Postoperative Recurrent Non-small Cell Lung Cancer Research Articles

Second malignancy in advanced or recurrent non-small cell lung cancer after the advent of molecular targeted drugs and immunotherapy.

This study aimed to investigate the characteristics of patients with recurrent or advanced non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) or immune-checkpoint inhibitors (ICIs) who developed secondary malignancies, as well as evaluate the impact of these secondary malignancies on the course of lung cancer. This study included 112 patients with postoperative recurrent or advanced NSCLC, who received TKIs, ICIs, or immune combination therapy as the primary treatment modality between April1, 2013, and March 31, 2020, and achieved long-term survival (≥2 years). Secondary malignancies were defined as newly diagnosed cancers in other organs occurring after NSCLC treatment initiation. Among the 112 patients, 10 (8.9%) developed 12 carcinomas, including third primary malignancies. Univariate analysis, considering secondary malignancies as the outcome, revealed a non-significant trend towards a higher incidence of secondary malignancies in smokers compared to non-smokers. This study found that 8.9% of patients with advanced NSCLC who received TKIs, ICIs, or immune combination therapy and survived ≥2 years developed secondary malignancies. This underscores the importance of early diagnosis and treatment, even during lung cancer treatment, to identify suspicious lesions in other organs either via imaging or physical examinations.

Abstract 2519: Alteration of tumor immune microenvironment after recurrence and its impact on the efficacy of anti-PD-1 antibody in resected non-small cell lung cancer patients

Abstract Background: Tumor immune microenvironment (TIME), including programmed death-1 ligand-1 (PD-L1) and CD8-positive tumor-infiltrating lymphocytes (TIL), has been suggested as a potential biomarker to predict the efficacy of anti-PD-1 antibody. Postoperative recurrence in patients with non-small cell lung cancer (NSCLC) is treated with therapeutic strategies similar to those for metastatic disease. However, in postoperative recurrence cases, PD-L1 evaluation is generally based on archival resection specimens, because there is little opportunity for a new biopsy of the recurrent site. Therefore, it remains unclear whether TIME of recurrent lesion is similar to TIME of primary lesion at surgery, and the efficacy of anti-PD-1 antibody for postoperative recurrent NSCLC patients based on TIME status at surgery is unknown. Materials and Methods: Cohort A included 59 patients with advanced and 25 patients with postoperative recurrence NSCLC who treated with first-line pembrolizumab monotherapy. PD-L1 expression and CD8-TIL were evaluated immunohistochemically in tumor specimens obtained at diagnosis in the advanced cases and at surgery in the postoperative recurrence cases. Tumor proportion score for PD-L1 and the extent of CD8-TIL were evaluated and classified as high or low. TIME was categorized into 4 subclasses, according to the respective PD-L1 and CD8-TIL, as follows: (class I) high/high; (class II) low/low; (class III) high/low; and (class IV) low/high. Progression-free survival (PFS) of pembrolizumab was compared based on TIME. Cohort B consisted of 50 NSCLC patients who underwent radical resection, and whose tumor specimens were obtained from recurrent site. As in cohort A, TIME was assessed for paired resection and recurrent tumor samples. Results: In cohort A, the median PFS of pembrolizumab for the advanced cases were 25.7 months in class I (n=25), 2.3 months in class II (n=8), 8.0 months in class III (n=20), and 6.5 months in class IV (n=6) (p<0.001), respectively; while those for the postoperative recurrence cases were 9.0 months (n=7), 4.3 months (n=7), 7.6 months (n=6), and 2.5 months (n=5) (p=0.55), respectively. In cohort B, TIME for resected primary lesion were observed in 9 with class I, 20 with class II, 3 with class III and 18 patients with class IV, respectively. The concordance of PD-L1 category (high vs low) between resected primary lesion and recurrent lesion was 88.0%, while that of TIME classification was 54.0%. Conclusion: TIME classification using tumor specimens just before administration of anti-PD-1 antibody was useful predictive biomarker. However, TIME alterations between resection and postoperative recurrence were observed in many cases, suggesting that TIME based on tumor specimens at surgery may not be useful for predicting the efficacy of anti-PD-1 antibody for postoperative recurrent NSCLC. Citation Format: Yoshiya Matsumoto, Tetsuya Watanabe, Megumi Mizutani, Akira Sugimoto, Hiroaki Nagamine, Yoko Tani, Kenji Sawa, Takuma Tsukioka, Hiroyasu Kaneda, Shigeki Mitsuoka, Noritoshi Nishiyama, Tomoya Kawaguchi. Alteration of tumor immune microenvironment after recurrence and its impact on the efficacy of anti-PD-1 antibody in resected non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2519.

