The impact of the tumor shrinkage by initial EGFR inhibitors according to the detection of EGFR-T790M mutation in patients with non-small cell lung cancer harboring EGFR mutations.

BACKGROUND: The EGFR-T790M mutation is clinically detected using re-biopsy in approximately 50% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) who harbor EGFR mutations. However, little is known about the population of NSCLC patients who develop acquired resistance due to the T790M mutation. In this study, we focused on the emergence of the T790M mutation and analyzed patients refractory to initial EGFR-TKIs with successful re-biopsy samples. METHODS: Seventy-eight advanced NSCLC patients with EGFR mutations who had successful re-biopsy samples after resistance to initial EGFR-TKI treatment were enrolled at 5 institutions in Japan. We validated the association between the emergence of the T790M mutation and their clinical profiles. RESULTS: Thirty-nine patients tested positive for T790M and 39 tested negative in the re-biopsy samples. The objective response rate to initial EGFR-TKIs was higher in patients with the T790M mutation than in those without the mutation (89.7% versus 51.2%, p < 0.001). Moreover, there was a significant difference in the maximal tumor shrinkage rate relative to baseline in T790M-positive tumors compared with T790M-negative tumors (42.7% versus 24.0%, p = 0.001). Multivariate analysis demonstrated that the maximum tumor shrinkage rate was a significant predictive factor for the detection of the T790M mutation (p = 0.023, odds ratio 1.03, 95% confidence interval 1.00-1.05). CONCLUSIONS: Our retrospective observations suggested that the maximum tumor shrinkage rate with initial EGFR-TKI treatment might be one of the promising predictive biomarkers for emerging refractory tumors with the EGFR-T790M mutation.

Impact of the response to platinum-based chemotherapy on the second-line immune checkpoint inhibitor monotherapy in non-small cell lung cancer with PD-L1 expression ≤49%: a multicenter retrospective study.

Introduction: The efficacy of second-line immune checkpoint inhibitor (ICI) therapy is limited in non-small cell lung cancer (NSCLC) patients with ≤ 49% PD-L1 expression. Although chemoimmunotherapy is a promising strategy, platinum-based chemotherapy followed by ICI monotherapy is often used to avoid synergistic adverse events. However, predictors of the efficacy of ICI monotherapy after platinum-based chemotherapy in NSCLC with ≤ 49% PD-L1 expression remain scarce. Methods: This multicenter retrospective study evaluated 54 advanced or recurrent NSCLC patients with ≤ 49% PD-L1 expression who were treated with second-line ICI monotherapy following disease progression on first-line platinum-based chemotherapy at nine hospitals in Japan. The impact of response to platinum-based chemotherapy on the efficacy of subsequent ICI monotherapy was investigated. Results: The response to first-line platinum-based chemotherapy was divided into two groups: the non-progressive disease (PD) group, which included patients who did not experience disease progression after four cycles of chemotherapy, and the PD group, which included patients who showed initial PD or could not maintain disease control during the four cycles of chemotherapy and switched to second-line ICI monotherapy. Among the 54 patients, 32 and 22 were classified into the non-PD and PD groups, respectively. The non-PD group showed better response rates (p = 0.038) and longer overall survival (OS) with ICI monotherapy (p = 0.023) than the PD group. Multivariate analysis identified that maintaining a non-PD status after four cycles of chemotherapy was an independent prognostic factor for ICI monotherapy (p = 0.046). Moreover, patients with a modified Glasgow Prognostic Score (mGPS) of 0 showed a tendency for longer OS with ICI monotherapy (p = 0.079), and there was a significant correlation between maintaining non-PD after four cycles of chemotherapy and an mGPS of 0 (p = 0.045). Conclusion: Maintaining a non-PD status after four cycles of platinum-based chemotherapy was a predictor of OS after second-line ICI monotherapy. These findings will help physicians select the most suitable treatment option for NSCLC patients who were treated with platinum-based chemotherapy and switched to second-line treatment. Those who experienced early PD during platinum-based chemotherapy should not be treated with ICI monotherapy in the second-line setting.

