8605 Background: Non–small cell lung cancers (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations exhibit considerable biological and clinical heterogeneity. Consequently, the optimal first-line EGFR tyrosine kinase inhibitor (EGFR-TKI) and the role of subsequent immune checkpoint inhibitor (ICI)–based regimens remain uncertain. Methods: This multicenter retrospective cohort study was conducted at 29 institutions in Japan and included patients with advanced or recurrent non-squamous NSCLC harboring uncommon EGFR mutations who received first-line afatinib or osimertinib between January 2015 and January 2024. Exon 20 insertions and de novo T790M mutations were excluded. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and the effectiveness of subsequent systemic therapies, including ICI plus platinum doublet chemotherapy (ICI-Chemo) and platinum doublet chemotherapy alone. To adjust for baseline imbalances, analyses used inverse probability of treatment weighting (IPTW) based on covariate-balancing propensity scores. Results: Among 162 patients, 95 received afatinib and 67 received osimertinib. After IPTW adjustment, no significant differences were observed in PFS (median, 11.3 vs 5.9 months; hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.60–1.80) or OS (28.0 vs 25.5 months; HR, 1.34; 95% CI, 0.73–2.44). Afatinib yielded a higher ORR (70.2% vs 47.2%) and DCR (93.7% vs 82.5%) than osimertinib, while adverse events requiring dose reduction were more frequent (76.8% vs 31.3%) but generally manageable. Subgroup analyses suggested greater benefit with osimertinib in L861X mutations and with afatinib in compound mutations. In patients with PD-L1 ≥50%, afatinib was associated with significantly longer PFS (15.5 vs 2.6 months; HR, 0.14; 95% CI, 0.04–0.46), whereas OS was numerically longer (30.5 vs 12.9 months; HR, 0.38; 95% CI, 0.07–1.93). Among 56 patients who received subsequent systemic therapy and were chemotherapy- and ICI-naïve, IPTW-adjusted analyses showed that ICI-Chemo did not improve outcomes compared with platinum doublet chemotherapy: median PFS, 6.7 vs 7.3 months (HR, 1.08; 95% CI, 0.53–2.19) and post–EGFR-TKI OS, 14.6 vs 19.7 months (HR, 1.30; 95% CI, 0.63–2.68). Conclusions: In one of the largest multicenter real-world cohorts, afatinib and osimertinib demonstrated comparable survival outcomes as first-line EGFR-TKIs in NSCLC with uncommon EGFR mutations, with treatment effects modulated by mutation subtype and PD-L1 expression. ICI-based regimens did not improve outcomes compared with platinum doublet chemotherapy and conferred no meaningful clinical benefit as post–EGFR-TKI therapy in this population.

Non-small cell lung cancers (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations (UMs) are clinically heterogeneous, and the optimal first-line EGFR tyrosine kinase inhibitor (EGFR-TKI), as well as the role of subsequent immune checkpoint inhibitor (ICI)-based regimens, remains uncertain. We conducted a multicenter retrospective cohort study including patients with advanced or recurrent non-squamous NSCLC harboring UMs who received first-line afatinib or osimertinib between January 2015 and January 2024 at 29 hospitals in Japan, excluding exon 20 insertions and de novo T790M mutations. Inverse probability of treatment weighting adjusted baseline imbalances, and post-EGFR-TKI treatment patterns were evaluated. Among 162 patients (afatinib, n = 95; osimertinib, n = 67), weighted analyses demonstrated no significant differences in time to treatment failure (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.61-1.77) or overall survival (HR, 1.34; 95% CI, 0.73-2.44). Afatinib was associated with higher response rates and more frequent adverse events requiring dose reduction. Subgroup analyses suggested differential treatment effects according to mutation subtype, with osimertinib favoring L861X mutations and afatinib favoring compound mutations. Among 56 patients who received subsequent systemic therapy, clinical outcomes were comparable between ICI plus platinum doublet and platinum doublet alone. These findings indicate that afatinib and osimertinib provide comparable survival outcomes as first-line therapies for NSCLC with UMs, with treatment effects varying by molecular subtype, while subsequent ICI-based regimens may confer limited additional benefit.

