e20748 Background: Osimertinib (+ chemotherapy) is the standard first-line treatment for EGFR -mutated non-squamous non-small cell lung cancer (NSqNSCLC). However, evidence regarding the efficacy of EGFR-TKI re-challenge after progression on osimertinib remains insufficient. This study evaluated the efficacy and safety of afatinib as a subsequent therapy following progression on osimertinib and conventional chemotherapy. Methods: This multicenter, single-arm, phase II study enrolled patients (pts) with advanced/recurrent EGFR -mutated (del19 or L858R) NSqNSCLC and an ECOG PS 0–1. All pts underwent NGS-based comprehensive genomic profiling (CGP) after progressing on osimertinib. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: Between Oct 2022 and Dec 2024, 19 pts were enrolled. Due to slow accrual, the study was terminated before reaching the planned sample size. Of 17 evaluable pts, the ORR was 11.8% (95% CI: 1.5-36.4), mPFS was 4.5 mos. (95% CI: 2.9-9.2), and mOS was 20.8 mos. (95% CI: 9.0-NA). CGP identified several biomarkers potentially involved in osimertinib resistance, including EGFR C797S (n = 1), ERBB2 mutation (n = 1), PIK3CA mutation (n = 1), RET mutation (n = 1), and METex14 skipping (n = 1); however, no clear correlation between these markers and afatinib efficacy was observed. Any-grade adverse events (AEs) occurred in 88.2% of pts, with Grade 3 AEs in 29.4% (5/17), primarily diarrhea, which were manageable with dose interruptions or reductions. Conclusions: Afatinib re-challenge showed limited efficacy in pts with EGFR -mutated NSqNSCLC pretreated with osimertinib and chemotherapy. While the safety profile was consistent with previous reports, these findings suggest that alternative therapeutic strategies should be prioritized in this clinical setting. (UMIN000049225). Clinical trial information: UMIN000049225 .

8649 Background: JCOG1404/WJOG8214L was an open label, multicenter, randomized phase III study comparing EGFR-TKI monotherapy (gefitinib [Gef] or osimertinib [Osi]) and EGFR-TKI with inserted cisplatin plus pemetrexed as a first-line treatment for advanced non-squamous non–small-cell lung cancer harboring EGFR mutation ( EGFR -NSqNSCLC). In the primary analysis, the insertion of platinum-doublet chemotherapy after the initial response to EGFR-TKI could improve progression-free survival (PFS), but not overall survival (OS) compared with EGFR-TKI monotherapy (Clin Cancer Res 2025;31:2317-26). This study was commenced using Gef in December 2015 and was switched to Osi in October 2018. 501 patients (pts) (308 in the Gef cohort, 193 in the Osi cohort) were enrolled to October 2020, but it resulted in later accrual and shorter follow-up for the Osi cohort at the time of the primary analysis (data cutoff November 2022; median follow-up of all randomized patients 36.0 months). Therefore, we conducted the five-year (5y) follow-up analysis of the Osi cohort. Methods: The key eligibility criteria were pts with advanced or recurrent EGFR -NSqNSCLC (exon 19 deletion or exon21 L858R), age 20 to 74 years, and PS 0 or 1. In the standard arm (SA), Gef or Osi was administrated until disease progression. In the experimental arm (EA), Gef or Osi was administered on days 1-56. Then, after a two-week drug-free period, three cycles of cisplatin and pemetrexed were administered on days 71, 92, and 113. Thereafter, Gef or Osi was reinitiated on day 134 and continued until disease progression. Results: From October 2018 to October 2020, 193 pts were enrolled in the Osi cohort (97 pts in SA and 96 pts in EA). Median follow-up was 64.8 months. Advanced stage and recurrent disease were 79% and 21%, female and male were 63% and 37%, exon 19 deletion and exon 21 L858R were 54% and 46%, PS 0 and 1 were 50% and 50%, ≥ 65 year and < 65 year were 57% and 43%, central nerve metastasis (+) and (-) were 27% and 73%, respectively. Median OS were 54.0 months (95% confidence interval [CI] 44.4 to 66.0) in SA and 50.4 months (95% CI 43.2 to 69.6) in the EA (HR, 0.984; 95% CI, 0.684-1.415; p = 0.9279). 5y OS were 43.9% and 40.4%, respectively. Median PFS were 20.4 months (95% CI 14.4 to 28.8) in SA and 25.2 months (95% CI 18.0 to 33.6) in EA (HR, 0.902; 95% CI, 0.663-1.227; p = 0.5147). 5y PFS were 14.3% and 16.3%, respectively. Conclusions: The insertion of platinum-doublet chemotherapy after the initial response to Osi could not improve PFS and OS of pts with advanced EGFR -NSqNSCLC. On the other hand, JCOG1404/WJOG8214L demonstrated that Osi-based first-line treatment achieved 5y PFS in approximately 15% of this population, providing a benchmark for emerging Osi-based strategies. Clinical trial information: UMIN000020242.

