Pan-HER inhibitors overcome lorlatinib resistance caused by NRG1/HER3 activation in ALK-rearranged lung cancer.

Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) with a broad coverage against ALK mutations, has demonstrated dramatic effects in patients with ALK-rearranged lung cancer. The mechanisms of acquired resistance to lorlatinib by secondary ALK compound mutations have recently been reported; however, resistance mechanisms other than secondary mutations remain unclear. Here, we investigated the molecular mechanisms of the acquired resistance in ALK-rearranged lung cancer cells in vitro. We established two different lorlatinib-resistant ALK-rearranged lung cancer cell lines (H3122LR and A925LLR) via long-term administration of lorlatinib. These resistant cells did not harbor the secondary ALK mutations and showed cross-resistance to the other kinds of ALK-TKIs (crizotinib or alectinib) compared with the parental cells; however, these resistant cells overexpressed the phosphorylated human epidermal growth factor receptor 3 (HER3) protein and the ligand of HER3 (neuregulin 1; NRG1). Pharmacological inhibition of HER3 with pan-HER inhibitors or genetic knockdown of HER3 with siRNA resensitized H3122LR and A925LLR cells to lorlatinib in vitro, indicating that H3122LR and A925LLR acquired resistance by NRG1/HER3 activation. These findings demonstrated that targeting NRG1/HER3 is a potential novel therapeutic option for lorlatinib-resistant ALK-rearranged lung cancer.

[Trends in Outpatient Chemotherapy for Thoracic Oncology].

We conducted a survey of the outpatient pharmacotherapy we administered from April 2016 to March 2019 to understand trends in chemotherapy for respiratory thoracic malignancies, such as lung cancer. Over the 3-year period, 19,408 were treated in the outpatient chemotherapy department. Of these, 1,270(6.5%)had respiratory thoracic malignancies. The total number of patients and the number of patients with thoracic malignancies(%) were 5,815 and 320(5.5%); 6,344 and 434(6.8%); and 7,247 and 516(7.1%)in FY2016, FY2017 and FY2018, respectively. This shows that both increased during the study period. Each patient was treated in the chemotherapy department multiple times, and treatment for thoracic malignancies was initiated in 161 patients. The female:male ratio was 27%:73%, and the patients' median age(range)was 68 years(range: 36-84 years). Lung cancer was the most common disease(91%), followed by malignant pleural mesothelioma(5%), thymoma(2%), thymic carcinoma(1%), and synovial sarcoma(1%). The most common histological type of lung cancer was adenocarcinoma(67%), followed by squamous cell carcinoma(17%), small cell carcinoma( 7%), and others(9%). Outpatient chemotherapy was introduced as a first-line, second-line, and third-line or later treatment in 46%, 28%, and 22% of cases, respectively. While the number of patients increased, the number of new patients with thoracic malignancies decreased from 58 in FY2016 to 52 in FY2017 and 51 in FY2018. Conversely, the number of visits to the chemotherapy department by each new patient almost doubled from 5.5 in FY2016 to 8.5 in FY2017 and 10.1 in FY2018. The proportion of patients for which immunotherapy was included in the induction treatment regimen increased from 28% and 24% in FY2016 and FY2017, respectively, to 39% in FY2018. The increase in the use of outpatient chemotherapy for respiratory thoracic malignancies was due to the increase in the proportion of patients undergoing immunotherapy and the number of visits to the chemotherapy department per patient. It is important to implement measures to help prolong and increase the use of outpatient pharmacotherapy for respiratory thoracic malignancies by cooperating with surrounding medical institutions and increasing the number of beds available.

Barcode sequencing identifies resistant mechanisms to epidermal growth factor receptor inhibitors in circulating tumor DNA of lung cancer patients.