INTRODUCTION:We aimed to evaluate the long-term follow-up overall survival (OS) of irinotecan plus cisplatin (IP) versus etoposide plus cisplatin (EP) as postoperative adjuvant chemotherapy in patients with pathological Stage I-IIIA high-grade neuroendocrine carcinoma (HGNEC) of the lung. METHODS:The JCOG1205/1206 randomized, open-label, phase III study compared the efficacy of IP and EP as adjuvant chemotherapy. Patients with pathological Stage I-IIIA and completely resected HGNEC of the lung were randomized to receive either the IP or EP arm. The primary endpoint was relapse-free survival (RFS), and the secondary endpoint included overall survival (OS). The analyses were performed using data from 5 years after the last patient enrollment. In addition, a central pathological review was planned for this study. RESULTS:Between April 2013 and October 2018, 221 patients were enrolled (EP arm, 111 patients; IP arm, 110 patients). Updated respective 3- and 5-year RFS rates were 68.5% and 65.7% in the EP arm versus 71.8% and 65.2% in the IP arm, with a hazard ratio (HR) of 1.026 (95% confidence interval [CI], 0.670-1.569). OS at 3 and 5 years was 85.6% and 73.5%, respectively, in the EP arm versus 83.6% and 72.4%, respectively, in the IP arm (HR, 1.175; 95% CI, 0.742-1.861). The concordance proportion of pathological diagnoses between each institution and central pathological reviews was 75.6% (95% CI, 69.4%-81.1%). CONCLUSIONS:Our results showed no significant difference in both updated RFS and OS between the two arms for patients with completely resected HGNEC.

BACKGROUND:Thyroid transcription factor-1 (TTF-1) is a diagnostic biomarker in non-squamous (non-sq) non-small cell lung cancer (NSCLC). TTF-1 negativity has been associated with poor outcomes following immunotherapy and pemetrexed-based chemotherapy in advanced non-sq NSCLC. However, the impact of TTF-1 expression on chemoimmunotherapy efficacy regimens remains unclear. METHODS:We retrospectively analyzed patients with advanced or recurrent non-sq NSCLC who received first-line platinum and pemetrexed plus pembrolizumab (Platinum/PEM/Pembro) or carboplatin and nab-paclitaxel plus atezolizumab (CBDCA/nab-PTX/Atezo) between March 2019 and May 2025 at our institution. RESULTS:Among 67 patients, 44 were TTF-1 positive and 23 were TTF-1 negative. In the overall cohort, TTF-1-positive patients had significantly longer progression-free survival (PFS) and overall survival (OS) than TTF-1-negative patients. In the Platinum/PEM/Pembro group, PFS and OS did not differ by TTF-1 status (median PFS: 8.5 vs. 7.0 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.39-1.86, and median OS: 23.7 vs. 26.1 months; HR, 0.93; 95% CI, 0.36-2.35). In univariate analysis of the overall population, TTF-1 expression and performance status (PS) were significantly associated with PFS, while TTF-1 expression, PS, and histological type were significantly associated with OS. The Platinum/PEM/Pembro group had a higher relative dose intensity of concomitant chemotherapy, a greater median number of immune checkpoint inhibitor cycles, and a longer median treatment duration. Immune-related adverse events (irAEs) were more frequent with Platinum/PEM/Pembro (50.0% vs. 17.4%, p = 0.0164). CONCLUSIONS:Platinum/PEM/Pembro may be a therapeutic option for TTF-1-negative non-sq NSCLC with good PS and adenocarcinoma histology, although careful management of irAE is required.

