Abstract
Introduction
Lung cancer is one of primary cancer type with high incidence and mortality, non-small cell lung cancer (NSCLC) is the most common type of lung cncer. For advanced lung cancer, traditional chemotherapy and targeted therapy become difficult to solve the dilemma of further progress. In recent years, with the clinical application of immunotherapy, the therapeutic strategy of lung cancer has changed dramatically. At present, immunotherapy has shown conspicuous efficacy in NSCLC patients with high expression of programmed death-ligand 1 (PD-L1) and high tumor mutational burden (TMB). The discovery of driver mutations brings delightful hope for targeted cancer therapy. However, it remains controversial whether immunotherapy can be used in NSCLC patients with these specific driver mutations.
Method
This article summarized the latest research progresses of immunotherapy in advanced NSCLC. We paid close attention to the relevance of various driver mutations and immunotherapy in NSCLC patients, and summarized the predictive effects of several driver mutations and immunotherapy.
Results
The mutations of KRAS, KRAS+TP53, EPHA (especially EPHA5), ZFHX3, ZFHX3+TP53, NOTCH, BRAF and LRP1B+FAT3 have potential to be used as biomarkers to predict the positive effectiveness of immunotherapy. ZFHX3, ZFHX3+TP53, STKII/LKB1+KEAP1+SMARCA4+PBRM1 mutations in LUAD patients get more positive effect in immunotherapy. While the mutations of EGFR, KEAP1, STKII/LKB1+KRAS, EML4-ALK, MET exon 14 skipping mutation, PBRM1, STKII/LKB1+KEAP1+SMARCA4+PBRM1, ERBB2, PIK3CA and RET often indicate poor benefit from immunotherapy.
Conclusion
Many gene mutations have been shown to be associated with immunotherapy efficacy. Gene mutations should be combined with PD-L1, TMB, etc. to predict the effect of immunotherapy.
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Introduction
Lung cancer is one of the primary cancer types with high incidence and mortality, and non-small cell lung cancer (NSCLC) is the most common pathological type (Molina et al. 2008). With the emergence of adverse effects and the toxicity of chemotherapy drugs, the resistance of targeted therapy, immunotherapy has stepped onto the historical stage of NSCLC treatment. Immunotherapy improves the anti-tumor immunity of tumor microenvironment through stimulating or mobilizing immune system. The discovery of programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) has promoted the development of tumor immunotherapy. Immunotherapy includes immune checkpoint inhibitors (ICIs) (targeting PD-1, PD-L1, TIGIT, Tim-3, Lag-3, etc.) (Anderson et al. 2016; Chauvin and Zarour 2020), immune checkpoint agonists (targeting CD40, TLR7, TLR8) (Freed-Pastor et al. 2021; Byrne et al. 2021; Mullins et al. 2019), cancer vaccines (Enokida et al. 2021), CAR-T therapy and other strategies. These treatments can effectively enhance the anti-tumor immune effect and inhibit the tumor growth. However, the curative effect of immunotherapy varies from patient to patient. How to predict the curative effect of immunotherapy to guide the clinical application of immunotherapy has become a hot research topic.
Recent researches have indicated that the expression of PD-L1 (Herbst et al. 2014), tumor mutation load (TMB) (Rizvi et al. 2018), special gene mutation, tumor-infiltrating lymphocytes (TIL) (Lu et al. 2019), antigen presentation defects (Thompson et al. 2021), gene expression profiles (GEPs) (Wang et al. 2019) could be used as predictive biomarkers of immunotherapy efficacy. Among them, PD-L1 expression, TMB (≥ 10 mut/Mb), microsatellite instability (MSI-H) and mismatch repair deficient (MMR) have been approved by health regulatory agencies, which can serve as predictive biomarkers for immunotherapy of NSCLC patients (Hellmann et al. 2018a, b; Marabelle et al. 2020; Bodor et al. 2020; Rizvi et al. 2018). In addition, being as the composite biomarkers, PD-L1 and TMB have stronger predictive abilities than alone (Rizvi et al. 2018; Carbone et al. 2017). In recent years, studies have shown that the mutation of TP53, one of the tumor suppressor genes, was related to high PD-L1 expression and high TMB (Dong et al. 2017). Besides, patients with TET1 mutation achieved longer progression-free survival (PFS) and overall survival (OS) after treated by immunotherapy than those without TET1 mutation in various cancers (Wu et al. 2019). Gene mutations may have some connection with DNA damage and repair (DDR) pathway to improve tumor immunogenicity by accumulating false DNA damage reaction, which shows good curative effect in immunotherapy (Wang et al. 2018; Teo et al. 2018). These findings manifest that some gene mutations can be new promising biomarkers for immunotherapy in NSCLC patients. Therefore, this review summarized the researches of immunotherapy in NSCLC patients with driver mutations in recent years, focusing on their relationship.
