Pemetrexed

Efficacy and safety of carboplatin and pemetrexed followed by maintenance with pemetrexed for elderly patients with advanced non-squamous non-small cell lung cancer: A single-arm, open-label, multicenter, phase II study

Masahiro Shinoda1,2 Masaharu Shinkai1,2 Yu Hara1 Kouji Tomaru1Saki Manabe3 Syuji Murakami4 Haruhiro Saito4 Nobuaki Kobayashi1Naoki Miyazawa5 Masanori Nishikawa6 Takeshi Kaneko1

Abstract

Purpose: Carboplatin plus pemetrexed followed by maintenance pemetrexed is expected to be well-tolerated by the elderly. This multicenter, prospective study examined the efficacy and tolerability of the regimen in elderly patients with previously untreated advanced non-squamous non-small cell lung cancer.
Methods: The primary endpoint was the 1-year survival rate, with secondary endpoints of response rate (RR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse event rate. Efficacy was compared between patients with performance status (PS) 0 and 1.
Results: Forty-one patients were enrolled between March 2011 and April 2016.
Median age was 76.0 years. The 1-year survival rate was 73% (95% confidence interval (CI), 56-84%). RR was 44%, DCR was 81%, median PFS was 7.2 months (95%CI, 3.989.20 months), and median OS was 17.4 months (95%CI, 13.60-22.83 months). Twentyone patients (51%) transitioned to maintenance therapy. Toxicities of grade ≥ 3 during the induction phase included anemia (37%), thrombocytopenia (29%), neutropenia (22%), appetite loss (15%), nausea (10%), bacterial pneumonia (7%), febrile neutropenia (5%), and interstitial pneumonia (2%). Treatment was discontinued in two patients with interstitial pneumonia, but no deaths were encountered. During the maintenance phase, one patient needed dose reductions due to phlegmon. No significant difference in efficacy was seen between PS 0 and PS 1.
Conclusion: Carboplatin and pemetrexed followed by maintenance pemetrexed for non-squamous non-small cell lung cancer in elderly patients appear effective and tolerable.

KEYWORDS
elderly, maintenance, pemetrexed

1 INTRODUCTION

Lung cancer is the most common cause of cancer mortality worldwide for both men and women.1 Aging of the population is considered one of the primary contributors to the rising number of cancer deaths.2 The increasing aging of the population has been striking in developed nations since around 1990. Japan has been among the most affected nations in terms of this trend, and the percentage of the total population made up of individuals 65 years and older (aging rate) reached 26.6% in 2015. By 2065, the aging rate is predicted to be about 35%.3
Among older adults who undergo chemotherapy, individual differences increase with age and determination by calendar age alone is thus considered inadequate.4 Phase 3 trials of primary pharmacotherapy and adjuvant therapy for lung cancer have shown no significant differences in treatment effects for patients above and below 65 years old, and the degree of independence in activities of daily living is reportedly related to prognosis more than calendar age.5 Individuals ≥80 years old who show a good performance status (PS) of 0 or 1 are reported to show no significant difference in overall survival (OS) compared with those < 80 years old, nor were any differences apparent in toxicity.6 In the lung cancer treatment guidelines in Japan, the standard therapy for elderly patients is considered to be docetaxel or another thirdgeneration cytotoxic chemotherapy agent alone. This was based on the finding that vinorelbine extended OS significantly more than best supportive care and showed chemotherapy to be effective7 and that docetaxel showed better outcomes than vinorelbine in a phase 3 trial (WJTOG9904 trial) conducted in Japan.8 With regard to platinumbased cytotoxic chemotherapy, the JCOG0803/WJOG4307L trial in Japan compared weekly cisplatin plus docetaxel with docetaxel, alone and in an interim analysis the outcomes with the combination therapy were no better than those with a single agent.9 The IFCT0501 trial compared carboplatin plus weekly paclitaxel and gemcitabine or vinorelbine,10 and while progression-free survival (PFS) and OS increased significantly with combination therapy, the results of combination therapy cannot be said to have significantly exceeded the results of single-agent therapy in Japan, with high treatment-related mortality rates seen in groups receiving combination chemotherapy. Carboplatin-based combination therapy is therefore mentioned as one option for patients ≥75 years old with PS 0-1. In 2008, treatment with cisplatin and pemetrexed was reported to significantly prolong OS compared with cisplatin and gemcitabine for stage IIIB/IV chemotherapy-naïve, non-squamous, non-small