Stage IIIB-IV Non-small Cell Lung Cancer Research Articles

Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study

Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

The proportion of tumour stroma predicts response to treatment of immune checkpoint inhibitor in combination with chemotherapy in patients with stage IIIB-IV non-small cell lung cancer.

Immunotherapy has brought a new era to cancer treatment, yet we lack dependable predictors for its effectiveness. This study explores the predictive significance of intratumour stroma proportion (iTSP) for treatment success and prognosis in non-small cell lung cancer (NSCLC) patients undergoing treatment with immune check-point inhibitors (ICIs) together with chemotherapy. We retrospectively collected data from patients with unresectable stage IIIB-IV NSCLC who were treated with first-line ICIs and chemotherapy. Each patient received a confirmed pathological diagnosis, and the pathologist evaluated the iTSP on haematoxylin and eosin (H&E)-stained sections of diagnostic tissue slides. Among the 102 H&E-stained biopsy samples, 61 (59.8%) were categorised as stroma-L (less than 50% iTSP), while 41 (40.2%) were classified as stroma-H (more than 50% iTSP). We observed that the stroma-L group exhibited a significantly better objective response rate (ORR) (72.1 versus 51.2%, P = 0.031) and deeper response depth (DpR) (-50.49 ± 28.79% versus -35.83 ± 29.91%, P = 0.015) compared to the stroma-H group. Furthermore, the stroma-L group showed longer median progression-free survival (PFS) (9.6 versus 6.0 months, P = 0.011) and overall survival (OS) (24.0 versus 12.2 months, P = 0.001) compared to the stroma-H group. Multivariate Cox proportional hazards regression analysis indicated that iTSP was a highly significant prognostic factor for both PFS [hazard ratio (HR) = 1.713; P = 0.030] and OS (HR = 2.225; P = 0.003). Our findings indicate that a lower iTSP corresponds to improved clinical outcomes and greater DpR in individuals with stage IIIB-IV NSCLC treated with first-line ICIs and chemotherapy. The iTSP could potentially serve as a predictive biomarker for ICIs therapy response.

Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer

BackgroundCombining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting...

Real-world evidence of efficacy of pembrolizumab plus chemotherapy and nivolumab plus ipilimumab plus chemotherapy as initial treatment for advanced non-small cell lung cancer.

For advanced non-small cell lung cancer (NSCLC), combination therapies including a PD-1 inhibitor plus chemotherapy or a PD-1 inhibitor, CTLA-4 inhibitor, and chemotherapy are standard first-line options. However, data directly comparing these regimens are lacking. This study compared the efficacy of pembrolizumab plus chemotherapy (CP) against nivolumab plus ipilimumab and chemotherapy (CNI) in a real-world setting. In this multicenter retrospective study, we compared the efficacy and safety of CP and CNI as first-line therapies in 182 patients with stage IIIB-IV NSCLC. Primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included the response rate (RR) and safety profiles. Kaplan-Meier survival curves and Cox proportional hazards models were utilized for data analysis, adjusting for confounding factors such as age, gender, and PD-L1 expression. In this study, 160 patients received CP, while 22 received CNI. The CP group was associated with significantly better PFS than the CNI group (median 11.7 vs. 6.6 months, HR 0.56, p = 0.03). This PFS advantage persisted after propensity score matching to adjust for imbalances. No significant OS differences were observed. Grade 3-4 adverse events occurred comparably, but immune-related adverse events were numerically more frequent in the CNI group. In real-world practice, CP demonstrated superior PFS compared with CNI. These findings can inform treatment selection in advanced NSCLC.

Who are the vulnerable lung cancer patients at risk for not receiving first-line curative or palliative treatment?