Here, we defined mutation rate of more than 5% as common mutation and mutation rate of less than 5% as rare mutation.
Common gene mutations and immunotherapy in NSCLC
TP53
As the most frequently mutant gene with more than 30% incidence in NSCLC (Dearden et al. 2013), the relevance of TP53 and immunotherapy has been extensively studied. Several researches revealed that TP53 mutation was regularly in connection with increased PD-L1 expression and TMB (Dong et al. 2017; Herbst et al. 2016). It also facilitated CD8 + T-cell infiltrations (CD8 + TILs) which were the predominant effector population following treatment with anti-PD-1/PD-L1 immunotherapy (Topalian et al. 2015). All these discoveries uncovered that TP53 mutation played a role in immune checkpoint inhibitor therapies.
Further, TP53 mutation included missense mutation and nonsense mutation (Bouaoun et al. 2016). Compared with the wild type, TP53 missense mutation showed significantly higher PD-L1 expression. And TP53 missense mutation was associated with a superior response to ICIs than TP53 nonsense mutation (Sun et al. 2020). But no clinical study has validated this outcome.
In addition, a meta-analysis which analyzed 19 studies that involved 6,084 patients with NSCLC found the TP53 wild type was correlated with a remarkable higher overall survival (OS) than the TP53 mutant type (Gu et al. 2016). Meanwhile, another analysis also identified that lung adenocarcinoma (LUAD) patients with TP53 mutation carried a poorer prognosis in contrast with those TP53 wild type (Wang and Sun 2017).
So, TP53 mutation is related with worse prognosis, but the efficacy with immunotherapy is still unclear.
EGFR
The incidence of EGFR mutation was about 27% in NSCLC (Dearden et al. 2013). According to the CheckMate 057, KEYNOTE 010 and POPLAR trials, PD-1 inhibitors prolong the OS compared with docetaxel in NSCLC patients. However, in subgroup analysis, there was no remarkable difference in EGFR mutant patients (Borghaei et al. 2015; Herbst et al. 2016; Fehrenbacher et al. 2016). Many studies have reverified above findings. Chee Khoon Lee has indicated that for NSCLC patients with EGFR mutation, those treated by immunotherapy did not possess any more significant survival benefits than those treated by chemotherapy in second and later lines of therapy (Lee et al. 2018). Namely, in EGFR mutant advanced NSCLC patients, there is no significant improvement in OS between immunotherapy and chemotherapy.
Another retrospective analysis has suggested that NSCLC patients with EGFR mutation were related with poor immunotherapy efficacy (Gainor et al. 2016). It observed a statistically inferior progression-free survival (PFS) and objective response rate (ORR) for EGFR mutant patients received anti-PD-1/PD-L1 immunotherapy compared with the EGFR wild type. Further exploring possible mechanisms, we learned that EGFR mutations were relevant with fewer CD8 + TILs (Akbay et al. 2013).
All these studies confirmed that EGFR mutation could be regarded as a negative biomarker to immune checkpoint inhibitors.
KEAP1
KEAP1 is a mutated gene with the third frequency in LUAD. Study has found the frequency of KEAP1 mutation is more than 17% in LUAD (Cancer Genome Atlas Research Network 2014).
A study evaluated the information from TCGA data has shown that KEAP1 mutation has negative prognostic effect on immunotherapy (Cheng et al. 2021). But it has been found that KEAP1 mutation showed close association with lower TILs and cytotoxic T lymphocyte. It indicated that KEAP1 mutation may be associated with lower tumor immunity (Cheng et al. 2021).
Furthermore, other researches have also confirmed that patients with KEAP1 and STK11 mutation have poor therapeutic effect with pembrolizumab (Aggarwal et al. 2020).
Based on Impower150 study, Howard Jack West et al. have found compared with the wild type, patients with KEAP1 mutation treated by atezolizumab and/or bevacizumab with carboplatin/paclitaxel were associated with inferior OS and PFS (West et al. 2022).