ABSTRACT Background Chemoimmunotherapy is widely used as the first‐line treatment for extensive‐stage small cell lung cancer (ES‐SCLC), but treatment options for second‐line have not changed. Amrubicin monotherapy is used as the standard treatment for relapsed SCLC, but since chemoimmunotherapy became an additional indication for ES‐SCLC, the efficacy and safety of second‐line amrubicin have not been sufficiently investigated. Methods We enrolled a total of 131 relapsed SCLC patients who received second‐line amrubicin at eleven institutions in Japan between August 2019 and June 2023. We retrospectively examined the efficacy and safety of second‐line amrubicin monotherapy. Results Twenty‐five (19.1%) and 106 patients (80.9%) had sensitive and refractory relapse, respectively. 51 (38.9%) and 80 (61.1%) patients received first‐line chemoimmunotherapy and first‐line chemotherapy, respectively. The median progression‐free survival (PFS) and overall survival (OS) were 3.6 months (95% confidence interval [CI], 3.1–4.1 months) and 7.9 months (95% CI, 6.7–9.1 months), respectively. The median PFS and OS were significantly longer in the sensitive group compared with the refractory group (PFS: 6.4 vs. 3.5 months, p = 0.008, OS: 9.4 vs. 6.4 months, p = 0.021, respectively). Treatment‐related adverse events were as follows: Grade 4 neutropenia in 51 patients (38.9%), grade 3 or higher febrile neutropenia in 18 patients (13.7%), and all grade interstitial lung disease in 13 patients (9.9%). Treatment‐related death was 1 patient (0.8%). Conclusion Second‐line amrubicin monotherapy for relapsed SCLC may be useful and well‐tolerated as a treatment option after first‐line chemoimmunotherapy or chemotherapy.

Background/Objectives: Extrapulmonary neuroendocrine carcinoma (EPNEC) is a rare, heterogeneous malignancy with no standard second-line treatment after progression on first-line platinum-doublet chemotherapy. We compared the efficacy and safety of amrubicin (AMR) versus platinum-based doublet as second-line therapy for advanced EPNEC. Methods: This multicenter retrospective study included patients with advanced EPNEC treated at five Japanese institutions who received second-line AMR or a platinum-based doublet. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events were assessed. Results: Forty-four patients were enrolled (platinum-based doublet, n = 25; AMR, n = 19). Median OS was 6.1 months (95% confidence interval [CI], 4.9-9.0) and 6.8 months (95% CI, 2.7-13.2), and median PFS was 2.2 months (95% CI, 1.6-4.4) and 2.1 months (95% CI, 1.5-6.8), respectively. ORR and DCR were 20.0% and 32.0% in the platinum group and 5.3% and 26.3% in the AMR group, respectively. No significant differences were observed for OS, PFS, ORR, or DCR. Grade 3-4 hematologic toxicity was more frequent in the platinum group, whereas severe non-hematologic toxicity was rare in both groups. Conclusions: AMR therapy and platinum-based doublet therapy may exhibit comparable efficacy and acceptable safety profiles as second-line treatment options for advanced EPNEC.