Background ROS1 fusions are present in approximately 2% of non-small cell lung cancers (NSCLCs), most of which are adenocarcinomas. Lung squamous cell carcinomas harboring ROS1 rearrangements are extremely rare, and their clinical characteristics and responses to targeted therapies remain unclear. Repotrectinib, a next-generation ROS1-tyrosine kinase inhibitor exhibits a durable response in advanced ROS1-rearranged NSCLC. However, its efficacy against ROS1-rearranged squamous cell carcinoma has not been previously reported. Case presentation An 80-year-old non-smoking woman presented with dyspnea and left-sided chest pain. Computed tomography (CT) revealed a mass in the left upper lobe with rib and pleural metastases, leading to the diagnosis of advanced lung squamous cell carcinoma harboring an EZR-ROS1 fusion. Repotrectinib was administered as the first-line therapy. Within one week of treatment initiation, visible shrinkage of the rib metastasis was noted, accompanied by an improvement in chest pain. CT at one month revealed marked tumor regression. Tumor shrinkage continued ten months later. No significant adverse events were reported, and the patient remained under treatment. Conclusion This is the first reported case of ROS1-rearranged lung squamous cell carcinoma treated with repotrectinib, which achieved a durable partial response and good tolerability in an older adult patient. This case highlights the importance of comprehensive molecular testing, even for squamous cell carcinoma, particularly among non-smokers. Identifying such alterations enables the use of targeted therapies that can result in substantial clinical benefits, including improved long-term prognosis.

Leptomeningeal metastatic disease (LMD) is associated with a poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who experience disease progression after EGFR tyrosine kinase inhibitor therapy. Amivantamab, an EGFR-mesenchymal-epithelial transition bispecific antibody, has demonstrated clinical efficacy in EGFR-mutated NSCLC; however, its effectiveness in treating symptomatic brain metastases and LMD remains unclear. We report on two cases of LMD that were managed with amivantamab. In Case 1, a 44-year-old woman developed symptomatic LMD during osimertinib therapy. Owing to prior prophylactic whole-brain irradiation during childhood, additional radiotherapy was not feasible. Carboplatin, pemetrexed, and amivantamab treatment resulted in remarkable LMD radiological improvement and gradual neurological symptom resolution. In Case 2, a 69-year-old man developed multiple asymptomatic brain metastases and LMD during osimertinib therapy. Second-line treatment with carboplatin, pemetrexed, and amivantamab resulted in a radiological response. To our knowledge, this is the first report to demonstrate the efficacy of carboplatin, pemetrexed, and amivantamab against LMD progression after osimertinib therapy, suggesting that this regimen may be a therapeutic option for patients with LMD, including those with symptomatic disease. Nevertheless, further studies are warranted to confirm efficacy in this population.

Bronchial papillomas have a median diameter of 15 mm at diagnosis and are classified as benign tumors; however, they may occasionally demonstrate increased fluorodeoxyglucose (FDG) uptake, requiring differentiation from malignant tumors. A 64-year-old man was referred to our hospital after chest computed tomography (CT) performed to evaluate a cough during a routine workplace health checkup revealed a 60-mm mass in segment 6 (S6) of the right lower lobe. The serum levels of carcinoembryonic antigen, cytokeratin 19 fragment, and squamous cell carcinoma antigen were elevated. FDG positron emission tomography/CT demonstrated intense FDG uptake in the right S6 mass, with a maximum standardized uptake value of 23.21. Bronchoscopy revealed a tumor protruding into the right B6 bronchus. Direct biopsy of the endobronchial lesion revealed a papilloma-like lesion composed of stratified mature squamous epithelium. Although no definite malignant features were identified, the possibility of secondary hyperplastic/dysplastic changes associated with neighboring malignancies, such as squamous cell carcinoma, could not be completely excluded. To evaluate the lesion, a CT-guided percutaneous lung biopsy was performed, which revealed similar histological findings without evidence of malignancy. As malignancy could not be definitively excluded, diagnostic and therapeutic surgery, consisting of uniportal video-assisted thoracoscopic right lower lobectomy with bronchoplasty and ND2a-1 lymph node dissection, was performed. Histopathological examination revealed a squamous cell papilloma measuring approximately 46 mm in diameter, with no evidence of malignancy. This squamous cell papilloma was larger and demonstrated higher FDG uptake, compared with previous cases.