KRAS
The incidence of KRAS mutation is about 17% in NSCLC (Dearden et al. 2013). ICIs can reduce the death risk of NSCLC patients with KRAS mutation compared with chemotherapy (Lee et al. 2018). Studies found that immunotherapy had a greater therapeutic benefit for KRAS mutation than KRAS wild type in NSCLC patients (Lee et al. 2018; Mazieres et al. 2019). The research which retrospectively analyzed 88 advanced NSCLC patients receiving immunotherapy disclosed that patients with KRAS mutation in immunotherapy had longer PFS and OS than the wild type (Dong et al. 2017). In addition, according to a prospective analysis of Song et al. patients who have higher rates of KRAS mutations treated by immunotherapy obtained durable benefit (Song et al. 2020).
The underlying mechanism why patients with KRAS mutation might benefit from anti-PD-1/PD-L1 immunotherapy remains unclear. Some researches pointed out that it might because KRAS-mutant tumors had more tumor-infiltrating lymphocytes in the microenvironment and were almost always active. On top of this, KRAS-mutant NSCLC expressed more PD-L1, and as mentioned above, the high expression of PD-L1 was confirmed to be related to better therapeutic effect (Mazieres et al. 2019; Rizvi et al. 2018).
Generally, tumor suppressor genes, such as TP53, KEAP1, STK11/LKB1, ATM and CDKN2A, are the most frequently co-mutated genes with KRAS (Aredo et al. 2019; Lee et al. 2018; Skoulidis et al. 2015). Studies suggested that the PD-L1 expression in KRAS + TP53 co-mutation are much higher than the single mutation of KRAS (Skoulidis et al. 2018; Dong et al. 2017). A recent study which contained 165 patients with KRAS-mutant NSCLC undergoing anti-PD-1/PD-L1 immunotherapy demonstrated that the co-mutation of TP53 might be associated with higher response (Lee et al. 2018). It can be inferred that NSCLC patients with co-mutation of KRAS and TP53 are more sensitive to immunotherapy.
Therefore, it is speculated that KRAS mutation and KRAS + TP53 co-mutation will become the predictive biomarkers for immunotherapy in NSCLC.
STK11/LKB1
STK11/LKB1 mutations are prevalent in NSCLC with 9% incidence (Dearden et al. 2013). They are related to lower a PD-L1 expression and an intermediate or high TMB. According to research findings, The STK11/LKB1-mutant tumors revealed significantly lower ORR/PFS/OS to anti-PD-1/PD-L1 immunotherapy (Skoulidis et al. 2018). And another research also uncovered that patients who harbored STK11 mutation treating with immunotherapy showed progress disease and the PFS was only 4.2 weeks (Kauffmann-Guerrero et al. 2020). But another research indicated that there was no direct link to poor ICIs outcomes and STK11/LKB1 mutation (Di Federico et al. 2021).
As mentioned above, STK11/LKB1 are particularly prevalent among KRAS-mutant tumors. STK11/LKB1 loss directly promotes the formation of non-T-cell-inflamed tumor immune microenvironment in immune competent murine models of KRAS-mutant LUAD (Skoulidis et al. 2018). Numerous researches found the co-mutation of KRAS and STK11/LKB1 in NSCLC patients receiving immunotherapy has been confirmed to be related to poor therapeutic effect (Di Federico et al. 2021; Skoulidis et al. 2018). Indeed, co-existence of both mutations is associated with more metastatic sites at diagnosis and a higher risk of brain metastases (Calles et al. 2015).
In conclusion, the co-mutation of STK11/LKB1 and KRAS can be considered as a negative predictive marker for immunotherapy in NSCLC.
EPHA
Ephrin A receptor (EPHA) is an important member in receptor tyrosine kinase family, and it is a key regulator of intercellular signal transduction in normal development and diseases. EPHA3-7 are all common mutant genes in NSCLC (about 5%–15%) (Jamal-Hanjani et al. 2017; Campbell et al. 2016; Hellmann et al. 2018a, b). At present, studies have indicated that EPHA mutation is a new predictor that significantly prolonged PFS in NSCLC patients with immunotherapy, which may independently predict the clinical benefits of immunotherapy in NSCLC without being affected by other gene mutations. Like ZFHX mutation, the superior clinical efficacy to immunotherapy with EPHA mutation is mostly manifested in LUAD patients (Bai et al. 2020).