BACKGROUND:Chemoimmunotherapy is the standard first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC); however, a limited number of real-world cases meet the inclusion and exclusion criteria of clinical trials. This study investigated whether chemoimmunotherapy is selected in patients with ES-SCLC who meet eligibility criteria in real-world practice and identified their clinical characteristics. METHODS:A total of 198 patients diagnosed with ES-SCLC received first-line treatment at 11 institutions between August 2019 and June 2023. We evaluated the efficacy and safety of first-line treatment in patients meeting the eligibility criteria of the IMpower133 and CASPIAN trials. This multicenter retrospective study included 78 patients (39.4%) who met the eligibility criteria. RESULTS:Fifty-six (71.8%) and twenty-two (28.2%) underwent chemoimmunotherapy and chemotherapy, respectively. The proportion of patients aged ≥75 years was higher in the chemotherapy group. The median progression-free survival in the chemoimmunotherapy and chemotherapy groups was 5.1 versus 4.6 months (hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.29-0.84), respectively. The median overall survival in the chemoimmunotherapy and chemotherapy groups was 17.1 versus 9.4 months (HR 0.51; 95% CI, 0.29-0.88), respectively. The discontinuation rate of treatment-related adverse events did not differ significantly between the two groups (5.4% vs. 0.0%, p = 0.555). CONCLUSION:First-line chemoimmunotherapy is considered a valuable treatment option for patients with ES-SCLC who meet the eligibility criteria for clinical trials. However, even among eligible patients, chemotherapy alone may be selected based on various reasons, such as older age. Furthermore, a comprehensive analysis of real-world data is required. TRIAL REGISTRATION:This study was registered in the UMIN Clinical Trial Registry (A multicenter retrospective study to evaluate the efficacy and safety of platinum-based chemotherapy in combination with immunotherapy for extensive-stage small cell lung cancer in the real-world setting, UMIN000053134).

Introduction: Peritoneal mesothelioma is an extremely rare malignancy of the peritoneum. It has a poor prognosis, and the optimal systemic chemotherapy remains controversial. Here, we report two cases of peritoneal mesothelioma with long-term survival and complete response to carboplatin, pemetrexed, and bevacizumab chemotherapy. Case Presentation: Both patients were treated with six cycles of carboplatin (AUC 5), pemetrexed (750 mg/m2), and bevacizumab (15 mg/kg) followed by pemetrexed and bevacizumab as maintenance therapy. Partial response continued for over 6 years in case 1, and complete response was obtained in case 2. The patient in case 1 died after 7 years due to accidental pneumonia, and the patient in case 2 remained disease-free for over 2 years after initiation of chemotherapy. Conclusion: Little information is available regarding angiogenesis in malignant peritoneal mesothelioma, and carboplatin/pemetrexed/bevacizumab are off-labeled chemotherapy by Japanese healthcare system as yet. However, our experience suggested that combined chemotherapy with bevacizumab is a feasible option for systemic chemotherapy in cases of peritoneal mesothelioma.

BACKGROUND:First-line combination therapy with anti-programmed cell death ligand 1 antibodies and platinum-based chemotherapy (chemoimmunotherapy) for extensive-disease small cell lung cancer (ED-SCLC) has been shown to be effective in clinical trials and widely used. Since the introduction of chemoimmunotherapy, very few studies have evaluated the treatment details and outcomes for patients with ED-SCLC in clinical settings. METHODS:We enrolled 181 ED-SCLC patients who received first-line chemotherapy or chemoimmunotherapy at 11 institutions in Japan between August 2019 and June 2023. We retrospectively investigated the characteristics and treatment regimens of patients with ED-SCLC who received first-line treatment. RESULTS:Ninety-six (53.0 %) and 85 (47.0 %) ED-SCLC patients received chemoimmunotherapy and chemotherapy, respectively. The proportions of older patients (≥75 years) and those with interstitial pneumonia were significantly higher in the chemotherapy group than in the chemoimmunotherapy group (age: 56.5 % vs. 28.1 %, p < 0.001; interstitial pneumonia: 41.2 % vs. 9.4 %, p < 0.001, respectively). The median overall survival in chemoimmunotherapy and chemotherapy groups were 15.0 and 9.7 months, respectively. The most common reasons for not selecting chemoimmunotherapy were interstitial pneumonia (34 patients,18.8 %), older age (27 patients, 14.9 %), and poor performance status (24 patients, 13.3 %). CONCLUSION:Although the efficacy of chemoimmunotherapy for patients with ED-SCLC has been suggested, only about half of the patients with ED-SCLC select chemoimmunotherapy, and there are various challenges in the treatment of ED-SCLC in clinical settings.