Most patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) will inevitably develop acquired resistance induced by treatment with EGFR tyrosine kinase inhibitors (EGFR-TKI). The mechanisms of resistance to EGFR-TKI are multifactorial, and the detection of these mechanisms is critical for treatment choices in patients who have progressed after EGFR-TKI therapy. We evaluated the feasibility of a molecular barcode method using next-generation sequencing to detect multifactorial resistance mechanisms in circulating tumor DNA and compared the results with those obtained using other technologies. Plasma samples were collected from 25 EGFR mutation-positive NSCLC patients after the development of EGFR-TKI resistance. Somatic mutation profiles of these samples were assessed using two methods of next-generation sequencing and droplet digital PCR (ddPCR). The positive rate for EGFR-sensitizing mutations was 18/25 (72.0%) using ddPCR, 17/25 (68.0%) using amplicon sequencing, and 19/25 (76.0%) using molecular barcode sequencing. Rate of the EGFR T790M resistance mutation among patients with EGFR-sensitizing mutations was shown to be 7/18 (38.9%) using ddPCR, 6/17 (35.3%) using amplicon sequencing, and 8/19 (42.1%) using molecular barcode sequencing. Copy number gain in the MET gene was detected in three cases using ddPCR. PIK3CA, KRAS and TP53 mutations were detected using amplicon sequencing. Molecular barcode sequencing detected PIK3CA, TP53, KRAS, and MAP2K1 mutations. Results of the three assays were comparable; however, in cell-free DNA, molecular barcode sequencing detected mutations causing multifactorial resistance more sensitively than did the other assays.

Hypertrophic osteoarthropathy associated with lung cancer: Possible links among hypoxia-inducible factor-1α, vascular endothelial growth factor, and hypervascularization.

Hypertrophic osteoarthropathy (HOA) is a paraneoplastic syndrome, the exact pathogenesis of which remains to be elucidated. The case of a 69-year-old man who developed intractably painful HOA secondary to lung cancer is presented. Contrast-enhanced computed tomography of the chest showed an 80-mm solid nodule with a large low-density area. The patient was diagnosed as having stage IIIA undifferentiated non-small cell lung cancer. The combination of carboplatin and paclitaxel with bevacizumab reduced tumor size and plasma vascular endothelial growth factor (VEGF) levels, relieving his leg pain. On immunohistochemical examination, lung cancer cells were positive for VEGF. A hypoxic tumor microenvironment may have caused some lung cancer cells to express hypoxia-inducible factor-1α, which contributed, at least in part, to the production of VEGF. The deep dermis vessels showed proliferation in the shin, with their thickened walls positive for VEGF. These findings may encourage investigators to explore novel management strategies for painful HOA.

Phase II study of IRInotecan treatment after COmbined chemo-immunotherapy for extensive-stage small cell lung cancer: Protocol of IRICO study.

INTRODUCTION: Combined treatment using anti-programmed death-ligand 1 antibody (anti-PD-L1) and platinum-etoposide is the current standard first-line treatment for patients with extensive-stage (ES) small cell lung cancer (SCLC). However, the best treatment for relapsed ES-SCLC after the first-line treatment remains unclear. There are some approved chemotherapeutic agents that can be used against ES-SCLC, and treatment with irinotecan is well established as both a monotherapy and a combined therapy, in combination with platinum. Therefore, we conduct a phase II study with irinotecan in the second- or later-line setting for patients with ES-SCLC who have been previously treated with combined treatment. METHODS: Our study will enroll total 30 patients who are diagnosed with ES-SCLC and have experienced disease progression after the combined treatment. Patients will receive irinotecan on days 1, 8, and 15, which will be repeated every 4 weeks. Doses of irinotecan (100/80/60 mg/m2 ) will be determined according to the type of UGT1A1 gene polymorphism, and the treatment will be discontinued following disease progression, intolerance, withdrawal of patient consent, and based on the investigator's decision. The primary endpoint of the study is the response rate, and the secondary endpoints are overall survival, progression-free survival, and safety. DISCUSSION: Since the present first-line treatment has been changed to the combined treatment, the second- or later-line treatment should be re-evaluated for patients with relapsed SCLC. Irinotecan is a major chemotherapeutic agent used for SCLC. This study demonstrates and re-evaluates the clinical benefits of irinotecan after combined treatment with anti-PD-L1 and platinum-etoposide for patients with ES-SCLC. REGISTRATION DETAILS: This study was registered in the Japan Registry of Clinical Trials (no. jRCT s071210090) on November 4, 2021.

Chemical augmentation of mitochondrial electron transport chains tunes T cell activation threshold in tumors.