EPHA5, as a member of the Eph receptor family, is a common mutation in LUAD (Chen et al. 2020). Chen et al. have found that compared with the wild type, the EPHA5 mutant significantly changed tumor microenvironment, and the TMB level increased. It was speculated that immunotherapy was an effective treatment to the EPHA5 mutant patients. And this study also indicated that the survival time of LUAD patients with EPHA5 mutation who received immunotherapy was more prolonged (Chen et al. 2020). It implies that EPHA5 mutation is a promising positive biomarker for immunotherapy in NSCLC, especially in LUAD patients. More importantly, this research pointed out that although patients with EPHA5 mutation and high TMB showed a longer OS than those with low TMB, the OS time of EPHA5 wild-type patients with high TMB was the same as that of patients with low TMB. Therefore, detecting EPHA5 mutation may be useful to prevent over-treatment of patients who choose immunotherapy only based on high TMB.
ZFHX3
ZFHX3, namely zinc finger homeobox 3, is an inhibitor of alpha-fetoprotein gene and one of the tumor suppressor genes in many cancers (Hu et al. 2019; Walker et al. 2015). According to the COSMIC database, the mutant rate of ZFHX3 is about 7–8%. It may be related to brain metastasis in lung cancer (Song et al. 2021). Recently, studies have suggested that NSCLC patients with ZFHX3 mutation had a good prognosis after immunotherapy, and their PFS and OS were significantly longer than those of ZFHX3 wild-type patients, especially the ZFHX3 mutated LUAD patients (Zhang et al. 2021b, a). Further analysis suggests that it may be due to the positive correlation between ZFHX3 mutation and the previously mentioned immunotherapy biomarkers, such as TILs, TMB, DDR pathway in NSCLC, etc. At the same time, the study revealed that activated CD4 + T cells, dendritic cells (DCs) and M1 macrophages were more abundant in ZFHX3 mutated LUAD patients.
In addition, Zhang et al. have indicated that the ZFHX3 mutation predicted higher survival rate in NSCLC patients treated with immunotherapy. And patients with the co-mutation of TP53 and ZFHX3 had longer OS than those with TP53 mutation after immunotherapy (Zhang et al. 2021a, b).
All the above results indicate that ZFHX3 mutation can be regarded as a valuable predictive biomarker for immunotherapy in NSCLC, and it shows a positive therapeutic effect, especially for LUAD patients with ZFHX3 and TP53 co-mutation.
SMARCA4
SMARCA4 alterations include two categories: class 1 are truncating mutations, fusions, and homozygous deletion and class 2 are missense mutations (Chakravarty et al. 2017). According to a large retrospective study gathering data from three institutions, the prevalence of SMARCA4 mutation in NSCLC is about 6% (Cancer Genome Atlas Research Network 2014). Another study gathered the information of 532 patients from the immunotherapy-treated cohort has found that the ORR/PFS/OS of SMARCA4 mutant patients had no significant extension with immunotherapy therapeutic efficacy (Alessi et al. 2021).
But previously another large study has indicated that SMARCA4 mutant tumors tended more to have lower PD-L1 expression and higher TMB. It moved forward to illuminate those patients with SMARCA4 mutant seemed to obtain benefit from immunotherapy, despite the negative PD-L1 expression (Schoenfeld et al. 2020).
In addition, Alessi et al. have found that STK11 or KEAP1 mutation often co-mutated with SMARCA4 in NSCLC patients (Alessi et al. 2021). But the co-mutations of STK11, KEAP1 and SMARCA4 were associated with the negative immunotherapy effect (Di Federico et al. 2021; Marinelli et al. 2020).
Therefore, the relationship of immunotherapy and SMARCA4 mutation remains unclear and further research is needed.
EML4-ALK
The incidence of EML4-ALK mutation in NSCLC is about 5.3% (Dearden et al. 2013). The POPLAR and ATLANTIC trails have indicated that anti-PD-1/PD-L1 immunotherapy had lower therapeutic effect on NSCLC patients with EML4-ALK mutation than those with wild type (Fehrenbacher et al. 2016; Garassino et al. 2018). And a retrospective analysis also observed a significant shorter PFS and objective response rate (ORR) in EML4-ALK mutant patients with anti-PD-1/PD-L1 immunotherapy compared with those with wild type (Gainor et al. 2016). There were a large number of clinical researches proved that ICIs are ineffective in NSCLC patients with EML4-ALK mutation. That was likely because EML4-ALK mutation was not related with increased effector T cells which adjusted anti-tumor immune responses, despite it was associated with high expression of PD-L1 (Pyo et al. 2020).