First-Line Chemoimmunotherapy versus Sequential Platinum-Based Chemotherapy Followed by Immunotherapy in Patients with Non-Small Cell Lung Cancer with ≤49% Programmed Death-Ligand 1 Expression: A Real-World Multicenter Retrospective Study.

BACKGROUND: The long overall survival (OS) observed among patients with non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression in chemoimmunotherapy (CIT) groups in previous phase III trials suggests the limited efficacy of CIT among the subgroup with ≤49% PD-L1 expression on tumor cells. Hence, sequential treatment with first-line platinum-based chemotherapy followed by second-line immune checkpoint inhibitor treatment (SEQ) is an option. This study examined whether first-line CIT would provide better outcomes than SEQ in patients with advanced NSCLC with ≤49% PD-L1 expression. METHODS: This retrospective study evaluated patients with untreated NSCLC who received first-line CIT or SEQ at nine hospitals in Japan. OS, progression-free survival (PFS), PFS-2 (the time from first-line treatment to progression to second-line treatment or death), and other related outcomes were evaluated between the CIT and SEQ groups. RESULTS: Among the 305 enrolled patients, 234 eligible patients were analyzed: 165 in the CIT group and 69 in the SEQ group. The COX proportional hazards model suggested a significant interaction between PD-L1 expression and OS (p = 0.006). OS in the CIT group was significantly longer than that in the SEQ group in the 1-49% PD-L1 expression subgroup but not in the <1% PD-L1 expression subgroup. Among the subgroup with 1-49% PD-L1 expression, the CIT group exhibited longer median PFS than the SEQ group (CIT: 9.3 months (95% CI: 6.7-14.8) vs. SEQ:5.5 months (95% CI: 4.5-6.1); p < 0.001), while the median PFS in the CIT group was not statistically longer than the median PFS-2 in the SEQ group (p = 0.586). There was no significant difference between the median PFS in the CIT and SEQ groups among the <1% PD-L1 expression subgroup (p = 0.883); the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group (10.5 months (95% CI: 5.9-15.3) vs. 6.4 months (95% CI: 4.9-7.5); p = 0.024). CONCLUSIONS: CIT is recommended for patients with NSCLC with 1-49% PD-L1 expression because it significantly improved OS and PFS compared to SEQ. CIT had limited benefits in patients with <1% PD-L1 expression, and the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group. These findings will help physicians select the most suitable treatment option for patients with NSCLC, considering PD-L1 expressions.

Heterogeneity among tumors with acquired resistance to EGFR tyrosine kinase inhibitors harboring EGFR-T790M mutation in non-small cell lung cancer cells.

EGFR-T790M mutation is a major mechanism underlying acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung cancer with mutated EGFR. However, differences in the biological characteristics of T790M tumors based on treatment regimens with each generation of EGFR-TKI are not fully understood. We established cell lines with acquired resistance harboring EGFR-T790M mutation derived from xenograft tumors treated with each generation of EGFR-TKI and examined their biological characteristics with respect to third-generation EGFR-TKI osimertinib sensitivity. Second-generation EGFR-TKI dacomitinib-resistant cells with T790M-exhibited higher sensitivity to osimertinib than first-generation EGFR-TKI gefitinib-resistant cells with T790M via inhibition of AKT and ERK signaling and promotion of apoptosis. Furthermore, gefitinib-resistant cells showed enhanced intratumor heterogeneity accompanied by genomic instability and activation of alternative resistance mechanisms compared with dacomitinib-resistant cells; this suggests that the maintenance of EGFR dependency after acquiring resistance might depend on the type of EGFR-TKI. Our results demonstrate that the progression of tumor heterogeneity via both genetic and non-genetic mechanisms might affect osimertinib sensitivity in tumors with acquired resistance harboring EGFR-T790M mutation.

Late-onset Pleural and Pericardial Effusion as Immune-related Adverse Events after 94 Cycles of Nivolumab.