cell lung cancer,11 and this is recognized as the standard treatment. Carboplatin plus pemetrexed has also been shown to offer equal efficacy to carboplatin plus gemcitabine.12 The results of a phase 1 trial of carboplatin plus pemetrexed were also reported in Japan, for the clinically recommended dose of pemetrexed 500 mg/m2 and carboplatin area under the concentration-time curve (AUC) 6.13 However, the results were good even in an AUC 5 group, showing a four-course completion rate of 87%, a response rate (RR) of 66.7%, and tolerability. Carboplatin with pemetrexed was found to offer promise for elderly individuals. In 2009, pemetrexed was also shown to be effective as maintenance therapy following the induction phase.14 Prospective clinical studies in accordance with regular clinical practice for elderly individuals are thought to be very important in Japan, which was one of the first nations in the world to develop a super-aging population. Here, we report the results of a phase 2 trial evaluating the efficacy and safety of pemetrexed maintenance therapy following carboplatin and pemetrexed for previously untreated non-squamous nonsmall cell lung cancer in the elderly (70-85 years old). 2METHODS 2.1Study design This was a single-arm, open-label, multicenter, phase 2 study. The primary objective was the 1-year OS rate, and the secondary objectives were RR, disease control rate (DCR), PFS, OS, and safety. Furthermore, we performed subgroup analyses to compare treatment effectiveness between PS 0 and PS 1. This study was conducted in compliance with the Declaration of Helsinki and was approved by the local institution review board of all participating centers (Yokohama City University Respiratory & Research Group: Yokohama City University Medical Center, Yokohama City University Hospital, Kanagawa Cancer Center, Saiseikai Yokohamasi Nanbu Hospital, Fujisawa City Hospital, National Hospital Organization Yokohama Medical Center, Yokohama Minami Kyosai Hospital, National Defense Medical College Hospital, Kanto Rosai Hospital, Yamato Municipal Hospital, Yokohama Sakae Kyosai Hospital) and all patients provided written informed consent before study inclusion. This study was registered at UMIN (UMIN: 000005221). 2.2 Eligibility criteria Eligible patients were ≥70 years and ≤85 years old, with an estimated life expectancy of ≥3 months, and an Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1, who met the following eligibility criteria: ∙ Histologic or cytologic diagnosis of Stage IIIB or IV, or postoperative recurrent non-small cell lung carcinoma (using the seventh edition of the TNM staging system) with non-squamous histology that was not amenable to curative therapy; ∙ Patients who had received no prior systemic anticancer therapy for lung cancer, or patients who had not received postoperative adjuvant chemotherapy in the preceding 6 months; ∙ Measurable lesions according to Response Evaluated Criteria in Solid Tumors (RECIST) version 1.1); ∙ No brain or bone metastatic lesions or, if such metastases are present, the lesions remain stable after palliative radiotherapy (ie, excluding cases requiring continued use of steroid); ∙ No history of chemotherapy or radiotherapy for other carcinoma; ∙ Adequate functioning of major internal organs; and ∙ Meeting all the following within 14 days before registration: White blood cell count ≥4000/mm3, neutrophil count ≥2000/mm3, platelet count ≥100 000/mm3, hemoglobin ≥9.0 g/dL, aspartate aminotransferase (AST) ≤100 IU/L, alanine transaminase (ALT) ≤100 IU/L, total bilirubin ≤2.0 mg/dL, serum creatinine ≤1.2 mg/dL, PaO2≥60 torr, and percutaneous oxygen saturation (SpO2) ≥90%. Exclusion criteria were as follows: ∙ A history of radiotherapy for the primary lesion; ∙ Interstitial pneumonia on chest X-ray or chest computed tomography (CT); ∙ Uncontrolled angina pectoris, serious heart disease such as myocardial infarction or heart failure within 3 months; ∙ Uncontrolled hypertension or diabetes mellitus; ∙ Severe infectious disease; ∙ Intestinal paralysis or intestinal obstruction; ∙ Pleural effusion, ascites or pericardial effusion requiring drainage (regardless of whether pleurodesis is performed, if pleural effusion is stable after drain withdrawal, the case can be included); ∙ Symptomatic brain metastases; ∙ Superior vena cava syndrome; ∙ Active multiple primary cancer; or ∙ History of serious drug allergy. 