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Abstract Background Although the incidence of lung cancer in elderly individuals has been increasing in recent years, the number of clinical trials designed specifically for elderly patients with advanced non‐small cell lung cancer (NSCLC) is still limited. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of pemetrexed (PEM) plus bevacizumab (Bev) combination chemotherapy in elderly patients with nonsquamous NSCLC. Methods A total of 29 elderly patients (≥75 years old) with nonsquamous NSCLC were enrolled in this multicenter, open‐label, phase II study, and 27 patients were finally analyzed. PEM at 500 mg/m2 on day 1 plus Bev at 15 mg/kg on day 1 were administered triweekly. The primary endpoint was the investigator‐assessed objective response rate. Results The median age at initiating chemotherapy was 80 years old. Almost all patients (92.6%) had adenocarcinoma histology. The median number of cycles administered was 6, and the objective response rate was 40.7%. The median progression‐free survival, overall survival and 1‐year survival were 8.8 months, 27.2 months and 79%, respectively. The treatment was well‐tolerated, and no treatment‐related death was observed. Conclusion Combination chemotherapy with PEM plus Bev in elderly patients with previously untreated advanced non‐squamous NSCLC exhibited favorable antitumor activity and tolerability, suggesting that a combination of PEM plus Bev might be a promising treatment option for this population.

Background: Immune checkpoint inhibitors (ICIs) are a revolutionary paradigm in the treatment of thoracic malignancies and chemoimmunotherapy is a current standard care in this field. Chemotherapeutic agents are known to induce not only direct cytotoxic effects on tumor cells but also immune modulating effects, such as stimulating immunogenic cell death (ICD). Currently, either pemetrexed (PEM) or taxane plus platinum are combined with ICIs for patients with non‐small cell lung cancer (NSCLC); however, it is still unknown whether these agents are immunologically optimal partners for ICIs. Methods: To determine the immunologically optimal chemotherapeutic agent, we first evaluated the ability of several chemotherapeutic agents, including platinum, PEM, taxane, and 5‐fluorouracil (5‐FU) to induce ICD using several thoracic tumor cell lines in vitro. ICD was evaluated by the cell surface expression of calreticulin (CRT) and adenosine‐triphosphate (ATP) secretion. We further performed an antitumor vaccination assay in vivo. Results: 5‐FU induced cell surface expression of CRT and ATP secretion most efficiently among the several chemotherapeutic agents. This effect was enhanced when it was combined with platinum. In the antitumor vaccination assay in vivo, we found that vaccination with dying‐AB1‐HA (a murine malignant mesothelioma cell line) cells treated with 5‐FU, but neither PEM nor PTX, reduced the tumor growth of living‐AB1‐HA cells inoculated 1 week after vaccination by recruiting CD3+CD8+ T cells into the tumor microenvironment. Conclusion: Our findings indicate that fluoropyrimidine can be an immunologically optimal partner of ICIs through the induction of ICD for thoracic malignancies. [ABSTRACT FROM AUTHOR]

Combination immunotherapy with multiple immune checkpoint inhibitors (ICIs) has been approved for various types of malignancies, including malignant pleural mesothelioma (MPM). Podoplanin (PDPN), a transmembrane sialomucin‐like glycoprotein, has been investigated as a diagnostic marker and therapeutic target for MPM. We previously generated and developed a PDPN‐targeting Ab reagent with high Ab‐dependent cellular cytotoxicity (ADCC) and complement‐dependent cytotoxicity (CDC). However, the effects of anti‐PDPN Abs on various tumor‐infiltrating immune cells and their synergistic effects with ICIs have remained unclear. In the present study, we established a novel rat–mouse chimeric anti‐mouse PDPN IgG2a mAb (PMab‐1‐mG2a) and its core‐fucose‐deficient Ab (PMab‐1‐mG2a‐f) to address these limitations. We identified the ADCC and CDC activity of PMab‐1‐mG2a‐f against the PDPN‐expressing mesothelioma cell line AB1‐HA. The antitumor effect of monotherapy with PMab‐1‐mG2a‐f was not sufficient to overcome tumor progression in AB1‐HA‐bearing immunocompetent mice. However, PMab‐1‐mG2a‐f enhanced the antitumor effects of CTLA‐4 blockade. Combination therapy with anti‐PDPN Ab and anti‐CTLA‐4 Ab increased tumor‐infiltrating natural killer (NK) cells. The depletion of NK cells inhibited the synergistic effects of PMab‐1‐mG2a‐f and CTLA‐4 blockade in vivo. These findings indicated the essential role of NK cells in novel combination immunotherapy targeting PDPN and shed light on the therapeutic strategy in advanced MPM. [ABSTRACT FROM AUTHOR]