9044 Background: To date, osimertinib has been commonly used as a first-line treatment for EGFR mutated advanced NSCLC. However, the issue of what constitutes effective treatment after osimertinib failure remains．We evaluated treatment with afatinib plus chemotherapy for EGFR mutated NSCLC resistant to osimertinib. Methods: Patients (pts) with EGFRm (Del19 or L858R) after failure of osimertinib treatment were assigned to a regimen of afatinib 20mg daily combined with carboplatin AUC5 mg/ml/min and pemetrexed 500mg/m2 every 3 weeks followed by maintenance treatment with afatinib plus pemetrexed until disease progression or unacceptable toxicity was noted. The primary endpoint was rate of PFS at 6 months after initiation of treatment (6M-PFSR). The threshold was set at 35% and the expected value at 60% (two-sided P-value of 5% and power of 80%). Thirty-one patients were required, and the target number of patients was set at 35 after accounting for ineligible cases. Secondary endpoints were PFS, OS, ORR, DOR, and Safety. In this study, blood samples were collected before and after study treatment and at the time of PD to examine biomarkers using CAPP-SEQ. This biomarker study is ongoing. Results: Between June 7, 2020 and January 19, 2022, 36 pts were enrolled. One patient was found to meet the exclusion criteria, and the efficacy was analyzed in the other 35 patients. The mean age was 70 years, 60% were women, and 54.3% were nonsmokers. The 6M-PFSR, the primary endpoint, was 57.1%. The confidence interval of 39.3%-71.5% exceeded the threshold of 35%, and the study met its primary endpoint. Notably, 24.1% of pts had a long-term PFS of 1 year or longer. ORR was 48.6%, DCR was 88.6%, median PFS was 8.2M, median DOR was 5.6 M, and median OS was not reached. By mutation type, ORR were similar for Del19 and L858R (46.7% and 50.0%, respectively), but median PFS tended to be longer for Del19 compared to L858R (9.6M and 5.2M, respectively). Pts who responded to previous osimertinib therapy (CR and PR: n = 29) tended to have longer mPFS compared to non-responders (SD, PD, and NE: n = 6) (8.5M and 5.8M, respectively). Adverse events due to TKI and chemotherapy were observed. Diarrhea (52.8%), anorexia (44.4%), fatigue (33.3%), and paronychia (36.1%) were the most frequent adverse events, and these adverse events were predictable and manageable. Interstitial pneumonia developed in three patients (8%), one of whom was the only death in the study. Conclusions: The combination of afatinib and the platinum doublet showed satisfactory efficacy with manageable adverse events in tumors refractory to osimertinib, and met its primary endpoint. OS follow-up and biomarker analyses are still ongoing. This regimen is expected to be a candidate for second-line therapy after osimertinib. Clinical trial information: jRCTs021200005 .

The survival benefit of combining chemotherapy (chemo) with immune checkpoint inhibitors (ICIs) in older patients with advanced non-small cell lung cancer (NSCLC) remains unclear. We evaluated the lung immune prognostic index (LIPI) as a predictive biomarker in this NEJ057 secondary analysis. This analysis included 600 patients aged ≥ 75 years with NSCLC and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 1

BACKGROUND:Immune checkpoint inhibitor plus chemotherapy (ICT) is the standard treatment for extensive-stage small cell lung cancer (ES-SCLC). We previously reported that oligometastasis (OM) is a predictor of ICT efficacy, however, the relationship between ICT efficacy and OM in older patients remains unknown. Therefore, this study examined the efficacy of ICT in the older patients including the influence of OM. METHODS:We enrolled patients with ES-SCLC who received ICT as first-line treatment between September 2019 and June 2022. Patient characteristics and treatment efficacy were compared between older (≥75 years) and non-older (<75 years) patients. RESULTS:We enrolled 228 patients, including 42 older patients. The prevalence of synchronous oligometastasis (SOM) at the start of first-line treatment was 21.0 % and 21.4 % (p = 1.0) in the older and non-older groups, respectively. The progression-free survival (PFS) with first-line therapy was 5.4 and 4.5 months (p = 0.55) and overall survival (OS) was 11.5 and 12.6 months (p = 0.74) for the SOM and non-SOM subgroups in the older group, respectively. For second-line treatment, PFS was 4.5 and 6.3 months (p = 0.79), and OS after second-line initiation was 16.0 and 13.2 months (p = 0.55) in oligoprogression (OP) and non-OP patients in the older group, respectively. CONCLUSIONS:The frequencies of SOM and OP were not significantly different between older and non-older patients. Although the small number of older patients in this study makes it impossible to conclude definitively, we did not observe a significant prognostic prolongation in older patients with OM as in non-older patients.