A 67-year-old man with primary lung adenocarcinoma was hospitalized due to massive bilateral pleural effusion and pericardial effusion after 94 cycles of nivolumab therapy. We were unable to identify the cause of these effusions using blood tests, cytology tests, or bacterial culture of pleural effusion and thoracoscopy. Finally, we administrated corticosteroids, which immediately improved the fluid accumulation. This case may support the introduction of corticosteroids for late-onset pleural and pericardial effusion during immune checkpoint inhibitor (ICI) treatment. However, the safety of rechallenge of ICIs after the improvement of fluid accumulation is controversial.

Endocrinopathies Associated with Immune Checkpoint Inhibitor Cancer Treatment: A Review.

Treatment with immune checkpoint inhibitors has shown efficacy against a variety of cancer types. The effects of nivolumab and pembrolizumab on lung cancer have been reported, and further therapeutic advances are ongoing. The side effects of immune checkpoint inhibitors are very different from those of conventional cytocidal anticancer drugs and molecular targeted drugs, and they involve various organs such as the digestive and respiratory organs, thyroid and pituitary glands, and skin. The generic term for such adverse events is immune-related adverse events (irAEs). They are relatively infrequent, and, if mild, treatment with immune checkpoint inhibitors can be continued with careful control. However, early detection and appropriate treatment are critical, as moderate-to-severe irAEs are associated with markedly reduced organ function and quality of life, with fatal consequences in some cases. Of these, endocrinopathies caused by immune checkpoint inhibitors are sometimes difficult to distinguish from nonspecific symptoms in patients with advanced cancer and may have serious outcomes when the diagnosis is delayed. Therefore, it is necessary to anticipate and appropriately address the onset of endocrinopathies during treatment with immune checkpoint inhibitors. Here, we present a review of endocrine disorders caused by immune checkpoint inhibitor treatment.

Significance of inflammatory indexes in atezolizumab monotherapy outcomes in previously treated non-small-cell lung cancer patients.

Cancer immunotherapy, including atezolizumab monotherapy, is a promising alternative strategy for patients with advanced non-small-cell lung cancer (NSCLC). Several inflammatory indices have been reported as potential biomarkers regarding the effectiveness of various treatments. This study aimed to analyze the efficacy of atezolizumab monotherapy using baseline inflammatory markers in NSCLC patients. We retrospectively enrolled 81 NSCLC patients who received atezolizumab monotherapy at six different medical institutions in Japan. The Cox proportional hazards model was used to assess the impact of the clinical variables, including inflammatory indexes, on clinical outcomes. Median progression-free survival (PFS) and overall survival (OS) were 60 days and 252 days, respectively. The objective response rate was 7.4%, and the disease control rate was 54.3%. Patients with high neutrophil to lymphocyte ratio (NLR), low lymphocyte to monocyte ratio (LMR), and/or high platelet to lymphocyte ratio (PLR), at baseline, demonstrated substantially shorter PFS and OS compared to those with a low NLR, high LMR, and/or low PLR. The multivariate analysis demonstrated that a high baseline NLR was substantially associated with short PFS and short OS. Our retrospective observations suggest that inflammatory indices may be a potential negative prognostic factor of atezolizumab monotherapy outcomes in NSCLC patients.

ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in EGFR-Mutated Non-Small Cell Lung Cancer.

PURPOSE: Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475. EXPERIMENTAL DESIGN: We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR-mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR-mutated NSCLC patients with acquired resistance to initial EGFR-TKIs. RESULTS: ONO-7475 sensitized AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI-tolerant cells. In the cell line-derived xenograft models of AXL-overexpressing EGFR-mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor regrowth compared with osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib. CONCLUSIONS: These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.

Clinical Characteristics of Osimertinib Responder in Non-Small Cell Lung Cancer Patients with EGFR-T790M Mutation.