BACKGROUND: Cancer immunotherapy shows insufficient efficacy for low immunogenic tumors. Furthermore, tumors often downregulate antigen and major histocompatibility complex expression to escape recognition by T cells, resulting in insufficient T cell receptor (TCR) stimulation in the tumor microenvironment. Thus, augmenting TCR-mediated recognition of tumor antigens is a useful strategy to improve the efficacy of cancer immunotherapy. METHODS: We screened 310 small molecules from our library and identified PQDN, a small molecule that activates CD8 T cells after TCR engagement, even when antigen stimulation is too weak for their activation. We used inhibitors of mitochondrial functions and Seahorse Flux Analyzer to investigate the mechanism underlying the effect of PQDN on T cells. Effect of PQDN on tumor-infiltrating CD8 T cells was examined using flow cytometry and TCR repertoire analysis. RESULTS: PQDN increased mitochondrial reciprocal capacity through enhancement of electron transport chains (ETCs) and facilitated glycolysis via mTOR/AKT signaling, resulting in augmented CD8 T cell activation, even when antigen stimulation is extremely weak. Intratumoral administration of this compound into tumor-bearing mice tunes inactivated T cell with tumor antigen recognition potent and expanded functional T cell receptor diversity of tumor-infiltrating T cells, augmenting antitumor immune responses and retarding tumor growth. Furthermore, PQDN has a synergistic potent with T cell dependent immunotherapy, such as checkpoint inhibitory therapy or adoptive cell therapy, even in a low immunogenic tumor. We also demonstrated that this compound enhances the activation of human CD8 T cells. CONCLUSIONS: These data suggest that tuning the T cell activation threshold by chemical activation of mitochondrial ETC is a new strategy for improving therapeutic efficacy through the activation of low-avidity tumor-specific T cells.

Immunosuppressive tumor microenvironment in extraskeletal myxoid chondrosarcoma: A case of pleural metastases.

Extraskeletal myxoid chondrosarcoma (EMCS) is an undifferentiated mesenchymal malignancy; however, its immune microenvironment remains to be elucidated. The case of a 34-year-old woman who developed EMCS metastasizing to the pleura is presented here. The pleural EMCS showed hypervascularity, absent PD-L1 expression, and a lack of tumor mutational burden and pathogenic variants. Immunohistological examination of the pleural lesions showed predominant M2 macrophages and sparse CD8+ T cells. EMCS and the tumor stroma were positive for transforming growth factor-ß1 (TGF-ß1) and vascular endothelial growth factor (VEGF). In contrast, a small number of the stromal vessels were positive for hypoxia inducible factor-1α (HIF-1α). TGF-ß1 and VEGF in the tumor stroma and low antigenicity of the tumor cells may help explain how EMCS induced the immunosuppressive microenvironment. These findings may encourage investigators to explore novel combined immunotherapy for EMCS, such as TGF-ß1 and VEGF inhibitors, and specific therapy for enhancing tumor antigens.

Proportion of biopsy specimens containing a tumor when compared to all biopsy specimens by transbronchial biopsy.

Background: The lung cancer biopsy specimens obtained by endobronchial ultrasound-guide sheath (EBUS-GS) trans lung biopsy occasionally do not contain cancer cells. It is a problem that there is a possibility that they may not contain cancer cells. Aim of the study: To investigate the proportion of biopsy specimens containing cancer cells in total biopsy specimens. Materials & methods: Patients with lung cancer diagnosed by EBUS-GS were selected. The primary end point was the proportion of specimens containing tumors in the total specimens obtained by EBUS-GS. Results: Twenty-six patients were investigated. The percentage of specimens containing cancer cells in the total specimens was 79.0%. Conclusion: The proportion of biopsy specimens containing cancer cell to all biopsy specimens by EBUS-GS was high, but not 100%.

The lung cancer biopsy specimens obtained by trans lung biopsy occasionally do not contain cancer cells. It is a problem that there is a possibility that they may not contain cancer cells. If the biopsy specimens contained no malignant cells, there was a possibility that accurate genetic test would not be performed and as a result, the correct molecular targeted drug would not be used. It is important to investigate the proportion of biopsy specimens containing cancer cells in total biopsy specimens. In this study, we showed the percentage of specimens containing cancer cells in the total specimens was 79.0%. This result should be considered to perform genetic test from biopsy specimens.

Phase I study of amrubicin plus cisplatin and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-disease small cell lung cancer: protocol of ACIST study.