BACKGROUND:In treatment-naïve advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, approximately 10% to 15% correspond to uncommon mutations. For patients with EGFR uncommon mutations, monotherapy with either a second-generation EGFR tyrosine kinase inhibitor (TKI), afatinib, or a third-generation EGFR-TKI, osimertinib, is recommended as the initial therapy. However, needs remain unmet for patients with central nervous system (CNS) metastases and those who do not respond adequately to single-agent TKI therapy for EGFR uncommon mutations. The recently published FLAURA2 trial showed that osimertinib in combination with platinum-pemetrexed significantly prolonged progression-free survival (PFS) and provided high disease control compared with osimertinib monotherapy for common mutations. Therefore, we planned this phase II study to evaluate the efficacy and safety of osimertinib in combination with platinum-pemetrexed in treatment-naïve NSCLC patients with EGFR uncommon mutations. PATIENTS AND METHODS:Forty patients will be enrolled in the study. The primary endpoint is the objective response rate, and the secondary endpoints include safety, PFS and overall survival in overall patients, patients with and without CNS lesions at baseline and according to mutation subtype. CONCLUSIONS:In this study, we will explore the efficacy and safety of osimertinib in combination with platinum-pemetrexed in treatment-naïve NSCLC patients with EGFR uncommon mutations. Our findings may provide treatment options for patients with EGFR uncommon mutations, especially those with CNS metastases or those requiring more intensive treatment.

center dot Repotrectinib is a next-generation ROS1 tyrosine kinase inhibitor that demonstrates clinical activity against the ROS1 G2032R resistance mutation, commonly acquired after treatment with crizotinib and entrectinib. Preclinical studies have shown that repotrectinib has potent activity against another solvent-front resistance mutation, D2033N, although clinical data regarding its efficacy in this setting remain lacking. center dot We present the first case of a patient with advanced ROS1-positive non-small cell lung cancer (NSCLC) harboring the D2033N mutation detected by comprehensive genomic profiling, who experienced clinical benefit from repotrectinib after 11 prior lines of systemic therapy. center dot Repotrectinib resulted in a marked clinical and radiographic response. Although the patient developed neurally mediated syncope after initiation, the adverse event was managed by temporary treatment interruption, dose reduction, and co-administration of adrenergic a1 receptor agonist. center dot This report highlights the potential clinical activity of repotrectinib against the ROS1 D2033N mutation in heavily pretreated patients. Our findings underscore the utility of comprehensive genomic profiling in identifying resistance mutations and support the feasibility of late-line repotrectinib treatment with appropriate supportive care and dose modification strategies.

INTRODUCTION:Most patients with non-small cell lung cancer (NSCLC) who have never smoked possess tumors bearing tyrosine kinase oncogenes. While such tumors may exhibit robust responses to front-line tyrosine inhibitors (TKIs), disease progression is inevitable. Subsequent available therapies confer limited benefit, thus developing effective treatments for these patients remains a critical need. LP-300 is a novel compound that enhances chemotherapy sensitivity and inhibits the activity of tyrosine kinase oncogenes. Retrospective subset analyses of prior phase III studies found females and never-smokers, groups likely to have oncogene-driven tumors, obtained a considerable survival advantage with LP-300 combined with platinum-based chemotherapy as compared to chemotherapy alone. Prospective validation of these findings in patients with oncogene-driven NSCLC is needed. METHODS:The HARMONIC clinical trial, which is currently in progress, is a global, randomized, phase II study (NCT05456256) evaluating the 3-drug regimen of LP-300 with pemetrexed and carboplatin versus pemetrexed and carboplatin alone in 90 patients with advanced primary lung adenocarcinoma bearing tyrosine kinase oncogenes. Patient randomization is stratified by gender and favors the LP-300 containing arm (2-1). Patients must have tumors bearing tyrosine kinase actionable alterations (i.e. EGFR, ALK, ROS1, MET, RET, BRAF, or NTRK) and have prior TKI progression or intolerance. Primary endpoints are progression-free survival (PFS) and overall survival (OS). Secondary endpoints include objective response rate, duration of objective response, clinical benefit rate, and incidence of adverse events. CONCLUSION:This phase II trial is accruing patients at sites in the U.S, Japan, and Taiwan. Patient accrual is expected to be completed in the Fall of 2026.