PURPOSE:This study was performed to confirm the superiority in overall survival (OS) of EGFR tyrosine kinase inhibitor (TKI gefitinib or osimertinib) monotherapy versus EGFR TKI with intercalation of cisplatin plus pemetrexed as the first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSqNSCLC) harboring EGFR mutation. PATIENTS AND METHODS:This was an open-label, multicenter, randomized phase III study. Patients with chemotherapy-naïve advanced or recurrent NSqNSCLC harboring EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were randomly assigned (1:1) to EGFR-TKI monotherapy or the EGFR TKI plus intercalated chemotherapy group. The primary endpoint was OS, and the secondary endpoints included progression-free survival (PFS). RESULTS:From December 2015 to October 2020, 501 patients were randomized. The EGFR TKI was changed from gefitinib to osimertinib in October 2018 (gefitinib cohort: n = 308 and osimertinib cohort: n = 193). There was no survival advantage in the EGFR TKI plus intercalated chemotherapy group; the median survival time of both groups was 48.0 months (HR, 0.985; 91.4% confidence interval, 0.796-1.219; one-sided P = 0.4496). The median PFS time was 12.0 months in the EGFR-TKI monotherapy group and 18.0 months in the EGFR TKI plus intercalated chemotherapy group (HR, 0.762; 95% confidence interval, 0.628-0.925; one-sided P = 0.003). The OS and PFS trends in both gefitinib and osimertinib cohorts were identical to those in the entire population. CONCLUSIONS:The intercalation of cisplatin plus pemetrexed after the response to EGFR TKI improved PFS but not OS compared with EGFR TKI monotherapy as the first-line treatment for patients with advanced NSqNSCLC harboring EGFR mutation.

BACKGROUND:The aim of this study was to explore the biological impact of chemotherapy during epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in individuals with non-small cell lung cancer (NSCLC). METHODS:Plasma and tumor tissue specimens were prospectively collected from NSCLC patients with EGFR activating mutations who participated in a randomized phase III study comparing EGFR-TKI therapy with or without inserted chemotherapy (JCOG1404/WJOG8214L). The specimens were analyzed for genetic mutations by droplet digital polymerase chain reaction analysis and next-generation sequencing. RESULTS:Two hundred patients were enrolled in this biomarker study, with 113 and 87 individuals receiving EGFR-TKI monotherapy and EGFR-TKI treatment plus inserted chemotherapy, respectively. Although progression-free survival (PFS) for EGFR-TKI monotherapy was shorter in patients with than in those without detectable EGFR activating mutations in cell-free DNA at baseline, inserted chemotherapy improved PFS compared with EGFR-TKI monotherapy for the former patients (median, 17.5 vs. 11.8 months). Inserted chemotherapy suppressed the number of alleles positive for activating and T790M mutations of EGFR in cell-free DNA at disease progression. The benefit of inserted chemotherapy relative to EGFR-TKI monotherapy was more apparent in patients with (median PFS, 18.8 vs. 13.5 months) than in those without detectable concurrent mutations of TP53. CONCLUSIONS:Chemotherapy has the potential to suppress the development of EGFR-TKI resistance as well as to inhibit tumor growth for NSCLC positive for EGFR activating mutations. Our results provide biological insight into combination treatment with EGFR-TKIs and chemotherapy for such patients.

A 42-year-old man visited our hospital due to a gradually swelling subcutaneous mass on the back of the right shoulder. The biopsy specimen was diagnosed pathologically as pleomorphic liposarcoma. Systemic computed tomography and 18F-fluorodeoxyglucose positron emission tomography revealed multiple organ metastases, including involvement of the heart, skin, liver, bone, and lung. Six cycles of doxorubicin plus ifosfamide initially controlled the disease. However, newly developed lung metastases grew rapidly during subsequent cycles of chemotherapy, and the patient died 10 months after the initial diagnosis. The initial presentation of multiple organ involvement, including the heart, is a rare clinical manifestation of pleomorphic liposarcoma.