BACKGROUND: Etoposide plus cisplatin (EP) combined with concurrent accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard treatment strategy for unresectable limited-disease (LD) small cell lung cancer (SCLC), which has remained unchanged for over two decades. Based on a previous study that confirmed the non-inferiority of amrubicin (AMR) plus cisplatin (AP) when compared with EP for extensive-disease (ED) SCLC, we have previously conducted a phase I study assessing AP with concurrent TRT (2 Gy/time, once daily, 50 Gy in total) for LD-SCLC therapy. Our findings revealed that AP with concurrent TRT could prolong overall survival to 39.5 months with manageable toxicities. Therefore, we plan to conduct a phase I study to investigate and determine the effect of AP combined with AHTRT, recommended dose (RD), maximum tolerated dose (MTD), and dose-limiting toxicity (DLT) of AP in patients with LD-SCLC. METHODS: Treatment-naive patients with LD-SCLC, age between 20 and 75 years, who had a performance status of 0 or 1 and adequate organ functions will be enrolled. For chemotherapy, cisplatin 60 mg/m2 /day (day 1) and AMR (day 1 to 3) will be administered with AHTRT (1.5 Gy/time, twice daily, 45 Gy in total). The initial AMR dose is set to 25 mg/m2 /day. RD and MTD will be determined by evaluating toxicities. DISCUSSION: Based on our previous study, the initial dose of AMR 25 mg/m2 is expected to be tolerated and acceptable. Here, we aim to determine whether treatment with AP and concurrent AHTRT would be an optimal choice with manageable toxicities for LD-SCLC.

Efficacy of S-1 after pemetrexed in patients with non-small cell lung cancer: A retrospective multi-institutional analysis.

BACKGROUND: S-1 and pemetrexed (PEM) are key treatments for non-small cell lung cancer (NSCLC). However, the mechanism of anticancer activity of S-1 and PEM is similar. Cross-resistance between S-1 and PEM is of concern. This exploratory study was designed to evaluate the treatment effect of S-1 following PEM-containing treatment. METHODS: This retrospective study included patients with advanced (c-stage III or IV, UICC seventh edition) or recurrent NSCLC who received S-1 monotherapy following the failure of previous PEM-containing chemotherapy at six hospitals in Japan. The primary endpoint of the study was the overall response rate (ORR). The secondary endpoint was the disease control rate (DCR), time to treatment failure (TTF), progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 53 NSCLC patients met the criteria for inclusion in the study. Forty-six patients had adenocarcinoma (88.7%) and no patients had squamous cell carcinoma. Thirty-one patients (58.5%) received the standard S-1 regimen and 18 patients (34.0%) received the modified S-1 regimen. ORR was 1.9% (95% confidence interval [CI]: 0.00%-10.1%). Median TTF, PFS, and OS were 65, 84, and 385 days, respectively. CONCLUSIONS: Although there were several limitations in this study, the ORR of S-1 after PEM in patients with nonsquamous (non-SQ) NSCLC was low compared to the historical control. One of the options in the future might be to avoid S-1 treatment in PEM-treated patients who need tumor shrinkage.

Remarkable response to pembrolizumab with platinum-doublet in PD-L1-low pulmonary sarcomatoid carcinoma: A case report.

Pulmonary sarcomatoid carcinoma (SC) is an aggressive subtype of lung cancer that exhibits resistance to cytotoxic chemotherapy. Although programmed cell death 1 (PD-1) inhibitors have been reported to show antitumor effects in patients with high programmed death-ligand 1 (PD-L1) expressing SC, the efficacy of combined therapy with PD-1 inhibitor plus cytotoxic chemotherapy has not previously been clarified. We herein report a case of SC with low expression of PD-L1 and few pre-existing tumor-infiltrating lymphocytes which showed a remarkable response to pembrolizumab plus cytotoxic chemotherapy as first-line treatment. Our findings suggest that combined treatment might enhance the immunogenic response, even in immunologically ignored SCs.

Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.

Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.

Real-World Incidence of Febrile Neutropenia among Patients Treated with Single-Agent Amrubicin: Necessity of the Primary Prophylactic Administration of Granulocyte Colony-Stimulating Factor.