An 80-year-old woman presented to our hospital with the chief complaint of left lateral thoracic pain. Chest computed tomography showed multiple nodular lesions in the left pleura and massive left pleural effusion. Based on clinical findings, imaging, and thoracoscopic pleural biopsy, a diagnosis of sarcomatoid diffuse pleural mesothelioma clinical T2N0M0 Stage IB was made. We administered nivolumab plus ipilimumab as first-line treatment, which resulted in significant reduction of pleural lesions and complete resolution of pleural effusion after two courses. No immune-mediated adverse events except fever were observed. Treatment was discontinued after 16 courses, with no disease recurrence for more than 2 years following the initial treatment. This case suggests that nivolumab plus ipilimumab can be an effective treatment option for older adults with pleural mesothelioma who maintain a good performance status.

Pulmonary pleomorphic carcinoma (PPC) is a rare and aggressive lung malignancy with limited treatment options. While immune checkpoint inhibitors (ICIs) have shown promise in treating PPC, evidence regarding their efficacy in epidermal growth factor receptor (EGFR)-mutated cases remains scarce. We report a case of a woman in her 70s diagnosed with PPC harboring EGFR L858R + E709K mutations and high expression (95 %) of programmed death-ligand 1 (PD-L1). After relapsing from concurrent chemoradiotherapy for a Pancoast tumor, the patient received osimertinib as second-line therapy. Despite an initial response, rapid disease progression necessitated left lower lobectomy, confirming PPC diagnosis. Subsequent treatment with pembrolizumab achieved notably tumor response. Although Grade 3 immune-related colitis developed, it was successfully managed with prednisolone, allowing completion of six courses of pembrolizumab. This case demonstrates the potential efficacy of ICIs in EGFR-mutated PPC, even after epidermal growth factor receptor -tyrosine kinase inhibitor (EGFR-TKI) failure and highlights the importance of appropriate adverse event management. Our findings suggest that ICIs may be a viable treatment option for EGFR-mutated PPC patients, particularly those with high PD-L1 expression.

8596 Background: Osimertinib is commonly used as a first-line treatment for EGFR-mutated advanced NSCLC. However, the optimal treatment following osimertinib failure remains unclear. This study evaluated afatinib plus chemotherapy for EGFR-mutated NSCLC resistant to osimertinib. Initial findings were presented at ASCO2023, and this report provides final data, including blood NGS analysis. Methods: Patients (pts) with EGFR mutations (Del19 or L858R) after osimertinib failure were treated with afatinib (20 mg daily) combined with carboplatin (AUC5 mg/mL/min) and pemetrexed (500 mg/m² every 3 weeks), followed by maintenance therapy with afatinib plus pemetrexed until progression or unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (6M-PFSR). Secondary endpoints included PFS, OS, ORR, DOR, and safety. Blood samples were collected before and during treatment, and at progression, to evaluate biomarkers using CAPP-SEQ. Results: Between June 7, 2020, and January 19, 2022, 36 pts were enrolled. One pt met exclusion criteria, leaving 35 pts for efficacy analysis. The mean age was 70 years; 60% were women, and 54.3% were nonsmokers. The median observation period was 29.1 months (cutoff date: January 18, 2024). The primary endpoint, 6M-PFSR, was 57.1% (95% CI, 39.3–71.5), exceeding the threshold of 35%. Notably, 28.6% of pts achieved long-term PFS of ≥1 year. ORR was 51.4%, DCR was 88.6%, median PFS was 8.2 months, median DOR was 5.6 months, and median OS was 22.5 months. By mutation type, ORRs were similar for Del19 and L858R (46.7% and 55.0%, respectively), but median PFS was longer for Del19 than for L858R (9.6 vs. 5.2 months). Pts who had responded to prior osimertinib (CR/PR, n=29) had longer median PFS than non-responders (SD/PD/NE, n=6) (8.5 vs. 5.8 months). Adverse events (AEs) from TKI and chemotherapy were common but manageable. The most frequent AEs were diarrhea (52.8%), anorexia (47.2%), fatigue (36.1%), and paronychia (36.1%). Interstitial pneumonia occurred in 3 pts (8.3%), with one treatment-related death. In plasma NGS analysis, clearance of EGFR mutations during treatment was a key predictive factor. Pts without EGFR mutation clearance had shorter PFS and OS compared to those with clearance (PFS: 5.7 vs. 12.0 months; OS: 15.7 vs. 34.4 months). Efficacy was observed even in pts with p53 mutations, a known resistance factor. MET gene amplification was detected in 4 pts upon resistance. Conclusions: Afatinib combined with platinum-based chemotherapy demonstrated satisfactory efficacy and manageable toxicity in pts with tumors refractory to osimertinib. EGFR mutation clearance during treatment was predictive of therapeutic outcomes. This regimen may be a promising second-line option after osimertinib failure. Clinical trial information: 021200005 .

