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Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With EGFR Mutations

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients’ reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.


ABSTRACT
Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.

Introduction
Therapies for stage IV NSCLC are evolving day by day, and the progress achieved over the past decade has been impressive. Since 2010, the Japanese Society of Lung Cancer (JLCS) Guidelines Committee has provided treatment guidelines for community-based physicians to adequately treat their patients. Based on this, we published the latest full clinical practice guidelines in 2018. 1 In this study, we conducted a literature search and systematic review from 2018 to 2019 to update these guidelines, specifically focusing on studies that involved mutations in the sequence encoding for EGFR, which is one of the most altered regions.

Process of Systematic Review
We conducted a systematic review on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation system, 2 to develop lung cancer medical treatment guidelines in Japan. The detailed collection of these reviews is described in the Supplementary Data. The recommendation (R) level was determined on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation grid method 3 and the votes from the JLCS Expert Panel, composed of individuals with various occupations, and whose conflicts of interest were strictly controlled according to the regulations of the JLCS.

Key Outcomes of Interest
We focused on the efficacy of overall survival (OS) and progression-free survival (PFS) as the key outcomes when assessing clinical questions (CQs). In addition, toxicity and patient-reported outcomes were evaluated according to the recommended level determined by the Expert Panel. Because of the difficulty in analyzing the cost-effectiveness in the Japanese universal health insurance system, the impact of treatment costs was not reflected in this set of guidelines. The voting results for each CQ provided by the Expert Panel are summarized in Supplementary Tables 4 to 11. The objectivity of the guidelines was also enhanced through public comments to the JLCS members in July 2020.

Characteristics of the Identified Studies
Six nonrandomized and 18 randomized controlled trials (RCTs) summarized in Tables 1 and 2 met our criteria for study selection as they assessed CQs in patients with NSCLC harboring EGFR mutations. Besides the RCTs analyzed when we created the guidelines published in 2018, 1 we included six new RCTs and updated the results of two RCTs. In addition, we recently analyzed two exploratory RCTs: (1) the combination therapy with an immune checkpoint inhibitor (ICI); and (2) cytotoxic chemotherapy targeting EGFR mutations (one including ALK fusions) (summarized in Table 3). In this review, three meta-analysis studies were performed on each CQ using multiple RCTs with the same design, and the resulting funnel plots are illustrated in Supplementary  Figures 1 to 3. In contrast, for the analysis of the efficacy of ICI monotherapy, we adopted a high-quality metaanalysis already published. 4 The quality assessments of all the included interventional studies are provided in Supplementary Tables 2 (for RCTs) and 3 (for nonrandomized trials). RCTs that were not approved by the Expert Panel were not considered in the development of the current recommendations. [5][6][7][8] One notable RCT was not approved because it was not possible to extract sufficient meta-analytical data from published literature. 9