BACKGROUND: Single-agent amrubicin chemotherapy is a key regimen, especially for small cell lung cancer (SCLC); however, it can cause severe myelosuppression. PURPOSE: The purpose of this study was to determine the real-world incidence of febrile neutropenia (FN) among patients treated with single-agent amrubicin chemotherapy for thoracic malignancies. PATIENTS AND METHODS: The medical records of consecutive patients with thoracic malignancies, including SCLC and non-small cell lung cancer (NSCLC), who were treated with single-agent amrubicin chemotherapy in cycle 1 between January 2010 and March 2020, were retrospectively analyzed. RESULTS: One hundred and fifty-six patients from four institutions were enrolled. Their characteristics were as follows: median age (range): 68 (32-86); male/female: 126/30; performance status (0/1/2): 9/108/39; SCLC/NSCLC/others: 111/30/15; and prior treatment (0/1/2/3-): 1/96/31/28. One hundred and thirty-four (86%) and 97 (62%) patients experienced grade 3/4 and grade 4 neutropenia, respectively. One hundred and twelve patients (72%) required therapeutic G-CSF treatment, and 47 (30%) developed FN. Prophylactic PEG-G-CSF was not used in cycle 1 in any case. The median overall survival of the patients with FN was significantly shorter than that of the patients without FN (7.2 vs. 10.0 months, p = 0.025). CONCLUSIONS: The real-world incidence rate of FN among patients with thoracic malignancies that were treated with single-agent amrubicin chemotherapy was 30%. It is suggested that prophylactic G-CSF should be administered during the practical use of single-agent amrubicin chemotherapy for patients who have already received chemotherapy.

Amrubicin in previously treated patients with malignant pleural mesothelioma: A phase II study.

BACKGROUND: The aim of this study was to assess the efficacy and safety of amrubicin for previously treated malignant pleural mesothelioma. METHODS: The eligibility criteria were: previously treated unresectable malignant pleural mesothelioma; performance status 0-1; age ≤ 75; adequate hematological, hepatic, and renal function. The patients were injected with 35 mg/m2 amrubicin on days one, two, and three every 3-4 weeks. The planned number of patients was 32. RESULTS: The study was terminated due to delay in enrollment and 10 patients were subsequently enrolled (nine males and one female; median age 67 [range 49-73]), of which four had epithelioid tumors, three had sarcomatoid tumors and three had biphasic tumors, respectively. According to the International Mesothelioma Interest Group (IMIG), one, four, and four patients had stage II, III, and IV, respectively, and one had postoperative recurrence. There was one (10%) partial response, four (40%) had stable disease, and five (50%) patients exhibited disease progression. The overall response and disease control rates were 10% (95% CI: 0.3-44.5%) and 60% (95% CI: 26.2-87.8%), respectively. The median progression-free survival time was 1.6 months. The median overall survival time was 6.6 months, and the one-, two-, and three-year survival rates were 23%, 23%, and 0%, respectively. The observed grade 3 or 4 toxicities included neutropenia in six (60%) patients; leukopenia in five (50%) patients; and febrile neutropenia, thrombocytopenia, anemia, and pneumonia in one (10%) patient each. CONCLUSIONS: There was not enough data to evaluate the efficacy because the study was terminated early. However, amrubicin showed limited activity and acceptable toxicities when used in previously treated malignant pleural mesothelioma patients.

Phase II study of ramucirumab and docetaxel for previously treated non-small cell lung cancer patients with malignant pleural effusion: Protocol of PLEURAM study.

INTRODUCTION: Anti-vascular endothelial growth factor therapy has been shown to be effective in non-small cell lung cancer (NSCLC) patients with malignant pleural effusion (MPE); however, there are no data to suggest that ramucirumab has the same effects. METHODS: We therefore decided to conduct a phase II study of ramucirumab plus docetaxel for NSCLC patients with MPE. The MPE control rate at eight weeks after the start of treatment will be the primary endpoint, and the objective response rate, progression-free survival, one-year survival rate, overall survival, and toxicity profile will be secondary endpoints. DISCUSSION: A previous study indicated that administering chemotherapy in combination with bevacizumab was effective at controlling pleural effusion in patients with NSCLC with carcinomatous pleurisy. It is expected that ramucirumab will have a similar effect to the same group.

Correlation between thyroid transcription factor-1 expression, immune-related thyroid dysfunction, and efficacy of anti-programmed cell death protein-1 treatment in non-small cell lung cancer.