Immunotherapy or Chemoimmunotherapy in Older Adults With Advanced Non–Small Cell Lung Cancer

Immune checkpoint inhibitor (ICI) plus chemotherapy combination treatment (ICI-chemotherapy) is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alterations, but there are few data on ICI-chemotherapy for patients 75 years and older. To inform the choice of first-line drugs in clinical practice and assess the safety and efficacy of ICI-chemotherapy combination treatment in older adult patients with previously untreated advanced NSCLC. This retrospective cohort study included 58 centers in Japan. The cohort consisted of patients 75 years and older with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC. Patients started first-line systemic therapy between December 2018 and March 2021. Those receiving first-line molecular targeted drugs were excluded. The data were analyzed from February 2022 to October 2022. Systemic therapy. The main outcomes were overall survival (OS), progression-free survival (PFS), and safety. A total of 1245 patients (median [range] age, 78 [75-95] years; 967 [78%] male) with NSCLC were included in the cohort. Programmed death ligand-1 (PD-L1) expression of less than 1% occurred in 268 tumors (22%); 1% to 49% in 387 tumors (31%); 50% and higher in 410 tumors (33%), and unknown expression in 180 tumors (14%). Median OS was 20.0 (95% CI, 17.1-23.6) months for the 354 patients receiving ICI-chemotherapy (28%); 19.8 (95% CI, 16.5-23.8) months for the 425 patients receiving ICI alone (34%); 12.8 (95% CI, 10.7-15.6) months for the 311 patients receiving platinum-doublet chemotherapy (25%); and 9.5 (95% CI, 7.4-13.4) months for the 155 patients receiving single-agent chemotherapy (12%). After propensity score matching, no differences in OS and PFS were found between the patients receiving ICI-chemotherapy vs ICI alone. Each group consisted of 118 patients. For PD-L1 expression of 1% and higher the OS hazard ratio (HR) was 0.98 (95% CI, 0.67-1.42; P = .90), and the PFS HR was 0.92 (95% CI, 0.67-1.25; P = .59). Significance was also not reached when separately analyzed for lower or higher PD-L1 expression (1%-49% or ≥50%). However, grade 3 or higher immune-related adverse events occurred in 86 patients (24.3%) treated with ICI-chemotherapy and 76 (17.9%) with ICI alone (P = .03). In this study, ICI-chemotherapy combination treatment did not improve survival and increased the incidence of grade 3 and higher immune-related adverse events compared with ICI alone in patients 75 years and older. Based on these results, ICI alone may be recommended for older adult patients with PD-L1-positive NSCLC.

First-line immune checkpoint inhibitors alone or in combination with chemotherapy in real-life elderly patients with advanced non-small cell lung cancer (NEJ057).

9012 Background: Immune checkpoint inhibitor (ICI) plus chemotherapy is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alternations. However, the efficacy and safety of ICI plus chemotherapy (ICI-chemo) in 75 years or older patients have not been elucidated. The aim of this study is to reveal the real-world choice of first-line drugs in elderly patients (pts) and evaluate the efficacy and safety of ICI-chemo. Methods: We conducted a multicenter (58 centers in Japan), retrospective cohort study of consecutive 75 years or older pts with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC who started first-line systemic therapy between December 2018 and March 2021. Pts with epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or whose first-line systemic therapy was molecular targeted therapy were excluded. Results: A total of 1245 pts were enrolled: median (range) age 78 (75-95) years; 278 (22%) female; 367 (29%) ECOG PS 0, 680 (55%) PS 1 and 171 (14%) PS 2; 678 (54%) adenocarcinoma; PD-L1 tumor proportion score 268 (22%) <1%, 387 (31%) 1-49% and 410 (34%) ≥50%; 354 (28%) ICI-chemo, 425 (34%) ICI alone, 311 (25%) platinum-doublet chemotherapy and 155 (12%) single agent chemotherapy. The median overall survival (OS) was 20.0 months (95%CI, 17.1–23.6) in the ICI-chemo group, 19.8 months (95%CI, 16.5–23.8) in the ICI alone group, 12.8 months (95%CI, 10.7–15.6) in the platinum-doublet chemotherapy group and 9.5 months (95%CI, 7.4–13.4) in the single agent chemotherapy group, respectively. After propensity score matching, there was no difference in OS and progression-free survival (PFS) between ICI-chemo group (n=96) and ICI alone group (n=95) in PD-L1 ≥1% (OS: HR, 0.98; 95% CI, 0.67-1.42, PFS: HR, 0.92; 95% CI, 0.67-1.25). Regardless of PD-L1 subgroups (1-49% or ≥50%), no significant differences in OS and PFS were observed. Concerning safety, Grade 3 or higher immune-related adverse events (irAEs) occurred in 86 pts (24.3%) in the ICI-chemo group and 76 pts (17.9%) in the ICI alone group (p = 0.03). The number of pts who required steroids for irAEs was 115 (32.5%) in the ICI-chemo group and 105 (24.7%) in the ICI alone group (p = 0.02). Pneumonitis was reported in 83 pts (23.4%) in the ICI-chemo group and 66 pts (15.6%) in the ICI alone group (p = 0.006). Conclusions: In real-world data for pts aged 75 years or older, ICI-chemo did not improve survival and increased the incidence of grade 3 or higher irAEs compared to ICI alone. Based on our results, ICI alone is recommended for elderly pts with PD-L1 positive NSCLC. Clinical trial information: UMIN000046700 .

