Tomohiro Tanaka

Background/Objectives: We evaluated the efficacy and safety of first-line treatment with a programmed death-ligand 1 (PD-L1) inhibitor plus platinum-based chemotherapy versus chemotherapy alone in patients aged ≥75 years with extensive-stage small cell lung cancer (ES-SCLC). Methods: We retrospectively analyzed the patients with ES-SCLC treated within the Niigata Lung Cancer Treatment Study Group between August 2019 and April 2024. Results: A total of 364 consecutive patients were enrolled. After excluding 21 patients who did not receive treatment or had ineligible histological types, 343 patients were included in the analysis. Of these, 132 were aged ≥75. Compared with chemotherapy alone, administering a PD-L1 inhibitor with chemotherapy significantly improved the median overall survival among elderly patients (13.6 vs. 8.4 months; hazard ratio, 0.543; p = 0.0277). The median progression-free and overall survivals were similar between the ≥75-year and p = 0.7611 and 13.6 vs. 15 months; p = 0.732, respectively). Immune-related adverse events (irAE) of ≥grade 3 occurred in 4 and 12 patients (p = 0.7823), and non irAE of ≥grade 3 occurred in 47 and 103 patients (p = 0.5247) in the ≥75-years and <75-years subgroups, respectively. Conclusions: In this retrospective study, among patients aged ≥75 years with ES-SCLC, the addition of a PD-L1 inhibitor to platinum-based chemotherapy was associated with longer overall survival. Progression-free and overall survival outcomes were comparable between elderly and younger patients, with no clear age-related difference observed in the incidence of adverse events of ≥grade 3.

IntroductionWe evaluated the efficacy and safety of first-line treatment with a programmed death-ligand 1 (PD-L1) inhibitor plus platinum-based chemotherapy versus chemotherapy alone in patients aged ≥75 years with extensive-stage small cell lung cancer (ES-SCLC).MethodsWe retrospectively analyzed the patients with ES-SCLC treated within the Niigata Lung Cancer Treatment Study Group between August 2019 and April 2024.ResultsAmong 364 consecutive patients were enrolled. After excluding 21 patients with prior treatment or ineligible histological types, 343 patients were included in the analysis. Of these, 133 were aged ≥75. Compared with chemotherapy alone, administering a PD-L1 inhibitor with chemotherapy significantly improved the median overall survival among elderly patients (13.9 vs. 8.4 months; hazard ratio, 0.543; P = 0.0277). The median progression-free and overall survivals were similar between the ≥75-year and <75-year groups treated with PD-L1 inhibitor plus chemotherapy (4.9 vs. 4.8 months; P = 0.7611 and 13.6 vs. 15 months; P = 0.732, respectively). Immune-related adverse events (irAE) of ≥grade 3 occurred in 4 and 12 patients (P = 0.7823), and non irAE of ≥grade 3 occurred in 47 and 103 patients (P = 0.5247) in the ≥75-years and <75-years subgroups, respectively.ConclusionsIn this retrospective study, among patients aged ≥75 with ES-SCLC, the addition of a PD-L1 inhibitor to platinum-based chemotherapy was associated with significantly longer overall survival. Progression-free and overall survival outcomes were comparable between elderly and younger patients, and the incidence of adverse events of ≥grade 3 did not differ according to age.

Histological transformation to sarcomatoid carcinoma is an extremely rare mechanism of resistance to tyrosine kinase inhibitors. Among adenocarcinoma subtypes, transformation of pulmonary invasive mucinous carcinoma (IMA) into other histological types has not previously been reported. We present the case of a 74‐year‐old man referred to our hospital with abnormal lung shadows. Chest computed tomography (CT) revealed extensive consolidation predominantly in the right lower lobe. Transbronchial biopsy specimens confirmed IMA, which was negative for thyroid transcription factor‐1, and a BRAF D594G mutation was detected. As surgical resection was not feasible, first‐line treatment with ipilimumab plus nivolumab combined with chemotherapy was initiated, resulting in a partial response. After 19 cycles of maintenance therapy, treatment was discontinued because of suspected interstitial lung disease (ILD). Thirteen months later, the patient developed radiographic worsening of ILD, for which oral prednisolone was initiated. Two months later, CT imaging revealed rapid disease progression, with enlargement of right supraclavicular, mediastinal, and abdominal lymph nodes. Re‐biopsy of a mediastinal lymph node demonstrated sarcomatoid carcinoma positive for vimentin and pan‐cytokeratin AE1/AE3. Genomic analyses again identified the BRAF D594G mutation, confirming sarcomatous transformation of the original IMA. The patient received two cycles of nab‐paclitaxel plus carboplatin without response and subsequently died. These findings emphasize that clinicians should recognize that IMA may undergo sarcomatous transformation.

Background: Pemetrexed is used for the chemotherapy of advanced thymoma. Exceptional responses of thymoma to pemetrexed treatment are not frequently observed. The underlying genetic mechanism of the exceptional responses remains unclear. We used whole-exome sequencing to explore the specific genomic aberrations that lead to an extreme and durable response. Methods: Whole-exome sequencing using NovaSeq6000 (150 bp paired-end sequencing) was performed on nine formalin-fixed paraffin-embedded tissues from patients with advanced thymomas treated with pemetrexed (two exceptional responders and seven typical responders). Results: We identified 284 somatic single-nucleotide variants (SNVs; 272 missense, 8 missense/splice-site, 3 stop-gain, and 1 stop-gain/splice-site), 34 insertions and deletions (Indels; 33 frameshift and one splice region), and 21 copy number variations (CNVs; 15 gains and six losses). No difference in the number of SNVs variants and distribution of deleterious Indels was observed between the exceptional and typical responders. Interestingly, arm-level chromosomal CNVs (15 gains and six losses) were detected in four patients, including an exceptional responder. The highest number of arm-level CNVs was observed in an exceptional responder. Conclusion: Exceptional responders to pemetrexed for metastatic thymomas may be characterized by arm-level CNVs. Further, whole-genome and RNA sequencing studies should be performed.

Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2–16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.

The CC chemokine receptor 6 (CCR6) is a G protein-coupled receptor family member that is highly expressed in B lymphocytes, certain subsets of effector and memory T cells, and immature dendritic cells. CCR6 has only one chemokine ligand, CCL20. The CCL20–CCR6 axis has been recognized as a therapeutic target for autoimmune diseases and tumor. This study developed specific monoclonal antibodies (mAbs) against mouse CCR6 (mCCR6) using the peptide immunization method. The established anti-mCCR6 mAb, C ₆ Mab-13 (rat IgG ₁ , kappa), reacted with mCCR6-overexpressed Chinese hamster ovary-K1 (CHO/mCCR6), and mCCR6-endogenously expressed P388 (mouse lymphoid neoplasma) and J774-1 (mouse macrophage-like) cells in flow cytometry. The dissociation constant ( K _D ) of C ₆ Mab-13 for CHO/mCCR6 cells was determined to be 2.8 × 10 ⁻⁹ M, indicating that C ₆ Mab-13 binds to mCCR6 with high affinity. In summary, C ₆ Mab-13 is useful for detecting mCCR6-expressing cells through flow cytometry.