Safety of First-Line Nivolumab Plus Ipilimumab in Very Old (≥ 80 Years) Patients With Unresectable Malignant Pleural Mesothelioma: A Retrospective Single-Center Case Series.

Nivolumab plus ipilimumab as the first-line treatment results in superior survival outcomes in patients with malignant pleural mesothelioma (MPM). However, its safety in old (≥ 80 years) patients with MPM has not been elucidated yet. Three male patients with MPM, aged 80-90 years, were treated with nivolumab plus ipilimumab as the first-line treatment in our hospital. All of them discontinued the treatment due to adverse events. The overall survival from treatment initiation was 2.5, 3.5, and 4.0 months, respectively. Nivolumab plus ipilimumab should be used cautiously in very old patients with MPM.

Durable Response to Chemoimmunotherapy of a Lung Adenocarcinoma Harboring a MET Exon 14 Skipping Mutation.

Chemoimmunotherapy is the first-line standard treatment for patients with non-small cell lung cancer (NSCLC). However, there are few reports on the efficacy of chemoimmunotherapy in patients with NSCLC who harbor the MET exon 14 skipping mutation. We report the case of an 81-year-old male patient with lung adenocarcinoma with a MET exon 14 skipping mutation who was treated with chemoimmunotherapy and achieved a durable response. Chemoimmunotherapy may be a promising treatment option for patients with a MET exon 14 skipping mutation. However, further studies are needed to characterize the objective response rate and response duration in these populations.

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.

Rationale and design of a phase II trial of durvalumab treatment in patients with NSCLC ineligible for stage III chemoradiotherapy following radiation monotherapy (SPIRAL-RT study).

BACKGROUND: In the PACIFIC study, progression-free survival (PFS) and overall survival (OS) of patients with unresectable, locally advanced, stage III non-small cell lung cancer (NSCLC) were prolonged by durvalumab as maintenance therapy after radical concurrent chemoradiotherapy using platinum-based antitumor agents. However, no data were obtained to reveal the efficacy of durvalumab after radiation monotherapy in patients unsuitable for chemoradiotherapy. Here, we describe an ongoing single-arm, prospective, open-label, multicenter phase II trial of durvalumab in patients with NSCLC ineligible for stage III chemoradiotherapy following radiation monotherapy (SPIRAL-RT study). METHODS: Durvalumab at 10 mg/kg body weight is administered every 2 weeks after radiation therapy until individual patients meet the discontinuation criteria. The treatment duration is up to 12 months. The primary endpoint is the 1-year PFS rate. Secondary endpoints are response rate, PFS, OS, and safety. Durvalumab treatment after radiation monotherapy is expected to prolong 1-year PFS rate and have acceptable adverse events. DISCUSSION: We are conducting an intervention study to investigate the safety and efficacy of durvalumab treatment in patients with NSCLC ineligible for stage III chemoradiotherapy following radiation monotherapy.

Immune Checkpoint Inhibitors for Lung Cancer Treatment: A Review.

The treatment of lung cancer has changed drastically in recent years owing to the advent of immune checkpoint inhibitors (ICIs). A 1992 study reported that programmed cell death-1 (PD-1), an immune checkpoint molecule, is upregulated during the induction of T cell death. Since then, various immunoregulatory mechanisms involving PD-1 have been clarified, and the successful use of PD-1 blockers in anticancer therapy eventually led to the development of the current generation of ICIs. Nivolumab was the first ICI approved for treating lung cancer in 2014. Since then, various ICIs such as pembrolizumab, atezolizumab, and durvalumab have been successively introduced into clinical medicine and have shown remarkable efficacy. The introduction of ICIs constituted a major advancement in lung cancer treatment, but disease prognosis continues to remain low. Therefore, new molecular-targeted therapies coupled with existing anticancer drugs and radiotherapy have recently been explored. This review encompasses the current status, challenges, and future perspectives of ICI treatment in lung cancer.

Comparing three different anti-PD-L1 antibodies for immunohistochemical evaluation of small cell lung cancer.

OBJECTIVE: Small cell lung cancer (SCLC), which accounts for approximately 15% of all lung cancer cases, has high initial sensitivity to chemotherapy. However, clinical outcomes have not improved in the past two decades. Therefore, novel biomarkers are needed to prolong survival in patients with advanced SCLC. MATERIAL AND METHODS: In this retrospective study, we assessed 44 patients with SCLC who underwent first-line or adjuvant chemotherapy. We analyzed PD-L1 expression in SCLC tumors using three specific anti-PD-L1 antibody clones (28-8, 22C3, and SP263) and assessed their correlation with clinical profiles. RESULTS: Each clone yielded PD-L1 positivity as follows: 10 cases with 28-8, eight cases with 22C3, and six cases with SP263. Eleven patients tested positive with at least one of the three anti-PD-L1 antibodies, and 33 patients tested negative with all anti-PD-L1 antibodies. Serum neuron-specific enolase levels at diagnosis were significantly higher in negative tumors than in positive tumors with the 28-8 clone (p = 0.036) and, similarly, tended to be higher in negative tumors with the 22C3 and SP263 clones. CONCLUSION: These observations suggest that PD-L1 is detected in SCLC tumors at a similar rate and with similar clinical correlates when detected using any of these three anti-PD-L1 clones. Further large-scale investigations are warranted to reveal the roles of PD-L1 expression in patients with SCLC.