2.3 Treatment plan After the screening assessments were completed, eligible patients received first-line, induction chemotherapy with pemetrexed and cisplatin. Pemetrexed (500 mg/m2) and carboplatin (AUC 5) were administered intravenously on day 1 of each 21-day cycle up to a maximum of six cycles or until progressive disease (PD), unacceptable toxicity, or another permitted reason for discontinuation. After the completion of induction therapy, patients who remained in the study without disease progression were administered continuation maintenance therapy with pemetrexed (500 mg/m2 every 21 days). Maintenance chemotherapy was repeated until progressive disease or intolerance. During the study, patients received supplemental folic acid (500 µg/day) and vitamin B12 (1000 µg every 9 weeks). When an adverse event was encountered, we modified doses as follows. During induction therapy, dose reductions at the start of a subsequent cycle due to hematological toxicity were based on nadir platelet and neutrophil counts from the preceding cycle of therapy. If grade 4 leukopenia, grade 4 thrombocytopenia or febrile neutropenia, grade 3 increased creatinine or grade 3 non-hematological toxicities excluding fatigue, nausea, or anorexia were observed, pemetrexed was reduced from 500 to 400 mg/m2 and carboplatin was reduced from AUC 5 to4. When a similar event occurred again, pemetrexed was only reduced from 400 to 300 mg/m2. If further dose reductions were needed, protocol treatment was discontinued. During maintenance therapy, pemetrexed was reduced from 500 to 400 mg/m2 if grade 4 leukopenia, grade 4 thrombocytopenia or febrile neutropenia, grade 3 increased creatinine, or grade 3 nonhematological toxicities excluding fatigue, nausea, or anorexia were noted. If further dose reductions were needed after the initial two-dose reductions, protocol treatment was discontinued. 2.4 Study assessments All patients were evaluated for responses every two cycles, including in the maintenance phase.Response was determined according to RECIST guidelines. Adverse events were monitored and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 2.5 Statistical analysis The 1-year OS rate of platinum-doublet chemotherapy was 31.0-36.0% in a phase 3 trial (cisplatin + paclitaxel, cisplatin + gemcitabine, cisplatin + docetaxel, carboplatin + paclitaxel).15 In a subgroup analysis of a phase 3 trial in Japan (cisplatin + irinotecan, cisplatin + gemcitabine, cisplatin + vinorelbine, carboplatin + paclitaxel),16 the 1-year OS rate in elderly patients was 45.0-60.7%. We estimated that 39 patients would be sufficient to explain the hypothesis to disregard a 1-year OS rate of 40% and to provide a twosided significance level of 0.05 with 80% statistical power in assessing the expected 1-year OS rate of 60%. The target patient population was therefore set as 43 patients after factoring in the proportion of patients likely to prove ineligible for the study.PFS and OS were evaluated by Kaplan-Meier method with a 95% confidence interval (CI). Statistical significance was defined as P < .05. 3RESULTS 3.1Patient characteristics and patient disposition From March 2011 to April 2016, a total of 43 patients were enrolled. Two patients were excluded due to protocol violations: one patient showed stage IIIA disease after enrollment; and the other did not show an evaluable lesion after enrolment. Median PFS was able to be evaluated for 41 cases, but median OS was only evaluated for 40 cases, because the outcome was unknown in one case. Median age of the remaining 41 patients was 76.0 years (range, 7082 years). The 41 patients comprised 36 men (87.8%) and 5 women (12.2%), with stage IV disease in 27 (65.9%), and ECOG PS 0 in 26 (63.4%). Histological subtypes of cancer were adenocarcinoma (n = 39) and unspecified carcinoma (n = 2; Table 1). In one patient, EGFR TABLE 1 Baseline characteristicsmutation-positive status of the lung cancer was identified only after first-line chemotherapy had been started. 3.2 Efficacy Median follow-up time for patients was 17.6 months. Six patients remained alive as of the end of the study. Efficacies during the induction and maintenance treatment periods are shown in Table 2. RR was 43.9%, and DCR was 80.5%. RR of patients with PS 0 was 46.2%, and DCR was 84.7%. RR of patients with PS 1 was 40.0%, and DCR was 73.3%.The primary endpoint of the 1-year OS was 73% (95%CI, 56-84%; Figure 1A). Median PFS for all patients was 7.23 months (95%CI, 3.98-9.20 months; Figure 1B). Median OS was 17.41 months (95%CI, 13.6022.83 months; Figure 1A). In the subgroup analysis for PS, median OS of patients with PS 0 was 18.10 months (95%CI, 13.86-26.58 months), the 1-year OS was 80% (95%CI, 58-91%; Figure 1C), median PFS was 7.23 months (95%CI, 3.71-9.72 months; Figure 1D). Median OS of patients with PS 1 was 14.06 months (95%CI, 4.73-22.87 months), the 1-year OS was 60% (95%CI 32-80%; Figure 1C), median PFS was 8.11 months (95%CI, 2.37-13.31 months; Figure 1D). No significant difference was apparent between PS 0 and PS 1 (Figure 1C,D). Thirty-two patients (78.0%) completed the induction phase, including 11 patients who received induction therapy for six cycles. Twenty-one patients (51.2%) received maintenance pemetrexed therapy. The median number of cycles of maintenance therapy was 4 (range 1-28). 