Prognostic significance of immunotherapy in postoperative recurrent non-small cell lung cancer without EGFR mutations or ALK rearrangements.

Limited reports exist regarding postoperative recurrent non-small cell lung cancer (NSCLC) without major driver mutations [epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements] treated with immune checkpoint inhibitors (ICIs) when programmed cell death ligand 1 (PD-L1) is expressed in a real-world setting. The aim of this study was to evaluate the effect of ICIs for those NSCLC. We enrolled 255 patients with postoperative recurrent NSCLC lacking EGFR mutations or ALK rearrangements who underwent lobectomy or more extensive resection between 2012 and 2021. Factors associated with post-recurrence survival (PRS) were determined using the Cox proportional hazards model. PRS was analyzed using Kaplan-Meier curves and compared using the log-rank test. Multivariable analysis demonstrated that squamous cell carcinoma, pathological stage III, and an Eastern Cooperative Oncology Group (ECOG) performance status ≥2 were significantly associated with worse PRS. Conversely, ICI use at first line was associated with improved PRS. Patients who used ICIs during the first line and subsequent therapies had better PRS than those who received chemotherapy alone. Among patients who used ICIs, there was no significant difference in response rate at the first line, nor in PRS among those with PD-L1 expression ≥50%, 1-49%, and <1% in surgically resected specimens. ICI use at any treatment line improved the PRS of NSCLC patients without major driver mutations, irrespective of PD-L1 expression, in a real-world setting.

High levels of AXL expression in untreated EGFR-mutated non-small cell lung cancer negatively impacts the use of osimertinib.

For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the efficacy of osimertinib in the first-setting of EGFR-mutated advanced NSCLC patients. A total of 92 patients with EGFR-mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death-ligand 1 (PD-L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line-based assay and AXL-related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive-p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR-mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression-free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p= 0.026). Cell line-based assays indicated that the overexpression of AXL protein accelerated PD-L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD-L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR-mutated NSCLC patients. Trial Registration: UMIN000043942.

Chronological analysis of the gut microbiome for efficacy of atezolizumab‐based immunotherapy in non‐small cell lung cancer: Protocol for a multicenter prospective observational study

BackgroundCancer immunotherapy with immune checkpoint inhibitors (ICIs) is an innovative treatment for non‐small cell lung cancer (NSCLC). Recently, the specific composition of the gut microbiome before initiation of cancer immunotherapy has been highlighted as a predictive biomarker in patients undergoing cancer immunotherapy, mainly in the US or Europe. However, the fact gut microbiome status is completely different in races or countries has been revealed. In addition, how the microbiome composition and diversity chronologically change during cancer immunotherapy is still unclear.MethodsThis multicenter, prospective observational study will analyze the association between the gut microbiome and therapeutic response in NSCLC patients who received atezolizumab‐based immunotherapy. The aim of the present study is to clarify not only how the specific composition of the gut microbiome influences clinical response in NSCLC patients but the chronological changes of gut microbiota during atezolizumab‐based immunotherapy. The gut microbiota will be analyzed using 16S rRNA gene sequencing. The main inclusion criteria are as follows: (1) Pathologically‐ or cytologically‐confirmed stage IV or postoperative recurrent NSCLC. (2) Patients ≥20 years old at the time of informed consent. (3) Planned to treat with atezolizumab‐based immunotherapy combined with platinum‐based chemotherapy (cohort 1) and monotherapy (cohort 2) as a first immunotherapy. (4) Patients to provide fecal samples. A total of 60 patients will be enrolled prospectively. Enrollment will begin in 2020 and the final analyses will be completed by 2024.DiscussionThis trial will provide more evidence of how gut microbiota composition and diversity chronologically change during cancer immunotherapy and contribute to the development of biomarkers to predict ICI response as well as biotic therapies which enhance the ICI response.

