulting in aberrant tyrosine kinase expression. 2007 Soda first detected EML4-ALK rearranged fusion in postoperative specimens from NSCLC patients. Since then, it has been reported in the United States, Japan, Korea and Hong Kong, China, but the detection rate of EML4-ALK positivity in unselected NSCLC population is low, about 1.5% to 6.7%. Some characteristics of EML4-ALK-positive patients are similar to those of EGFR-mutated patients, and positivity is almost always found in non-smokers or light smokers with adenocarcinoma. However, this group of patients does not benefit from EGFR-TKI-targeted therapy, and therefore a shift in treatment strategy is needed for this group of patients, such as trying targeted therapy against ALK.
Crizotinib (PF02341006), a small molecule inhibitor of ALK gene, has shown good efficacy in phase I clinical trials due to its clear target and mechanism of action. The median number of prior treatments received by 82 patients with ALK fusion NSCLC was 3. The median duration of treatment with Crizotinib was 5.7 months, ORR was 57%, duration of remission was 1-15 months, >90% of patients had >30% tumor shrinkage, 87% disease control at 8 weeks, and 72% of patients had no disease progression at 6 months. Investigators concluded that Crizotinib treatment has a high remission rate and good safety profile in NSCLC patients carrying the EML4-ALK fusion gene [ 19 ]. Several clinical trials related to Crizotinib are currently underway, and we look forward to the early release of another new member of molecularly targeted therapies.
Acquired drug resistance
Acquired drug resistance is defined as.
1. Previously treated with EGFR-TKI monotherapy.
2, Patients with EGFR mutations associated with drug sensitivity and/or significant clinical benefit from EGFR-TKI treatment (efficacy evaluation of CR, PR, or efficacy evaluation of SD for ≥ 6 months of continuous dosing).
3. Tumor progression after at least 30 days of continuous treatment with EGFR-TKI. The main factors associated with acquired resistance to EGFR-TKI are T790M secondary mutation and c-MET gene amplification, which account for about 50% and 20%, respectively; recent studies suggest that it may also be associated with high expression of MET ligand hepatocyte growth factor (HGF).
Secondary drug resistance due to T790M mutation
T790M is a nucleotide secondary point mutation in EGFR exon 20 at position 2369, where cytosine (C) is replaced by thymine nucleoside (T), and at the protein level, where threonine is replaced by methionine in the tyrosine kinase functional domain at position 790. T790M mutations cause drug resistance by blocking the binding of EGFR to TKI or increasing the affinity of EGFR to ATP. The exact mechanism of T790M mutation in NSCLC tumor cells during treatment with gefitinib or erlotinib is not yet clear. This indicates that T790M mutations have a low incidence, but are significantly associated with TKI resistance. For NSCLC with TKI resistance due to T790M mutation, subsequent treatment can be given to irreversible multi-target inhibitors, which are currently under phase II or phase III clinical studies.
BIBW2992 (Tovok) is a dual irreversible tyrosine kinase inhibitor that targets epidermal growth factor receptor (EGFR/HER1) and human epidermal receptor 2 (HER2) receptor tyrosine kinases, and exerts its antitumor effects by irreversibly binding to the corresponding receptors. The results of previous clinical studies have shown that BIBW2992 has potential for antitumor activity in EGFR mutation-positive patients who are resistant to EGFR-TKI drugs. percent, with a median PFS of 12.0 months [ 20 ]. The results of this study confirm the effectiveness of BIBW2992 for the treatment of EGFR mutation-positive NSCLC. An international multicenter phase III clinical study is currently underway and the results are of great interest.