BACKGROUND:The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor. METHODS:This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing. FINDINGS:Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group. INTERPRETATION:The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival. FUNDING:The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development.

BACKGROUND Various resistance mechanisms of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) have been reported, and approximately half of the cases show a T790M point mutation as resistance to EGFR-TKI. In addition, 3-14% of cases of non-small cell lung cancer transform into small cell lung carcinoma (SCLC) during treatment. However, there are few reported cases in which 2 mechanisms of resistance have been observed simultaneously. This report describes a 66-year-old man with initial presentation of stage IIA right-sided lung adenocarcinoma with EGFR gene exon 21 L858R mutation and 3 years of stable disease. During treatment with erlotinib, the patient developed SCLC and adenocarcinoma with EGFR exon 21 L858R and exon 20 T790M mutation. CASE REPORT A 66-year-old man underwent right pneumonectomy plus nodal dissection 2a for right hilar lung cancer and was diagnosed with an EGFR exon21 L858R mutated lung adenocarcinoma. Three years later, pleural dissemination was observed in the right chest wall. Although erlotinib was continued for 52 months, new metastases to the right ribs were detected. Chest wall tumor resection was performed. Based on the World Health Organization classification, the patient was diagnosed with combined SCLC, with EGFR exon21 L858R and exon20 T790M mutation. The patient received 4 cycles of carboplatin plus etoposide, 14 cycles of amrubicin, and 2 cycles of irinotecan. Chemotherapy continued for 25 months. CONCLUSIONS Long-term survival was achieved by chemotherapy after transformation. Since EGFR mutation-positive lung cancer shows a variety of acquired resistances, it is important to consider the treatment strategy of performing re-biopsy.

MET exon14 skipping mutations (METex14s) are rarely reported as a potential resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). The efficacy of targeted therapy against METex14s emerging after osimertinib resistance is uncertain. Herein, we report a case of EGFR-mutated metastatic lung adenocarcinoma in which METex14 was detected in a re-biopsy upon first-line osimertinib resistance. The patient received capmatinib monotherapy as third-line therapy, which was ineffective, followed by an exceptional response to salvage therapy with afatinib. This report highlights the heterogeneity of EGFR-TKI resistance and that targeting rare resistance mechanisms remains challenging.

Background: Rechallenge therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is known to confer some clinical benefit for patients with metastatic EGFR-mutated non-small cell lung cancer (NSCLC). However, little is known about the efficacy of EGFR-TKI rechallenge after resistance to first-line (1L) osimertinib. This study aimed to assess the efficacy and safety of EGFR-TKI rechallenge therapy after resistance to 1L osimertinib in a Japanese clinical setting. Methods: Between April 2018 and August 2022, 26 patients who progressed after treatment with 1L osimertinib and received EGFR-TKI rechallenge were included in this multicenter retrospective analysis. Patients in whom 1L osimertinib was discontinued owing to toxicity and had subsequent disease progression were also included in the analysis. Results: Overall, the objective response rate for rechallenge therapy was 23.1%. The disease control rate was 53.9%, and the median progression-free survival (PFS) was 3.4 months. Patients who discontinued 1L osimertinib for toxicity had a higher response rate (42.9% vs. 15.8%) and longer PFS than those who discontinued it due to disease progression (median: 11.4 vs. 2.7 months, P = 0.001). Three patients (11.5%) developed rechallenge therapy-associated pneumonitis, two of which were grade >= 3. Conclusions: Rechallenge with EGFR-TKI after 1L osimertinib resistance showed limited clinical efficacy. However, it could be considered as a subsequent salvage therapeutic option for patients in whom 1L osimertinib was discontinued owing to toxicity.