3.3 Treatment after first-line therapy Of the 41 patients, 26 patients (63.4%) received treatment after first-line therapy. Nine patients continued maintenance pemetrexed therapy after failure from this trial. Docetaxel was administered to 16 patients. Vinorelbine was administered to four patients. Erlotinib was administered to four patients. Nivolumab was administered to two patients. Carboplatin plus pemetrexed was administered to two patients. Carboplatin plus paclitaxel plus bevacizumab was administered to two patients. Gefitinib was administered to one patient. Weekly paclitaxel was administered to one patient. Docetaxel plus bevacizumab was administered to one patient. Crizotinib was administered to one patient who showed positive results for an EML4-ALK fusion gene after failure from this trial. 3.4 Toxicities Drug-related adverse events in the induction and maintenance phase are summarized in Tables 3 and 4. Grade 3/4 hematological adverse events during the induction phase were anemia (37%), thrombocytopenia (29%), and neutropenia (22%). Grade 3/4 non-hematological adverse events during the induction phase included appetite loss (15%), nausea (10%), bacterial pneumonia (7%), respiratory tract infection (5%), febrile neutropenia (5%), and interstitial pneumonia (2%). During the maintenance phase, grade 3/4 hematological adverse events included anemia (19%) and neutropenia (14%). Grade G3/4 nonhematological adverse events were appetite loss (5%), fatigue (5%), and bacterial pneumonia (5%). Three of the 41 patients were unable to continue due to treatmentrelated adverse events (interstitial pneumonia, bacterial pneumonia, and intestinal perforation). During the induction phase, eight of 41 patients needed dose reductions due to grade 4 neutropenia (1 patient), febrile neutropenia (1 patient), grade 4 neutropenia and grade 4 thrombocytopenia (1 patient), grade 3 anemia (2 patients), grade 3 appetite loss (2 patients), and increased creatinine (1 patient). During the maintenance phase, one patient needed dose reductions due to phlegmon. Interstitial pneumonia and intestinal perforation occurred in the induction phase. Bacterial pneumonia occurred in the maintenance phase.No deaths from adverse events due to treatment were encountered. 4 DISCUSSION The present results showed that carboplatin plus pemetrexed induction therapy followed by maintenance pemetrexed represented a regimen with good efficacy and tolerable toxicity in elderly patients with non-squamous non-small cell lung cancer. In the lung cancer treatment guidelines in Japan, monotherapy with docetaxel or another third-generation cytotoxic chemotherapy agent is recommended based on results such as a phase 3 trial (WJTOG9904 trial)8 for first-line treatments in patients ≥ 75 years old with PS 0–1 who were negative for driver gene mutation or translocation and who showed fewer than 50% PD-L1-positive cells or unclear. Carboplatin combination therapy is also an option for PS 0–1 patients ≥75 years old.10 The results of this study showed better efficacy than previously reported chemotherapy using a single third-generation cytotoxic chemotherapy agent such as docetaxel, and tolerable toxicity. In a previous phase 3 trial in which carboplatin plus pemetrexed was used as first-line chemotherapy for non-small cell lung cancer patients from 35 to 90 years old, including 18% ≥75 years old, the 1-year survival rate was 34% and median survival was 7.3 months.12 Results in this study were much better, with a 1-year survival rate of 73% and median survival of 17.41 months. One reason for this is thought to be that in the earlier phase 3 trial, 22% of enrolled patients showed PS 2 and 26% had squamous cell carcinoma. In addition, maintenance therapy was also performed in this trial and OS may have been prolonged because 51.2% of patients could be moved to maintenance therapy. In the JACAL trial of pemetrexed plus carboplatin and maintenance therapy with pemetrexed for non-squamous non-small cell lung TABLE 3 Summary of adverse events in the induction phase cancer in chemotherapy-naïve patients including young individuals, RR was 35.8%, median PFS was 5.7 months, and median OS was 20.2 months. 