However, there was a case report showed that a EML4-ALK mutant patient treated twice with ICIs obtained remarkable curative effect which may because of high TMB and abundant CD8 + T-cell infiltration (Song et al. 2019).
Therefore, although EML4-ALK mutation was often related with negative immunotherapeutic effect, some patients with that mutation received good survival benefits.
PTEN
PTEN gene mutation in NSCLC is about 5.1% (Dearden et al. 2013). Little research has reported the association between PTEN mutation and immunotherapy in patients with NSCLC. Previously, a study has manifested that PTEN mutation was associated with immunotherapy resistance through enhancing the expression of immunosuppressive cytokines and inhibiting autophagy (Peng et al. 2016). Multiple clinical trials have confirmed the relevance of PTEN and immunotherapy resistance.
A case report observed that a patient who showed negative effect to Nivolumab was detected PTEN mutation by next-generation sequencing. It suggested that PTEN mutation in tumors was associated with immunotherapy resistance (Teng et al. 2022). Besides, another case also reported a NSCLC patient with PTEN mutation obtained poor immunotherapy efficacy (Ren et al. 2022). So, PTEN mutation may be hopefully considered as a new biomarker to predict negative therapeutic effect to immunotherapy in NSCLC.
A retrospective cohort study from the European Thoracic Oncology Platform (ETOP) Lungscape Project found that PTEN mutation was related with the expression of PD-L1 ≥ 1% cut-off (Kerr et al. 2019). However, another case report revealed a metastatic NSCLC patient with PTEN mutation expressed a poor response to the ICIs, although it exhibited high TMB and PD-L1 (Parikh et al. 2018).
In contrast to that, a prospective analysis reported by Peng Song has proved that patients who obtained durable benefit by immunotherapy in NSCLC had higher rates of PTEN mutation and TP53 + PTEN co-mutation, suggesting that patients with these gene mutations may achieve positive effect from immunotherapy. But there was no specific statistical correlation between these genetic mutations and long‐term benefit outcomes (Song et al. 2020).
Above all, PTEN mutation is often associated with negative immunotherapeutic effect, but it still needs more large-scale studies to verify this conclusion.
Rare gene mutations and immunotherapy in NSCLC
NOTCH
NOTCH family consists of four members, including NOTCH1/ NOTCH2/ NOTCH3/ NOTCH4 (Mumm and Kopan 2000). According to the COSMIC database, the mutant rate of NOTCH is just about 5%.
A study has demonstrated that NOTCH mutation reduced immune cell infiltration, such as myeloid-derived suppressor cells, tumor-associated macrophages and Tregs. And it also decreased the expression of PD-1, CTLA-4, TIM-3 and LAG-3 (Mao et al. 2018).
Kai Zhang et al. have detected the association between NOTCH mutation and positive immunotherapeutic clinical effect. The overall immunotherapy response rate was 20.7% in NSCLC patients with NOTCH mutation. In addition, the median PFS and OS were 3.1 months and 16.0 months, respectively (Zhang et al. 2020). It also found patients with NOTCH1, NOTCH2 or NOTCH3 mutations exerted longer ORR and PFS than the patients with NOTCH wild type, but patients with NOTCH4 mutation did not have this trend (Zhang et al. 2020). However, another research found NOTCH4 mutant tumors were characterized by the abundant expressions of TMB and high CD8 T-cell infiltration, which indicated the NOTCH4 mutation may also be associated with good immunotherapy benefit (Long et al. 2021).
MET
MET gene alteration existed in 3–4% of NSCLC. One of the gene mutations was MET exon 14 skipping mutation (Frampton et al. 2015; Awad et al. 2016).
A study enrolled 63 NSCLC patients with MET exon 14 skipping mutation, the duration of immunotherapy ranged from 2 weeks to 9.6 months and ORR was only 17%, the effect of immunotherapy was poor compared with that of targeted therapy which ORR was 32% and median PFS was 7.3 months (Drilon et al. 2020). Also, The ImmunoTarget multicentric worldwide retrospective study showed that 36 NSCLC patients with MET mutation reflected 16% ORR and the median PFS and OS were 3.4 months and 18.4 months, respectively (Mazieres et al. 2019). A recent study has also found patients treated with immune checkpoint blockade with MET mutation had short median PFS (only 2.69 months) (Negrao et al. 2021).