Background To identify non-small-cell lung cancer (NSCLC) patients in need of comprehensive support, we examined the association between patient and disease-related factors of vulnerability related to not receiving guideline-recommended treatment. Material and methods We identified 14,597 non-small-cell lung cancer (NSCLC) patients with performance status <3 during 2013–2018 in the Danish Lung Cancer Registry. Multivariate logistic regression models were used to estimate Odds Ratios (ORs) and 95% confidence intervals (CIs) for receiving guideline-recommended treatment according to stage, comorbidities, age, performance status, long distance to hospital, cohabitation status, education and alcohol abuse. Results 21% of stage I-IIIA NSCLC patients did not receive curative treatment while 10% with stage IIIB-IV did not receive any oncological therapy. Factors associated with reduced likelihood of receiving curative treatment included: advanced stage (OR = 0.45; 95% CI = 0.42–0.49), somatic comorbidity (OR = 0.72; 95% CI = 0.63–0.83), age ≥ 80 years (OR = 0.59; 95% CI = 0.55–0.64), performance status = 2 (OR = 0.33; 95% CI = 0.28–0.39) and living alone (OR = 0.79; 95% CI = 0.69–0.90). Results were similar for stage IIIB-IV NSCLC patients, although a statistically significant association was also seen for long distances to the hospital (OR = 0.71; 95% CI = 0.58–0.86). Conclusions Several factors are associated with not receiving guideline-recommended NSCLC treatment with age, performance status, comorbidity and stage being most predictive of no treatment receipt. Efforts should be made to develop support for vulnerable lung cancer patients to improve adherence to optimal first-line therapy.

Factors associated with outcomes of second-line treatment for EGFR-mutant non-small-cell lung cancer patients after progression on first- or second-generation EGFR-tyrosine kinase inhibitor treatment.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line treatments for advanced EGFR-mutant non-small-cell lung cancer (NSCLC) patients. However, factors associated with outcomes after progression on first-line therapy are seldom investigated. From January 2016 to December 2020, we enrolled 242 EGFR-mutant stage IIIB-IV NSCLC patients who progressed on first- or second-generation EGFR-TKI treatments, and 206 of them receive second-line treatments after disease progression. The factors that predict the survival outcomes of different second-line treatments after disease progression were evaluated. Clinical and demographic characteristics, including metastatic sites, neutrophil-to-lymphocyte ratio (NLR) at first-line progression, and second-line treatment regimens, and whether re-biopsied after disease progression or not, were reviewed for outcome analysis. The univariate analysis showed that the PFS was shorted in male patients (p =0.049), patients with ECOG performance state ≥ 2 (p =0.014), former smokers (p =0.003), patients with brain metastasis (p =0.04), second-line chemotherapy or EGFR-TKIs other than osimertinib (p =0.002), and NLR ≥5.0 (p=0.024). In addition, second-line osimertinib was associated with longer OS compared to chemotherapy and other EGFR-TKI treatment (p =0.001). In the multivariate analysis, only second-line osimertinib was an independent predictor of PFS (p =0.023). Re-biopsy after first-line treatment was associated with a trend of better OS. Patients with NLR ≥5.0 at disease progression had shorter OS than patients with NLR <5.0 (p = 0.008). The benefits of osimertinib necessitate that aggressive re-biopsy after progression on first- or second-generation EGFR-TKI treatment is merited for appropriate second-line treatments to provide better outcomes for these patients.

A phase III, multicenter, double-blinded, randomized, active-controlled study on the efficacy and safety of QL1706 with chemotherapy (CT) as first-line therapy for PD-L1–negative advanced or metastatic non–small-cell lung cancer (NSCLC).