7 In the present trial, in which patients were all ≥70 years old, the response rate was 43.9%, median PFS was 7.23 months, and median OS was 17.41 months. These results were nearly equivalent, although OS was slightly poorer in this trial. The percentage of patients moved to maintenance therapy was 56.6% in the JACAL trial17 and 51.2% in this trial, a result showing non-inferiority considering that this trial was targetedatelderlysubjects.Inanothertrialusing maintenancetherapy, the PARAMOUNT trial, the percentage moved to maintenance therapy was 57.4%.18 Even compared with that, the present results were not markedly different. Among previous reports on carboplatin plus pemetrexed and pemetrexed maintenance therapy for non-small cell lung cancer in elderly patients, a phase 2 trial by Tamiya et al showed a 1-year survival rate of 58.0%, median PFS of 5.7 months, median OS of 20.5 months, RR of 41.2%, and DCR of 85.3%.19 Another phase 2 trial by Zhao et al20 showed median PFS of 8.23 months, median OS of 22.6 months, RR after induction therapy of 36.2%, and DCR after induction therapy of 85.3%. A phase 1 trial by Tamiya et al21 showed median PFS of 142 days, median OS of 461 days, RR of 47.1%, and DCR of 76.5%. In a subgroup analysis of elderly patients by Nogami et al, median PFS was 5.2 months, median OS was 16.8 months, RR was 24%, and DCR was 68%.22 Regarding first-line chemotherapy with carboplatin plus pemetrexed for elderly patients, a meta-analysis that included any-phase trials and non-English articles, conference abstracts and subgroup analyses indicated that the pooled median PFS was 5.4 months (95%CI 4.5–6.4 months), and the pooled median OS was 14.9 months (95%CI, 12.0-18.4 months), and the pooled RR was 34.0% (95%CI, 27.540.5%).23 In a phase III trial comparing pemetrexed plus carboplatin and a maintenance therapy arm versus a docetaxel arm in patients ≥75 years old with PS 0–1 with advanced non-squamous non-small cell lung cancer (JCOG1210/WJOG7813L),24 non-inferiority of the pemetrexed plus carboplatin and maintenance therapy arm was confirmed in all enrolled patients (HR for OS, 0.850; 95%CI, 0.684-1.056, P < .01). Median OS for the docetaxel arm and the pemetrexed plus carboplatin and maintenance therapy arm were 15.5 and 18.7 months, respectively. In the pemetrexed plus carboplatin and maintenance therapy arm, PFS was significantly better (HR 0.739; 95%CI, 0.609-0.89) and response rate was better (28.2% vs 36.8%; P = .07) compared to the docetaxel arm. Adverse events were tolerable in the pemetrexed plus carboplatin and maintenance therapy arm. The present results showed efficacy similar to these previous reports, with a 1-year survival rate of 73%, median PFS of 7.23 months, median OS of 17.41 months, RR of 43.9%, and DCR of 80.5%. Median OS in a phase 2 trial by Zhao et al20 was longer than in other trials, including our own. This was because the phase 2 trial by Zhao et al included patients ≥65 years old. Furthermore, our study was prospective phase 2 and achieved the primary endpoint of a 1-year OS rate different from the previous study in Japan. This may reflect individual differences among the elderly, suggesting that better treatment can be achieved even in the elderly, if patients are selected appropriately. We performed subgroup analysis with PS, and no other reports appear to have undertaken analyses by PS with this regimen for the elderly. PS 1 patients tended to have somewhat poorer PFS and OS than PS 0 patients, although the differences were not significant. This regimen was shown to be usable regardless of whether patients are PS 0 or 1. This result suggests that we may consider PS 0 or 1 as an indication for induction therapy in elderly patients, just as in young patients. From the above results, elderly people in good general condition can be expected to show similar OS to young individuals. No major differences in adverse events were evident in this trial compared with the JACAL trial,17 the phase 2 trial by Tamiya et al19 or the phase 2 trial by Zhao et al,20 which were also conducted using an elderly population. The number of patients who needed dose reductions was also about the same as in those studies. This shows that if the dose can be adjusted so that carboplatin is administered at AUC 5, this regimen can be used as in young individuals. Although the number was small, some patients had to discontinue treatment because of interstitial pneumonia, bacterial pneumonia, or intestinal perforation, and caution is thus needed. The data in this study were from earlier this decade, and almost none of the patients were treated with immune checkpoint inhibitors. Recently, immunotherapy has become an important treatment option as first-line treatment for patients with advanced driver mutationnegative non-small cell lung cancer. Pembrolizumab monotherapy in patients with advanced NSCLC with PD-L1-positive tumors