General Remarks
Seven phase 3 trials comparing EGFR tyrosine kinase inhibitors (TKIs) and platinum-doublet chemotherapy in patients with NSCLC harboring EGFR mutations were analyzed. 10-21 Among them, EGFR TKI administration consistently prolonged PFS (as the primary end point) compared with that of platinum-doublet (pooled hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.27-0.44; p < 0.001); however, a strong heterogeneity in the overall PFS effect across the seven trials was noted (c2: 18.40; p ¼ 0.005; I 2 : 67.4%) (Fig. 1A). On the contrary, the risk of death was not significantly heterogeneous (c2: 4.28; p ¼ 0.638; I 2 : 0%) (Fig. 1B) or different between EGFR TKI and platinum-doublet chemotherapy   22 On the basis of these results, the best sequence of EGFR TKI and cytotoxic chemotherapy treatments is still unclear. EGFR TKIs administration resulted in improved quality of life and less toxicity than those obtained with cytotoxic chemotherapy; however, the profiles and degrees of toxicities were different depending on each EGFR TKI. 23,24 On the basis of a comprehensive evaluation of these results, our guideline recommends the use of EGFR TKIs as the first-line pharmacotherapy in patients with NSCLC harboring EGFR mutations (particularly exon 19 deletion and L858R mutation).  (5) was platinum-doublet chemotherapy, the evaluation criteria for evidence differed from other items.
ARCHER1050 was a phase 3 trial that compared dacomitinib with gefitinib in patients with stage IIIB/IV NSCLC harboring EGFR mutations (exon 19 deletion or L858R mutation). In this trial, patients with brain metastases were excluded. In the dacomitinib arm, the PFS, as a primary end point, was significantly prolonged (HR: 0.59; 95% CI: 0.47-0.74; p < 0.0001). 35 The OS also generally exhibited improved trends (HR: 0.760; 95% CI: 0.582-0.993); however, the original hypothesis was rejected by the gatekeeping procedure; therefore, the improvement was not significant. 36 Regarding toxicity, dacomitinib was worse than gefitinib in inducing diarrhea, paronychia, and acne-like rash.
None of the other approved EGFR TKIs (gefitinib, erlotinib, and afatinib) exhibited a clear survival advantage. The study CTONG0901, which compared gefitinib and erlotinib, revealed similar survival effects. 37 In a randomized phase 2 LUX-Lung 7 trial, which compared afatinib and gefitinib, the PFS was significantly prolonged in the afatinib arm. However, the improvement in OS in the afatinib arm was not significant, and the drug was more toxic than gefitinib. 38 The votes of the Expert Panel in this CQ1 with multiple treatment strategies are presented in Supplementary  the basis of balancing the benefits and harms of each regimen. Finally, our guideline concludes that osimertinib monotherapy is the most recommended among patients in good general condition. A combination of EGFR TKI and other agents is also recommended; however, its toxicity should be noted.  Moderate General Condition (ECOG PS 2). Regarding the question of what is the optimal first-line treatment for patients with ECOG PS 2 (CQ2), the use of EGFR TKI (gefitinib or erlotinib) is strongly recommended (R1, EL-C, AR 86%). The use of gefitinib plus carboplatin/pemetrexed cannot be determined because of uncertain outcomes. In two phase 3 trials comparing erlotinib with platinum-doublet chemotherapy, patients with EGFRmutant NSCLC with PS 2 were enrolled at around 6% to 14% of the total population 14,16,18 Both trials tended to prolong PFS in the erlotinib arm compared with the platinum-doublet arm, albeit in a small number of cases. Gefitinib was safe and effective against patients with poor PS with EGFR mutations in two nonrandomized phase 2 trials, 39,40 whereas afatinib and dacomitinib have not been adequately and prospectively considered. The efficacy of osimertinib in patients with PS 2 has not been confirmed in a reliable study; however, its toxicity other than interstitial lung disease may be milder than that of gefitinib or erlotinib. 25 In a phase 3 trial comparing gefitinib plus platinumbased chemotherapy (carboplatin/pemetrexed) and gefitinib monotherapy, patients with NSCLC with PS 2 were included in 21% to 22%. 28 A subgroup analysis revealed that the combination arm improved the OS in patients with PS 2 compared with gefitinib monotherapy (HR: 0.57; 95% CI: 0.33-0.98). The evaluation of patients with PS 2 noted AEs greater than grade 3 to be more significantly frequent in the combination treatment than EGFR TKI monotherapy (58% versus 28%). 41 The votes of the Expert Panel in this CQ2, including the two treatment strategies mentioned above, are presented in Supplementary Table 6. In the Expert Panel, the subgroup analysis against PS 2 by Noronha et al. 28 was evaluated to have a high risk of bias because of the unclear concealment and incomplete outcome data. Therefore, our guideline recommends EGFR TKI (especially gefitinib, or erlotinib) monotherapy. In contrast, any recommendation for the combination of gefitinib and chemotherapy could not be determined by our consensus.
Poor General Condition (ECOG PS 3). Regarding the question of what is the optimal first-line treatment for patients with poor general condition (CQ3), gefitinib is strongly recommended (R1, EL-C, AR 75%).
NEJ001 was a nonrandomized phase 2 trial that evaluated gefitinib monotherapy in patients harboring EGFR mutations with poor PS, which included 73% of patients with PS 3 to 4. 39 In the PS 3 to 4 group, gefitinib exhibited favorable effects (overall response rate [ORR]: 66%; median PFS: 6.5 mo; median OS: 17.8 mo), improving PS in approximately 80% of this population.