Background/Aim:Inflammation and nutrition-based biomarkers, such as the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), C-reactive protein/albumin ratio (CAR), prognostic nutritional index (PNI), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI), have prognostic value for several types of malignancies. Markers that precisely reflect the prognosis of patients with head and neck cancers (HNCs) treated with immune-checkpoint inhibitors remain unclear. This retrospective study aimed to investigate the prognostic value of hematological markers before and after treatment with nivolumab in patients with recurrent or metastatic HNC (RM-HNC).Patients and Methods:We evaluated the clinical data of 44 patients with recurrent/metastatic head and neck squamous cell carcinoma treated with nivolumab between April 2017 and April 2023 at Shinshu University Hospital. Values of hematological biomarkers (NLR, LMR, PLR, CAR, PNI, SII, and SIRI) were calculated before and 4-6 weeks after nivolumab initiation. Receiver operating characteristic curves were constructed to determine the cutoff values of pre- and post-treatment markers for overall survival (OS) and progression-free survival (PFS).Results:Among all pre- and post-treatment markers, post-treatment NLR showed the highest area under the curve (AUC=0.702). A high post-treatment NLR (cutoff value, 4.01) was associated with a poor OS (p=0.027) and a tendency for shorter PFS (p=0.117). Multivariate analysis showed that a high post-treatment NLR was significantly associated with poor OS (p=0.026).Conclusion:A high post-treatment NLR was associated with poor response to nivolumab in head and neck cancers.

Objective Appropriate monitoring and management of chemotherapy-induced nausea and vomiting (CINV) with prophylactic antiemetics is important for cancer patients. This study was performed to validate the clinical practice of antiemetic use with carboplatin-based chemotherapy in lung cancer patients in the Hokushin region (Toyama, Ishikawa, Fukui, and Nagano prefectures), Japan. Methods We surveyed retrospective data of newly diagnosed and registered lung cancer patients initially treated with carboplatin-based chemotherapy in 21 principal hospitals in the Hokushin region linked with health insurance claims data between 2016 and 2017. Results A total of 1082 lung cancer patients (861 [79.6%] men, 221 [20.4%] women; median age 69.4 years [range, 33–89 years]). All patients received antiemetic therapy, with 613 (56.7%) and 469 patients (43.3%) receiving 5-hydroxytryptamine-3 receptor antagonist/dexamethasone double regimen and 5-hydroxytryptamine-3 receptor antagonist/dexamethasone/neurokinin-1 receptor antagonist triple regimen, respectively. However, the rates of double regimen and use of palonosetron were higher in Toyama and Fukui prefectures. Thirty-nine patients (3.6%) changed from double to triple regimen, while 41 patients (3.8%) changed from triple to double regimen after the second cycle, but six of these returned to triple antiemetics in subsequent cycles. Conclusion Adherence to antiemetic guidelines in clinical practice was high in Hokushin region. However, rates of double and triple antiemetic regimens differed between the four prefectures. Simultaneous analysis of nationwide registry and insurance data was valuable for evaluating and comparing the differences in the status of antiemesis and management.

ObjectiveThis study was performed to validate the epidemiology, initial treatment, and clinical practice in lung cancer patients < 80 and ≥ 80 years in Hokushin region, Japan.MethodsWe retrospectively surveyed data of 5481 newly diagnosed and registered lung cancer patients (4311 [78.7%] < 80 years; 1170 [21.3%] ≥ 80 years ) in 22 principal hospitals in Hokushin region linked with health insurance claims data between 2016 and 2017. Stage, initial treatment, and clinical practice were compared between the 2 groups.ResultsThe distributions of clinical stage I/II/III/IV/unknown were 2535/387/654/1371/111 in non-small cell lung cancer (NSCLC) and 37/32/114/237/3 in SCLC. Initial surgery for stage I NSCLC was performed in 90.0% and 60.2% of cases in the < 80 and ≥ 80 years groups, respectively. Rates of treatment with best supportive care (BSC) for stage IV disease were significantly higher in the ≥ 80 than the < 80 years group (NSCLC:58.9% vs. 18.7%; SCLC: 42.3% vs. 6.8%, respectively), regardless of the presence/absence of comorbidities. Propensity score matching showed that age ≥ 80 years itself was significantly related to choice of BSC in patients with lung cancer. The ratio of initial cytotoxic chemotherapy for NSCLC was low (49.9%) but that of biomarker-based therapy including tyrosine kinase inhibitors and immune checkpoint inhibitors (50.0%) was significantly higher in the ≥ 80 than < 80 years group (70.2% vs. 29.8%, respectively).ConclusionThere are several differences in treatment pattern between patients < 80 and ≥ 80 years. Age ≥ 80 years may be related to BSC choice in patients with lung cancer.