TPS9139 Background: PD-(L)1 immunotherapy plus platinum-doublet chemotherapy has been the standard 1L treatment for EGFR/ALK wild-type advanced NSCLC pts. However, pts with PD-L1 negative achieve minimal benefit from the PD-(L)1 immunotherapy plus CT. PD-(L)1 plus CTLA-4 blockade with CT in 1L treatment of PD-L1 negative NSCLC derived an improved median overall survival (OS) versus CT alone in CheckMate-9LA study ( Luis Paz-Ares et al., Lancet Oncol 2021) and POSEIDON study ( M L. Johnson et al., JCO 2022). QL1706 is a novel bifunctional antibody, containing a mixture of anti-PD-1 IgG4 and anti-CTLA-4 IgG1 antibodies produced in a fixed ratio (2:1) from the same single cell and manufactured together as one product (MabPair). QL1706 monotherapy or plus CT showed impressive safety and efficacy in advanced NSCLC both in phase I and phase II studies (data have been submitted for publication). Of note, QL1706+CT exhibited promising antitumor activity in advanced PD-L1 negative NSCLC. The phase III study aims to compare the efficacy of QL1706+CT versus anti-PD-1 (tislelizumab) + CT (approved in China for 1L treatment of mNSCLC) as 1L treatment in advanced PD-L1 negative NSCLC. Methods: The phase III, multicenter, double-blinded, randomized, active-controlled study is enrolling pts aged 18-75 years with ECOG PS of 0-1, previously untreated, PD-L1 negative (TPS &lt; 1%), EGFR/ALK wild-type, and pathologically identified stage IIIB-IV NSCLC. Eligible pts will be randomized (1:1) to receive 4-cycle treatment of QL1706 (5 mg/kg, Q3W) plus CT or tislelizumab (200 mg, Q3W) plus CT followed with maintenance treatment of QL1706 or tislelizumab monotherapy (squamous), or in combination with pemetrexed (non-squamous), until disease progression, intolerable toxicity, or for up to 2 years of immunotherapy. Stratification factors include histology (squamous vs non-squamous), brain metastasis (yes vs no), and sex (male vs female). Co-primary endpoints are progression-free survival (PFS) and OS. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), duration of response (DOR) assessed by investigator per RECIST v1.1, 6 mo- and 12 mo-PFS, 6 mo- and 12 mo-OS, and safety. Exploratory endpoints include PK characteristics, immunogenicity, PFS2 (defined as time from randomization to progression after first subsequent therapy or any-cause death), and efficacy (iPFS, iORR, iDCR, iDOR) by investigator per iRECIST, biomarker analysis of tumor mutation burden. The study planned to enroll 650 pts to obtain approximately 493 PFS events (HR = 0.69; Power = 94%) and 445 OS events (HR = 0.75; Power = 83%) across the QL1706+CT and tislelizumab+CT arms for the final analyses of PFS and OS, respectively. The alpha was split between PFS (α = 0.005) and OS (α = 0.02). Enrollment began from Feb 2023. Clinical trial information: NCT05690945 .

Clinical outcomes of patients with advanced NSCLC with different EGFR exon 19 deletion subtypes treated with first-line tyrosine kinase inhibitors.

e21034 Background: Epidermal growth factor receptor (EGFR) exon 19 deletion (Ex19del) in non-small cell lung cancer (NSCLC) consists of many subtypes, and their sensitivity to tyrosine kinase inhibitors (TKIs) has not been clearly defined. This study aimed to investigate the clinical outcomes of advanced NSCLC patients with different EGFR ex19del subtypes treated with different TKIs. Methods: We retrospectively analyzed stage IIIB-IV NSCLC patients with EGFR Ex19del and first-line TKIs therapy. E746_A750del was defined as classic group, and the others as non-classic group, which was further divided into subgroups according to deletion with or without insertion, starting codon or length of deletion. The primary endpoint was progression free survival (PFS). Results: There were 17 Ex19del subtypes identified in 101 patients. The frequency of E746_A750del was 64.4% (65/101), and the top three frequent non-classic subtypes were L747_T751del (6.9%, 7/101), L747_P753delinsS (5.9%, 6/101) and E746_S752delinsV (5.0%, 5/101). In all patients, the median PFS (mPFS) of first-line TKIs in classic and non-classic groups were 14.3 months (m) and 19.3 m ( p &gt; 0.05). In non-classic group, the mPFS in deletion with insertion (delins) and without insertion subgroups were 25.3 m and 11.2 m; in deletion starting with E746 and with other codon subgroups were 29.7 m and 19.3 m; and in deletion length of 15 nucleotides (n) and of other length subgroups were 11.2 m and 25.3 m. The mPFS of these non-classic subgroups were not statistically different with that of classic group ( p &gt; 0.05). In all patients, the mPFS of first-line therapy with the 1st, 2nd and 3rd generation TKIs were 17.4 m, 15.6 m and 20.5 m, respectively ( p＞0.05); in classic group, the mPFS were 14.3 m, 16.9 m and 20.5 m, respectively ( p＞0.05). However, in non-classic delins subgroup (29.7 m, 15.6 m and 11.9 m) and in deletion length of ≥18 n subgroup (25.3 m，12.3 m and 11.9 m), the 1st generation TKIs had an insignificantly longest mPFS ( p＞0.05). When resistant to 1st or 2nd generation TKIs, patients in classic group showed a trend of higher incidence of T790M mutation than non-classic group (72.0% vs 43.8%, p = 0.070). In multivariant analysis, pleural metastasis (PM) had interaction with Ex19del grouping, warranting stratification analysis. In patients without PM, the mPFS of first-line TKIs in classic group was significantly shorter than non-classic group (13.8 m and 29.7 m, p = 0.026). However, in patients with PM, the mPFS of classic group was numerically longer than non-classic group (16.9 m and 11.7 m, p &gt; 0.05), with the shortest mPFS in non-classic without insertion subgroup, and in non-classic with 15 n deletion subgroup. Conclusions: In advanced NSCLC patients with EGFR Ex19del, the efficacy of first-line TKIs therapy was affected by the presence of pleural metastasis, Ex19del subtypes and different generation of TKIs.