Immune checkpoint inhibitors have drastically improved cancer treatment. However, they may induce immune-related adverse events (irAEs). Here, we report a case of significantly delayed rheumatic irAEs (Rh-irAEs) with prior possible temporary neutropenic irAEs in a patient with atezolizumab-treated non-small-cell lung cancer and its management. A man in his sixties received atezolizumab monotherapy as the sixth-line treatment. He experienced an infusion-related reaction (fever) during the first cycle. On day 22 of cycle 2, grade 4 neutropenia suddenly appeared, but it disappeared on the next day. Cycle 3 was initiated after seven days; the patient did not exhibit any symptoms for approximately 500 days. However, on day 534 (day 1 of cycle 21), the patient complained of pain in the shoulders, back, and wrists. On day 644, the shoulder and back pain worsened with obvious swelling of the fingers. We thus suspended treatment and consulted a rheumatologist. A diagnosis of polyarthritis with active tenosynovitis was made based on joint ultrasound and laboratory tests. Prednisolone 15 mg attenuated the symptoms, allowing suspension of analgesics; however, dose reduction from 15 mg/day was difficult because of symptom flares. Finally, iguratimod 25 mg twice daily was initiated on day 764; prednisolone was reduced to 10 mg without flares, and its dosage was slowly reduced to 5 mg/day. Although irAEs exhibit multisystem features, delayed development of polyarthritis with active tenosynovitis after possible temporary neutropenic irAEs is rare. Thus, irAEs need to be monitored for a long time in patients with suspected irAE development even if it appears transiently.

IMPORTANCE Immune checkpoint inhibitor (ICI) plus chemotherapy combination treatment (ICI-chemotherapy) is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alterations, but there are few data on ICI-chemotherapy for patients 75 years and older. OBJECTIVE To inform the choice of first-line drugs in clinical practice and assess the safety and efficacy of ICI-chemotherapy combination treatment in older adult patients with previously untreated advanced NSCLC. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included 58 centers in Japan. The cohort consisted of patients 75 years and older with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC. Patients started first-line systemic therapy between December 2018 and March 2021. Those receiving first-line molecular targeted drugs were excluded. The data were analyzed from February 2022 to October 2022. EXPOSURES Systemic therapy. MAIN OUTCOMES AND MEASURES The main outcomes were overall survival (OS), progression-free survival (PFS), and safety. RESULTS A total of 1245 patients (median [range] age, 78 [75-95] years; 967 [78%] male) with NSCLC were included in the cohort. Programmed death ligand-1 (PD-L1) expression of less than 1% occurred in 268 tumors (22%); 1% to 49% in 387 tumors (31%); 50% and higher in 410 tumors (33%), and unknown expression in 180 tumors (14%). Median OS was 20.0 (95% CI, 17.1-23.6) months for the 354 patients receiving ICI-chemotherapy (28%); 19.8 (95% CI, 16.5-23.8) months for the 425 patients receiving ICI alone (34%); 12.8 (95% CI, 10.7-15.6) months for the 311 patients receiving platinum-doublet chemotherapy (25%); and 9.5 (95% CI, 7.4-13.4) months for the 155 patients receiving single-agent chemotherapy (12%). After propensity score matching, no differences in OS and PFS were found between the patients receiving ICI-chemotherapy vs ICI alone. Each group consisted of 118 patients. For PD-L1 expression of 1% and higher the OS hazard ratio (HR) was 0.98 (95% CI, 0.67-1.42; P = .90), and the PFS HR was 0.92 (95% CI, 0.67-1.25; P = .59). Significance was also not reached when separately analyzed for lower or higher PD-L1 expression (1%-49% or >= 50%). However, grade 3 or higher immune-related adverse events occurred in 86 patients (24.3%) treated with ICI-chemotherapy and 76 (17.9%) with ICI alone (P = .03). CONCLUSIONS AND RELEVANCE In this study, ICI-chemotherapy combination treatment did not improve survival and increased the incidence of grade 3 and higher immune-related adverse events compared with ICI alone in patients 75 years and older. Based on these results, ICI alone may be recommended for older adult patients with PD-L1-positive NSCLC.