Another retrospective study recruited 147 patients with MET exon 14 skipping mutation in lung cancer has showed that responses of immunotherapy were related to neither high PD-L1 expression nor high TMB (Sabari et al. 2018).
PBRM1
PBRM1 is a tumor suppressor gene which regulates the cell cycle, maintains the stability of the genome and improves centromere cohesion (Mota et al. 2019). It has been found that PBRM1 mutation was particularly common in renal clear cell carcinoma, and it has been proved that PBRM1 mutation was considered as a significant biomarker for immunotherapy in renal clear cell carcinoma (Braun et al. 2019).
The relevance of PBRM1 mutation and immunotherapy in lung cancer is still unclear. Recently, a large retrospective study gathering data from three institutions found the prevalence of PBRM1 mutation in NSCLC was about 3.04% (Zhou et al. 2020). It also pointed out that the mutation of PBRM1 often indicated poor efficacy of immunotherapy in NSCLC patients (Zhou et al. 2020). According to this study, patients with PBRM1 mutation tended to have higher TMB, but in both the high TMB and low TMB groups, patients with PBRM1 mutation who received immunotherapy had lower OS than those with wild type. Therefore, PBRM1 is more likely to be a promising biomarker to forecast poor survival benefit of receiving immunotherapy.
Another study combined the date from 240 advanced NSCLC patients to find the relevance between PBRM1 mutation and the PFS after treating with anti-PD-L1 immunotherapy. It also indicated that PBRM1 mutant patients in LUAD tended to express higher TMB but a less PFS (Yang et al. 2021).
Moreover, studies have shown that two or more co-mutations often occurred in KEAP1, LKB1/STK11, PBRM1 and SMARCA4, which were related to the decline of immunotherapy effect (Marinelli et al. 2020; Di Federico et al. 2021). This study revealed that the co-mutation of the above four genes showed higher TMB in LUAD. But the survival time is significantly less than those patients without these co-mutations. Therefore, when two or more gene mutations of KEAP1, STK11, PBRM1 and SMARCA4 coexist in NSCLC patients, especially in LUAD patients, it is still necessary to use immunotherapy with caution.
ERBB2
ERBB2 mutation occurs in 2–4% of NSCLC patients, more frequently in LUAD and never-smokers (Ekman 2019). Most of patients with ERBB2 mutation were with in-frame insertions in exon 20 (ERBB2-ex20ins) mutation, which were found about 1.7% incidence in NSCLC patients (Mazières et al. 2013). Nowadays, the therapeutic effect of immunotherapy in NSCLC patients with ERBB2 mutation was still unclear. What we already learned is that ERBB2 amplified tumors were associated with higher TMB (Dudnik et al. 2018a, b), but PD-L1 expression was low (Guisier et al. 2020). Some researchers have speculated the negative efficacy of ICIs in ERBB2-ex20ins mutant patients might be attributed to lower cytotoxic CD8 + T-cell infiltration and lower PD-L1 expression (Gainor et al. 2016).
The ImmunoTarget multicentric worldwide retrospective study showed a negative therapeutic effect of anti-PD-1/PD-L1 immunotherapy in ERBB2 mutation subgroups (Mazieres et al. 2019). A study which performed genomic profiling of 78 NSCLC patients has indicated that patients with ERBB2 mutation manifested lower PFS than those with wild type (Fang et al. 2019). Another large retrospective analysis indicated that patients with ERBB2 mutation have showed poor response to immunotherapy (Guisier et al. 2020).
However, a case report showed a patient with ERBB2-ex20ins mutation significantly benefited from anti-PD-1 therapy plus chemotherapy treatment and showed more than half of tumor reduction (Tian et al. 2021).
BRAF
The incidence of BRAF mutation is about 2.5% in NSCLC (Dearden et al. 2013). BRAF V600E is uniformly considered as the most common type. It consists in more than half of the patients in BRAF mutation (Ding et al. 2017). At present, the significantly potential efficacy of BRAF mutation in immunotherapy in melanoma has already been suggested (Welsh et al. 2016).