BACKGROUND: Recent studies have suggested a correlation between immune-related thyroid dysfunction (irTD) and the superior efficacy of anti-programmed cell death protein-1 (anti-PD-1) treatment in non-small cell lung cancer (NSCLC). Embryologically, the lung and thyroid are similar in origin, and thyroid transcription factor-1 (TTF-1) expresses in both organs, including NSCLC. We explored our hypothesis that TTF-1 expression in NSCLC might correlate with irTD incidence and anti-PD-1 treatment efficacy. METHODS: We identified 132 patients with NSCLC treated with anti-PD-1 antibody at our hospital between December 2015 and June 2017. We evaluated TTF-1 expression in tumor by immunohistochemistry using a mouse monoclonal antibody (clone 8G7G3/1, 1:100, Dako). IrTD was defined as two or more successive abnormal levels of thyroid-stimulating hormone (TSH) during anti-PD-1 treatment. We retrospectively assessed correlations between TTF-1 expression in tumor, irTD incidence, and anti-PD-1 treatment efficacy. RESULTS: Of 132 patients, 67 (51%) and 65 (49%) were positive and negative for TTF-1, respectively. We observed irTD in 19 patients (6 positives and 13 negatives for TTF-1). The incidence of irTD was 9% and 20% in TTF-1-positive and TTF-1-negative NSCLCs, respectively (P=0.086). Particularly, in non-squamous (NSQ) cell carcinomas, the irTD incidence was significantly higher in patients negative for TTF-1 (30%) than in those positive for TTF-1 (9%; P=0.010), and TTF-1 expression was identified as a significant risk factor for irTD on multivariate logistic regression analysis [odds ratio (OR), 0.18; 95% confidence interval (CI), 0.05-0.59; P=0.005]. Furthermore, longer median progression-free survival (10.3 months) was observed in patients with TTF-1-negative NSCLC with irTD compared to those with TTF-1-positive NSCLC with irTD, TTF-1-positive NSCLC without irTD, and TTF-1-negative NSCLC without irTD (4.2, 1.4, and 2.4 months, respectively). CONCLUSIONS: TTF-1 expression in NSCLC might correlate with irTD and anti-PD-1 treatment efficacy.

Correlation between serum adenosine deaminase activity and efficacy of anti-programmed cell death-1 antibody.

OBJECTIVE: Serum adenosine deaminase (ADA) activity is a marker of immune reaction to several diseases. We evaluated changes in serum ADA in patients with lung cancer undergoing chemotherapy or anti-programmed cell death-1 (PD-1) therapy to examine the correlation between serum ADA and the therapy efficacy. MATERIALS AND METHODS: We assessed 50 patients with advanced lung cancer receiving chemotherapy or anti-PD-1 therapy. Serum ADA was measured before and on day 7 of the first treatment cycle and day 0 of subsequent cycles. Correlations between ADA change and efficacy of treatment were evaluated. RESULTS: Of the 50 patients, 20 were treated with chemotherapy and 30 were treated with anti-PD-1 therapy. Serum ADA decreased significantly between baseline and day 7 of the first cycle in patients undergoing chemotherapy, regardless of response (partial response [PR] or stable disease [SD]: -23% [-38 to +32; p = 0.002]; progressive disease [PD]: -12% [-42 to +6; p = 0.500]). Conversely, in patients undergoing anti-PD-1 therapy, serum ADA increased significantly between baseline and 7 days after the first dose and before subsequent doses in patients who had PR or SD. (day 7 of first cycle: +6% [-10 to +34; p = 0.034], day 0 of second cycle: 8% [-5 to +37; p = 0.002], day 0 of third cycle: 9% [-3 to +55; p = 0.002]). However, serum ADA did not significant change in PD patients undergoing anti-PD-1 therapy. Furthermore, early increases in serum ADA were associated with longer progression-free survival in patients receiving anti-PD-1 therapy (p = 0.006). CONCLUSION: Changes in serum ADA could be used to predict clinical benefit from anti-PD-1 therapy in patients with lung cancer. The association between changes in serum ADA and the efficacy of ant-PD-1 therapy thus remains inconclusive and requires further study.

Dose escalation study of amrubicin and cisplatin with concurrent thoracic radiotherapy for limited-disease small cell lung cancer.