Background: An increased relative eosinophil count (REC) has potential as a predictive biomarker for a beneficial clinical response and outcome to cancer immunotherapies. Therefore, the present study investigated the impact of an increased posttreatment REC on the prognosis of non‐small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). Methods: We retrospectively reviewed all 151 patients diagnosed with NSCLC and treated with ICI monotherapy and blood test data between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University. Results: A total of 151 patients with a mean age of 69 years were included. REC after 4 weeks of initial ICI monotherapy was higher than pretreatment REC in 87 patients but not in 64. REC after 4 weeks of the ICI treatment with and without an increased REC were 4.4 and 1.8%, respectively (p < 0.001). Disease control rates (DCR) were significantly higher in patients with than in those without an increased REC (84% vs. 47%, p < 0.001). The median overall survival (OS) of lung cancer patients with or without an increased REC were 674 and 234 days, respectively. A Kaplan–Meier univariate analysis revealed a significant difference in OS between the two groups (p < 0.001). A Cox proportional regression analysis identified an increased REC as an independent predictor of OS (p = 0.003). Conclusion: ICI‐treated NSCLC patients with an increased REC after 4 weeks of treatment had a better DCR and prognosis than the other patients examined. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis is often associated with lung cancer, but early malignant lesions mixed with fibrous lesions are not always easy to diagnose. A 78-year-old woman was referred to our hospital due to a ground-glass nodule in the left upper lobe detected on chest high resolution computed tomography during follow-up of chronic idiopathic interstitial pneumonia. Pathological examination of the resected specimen revealed that the ground-glass nodule was locally progressed usual interstitial pneumonia (UIP). It should be noted that focal progression of UIP may occur and present with ground-glass nodule mimicking lung cancer, even if lesions in other areas remain unchanged. Moreover, in such cases, recognition of nodular lesions by the gross findings on the pleural surface and palpation during surgical resection are difficult and require precise marking. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSCs) have been known to play a pivotal role in the induction of immune tolerance, which limits the benefits of immune checkpoint inhibitors (ICIs). Recent studies revealed that several chemotherapeutic agents decreased tumor‐infiltrating MDSCs. Therefore, combination therapy with cytotoxic chemotherapeutic agents and ICIs was approved for first‐line treatment for lung cancer. However, the impact of chemotherapeutic agents on MDSCs and an optimal partner of ICIs has not been fully investigated in thoracic tumors, including lung cancer and malignant pleural mesothelioma. In the present study, we found that treatment with 5‐FU and its oral formulation, S‐1, suppressed tumor progression and inhibited the accumulation of MDSCs in thoracic tumor‐bearing mice. Tumor‐infiltrating T cells and dendritic cells were significantly expanded in S‐1‐treated mice. 5‐FU suppressed the ability of tumor cells to recruit MDSCs, while it did not suppress the survival and differentiation of mouse MDSCs in vitro. We also revealed that 5‐FU or S‐1 significantly downregulated the expression of tumor‐derived Bv8 and S100A8. The knockdown of Bv8 or S100A8 in tumor cells suppressed tumor growth and MDSC recruitment in vivo. Furthermore, in comparison with pemetrexed, administration of S‐1 improved the synergistic therapeutic efficacy of anti‐PD‐1 antibodies with or without carboplatin. Our findings revealed a novel mechanism wherein S‐1 primed a favorable tumor microenvironment to provide the rationale for combination therapy with S‐1 and ICIs as the optimal therapy for thoracic cancer. [ABSTRACT FROM AUTHOR]

Lung cancer with complex epidermal growth factor receptor (EGFR) and CTNNB1 comutations is rare, and the efficacy of tyrosine kinase inhibitors (TKIs) is generally poor. Here, we encountered a lung cancer patient with complex EGFR (L858R and E709X) and CTNNB1 comutations who successfully responded to afatinib. A 78‐year‐old woman visited our hospital with a cough and bloody sputum that had worsened over the past year. She had multiple mass shadows in both lungs and nodular shadows in the bronchi. The patient was diagnosed with lung adenocarcinoma cT4N3M1c stage IVB. A genetic analysis of the primary tumor using the Oncomine Dx target test multi‐CDx system revealed positivity for EGFR (L858R and E709X) and CTNNB1 mutations. The expression of programmed death ligand 1 (22C3 clones) in tumor cells was negative by immunostaining. The patient was treated with afatinib as first‐line therapy and achieved clinical improvement and a partial response and is continuing treatment 1 year later. Case reports of lung cancer patients with EGFR/CTNNB1 comutations are rare, and TKIs are not considered to be effective. We herein present the first case report of lung cancer with the co‐occurrence of uncommon and complex EGFR (L858R and E709X) and CTNNB1 mutations that was successfully treated with afatinib. [ABSTRACT FROM AUTHOR]