According to a retrospective analysis, BRAF mutation in NSCLC is connected with higher PD-L1 expression, lower TMB and lower MS-Stable status. And ICIs are effective in NSCLC patients with both BRAF V600E and non-V600E mutations (Dudnik et al. 2018a, b). A large retrospective study indicated that BRAF mutation was related to a better immunotherapy effect. It has been found that patients with BRAF mutation might be considered for immunotherapy after targeted therapy and first-line chemotherapy (Mazieres et al. 2019). Another large retrospective analysis also proved that patients with BRAF mutation in immunotherapy have showed effective responses (Guisier et al. 2020).
PIK3CA
The prevalence of SMARCA4 mutation in NSCLC is about 2%. Many researches showed patients with PIK3CA mutation had poor immunotherapy effect.
A retrospective study including 84 NSCLC patients who were treated with immunotherapy analyzed the correlation of molecular findings and immunotherapy response. It indicated that all 5 patients existing PIK3CA mutation expressed low PFS to immunotherapy and showed minimal or even no PD-L1 expression (Kauffmann-Guerrero et al. 2020).
Besides, PIK3CA mutant LUSC exhibited substantially low expression of PD-L1 and its surrounding immune cells reduced the expression of PD-1 receptor compared with wild-type tumors (Choi et al. 2017). Meanwhile, Kadara et al. found the expression of PD-L1 was also significantly decreased in PIK3CA mutant LUAD (Kadara et al. 2017). Since objective response to atezolizumab was found to be remarkably associated with high expression of PD-L1, this tended to show that PIK3CA mutation might be a biomarker for negative response to immunotherapy (Herbst et al. 2014).
ROS1
ROS1 rearrangement was initially identified from the cell of glioblastoma (Birchmeier et al. 1987), and was first identified in NSCLC in 2007(Rikova et al. 2007). The incidence of ROS1 rearrangement was about 1%–2% in NSCLC patients (Gainor and Shaw 2013).
There were fewer studies investigate the relationship of this gene mutation and immunotherapy. In a retrospective study, only one NSCLC patient treated with ICIs harboring ROS1 rearrangement, and the PFS and OS were both only 0.1 month (Dudnik et al. 2018a, b).
According to a recent study, patients treated with immune checkpoint blockade with ROS1 rearrangement had short PFS, although they expressed high PD-L1 (up to 55%) (Negrao et al. 2021). This suggested that there were oncogene-specific factors apart from PD-L1 expression influenced clinical immunotherapeutic effect. Thus, PD-L1 might not be independent predictors to immunotherapy effect (Negrao et al. 2021).
Therefore, ROS1 rearrangement was correlated with negative immunotherapeutic effect. But large-scale researches were needed to verify that.
RET
RET fusion was also identified less than 5% (at approximately 1%-2%) frequency in NSCLC. And it was more prevalent among LUAD never-smokers (Takeuchi et al. 2012; Kohno et al. 2012). Multiple studies have evaluated that NSCLC patients with RET fusion had negative effect in ICIs.
Jiyun Lee et al. have found the median PFS of NSCLC patients with RET fusion treated by immunotherapy was only 2.1 months, and the ORR was just 7.7%. On the contrary, the ORR among patients treated with pemetrexed-based regimens was 63.0%, and the median PFS was 9.0 months (Lee et al. 2020). Besides, this study also found patients with RET fusion were more likely to develop intracranial metastases.
Meanwhile, a large retrospective multicenter study indicated that patient with RET mutation was only one and had showed negative response in immunotherapy (Guisier et al. 2020). And Marcelo V Negrao et al. have also found patients with RET fusion treated with immune checkpoint blockade had short PFS (Negrao et al. 2021).
FBXW7
The FBXW7 gene, lies at chromosome 4q31q.3, is also one of the tumor suppressor genes. No study has counted the incidence of FBXW7.
The clinical significance of its mutation is obvious in various cancers, such as lung, hematopoietic, colon, esophageal, gastric, etc., and it is closely associated with the occurrence of cancer, tumor metastasis, poor prognosis and drug resistance of adjuvant therapy (Fan et al. 2022; Yeh et al. 2018). Little is known as regards the treatment effect of immunotherapy in NSCLC patients with FBXW7 mutation. At present, another research has found if FBXW7 mutation existed in malignant melanoma, it would become resistant to immunotherapy (Gstalder et al. 2020).