MA06.04 Phase II Study of Durvalumab Plus Concurrent Radiotherapy in Unresectable Locally Advanced NSCLC: DOLPHIN Study (WJOG11619L)

Durvalumab after concurrent chemoradiotherapy (cCRT) has been standard of care with unresectable locally advanced (LA) non-small cell lung cancer (NSCLC) (stage III /postoperative recurrent NSCLC). But, some patients are unable to complete cCRT and cannot receive durvalumab. Immunotherapy plays an important role in NSCLC and combination of radiotherapy and immunotherapy have been reported to have a synergistic effect. Here, we reported on DOLPHIN study (JapicCTI- 194840), the first phase II study to evaluate the efficacy and safety of durvalumab plus concurrent curative radiation therapy for PD-L1-positive unresectable LA-NSCLC without chemotherapy.

Clinical impact of cerebral infarction in patients with non-small cell lung cancer.

Lung cancer patients have a high risk of cerebral infarction, but the clinical significance of cerebral infarction in advanced non-small cell lung cancer (NSCLC) remains unclear. This study aimed to comprehensively investigate the incidence, prognostic impact, and risk factors of cerebral infarction in patients with NSCLC. We retrospectively examined 710 consecutive patients with advanced or post-operative recurrent NSCLC treated between January 2010 and July 2020 at Kumamoto University Hospital. Cerebral infarction was diagnosed according to the detection of high-intensity lesions on diffusion-weighted magnetic resonance imaging regardless of the presence of neurological symptoms during the entire course from 3months before NSCLC diagnosis. The prognostic impact and risk factors of cerebral infarction were evaluated based on propensity score matching (PSM) and multivariate logistic regression analysis. Cerebral infarction occurred in 36 patients (5%). Of them, 21 (58%) and 15 (42%) patients developed asymptomatic and symptomatic cerebral infarction, respectively. PSM analysis for survival showed that cerebral infarction was an independent prognostic factor (hazards ratio: 2.45, 95% confidence interval (CI): 1.24-4.85, P = 0.010). On multivariate logistic regression analysis, D-dimer (odds ratio [OR]: 1.09, 95% CI 1.05-1.14, P < 0.001) and C-reactive protein (OR: 1.10, 95% CI 1.01-1.19, P = 0.023) levels were independent risk factors. Cerebral infarction occurred in 5% of NSCLC patients, and asymptomatic cerebral infarction was more frequent. Cerebral infarction was a negative prognostic factor and was associated with hyper-coagulation and inflammation. The high frequency of asymptomatic cerebral infarction and its risk in NSCLC patients with these conditions should be recognized.

The clinical impact of concomitant medicationuse on the outcome of postoperative recurrent non-small-cell lung cancer in patients receiving immune checkpoint inhibitors.

A recent study suggested that proton pump inhibitor (PPI) use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) was associated with poor clinical outcomes. However, the clinical impact of PPI use on the outcome of patients receiving ICIs for postoperative recurrent NSCLC is unknown. The outcomes of 95 patients with postoperative recurrence of NSCLC receiving ICIs at 3 medical centers in Japan were analyzed. We conducted adjusted Kaplan–Meier survival analyses with the log-rank test, a Cox proportional hazards regression analysis, and a logistic regression analysis using inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients’ backgrounds. The IPTW-adjusted Kaplan–Meier curves revealed that the progression-free survival (PFS), but not the overall survival (OS), was significantly longer in patients who did not receive PPIs than in those who did receive them. The IPTW-adjusted Cox regression analysis revealed that PPI use was an independent poor prognostic factor for the PFS and OS. Furthermore, in the IPTW-adjusted logistic regression analysis, PPI non-use was an independent predictor of disease control. In this multicenter and retrospective study, PPI use was associated with poor clinical outcomes in patients with postoperative recurrence of NSCLC who were receiving ICIs. PPIs should not be prescribed indiscriminately to patients with postoperative recurrence of NSCLC who intend to receive ICIs. These findings should be validated in a future prospective study.

The Ki-67 Proliferation Index-Related Nomogram to Predict the Response of First-Line Tyrosine Kinase Inhibitors or Chemotherapy in Non-small Cell Lung Cancer Patients With Epidermal Growth Factor Receptor-Mutant Status.