Osimertinib is a mutant-selective EGFR inhibitor that is effective against non-small cell lung cancer (NSCLC) in patients with the EGFR-T790M mutation, who are resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the factors affecting response to osimertinib treatment are unknown. In this retrospective study, 27 NSCLC patients with the EGFR-T790M mutation were enrolled at five institutions in Japan. Among several parameters tested, the progression-free survival (PFS) associated with the initial EGFR-TKIs was positively correlated with the PFS after osimertinib treatment (p = 0.021). The median PFS following osimertinib treatment and the overall survival (OS) were longer in patients who responded to osimertinib than in those who did not (17.7 months versus 3.5 months, p = 0.009 and 24.2 months versus 13.5 months, p = 0.021, respectively). A multivariate analysis demonstrated that the PFS with initial EGFR-TKIs was significantly related to the PFS with osimertinib treatment (p = 0.035), whereas osimertinib response was significantly related to the PFS and OS with osimertinib treatment (p = 0.016 and p = 0.006, respectively). Our retrospective observations indicate that PFS following the initial EGFR-TKI treatment and the response rate to osimertinib might be promising predictors for effective osimertinib treatment in NSCLC patients with the EGFR-T790M mutation.

Association of Sarcopenia with and Efficacy of Anti-PD-1/PD-L1 Therapy in Non-Small-Cell Lung Cancer.

Secondary sarcopenia is defined as a decrease in muscle mass due to disease or malnutrition. Several studies have reported that secondary sarcopenia is an indicator of postoperative recurrence. We hypothesized that there is a correlation between the effect of immune checkpoint inhibitors (ICIs) and sarcopenia. We retrospectively analyzed 38 patients with advanced non-small cell lung cancer (NSCLC) who were treated with ICIs between February 2016 and April 2018. Patients were divided into two groups according to the change rate of the psoas major muscle area (PMMA) at the L2-L3 position and investigated the correlation between the change rate of the PMMA and the efficacy of ICIs was investigated. The objective response and disease control rates were lower in patients with sarcopenia than in those without sarcopenia. Patients with sarcopenia exhibited a significantly shorter median progression-free survival (PFS) than non-sarcopenia patients. Moreover, focusing on good Eastern Cooperative Oncology Group performance status patients, sarcopenia patients showed a shorter PFS than non-sarcopenia patients. Patients with sarcopenia are associated with poor outcomes for immunotherapy among those with advanced NSCLC, based on retrospective analysis. Further research is needed to validate the clinical biomarkers involved in ICI responders.

Effective combined therapy with ramucirumab for advanced pulmonary pleomorphic carcinoma.

Pulmonary pleomorphic carcinoma (PPC) is a rare disease with a poor prognosis. Most patients with PPC are refractory to chemotherapy, whereas good responses to platinum-based chemotherapy in combination with the anti-angiogenesis agent bevacizumab have been reported. An 82-year-old man was diagnosed with PPC with a clinical stage of T3N0M0, coincident with primary lung adenocarcinoma in an early stage. We chose single-agent chemotherapy with docetaxel as an initial treatment, but both the primary adenocarcinoma and two PPC lesions in the right lung were enlarged after one treatment cycle. We subsequently started treatment with ramucirumab and docetaxel, and thereafter, the disease showed a good partial response. Here, we report the first case of advanced PPC that was effectively treated with chemotherapy and the anti-VEGFR-2 antibody ramucirumab. These observations suggest a potential therapeutic strategy for patients with PPC.

Successful sequential treatment of refractory tumors caused by small cell carcinoma transformation and EGFR-T790M mutation diagnosed by repeated genetic testing in a patient with lung adenocarcinoma harboring epidermal growth factor receptor mutations: A case report.

NSCLC patients with EGFR mutations respond to EGFR-TKIs; however, the management of refractory tumors to EGFR-TKIs remains unclear. We demonstrated that repeated genetic testing might be useful for detecting resistance mechanisms as well as for decision-making in EGFR mutated NSCLC patients, following the emergence of resistance to the initial EGFR-TKIs. A 69-year-old man was diagnosed with lung adenocarcinoma with an EGFR exon 19 deletion. After tumor re-growth treated with erlotinib and chemotherapy, he was diagnosed with an SCLC transformation and administered chemotherapy to treat the SCLC. After the resistance of chemotherapy, the EGFR-T790M mutation by liquid biopsy was detected and treated him with osimertinib, which resulted in a clinical response.