with a PDL1 Tumor Proportion Score (TPS) ≥ 1% improved OS and was well tolerated,25 and has become an important first-line treatment option. As for elderly patients, pembrolizumab improved OS as compared to chemotherapy, with a more favorable safety profile in the pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies.26 For patients with driver mutation-negative non-small cell lung cancer who have PS of 0 or 1, combination therapy with chemotherapy and immunotherapy is being used as first-line therapy, regardless of PD-L1 expression. In patients with non-squamous cell carcinoma, interim analysis of the KEYNOTE-189 trial showed that pembrolizumab plus platinum-based chemotherapy significantly prolonged PFS and OS compared with chemotherapy,27 and the IMpower150 trial showed that addition of atezolizumab to bevacizumab plus carboplatin plus paclitaxel significantly prolonged PFS and OS.28 Few reports have examined efficacy and safety in the elderly. As for elderly patients in the IMpower150 trial, combination therapy comprising immunotherapy and chemotherapy tended to be more effective for PFS compared with chemotherapy in patients ≥75 years old (HR 0.78 (9.7 months vs 6.8 months)), but the CI crossed 1. Although the IMpower131 trial investigated patients with squamous cell carcinoma, this trial showed that combination therapy with immunotherapy and chemotherapy tended to be more effective for PFS (HR 0.51 (7.0 months vs 5.6 months); 95%CI, 0.30-0.84) in patients ≥75 years old.29 Safety results were not shown in either study and we carefully considered whether to perform combination therapy in the elderly. A sub-analysis of the KEYNOTE-189 trial showed that OS HRs for the combination of pembrolizumab versus placebo were 0.43 (95%CI, 0.31-0.61) and 0.64 (95%CI, 0.43-0.95) in a comparison of patients <65 years old and ≥65 years old. The efficacy of combination therapy was shown in patients ≥65 years old, but no data were available regarding adverse events.30 In addition, in the CheckMate227 study that examined combination therapy with anti-PD-L antibody and anti-CTLA-4 antibody, firstline treatment with nivolumab plus ipilimumab resulted in a longer OS compared to chemotherapy in patients with NSCLC, independent of the PD-L1 expression level, but in patients ≥75 years old, combination therapy with nivolumab and ipilimumab tended to be better than with chemotherapy, but the 95%CI crossed 1 and efficacy remains controversial for the elderly.31 One EGFR-positive patient was included in this study. In a phase 3 trial by Nakamura32, gefitinib plus CBDCA plus pemetrexed therapy was effective compared with gefitinib monotherapy in patients with exon 19 deletion or L858R mutation-positive non-small cell cancer with good PS. This is one of the first-line treatments for exon 19 deletion- or L858R mutation-positive cases. However, no data are available for the elderly. A phase III trial comparing osimertinib plus platinum plus pemetrexed with osimertinib in the first-line treatment of patients with mutated EGFR non-small cell lung cancer is currently ongoing (ClinicalTrials.gov identifier: NCT04035486). That study has no upper limit for age and the results are expected to include a subanalysis for elderly patients. The combination of chemotherapy and immunotherapy or chemotherapy and molecularly targeted therapy should be limited to the elderly regarding tolerability, but elderly patients with good PS may be able to tolerate combination therapy. Prospective studies are needed to investigate combination therapies that are more effective and incur fewer adverse events, because of the greater difficulty of sequential treatment compared to younger patients. The present study was a prospective phase 2 that achieved the primary endpoint of a 1-year OS rate differing from the previous study in Japan, and showed this regimen was effective even in patients with PS 1. The results of this study were meaningful in showing efficacy and safety, particularly for elderly individuals in whom treatment options are a concern in unsuitable patients for immune checkpoint inhibitors or combination therapy. 5 CONCLUSION In summary, our study suggested that carboplatin plus pemetrexed combination therapy followed by maintenance pemetrexed provided effective and tolerable treatment for elderly patients with nonsquamous non-small cell lung cancer. REFERENCES 1. Brambilla E, Travis WD. Lung cancer. In: BW Stewart, Wild CP, eds.World Cancer Report. Lyon: World Health Organization; 2014. 2. Cancer Registry and Statistics. Cancer Information Service, National Cancer Center, Japan. https://ganjoho.jp/reg_stat/statistics/dl/index. html. 3. 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