In contrast, two retrospective studies reported that poor PS might be a risk factor for the development of interstitial pneumonia because of gefitinib. 42,43 The Expert Panel discussed the pros and cons of the treatment, especially for PS 4. Therefore, gefitinib was recommended in such a population as well. However, it is necessary to thoroughly evaluate whether EGFR TKIs could be expected to improve PS or symptoms.
EGFR Uncommon Mutations. Regarding the question on what is the optimal first-line treatment for patients harboring uncommon EGFR mutations with a good general condition (CQ4), the following are the recommendations: (1) EGFR TKIs are weakly recommended in patients harboring uncommon EGFR mutations, except for exon 20 insertion and de novo T790M mutations (R2, EL-C, AR 87%); (2) EGFR TKIs are strongly not recommended in patients harboring EGFR exon 20 insertion mutations (NR1, EL-C, AR 70%); and (3) osimertinib is weakly recommended in patients harboring de novo T790M mutations (R2, EL-D, AR 67%).
Except for EGFR-activating mutations (exon 19 deletion and L858R mutation), uncommon mutations in exons 18 to 21 are generally identified in about 10% of the cases. 44 The efficacy of EGFR TKIs was slightly inferior in the presence of uncommon rather than activating mutations. 45 Some of the above phase 3 trials excluded patients with these mutations. 10,14,16,18 The uncommon mutation is not clearly defined. Therefore, in the present guideline, all mutations in the exons 18 to 21 regions, excluding exon 19 deletion and L858R mutation, are classified as uncommon mutations. The coexistence of tumors with common and uncommon mutations was classified as an uncommon mutation.
The efficacy of EGFR TKIs varied and depended on the type of these uncommon mutations; meanwhile, the ORR was reported as 48.4% in a retrospective analysis. 45 In the pooled analysis of three prospective trials for uncommon mutations, excluding the T790M mutation and the exon 20 insertion, the use of afatinib resulted in an ORR of 71.1% and a median PFS of 10.7 months. 46 In a phase 2 trial of osimertinib for the same patients, the ORR was 50%, and the median PFS was 8.2 months. 47 Because these results had different frequencies and treatment efficacies of uncommon mutations, the Expert Panel concluded that the superiority of each EGFR TKI when treating patients with uncommon mutations, except for T790M and exon 20 insertion, should not be determined.
Exon 20 insertion is rare, and few retrospective studies have reported that the ORRs of EGFR TKIs were less than 10%. 46,48 Thus, treatment with EGFR TKIs is not recommended as first-line pharmacotherapy.
The detection of de novo T790M mutations in treatment-naive patients who participated in clinical trials that used EGFR TKIs was extremely rare. In a phase 1 trial that tested osimertinib for treatment of patients with EGFR mutations, a partial response was observed in six of seven (86%) treatment-naive patients with NSCLC harboring de novo T790M mutations. 49 Efficacy data were limited.
Regarding whether osimertinib is recommended as second-line treatment for patients harboring EGFR T790M-resistant mutation after the progression of EGFR TKIs (CQ5), the Expert Panel strongly recommended osimertinib (R1, EL-B, AR 100%).
AURA3 was a phase 3 trial that compared osimertinib and platinum plus pemetrexed treatments in patients with NSCLC who progressed after receiving a firstor second-generation EGFR TKIs and acquired T790M resistance mutations. The PFS medians, as the primary endpoint, was 10.1 months in the osimertinib arm and 4.4 months in the platinum plus pemetrexed arm, which were significant (HR: 0.30; 95% CI: 0.23-0.41; p < 0.001). In addition, the frequency of grade 3 AEs or greater was lower in the osimertinib rather than the platinum plus pemetrexed treatment group (6% versus 34%). 50 Cytotoxic Chemotherapy. Regarding the question as to whether cytotoxic chemotherapy is recommended for patients harboring oncogenic driver alterations (CQ6), the Expert Panel concluded that this is strongly recommended (e.g. platinum-doublet) (R1, ELA, AR 100%).
The administration of kinase inhibitor was the best treatment for patients harboring oncogenic driver alterations; however, in the analyzed RCTs, most patients received cytotoxic chemotherapy. According to the post hoc analyses of RCTs, the prognosis of patients receiving cytotoxic chemotherapy was slightly better. 11,13 The same tendency was observed in a Japanese real-world observational study. 51 If the patient is resistant to osimertinib, or resistant to other EGFR TKIs without T790M-acquired mutation, cytotoxic chemotherapy, such as platinum-doublet, is recommended.
ICI Monotherapy. Regarding the question as to whether ICI monotherapy is recommended for patients harboring oncogenic driver alterations (CQ7), the Expert Panel states that recommendations cannot be determined because of uncertain outcomes; as such, no specific recommendations can be made (EL-B, AR 73%).
Most of the phase 3 trials that evaluated the efficacy of ICI monotherapy as a first-line treatment excluded patients harboring EGFR mutations and ALK fusions. A meta-analysis of RCTs that compared programmed cell death protein 1/programmed death-ligand 1 (PD-L1) inhibitors with docetaxel as a second-line treatment did not illustrate OS superiority in the EGFR-mutant subgroup (pooled HR: 1.11; 95% CI: 0.80-1.53; p ¼ 0.54). 4 A retrospective study reported that the ORR of programmed cell death protein 1/PD-L1 inhibitors in EGFRmutant or ALK-positive patients was 3.6%. 52 The Expert Panel determined that the efficacy of ICI monotherapy on oncogenic driver alterations might be inferior to that of each TKI or platinum-based chemotherapy. The administration of ICI as the firstor second-line treatment is not recommended, although administration as a later-line treatment could be considered. However, evidence supporting the above perspective remains insufficient.