BACKGROUND: Amrubicin and cisplatin is one of the active regimens used to treat patients with extensive-disease (ED)-small cell lung cancer (SCLC), whereas combined therapy involving chemotherapy and concurrent thoracic radiotherapy is the standard treatment for limited-disease (LD)-SCLC. PURPOSE: This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of amrubicin and cisplatin with concurrent thoracic radiotherapy (TRT) for LD-SCLC. PATIENTS AND METHODS: Patients that fulfilled the following eligibility criteria were enrolled: being aged ≤ 75 years and chemotherapy-naïve and having a performance status (PS) of 0-1, LD-SCLC, and adequate organ function. The patients received escalating doses of amrubicin on days 1, 2, and 3, and a fixed 60-mg/m2 dose of cisplatin on day 1. Four cycles of chemotherapy were administered, with each cycle lasting 4 weeks. TRT involving 2 Gy/day, once daily, commenced on day 2 of the first cycle of chemotherapy. The initial dose of amrubicin was 20 mg/m2 (level 1), and the dose was escalated to 25 mg/m2 (level 2) and then 30 mg/m2 (level 3). RESULTS: Eight patients from three institutions were enrolled at three dose levels. The patients' characteristics were as follows: male/female: 3/5; median age (range): 68.5 (60-73); PS 0/1: 4/4; stage IIIA/IIIB disease: 3/5. Both level 3 patients experienced DLT (grade 4 neutropenia and/or leukopenia lasting > 4 days). Level 3 was defined as the MTD, and level 2 was recommended as the dose for this regimen. Seven patients exhibited partial responses, and 1 displayed progressive disease (response rate: 88%). The median progression-free survival and overall survival periods were 11.1 and 39.5 months, respectively. No treatment-related deaths occurred. CONCLUSIONS: When this regimen was combined with TRT for LD-SCLC, the MTD was 30 mg/m2 for amrubicin and 60 mg/m2 for cisplatin. In addition, neutropenia and leukopenia were DLT, and doses of 25 mg/m2 for amrubicin and 60 mg/m2 for cisplatin are recommended for this regimen.

Phase II study of nedaplatin and amrubicin as first-line treatment for advanced squamous cell lung cancer.

BACKGROUND: The first-line treatment for squamous cell lung cancer (SCC) has not necessarily been established; however, our previous exploratory study suggested that the combination of nedaplatin and amrubicin would be a promising treatment approach for patients with SCC. Therefore, a phase II study of this chemotherapeutic combination was designed to evaluate its efficacy and safety for treatment-naïve patients with advanced SCC. METHODS: A total of 21 treatment-naïve patients with stage IIIB/IV or postoperative recurrent SCC were enrolled from six institutions. Nedaplatin (100 mg/m2 ) on day 1 and amrubicin (25 mg/m2 ) on days 1-3 were administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR), while the secondary endpoints included overall survival (OS), progression-free survival (PFS), and drug toxicities. RESULTS: Partial response was observed in seven of 21 cases (ORR, 33.3%; 95% confidence interval [CI], 14.5-52.2). Disease control rate, which includes stable disease, was 71.4%. Median OS and PFS was 14.6 and 4.1 months, respectively. This regimen did not cause any treatment-related deaths. Grade 3/4 neutropenia developed in 8 of 21 cases (38.1%); however, febrile neutropenia developed in only 9.5% of the cases. Grade 3/4 gastrointestinal or neuromuscular toxicities were not observed. CONCLUSION: The efficacy of the combination of nedaplatin and amrubicin was comparable to that of other conventional chemotherapeutic regimens for treatment-naïve patients with advanced SCC, and no severe gastrointestinal or neuromuscular toxicities were observed. This combination therapy may be an alternative treatment approach, particularly in patients who cannot tolerate gastrointestinal or neuromuscular toxicities.

Diffuse alveolar hemorrhage with pseudoprogression during nivolumab therapy in a patient with malignant melanoma.

Nivolumab, an anti-PD-1 antibody, has been shown to be effective in many cancers, such as malignant melanoma and lung cancer; however, nivolumab therapy can result in pseudoprogression. Diffuse alveolar hemorrhage (DAH) is persistent or recurrent pulmonary hemorrhage as a result of drugs, autoimmune diseases, or infections. DAH with pseudoprogression during nivolumab administration has rarely been reported. Herein, we describe our experience with one such case. A 41-year-old woman exhibited bloody sputum and ground glass opacities in the lungs along with tumor growth during nivolumab therapy for multiple lung metastases of malignant melanoma. We diagnosed DAH with pseudoprogression as a result of nivolumab and administered steroid therapy. The DAH subsequently improved and the tumor shrank. This case illustrates that nivolumab can cause DAH with pseudoprogression, which can be controlled by steroid therapy. Thus, if bloody sputum and ground glass opacities in the lungs are observed with tumor growth during nivolumab administration, steroid therapy should be considered to control DAH with pseudoprogression.