Background: The correlation between Ki-67 and epidermal growth factor receptor (EGFR)- or Kristen rat sarcoma viral oncogene homolog (KRAS)-mutant status in advanced or postoperative-recurrent non-small cell lung cancer (NSCLC) has fewer studies reported, and the prognostic role of Ki-67 with first-line EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy remains controversial.Methods: A total of 295 patients were tested for EGFR-mutant status in advanced or postoperative-recurrent NSCLC and received first-line EGFR-TKIs or chemotherapy for treatment. Ki-67 expression was retrospectively analyzed by immunohistochemistry. The Kaplan-Meier method was used to calculate survival rates. The multivariate Cox proportional hazards model was used to generate a nomogram. The established nomogram was validated using the calibration plots.Results: The expression levels of Ki-67 were divided into low (<60%, n = 186) and high (≥60%, n = 109) groups, based on the receiver operating characteristic curve. The expression levels of Ki-67 were found to be higher in patients with KRAS mutations when compared to KRAS wildtype, and EGFR wildtype was higher than EGFR mutations. The median overall survival (OS) of the low Ki-67 expression group was significantly longer than that of the high Ki-67 group, no matter in all NSCLC, EGFR mutations, EGFR wildtype, KRAS-mutant status, EGFR-TKIs, or chemotherapy of patients (P < 0.05). Subgroup analysis showed that the KRAS wildtype or EGFR mutations combine with low Ki-67 expression group had the longest median OS than KRAS mutations or EGFR wildtype combine with Ki-67 high expression group (P < 0.05). In the training cohort, the multivariate Cox analysis identified age, serum lactate dehydrogenase (LDH), serum Cyfra211, EGFR mutations, and Ki-67 as independent prognostic factors, and a nomogram was developed based on these covariates. The calibration curve for predicting the 12-, 24-, and 30-month OS showed an optimal agreement between the predicted and actual observed outcomes.Conclusions: The Ki-67 expression-based nomogram can well predict the efficacy of first-line therapy in NSCLC patients with EGFR- or KRAS-mutant status, high expression levels of Ki-67 correlated with a poor prognosis.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors as a first-line treatment for postoperative recurrent and EGFR-mutated non-small-cell lung cancer.

OBJECTIVESTo clarify survival outcomes and prognostic factors of patients receiving epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) as first-line treatment for postoperative recurrence.METHODSA retrospective chart review was performed to identify consecutive patients who received EGFR-TKIs as first-line treatment for postoperative recurrence of non-small-cell lung cancer (NSCLC) harbouring EGFR gene mutations at our institution between August 2002 and October 2020. Therapeutic response, adverse events, progression-free survival (PFS) and overall survival (OS) were investigated. Survival outcomes were assessed using the Kaplan–Meier analysis. The Cox proportional hazards model was used for univariable and multivariable analyses.RESULTSSixty-four patients were included in the study. The objective response and disease control rates were 53% and 92%, respectively. Grade 3 or greater adverse events were noted in 4 (6.3%) patients, including 1 patient (1.6%) of interstitial pneumonia. The median follow-up period was 28.5 months (range 3–202 months). The total number of events was 43 for PFS and 23 for OS, respectively. The median PFS was 18 months, and the median OS was 61 months after EGFR-TKI treatment. In multivariable analysis, osimertinib showed a tendency to prolong PFS [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.12–1.1; P = 0.071], whereas the micropapillary component was significantly associated with shorter OS (HR 2.1, 95% CI 1.02–6.9; P = 0.045).CONCLUSIONSEGFR-TKIs as first-line treatment appeared to be a reasonable treatment option in selected patients with postoperative recurrent EGFR-mutated NSCLC. Osimertinib and the micropapillary component may be prognostic factors.

Harmonization across programmed death ligand 1 (PD-L1) assays for lung cancer by immunohistochemistry using noncontact alternating current electric field mixing.

BackgroundImmune checkpoint inhibitors (ICIs) are a promising advance in the treatment of patients with lung cancer. However, each ICI has been tested with an independently designed companion diagnostic assay that is based on a unique antibody. Consequently, the different trial‐validated programmed death ligand 1 (PD‐L1) immunohistochemistry (IHC) assays should not be considered interchangeable. Our aim was to compare the performance of each available PD‐L1 antibody for its ability to accurately measure PD‐L1 expression and to investigate the possibility of harmonization across antibodies through the use of a new rapid IHC system, which uses noncontact alternating current (AC) mixing to achieve more stable staining.MethodsFirst, 58 resected non‐small cell lung cancer (NSCLC) specimens were stained using three PD‐L1 IHC assays (28–8, SP142, and SP263) to assess the harmonization achieved with AC mixing IHC. Second, specimens from 27 patients receiving ICIs for postoperative recurrent NSCLC were stained using the same IHC method to compare the clinical performance of ICIs to PD‐L1 scores. All patients received a tumor proportion score (TPS) with the 22C3 companion diagnostic test.ResultsBetter staining was achieved with the new AC mixing IHC method than the conventional IHC in PD‐L1‐positive cases, and the interchangeability of some combinations of assays was increased in PD‐L1‐positive. In addition, AC mixing IHC provided more appropriate overall response rates for ICIs in all assays.ConclusionsStable PD‐L1 IHC driven by AC mixing helped to improve TPS scoring and patient selection for ICIs through interchangeable assays.