The latest clinical research shows that the expressions of TMB and CD8 + T cells and macrophages in NSCLC patients with FBXW7 mutation are significantly higher than those of patients with wild type. Patients can get better clinical benefits from immunotherapy (Liu et al. 2022). However, further research is needed to prove or overturn this conclusion.
LRP1B and FAT3 co-mutation
LRP1B is one of the tumor suppressor genes which encodes low-density lipoprotein (LDL) family receptor (Liu et al. 2001). FAT3 is also one of tumor suppressor genes, which is a part of FAT family genes encoding large proteins with extracellular Cadherin repeats, EGF-like domains, and Laminin G-like domains (Katoh 2012). At present, it has been found that FAT3 often co-mutates with LRP1B. And the expression of TMB and CD8A in co-mutation showed higher level than single mutation (Zhu et al. 2021).
On the basis of TCGA dataset, a study has found LRP1B evidently had much more than 5% mutation frequency (34.78%, 176/506) in LUAD patients. And the frequency of FAT3 mutation was 21.34% (108 out of 506) in LUAD. Co-mutation of FAT3 and LRP1B happened in 10.87% (55 out of 506) LUAD patients (Zhu et al. 2021). Most importantly, this study also indicated that patients with co-mutation of FAT3 and LRP1B showed remarkably longer PFS with immunotherapy than patients with single mutation. Therefore, the co-mutation of FAT3 and LRP1B genes can become another promising biomarker for NSCLC with immunotherapy. However, there is no research to prove whether LUAD patients with only FAT3 or LRP1B mutation can benefit from immunotherapy yet.
Conclusion and perspectives
In conclusion, as these clinical studies mentioned in this article, several gene mutations have shown potential as biomarkers for immunotherapy in NSCLC (Table 1). The mutations of KRAS, KRAS + TP53, EPHA (especially EPHA5), ZFHX3, ZFHX3 + TP53, NOTCH, BRAF and LRP1B + FAT3 have potential to be used as biomarkers to predict the positive effectiveness of immunotherapy. More importantly, ZFHX3, ZFHX3 + TP53, STKII/LKB1 + KEAP1 + SMARCA4 + PBRM1 mutations in LUAD patients get more positive effect in immunotherapy. While the mutations of EGFR, KEAP1, STKII/LKB1 + KRAS, EML4-ALK, MET exon 14 skipping mutation, PBRM1, STKII/LKB1 + KEAP1 + SMARCA4 + PBRM1, ERBB2, PIK3CA and RET often indicate poor benefit from immunotherapy. It is well known that the guidelines have clearly stated that EGFR mutant patients with NSCLC generally did not use immunotherapy. However, the current researches have not made a clear judgment on the predictive significance of the following common or rare mutant genes. The predicting significancy of mutations like TP53, STKII/LKB1, PTEN, SMARCA4, ROS1, FBXW7, LRP1B and FAT3 with immunotherapy is still controversial, further studies are needed to find out the relationship between these mutations and immunotherapy. In addition, the co-mutation of TP53 + ZFHX3 and FAT3 + LRP1B showed better effect in immunotherapy than single mutation (Tables 2 and 3).
This paper may provide guidance for the appliance of immunotherapy in NSCLC patients. Except EGFR mutation which is fully studied in various researches, more large-scale clinical studies for positive mutations are needed to guide clinical treatments. Furthermore, gene mutations should be combined with PD-L1, TMB, TILs, etc. to predict the effect of immunotherapy. There should not only consider one factor.
Data availability
Not applicable.
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Acknowledgements
This study was funded by the National Natural Science Foundation of China (grant no. 82273162) and the National Natural Science Foundation of China (grant no. 82203272).
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This work was supported by the National Natural Science Foundation of China (Grant numbers 82273162 and 82203272).
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All authors have read and approved the article. GZ has contributed significantly in the conception and design of the work. RC and HZ have contributed mainly in drafting the work and revising it critically for important intellectual content. HS, YL, WP, RY and YF have contributed in collecting and organizing data.
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Cai, R., Zhu, H., Liu, Y. et al. To be, or not to be: the dilemma of immunotherapy for non-small cell lung cancer harboring various driver mutations. J Cancer Res Clin Oncol 149, 10027–10040 (2023). https://doi.org/10.1007/s00432-023-04919-4
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DOI: https://doi.org/10.1007/s00432-023-04919-4