Background:Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and contributed to the development of precision medicine. Osimertinib is a standard first-line (1L) treatment for EGFR-mutated NSCLC and has demonstrated superior survival benefits over previous-generation TKIs. However, resistance to osimertinib is nearly inevitable, and subsequent treatment strategies remain unmet medical needs in this setting. Afatinib, a second-generation EGFR-TKI, exhibits activity against certain uncommon EGFR mutation types in the 1L setting. There are a few case reports on the efficacy of afatinib against EGFR-dependent resistance after osimertinib treatment, although these have not been prospectively investigated.Methods:The present phase II, single-arm multicenter trial aims to verify the efficacy and safety of afatinib rechallenge after 1L osimertinib resistance. Patients (aged ≥20 years) with advanced or recurrent non-squamous NSCLC harboring drug-sensitive EGFR mutations (deletion of exon 19 or L858R) who were previously treated with 1L osimertinib and second-line chemotherapy other than TKIs are considered eligible. Undergoing next-generation sequence-based comprehensive genomic profiling is one of the key inclusion criteria. The primary endpoint is the objective response rate; the secondary endpoints are progression-free survival, overall survival, and tolerability. Thirty patients will be recruited in December 2023.Discussion:The results of this study may promote incorporating afatinib rechallenge into the treatment sequence after 1L osimertinib resistance, a setting in which concrete evidence has not been yet established.Registration:UMIN Clinical Trial Registry: UMIN000049225.

Introduction. We prospectively examined current clinical practices in patients with inoperable epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) fusion-positive (EGFR+ and ALK+, respectively) non-small cell lung cancer (NSCLC) in Nagano Prefecture, Japan.Material and methods. The study population consisted of newly diagnosed patients with inoperable EGFR+ and ALK+ NSCLC in 14 hospitals in Nagano between May 2016 and March 2019. Both initial and subsequent treatment decisions were made at the discretion of the attending physician.Results. A total of 281 patients with EGFR+ NSCLC (mean age, 74 years, 59.1% female) and 26 patients with ALK+ NSCLC (mean age, 66 years, 53.8% female) were included in the study. The study population consisted of 148/107/29/20/3 cases with performance status 0/1/2/3/4 and 6/2/31/194/75 cases with clinical stage I/II/III/IV/recurrence, respectively. First-line therapy with tyrosine kinase inhibitors was performed in 259 (92.2%) and 22 (84.6%) patients with EGFR+ and ALK+ NSCLC, respectively. The median overall survival rate was 41.2 months (95% CI 36.8-45.6 months) with EGFR+. It was not reached with ALK+ .Conclusions. This observational analysis represents a valuable resource for evaluating the outcomes of treatment in patients with NSCLC.

Osimertinib, a third-generation EGFR TKI, is the standard therapy for previously untreated EGFR-mutated non-small cell lung cancer patients following the landmark FLAURA study. However, resistance inevitably hinders patient prognosis, increasing the need for new therapeutic strategies beyond osimertinib. Frontline osimertinib-based combination strategies (platinum-based chemotherapy and angiogenesis inhibitors) are currently being tested primarily to prevent initial resistance. In the later-line setting after osimertinib, many next-line therapeutic candidates have been actively examined in clinical trials. Notably, several drugs with novel mechanisms of action, such as antibody-drug conjugates and EGFR -MET bispecific antibodies, have shown promising efficacy despite the resistance mechanisms and are close to clinical application. In addition, genotype-based target strategies have been investigated for a better understanding of osimertinib resistance mechanisms based on molecular profiling tests at relapse. The C797S mutation and MET gene alterations are commonly identified following osimertinib resistance, for which targeting strategies are actively tested. This review describes current pharmacotherapeutic strategies for EGFR-mutated non-small cell lung cancer based on the results of clinical trials and the latest published data, broadly grouped into two sections: 1) EGFR TKIs-based combination therapy in the front-line setting and 2) novel therapeutic strategies after osimertinib resistance.