Introduction: Oligometastasis and oligoprogression (OP) has not been adequately defined in extensive-stage SCLC (ES-SCLC) and may be a good indication for adding local treatment. Therefore, this multicenter study aimed to investigate the prognostic impact of oligometastasis and OP in ES-SCLC. Methods: We enrolled patients who received chemoimmunotherapy between September 2019 and June 2022. Patients were classified into oligometastasis and non-oligometastasis groups by determining the number of original tumor lesions and distant metastases (worsening or newly appearing lesions) at the time of initial diagnosis and disease progression after first-line treatment. Results: We retrospectively analyzed 265 consecutive patients with ES-SCLC. Synchronous oligometastasis (SOM) and OP was defined as less than or equal to five lesions in less than or equal to two organs, including lungs; 21.0% and 53.2% of patients had SOM and OP, respectively. Median progression-free survival was 5.8 months and 4.9 months in patients with and without SOM, respectively (hazard ratio [HR] = 0.72, 95% confidence interval [CI]: 0.51-1.02, p = 0.065). Median overall survival was 20.5 months and 15.0 months in patients with and without SOM (HR = 0.58, 95% CI: 0.37-0.95, p = 0.027) from the initiation of first-line treatment. The OP group revealed a better progression- free survival of 5.2 months (versus 3.2 mo, HR = 0.69, 95% CI: 0.50-0.96, p = 0.026) and overall survival of 15.1 months (versus 7.5 mo, HR = 0.44, 95% CI: 0.29-0.66, p = 0.027) from the initiation of second-line treatment compared with the non-OP group. The Lung Immune Prognostic Index score was significantly lower in the SOM and OP group. Conclusions: ES-SCLC in patients with SOM and OP may be more indolent than that of the nonoligometastasis group, therefore, new treatment strategies, including the addition of local treatment, should be explored. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

Locoregional recurrence of non-small-cell lung cancer (NSCLC) after complete resection lacks standard treatment. Durvalumab after chemoradiotherapy (CRT) or CRT alone is often selected in daily clinical practice for patients with locoregional recurrence; however, the therapeutic efficacy of these treatments remains unclear, and we aimed to assess this. This retrospective observational study used data from patients with NSCLC diagnosed with locoregional recurrence after complete resection who subsequently underwent concurrent CRT followed by durvalumab (CRT-D group) or CRT alone (CRT group). We employed propensity score analysis with inverse probability treatment weighting (IPTW) to adjust for various confounders and evaluate efficacy in the CRT-D group. After IPTW adjustment, the CRT-D group contained 119 patients (64.7% male; 69.7% adenocarcinoma), and the CRT group contained 111 patients (60.5% male; 73.4% adenocarcinoma). Their mean ages were 66 and 65 years, respectively. The IPTW-adjusted median progression-free survival was 25.4 and 11.5 months for the CRT-D and CRT groups, respectively (hazard ratio, 0.44; 95% confidence interval, 0.30-0.64); the median overall survival was not reached in either group favoring CRT-D (hazard ratio, 0.49; 95% confidence interval, 0.24-0.99). Grade 3 or 4 adverse events were observed in 48.8% of patients during CRT, 10.7% after initiating durvalumab maintenance therapy in the CRT-D group, and 57.3% in the CRT group. Overall, the sequential approach of CRT followed by durvalumab is a promising treatment strategy for locoregional recurrence of NSCLC after complete resection.