Combination
of ICIs and Cytotoxic Chemotherapy. Regarding the question as to whether the combination of ICI and cytotoxic chemotherapy recommended for patients harboring oncogenic driver alterations (CQ8), the Expert Panel states that recommendations cannot be determined because of uncertain outcomes; as such, no specific recommendations can be made (EL-C, AR 64%).
The exploratory analysis of a phase 3 trial (IMpower150) that evaluated the treatment of patients with NSCLC harboring EGFR mutations with PD-L1 inhibitor atezolizumab plus carboplatin/paclitaxel plus bevacizumab indicated that the addition of atezolizumab slightly improved the PFS (HR: 0.61; 95% CI: 0.36-1.03) and OS (HR: 0.61; 95% CI: 0.29-1.28). 53 However, it should be noted that the number of cases evaluated was limited to 79 (out of which, exon 19 deletion and L858R mutation were 58). A phase 3 trial (IMpower130) that evaluated the efficacy of atezolizumab plus carboplatin/nab-paclitaxel also conducted an exploratory analysis of EGFR mutations and ALK fusions. According to the Kaplan-Meier curve of that trial, the addition of atezolizumab had a few advantages in PFS and OS. 54 The Expert Panel pointed this out as a bias because of the nonstratification in subgroup analyses. As with CQ7, the evidence for CQ8 is still inadequate.

Discussion
This set of guidelines has unique features that are unlike that of the European Society for Medical Oncology and National Comprehensive Cancer Network guidelines. [55][56][57] First, because of Japan's universal health insurance system, the selection of treatment options was not affected by costs. Second, CQs were specially developed according to the patient's condition, such as the older adults and those with poor PS. However, we will continue to make yearly revisions and provide recommendations that meet the needs in the actual clinical practice in Japan.

Limitations
The evidence reviewed in the guidelines included some limitations. First, few studies have directly compared the response to EGFR TKIs from different generations. Second, the information about factors that were harmful to patients between the studies, such as patient's reported outcomes and treatment costs, was insufficient. In addition, the results obtained from a unique population, such as the one containing the uncommon EGFR mutation or patients with poor PS, relied on nonrandomized or observational studies. Therefore, the Expert Panel made consensus recommendations on the basis of limited evidence from the literature.