Erlotinib plus bevacizumab vs erlotinib monotherapy as first-line treatment for advanced EGFR mutation-positive non-squamous non-small-cell lung cancer: Survival follow-up results of the randomized JO25567 study

ObjectivesThe JO25567 randomized Phase II study demonstrated a statistically significant progression-free survival (PFS) benefit with erlotinib plus bevacizumab compared with erlotinib monotherapy in chemotherapy-naïve Japanese patients with epidermal growth factor receptor mutation-positive (EGFR+) non-small-cell lung cancer (NSCLC). Here we present updated PFS and final overall survival (OS) data after a median follow-up of 34.7 months. Materials and methodsPatients with stage IIIB/IV or postoperative recurrent NSCLC were randomized to receive oral erlotinib 150 mg once daily (n = 77) or erlotinib in combination with intravenous bevacizumab 15 mg/kg every 21 days (n = 75) until disease progression or unacceptable toxicity. OS was analyzed using an unstratified Cox proportional hazards model. ResultsConsistent with the primary analysis, addition of bevacizumab to erlotinib was associated with a significant improvement in PFS (hazard ratio [HR] 0.52; 95 % confidence interval [CI]: 0.35–0.76; log-rank two-sided P = 0.0005; median 16.4 months vs 9.8 months, respectively). In contrast, a significant improvement in OS was not seen (HR 0.81; 95 % CI, 0.53–1.23; P = 0.3267; median 47.0 months vs 47.4 months, respectively). Post-study therapy was similar between the treatment arms and EGFR mutation type did not affect OS outcomes. The 5-year OS rate was numerically higher with erlotinib plus bevacizumab vs erlotinib monotherapy (41 % vs 35 %). Updated safety analyses confirmed the previously reported manageable tolerability profile, with no new safety issues. ConclusionAddition of bevacizumab to first-line erlotinib did not show significant improvement in OS in Japanese patients with stage IIIB/IV or postoperative recurrent EGFR+ NSCLC. Both treatment arms showed a similar median OS benefit (as long as 4 years), irrespective of individual patient characteristics. Results from ongoing studies evaluating the combination of EGFR and VEGF signaling inhibitors are eagerly awaited. Trial registrationJapicCTI-111390 and JapicCTI-142569.

Final analysis of a phase II, open label, randomized study of osimertinib versus osimertinib plus carboplatin/pemetrexed for patients with locally advanced or metastatic non-small cell lung cancer whose disease has progressed with previous EGFR-TKI and whose tumours harbour a T790M mutation (LOGIK1604/NEJ032A).

e21594 Background: Osimertinib is now available not only as a second line treatment for the patients with EGFR and T790M-mutation positive non-small cell lung cancer (NSCLC) after initial tyrosine kinase inhibitors (TKIs) but as a first line treantment for those who are TKI-naive. The efficacy and the safety of osimertinib plus palatinum-based chemotherapy has not yet been evaluated. Methods: This phase 2, open-label, randomized study enrolled adult patients (pts) with clinical stage IIIB or IV, or postoperative recurrent NSCLC harbouring susceptible EGFR and T790M mutations after preceded EGFR-TKI failure. Pts were randomly assigned to receive either an osimertinib [80 mg/day 1-21; q3w] or a combination of osimertinib [80 mg/day 1-21] with carboplatin/pemetrexed (hereafter combination) [area under the curve (AUC) = 5 and 500 mg/m2 day 1; q3w]. The primary endpoint was progression-free survival (PFS). Secondary endpoints included incidence of adverse events, response rate and overall survival. As indiction of osimertinib was expanded to a first line, we amended the protocol to discontinue the enrollment and perform final analyses. Results: From October 2016 to January 2019, 62 pts were enrolled [31 pts osimertinib; 31 pts combination] (median age 68 (37-80); 53.2% male; 83.3% stage IV; 100% adenocarcinoma; 59.7% exon 19 deletion and 40.3% L858R; 45.2% never smoker). The rate of grade (G) ≥ 3 treatment-related adverse events was 32.2% in the osimertinib group and 83.9% in the combination group. Neutropenia, anemia and thrombocytopenia were more common in the combination group and the rates of G ≥ 3 were 0%, 0% and 6.4% in the osimertinib group and 38.7%, 25.8% and 29.1% in the combination group, respectively. Three episodes (9.7%) of G ≥ 3 infection and one episode (3.2%) of G ≥ 3 febrile neutropenia were uniquely observed in the combination group, however, these were well managed. Two episodes (6.5%) of G ≥ 3 pneumonitis was observed only in the osimertinib group. Exaggeration of adverse events specific for osimertinib or any unknown adverse event was not observed in the combination group. Final PFS analysis is to be demonstrated in the presentation. Conclusions: Combination of osimertinib with carboplatin and pemetrexed demonstrated safety in patients with EGFR and T790M mutation-positive NSCLC and the efficacy should be validated in the future phase 3 study. Clinical trial information: 000024438.

Weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer complicated by idiopathic interstitial pneumonias: a single-arm phase II study

Idiopathic interstitial pneumonias (IIPs) are associated with increased risk of lung cancer. In Japan, acute exaberation of IIPs induced by anticancer treatment is a critical issue. For this reason, there is limited available evidence regarding the optimal treatment approach for lung cancer patients complicated with IIPs. Our previous prospective pilot study demonstrated the safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer (NSCLC) with IIPs. The current study was conducted to confirm the results of the same combination therapy used in a larger patient population. Chemotherapy-naïve patients with advanced stage or post-operative recurrent NSCLC patients complicated by IIPs were enrolled. Patients received paclitaxel (100mg/m2) on days 1, 8, and 15, and carboplatin (AUC 5.0) once every 4weeks. Thirty-three of 35 enrolled patients were evaluable for analysis and received a median of four treatment cycles (range 1-6). Four patients (12.1%; 95% confidence interval 3.4-28.2%) had acute exacerbation (AEx)-related IIPs to the study treatment. However, no fatalities due to AEx were observed. The overall response was 69.7%. The median progression-free survival, median survival time, and 1-year survival were 6.3months, 19.8months, and 55.4%, respectively. The efficacy of carboplatin plus weekly paclitaxel treatment for advanced NSCLC patients with IIPs was comparable to that of conventional chemotherapy in advanced NSCLC patients without IIPs. Moreover, the primary endpoint was set to the frequency of treatment-related acute exacerbation, and the primary endpoint was met. These results suggest that patients with advanced NSCLC complicated by IIPs may benefit from this combination chemotherapy.

Plasma ctDNA monitoring during epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment in patients with EGFR-mutant non-small cell lung cancer (JP-CLEAR trial).

Osimertinib, a third generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), is active against EGFR-mutant non-small cell lung cancer (NSCLC) resistant to first-/second-generation EGFR-TKIs with the T790M mutation. T790M monitoring in plasma circulating tumor DNA (ctDNA) in patients receiving EGFR-TKIs is less invasive than re-biopsy and could provide valuable clinical information. Patients with advanced or postoperative recurrent NSCLC with sensitizing EGFR mutations who were planned to receive or were receiving first-/second-generation EGFR-TKI treatment without disease progression were eligible for enrollment. Plasma samples at baseline and every 1-2 months thereafter were analyzed for EGFR mutation status using the cobas®EGFR Mutation Test v2. Between September 2016 and March 2017, 122 patients at 15 Japanese institutions were enrolled. In August 2018, 1291 plasma samples from 121 patients were analyzed for EGFR mutation status. At baseline, a sensitizing EGFR mutation was detected in 29 (23.9%) of 121 patients and T790M mutation was detected in three (2.5%). At follow-up, 66 (54.5%) patients experienced disease progression and 64 (52.9%) discontinued first-line EGFR-TKI treatment. Twenty-two (18.2%) patients showed T790M in plasma ctDNA, of which 15(68.2%) received osimertinib. Although 31 patients received re-biopsy to examine EGFR status at disease progression, T790M was detected in only nine (22.0%) patients, of which 7 (77.8%) received osimertinib. ctDNA monitoring during EGFR-TKI treatment is useful for detecting T790M mutation. The efficacy of osimertinib treatment based on T790M status in plasma ctDNA remains to be established, warranting further research.

Opioid Dose and Survival of Patients with Incurable Nonsmall Cell Lung Cancer: A Prospective Cohort Study.