PF299804 is a new pan-human epidermal growth factor receptor small molecule inhibitor that exerts its antitumor effects by irreversibly binding to HER-1, HER-2, and HER-4. The results of a previous study showed that PF299804 showed potential antitumor activity in gefitinib primary or secondary resistant NSCLC.Campbell et al. reported the results of a multicenter, open phase II clinical study of PF299804 monotherapy in third-line treatment of advanced NSCLC that had failed prior chemotherapy and erlotinib treatment, with partial remission of 5.3% and 63% of patients disease stabilization >6 weeks; 7 patients with clear secondary T790M mutations, 5 of whom received PF299804 with efficacy evaluated as SD and 2 evaluated as PD; patients with positive EGFR gene mutations had a PFS of 19.3 weeks and wild-type patients 11.1 weeks; OS was 45.3 weeks for adenocarcinoma patients and 25.6 weeks for non-adenocarcinoma patients [ 21].
Amplification of c-Met gene
The MET gene is located on chromosome 7q31 and encodes a transmembrane glycoprotein with a molecule of 190 KD, a member of the tyrosine kinase growth factor receptor family, whose protein product is the hepatocyte growth factor receptor (HGF), which is associated with the proliferative capacity of cells. Studies have shown that MET gene amplification activates the ErbB3/PI3K/AKT signaling pathway, triggering resistance to EGFR kinase inhibitors. 2007 Engelman et al. detected MET gene amplification in their established gefitinib-resistant cell lines and restored sensitivity to gefitinib by blockade of the MET signaling pathway.
Among the 18 NSCLC specimens resistant to gefitinib or erlotinib, MET gene amplification was detected in 4 (22%); MET amplification was detected in 8 patients before and after treatment with targeted drugs, including 2 patients without MET gene amplification before treatment who showed amplification after targeted treatment; MET gene amplification was detected in 1 patient with secondary resistance to TKI. and T790M mutation in one patient with secondary resistance to TKI, and T790M mutation and MET gene amplification in another patient were detected in different metastases. It was also reported that 20% of NSCLC TKI resistance was associated with c-MET gene amplification, the occurrence of which was not correlated with the presence of T790M, and the efficiency of targeted therapy for lung cancer could be increased from 71% to 93% by inhibiting MET gene amplification.
No small molecule inhibitors targeting MET are currently available, but some drugs have entered phase II clinical studies. ARQ197 is a novel selective c-MET inhibitor. Because of the association between c-MET gene amplification and poor prognosis in NSCLC and resistance to epidermal growth factor receptor (EGFR) inhibitors such as erlotinib, c-MET receptor tyrosine kinase has become a target of interest in the treatment of NSCLC. 2010 ASCO Congress featured a presentation of this study of erlotinib in combination with ARQ197 (E+A) versus erlotinib The results showed that patients in the E+A group had a median progression-free survival of 16.1 weeks compared to 9.7 weeks in the E+P group, and that patients with non-squamous cancer, wild-type EGFR and K-ras mutation-positive patients had a significantly better PFS than other patients. There was no significant difference in the adverse effects between the two groups of patients. Therefore, we are looking forward to the launch of ARQ197 and other MET inhibitors.
Hepatocyte growth factor (HGF high expression)
Hepatocyte growth factor (HGF) is a ligand for MET protein, which is expressed in a variety of mesenchymal and tumor cells. Studies have shown that overexpressed HGF may induce secondary resistance to TKI in EGFR mutation-positive adenocarcinoma cells through the GAB1 signaling pathway. HGF was found to be highly expressed in lung cancer patients who smoked, and nicotine induced overexpression of HGF in NSCLC cell lines, which may also be related to the insensitivity of smokers to EGFR-TKI therapy. The correlation between HGF and TKI resistance needs to be further confirmed as there are few relevant studies on HGF.
Conclusion: In view of the increasing number of patients with advanced NSCLC who have failed or are resistant to EGFR-TKI therapy, follow-up treatment for these patients is urgent. However, we are still looking forward to the results of rigorous and scientific clinical trials, and to the implementation of more effective individualized treatment for these patients with different causes of TKI failure, guided by molecular biological indicators, after the molecular mechanism of EGFR-TKI treatment failure or drug resistance is fully clarified.