Rationale and design of a phase II study to evaluate prophylactic treatment of dacomitinib-induced dermatologic adverse events in epidermal growth factor receptor-mutated advanced non-small cell lung cancer (SPIRAL-Daco study).

BACKGROUND: Dacomitinib is the first second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) to significantly improve overall survival in the patients of EGFR mutation-positive inoperable or postoperative recurrent non-small cell lung cancer (NSCLC). However, dermatologic adverse events (AEs) increase with dacomitinib treatment, and the management strategy for dermatologic AEs is crucial. In particular, a proactive strategy has become desirable in clinical practice settings. We designed a trial to assess a proactive strategy for dermatologic AEs associated with dacomitinib treatment. METHODS: This is a single-arm, prospective, open-label, multicenter, phase II trial. Patients with advanced NSCLC harboring EGFR-activating mutations will receive dacomitinib and prophylactic treatment as follows: minocycline, skin moisturizer, topical steroid, and sunscreen. Treatment will be continued until progressive disease or any of the discontinuation criteria are met. The primary endpoint is the incidence of dermatologic AEs (≥ grade 2) in the first 8 weeks of dacomitinib treatment. Secondary endpoints are the proportion of dose reduction of dacomitinib, progression-free survival, and safety. DISCUSSION: We are conducting a phase II study to explore the preventive efficacy of prophylactic medication against dacomitinib-induced dermatologic AEs. TRIAL REGISTRATION: jRCTs071190015.

The role of the gut microbiome on the efficacy of immune checkpoint inhibitors in Japanese responder patients with advanced non-small cell lung cancer.

BACKGROUND: Cancer immunotherapy is being developed as a promising alternative for advanced non-small cell lung cancer (NSCLC). However, novel biomarkers are required to select patients that will benefit from treatment with immune checkpoint inhibitors (ICIs) for a long period of time. The gut microbiome is expected to be a promising biomarker of ICI response owing to the regulation of the immune status within the host. METHODS: In this retrospective study, we included 17 Japanese patients with advanced NSCLC who were treated with ICIs for >3 months in our hospital. Fecal samples obtained from the patients during ICI treatment were analyzed by 16S ribosomal RNA gene sequencing. We examined the correlation between the diversity of the gut microbiome and treatment with ICIs. RESULTS: Several bacterial species were more abundant in ICI responders than in non-responders. Patients with abundant Lactobacillus and Clostridium tended to have a longer time to treatment failure (TTF) after receiving ICI than those with a lower abundance. CONCLUSIONS: In conclusion, the composition of the gut microbiome is associated with better clinical benefits from ICI treatment in Japanese patients with NSCLC. A further large-scale study is warranted to validate the composition of the gut microbiome as a novel clinical factor influencing the response to ICIs for an extended time in NSCLC.

Retrospective Efficacy Analysis of Immune Checkpoint Inhibitor Rechallenge in Patients with Non-Small Cell Lung Cancer.

Little is known regarding the effectiveness and tolerability of immune checkpoint inhibitor (ICI) rechallenge after disease progression following initial ICI treatments. To identify eligible patients for ICI rechallenge, we retrospectively analyzed the relationship between clinical profiles and the effect of ICI rechallenge in patients with non-small cell lung cancer (NSCLC). We enrolled 35 NSCLC patients at six different institutions who were retreated with ICIs after discontinued initial ICI treatments due to disease progression. Cox proportional hazards models were used to assess the impact of clinical profiles on overall survival (OS) and progression-free survival (PFS). Median PFS and OS were 81 d (95% confidence interval, CI, 41-112 d) and 225 d (95% CI 106-361 d), respectively. The objective response rate was 2.9%, and the disease control rate was 42.9%. Multivariate analysis demonstrated that Eastern Cooperative Oncology Group Performance Score (ECOG-PS) ≥ 2 (hazard ratio, HR, 2.38; 95% CI 1.03-5.52; p = 0.043) and body mass index (BMI) > 20 (HR 0.43, 95% CI 0.19-0.95, p = 0.036) were significantly associated with PFS of ICI rechallenge. Our observations suggest that poor ECOG-PS and low BMI at intervention with ICI rechallenge may be negative predictors for ICI rechallenge treatment in patients with NSCLC.