Preclinical studies show that opioids promote angiogenesis, tumor progression, and metastasis, resulting in shorter survival. To explore whether opioids are associated with the overall survival (OS) of patients with incurable nonsmall cell lung cancer (NSCLC). Prospective cohort study of patients with NSCLC. We investigated patients newly diagnosed with advanced or post-operative recurrent NSCLC between April 2013 and December 2015 at a single institute. We evaluated OS, opioid requirements, opioid doses, pain levels, and prognostic factors of advanced NSCLC. The effects of variables on survival were analyzed using univariable and multivariable models. Patients were stratified according to oral morphine equivalents (OMEs)/day (<60 or ≥60 mg) to assess the association between opioid dose and OS. We analyzed 150 patients, including 64 who received opioid treatment during follow-up. The median OS was 242 days in the opioid group and 627 days in the no-opioid group (log-rank p < 0.001). Multivariable models revealed that the opioid requirement was an independent predictor of shorter OS, after adjustment for prognostic variables, including sex, histology, stage, history of systemic chemotherapy, and performance status (hazard ratio 1.73, 95% confidence interval 1.137-2.631). There was no significant difference in OS between patients who received ≥60 mg OME/day for 250 days versus <60 OME/day for 242 days. The opioid dose does not shorten the survival of patients with advanced NSCLC. The opioid requirement is associated with shorter survival when opioids are administered any time during the clinical course, independent of the influence of other key factors.

Salvage chemoradiotherapy with cisplatin and vinorelbine for postoperative locoregional recurrence of non-small cell lung cancer.

Although a few investigators have demonstrated the effect of concurrent chemoradiotherapy (CRT) for postoperative recurrent non-small cell lung cancer (NSCLC), the outcome of this treatment remains unclear. The aim of this study was to elucidate the efficacy and tolerability of concurrent CRT with cisplatin (CDDP) and vinorelbine (VNR) in patients with postoperative locoregional recurrent NSCLC. A total of 40 patients who had received concurrent CRT with CDDP and VNR between January 1999 and December 2014 were retrospectively analyzed. Patients were treated with CDDP (80 mg/m2 on day 1) and VNR (20 mg/m2 on days 1 and 8) every 4 weeks. Radiotherapy was administered concurrently during cycle 1. The delivered x-ray radiation dose was 60 Gy in all 37 patients who received x-ray radiotherapy; 3 patients received proton beam radiation (66 Gy [RBE] in 1 patient and 60 Gy [RBE] in 2 patients). The objective response rate was 85% (95% confidence interval [CI], 70.9%–92.9%). The median progression-free survival was 20.3 months (95% CI, 12.9 months–not reached). The 2-year survival rate was 78.9% (95% CI, 63.0%–89.1%). The most common grade ≥3 toxicity was neutropenia (18%). No grade ≥3 radiation pneumonitis and no treatment-related deaths were observed.Our study revealed that concurrent CRT with CDDP and VNR was active and safe for patients with postoperative locoregional recurrent NSCLC. Salvage CRT for postoperative locoregional recurrent NSCLC might be a promising treatment for selected patients.

Cerebral infarction in advanced non-small cell lung cancer: a case control study.

BackgroundAdvanced non-small cell lung cancer (NSCLC) patients often develop thromboembolic events, including cerebral infarction (CI). However, the relationship between advanced NSCLC and CI has not been thoroughly investigated. We examined the association between advanced NSCLC and CI and risk factors for CI in advanced or post-operative recurrent NSCLC patients.MethodsWe retrospectively investigated 515 patients diagnosed with advanced or post-operative recurrent NSCLC at Juntendo University Hospital between April 2009 and March 2014.ResultsAmong the 515 patients evaluated, 15 patients (2.9 %) developed CI after diagnosis of advanced or post-operative recurrent NSCLC. Univariate and multivariate analyses were conducted, and brain metastasis was the only significant independent risk factor for CI (odds ratio 5.24, 95 % confidence interval 1.72–16.10, p = 0.004). The incidence was 6.3 % in these patients. The median survival time was 36 days, and 1-year survival rate was 6.7 % after development of CI. Overall survival from diagnosis of advanced NSCLC or post-operative recurrence was significantly shorter in patients with CI than in patients without CI (223 days versus 895 days; HR, 3.46; 95 % confidence interval, 2.04–6.02; p = 0.001).ConclusionsThe incidence of CI is high in advanced or post-operative recurrent NSCLC, and is especially higher in patients with brain metastasis than in those without brain metastasis. Moreover, CI may affect patient’s prognosis. Careful monitoring for the development of CI in patients with advanced or post-operative recurrent NSCLC is needed, especially for patients with brain metastasis.