Decreased monocyte-to-lymphocyte ratio was associated with satisfied outcomes of first-line PD-1 inhibitors plus chemotherapy in stage IIIB-IV non-small cell lung cancer.

Immune-checkpoint inhibitors (ICIs) combined with chemotherapy are more widely used than monotherapy and have shown better survival in patients with advanced non-small cell lung cancer (NSCLC) without oncogenic driver alterations. The monocyte-to-lymphocyte ratio (MLR) might predict the treatment outcomes of ICI therapy in advanced NSCLC patients but has not yet been investigated. In addition, the cutoff of MLR is controversial. Therefore, the present study aimed to explore the associations between changes in MLR at the initial stage of treatment and clinical outcomes in stage IIIB-IV NSCLC patients receiving first-line PD-1 inhibitor combined with chemotherapy. The present study included 139 stage IIIB-IV NSCLC patients treated with first-line PD-1 inhibitor combined with chemotherapy. The blood results were assessed 10 days before initiation of PD-1 inhibitor-based combination therapy (time point 1, baseline) and before the third cycle of combined therapy (time point 2). Compared to altered MLR, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in baseline and in time point 2, patients were divided into decreased MLR/NLR/PLR and increased MLR/NLR/PLR groups. The objective response rate (ORR), progression-free survival (PFS), and the association with the changes in blood indicators were analyzed. A total of 48 patients were categorized in the decreased MLR group and 91 in the increased MLR group. Patients with decreased MLR had a significantly higher ORR in the univariate (P<0.001) and multivariate (P<0.001) Cox proportional hazards models. On the other hand, decreased MLR was significantly associated with prolonged PFS in the univariate (P=0.007) and multivariate (P=0.016) analyses. Next, 91 patients comprised the decreased NLR group and 48 as the increased NLR group. Patients with decreased NLR exhibited high ORR (P=0.001) and prolonged PFS in univariate analysis (P=0.033). Then, 64 patients comprised the decreased PLR group and 75 the increased PLR group. Decreased PLR was significantly associated with high ORR in univariate (P<0.001) and multivariate (P=0.017) analyses. The subgroup analyses showed that decreased MLR was significantly associated with satisfactory outcomes in patients with all PD-L1 expressions. Decreased MLR was associated with high ORR and long PFS and might have a potential predictive value in patients with stage IIIB-IV NSCLC treated with first-line PD-1 inhibitor combined with chemotherapy. In addition, changes in MLR might have predictive value in all PD-L1-expressing populations. Decreased NLR and PLR also showed improved survival, suggesting that changes in NLR and PLR may be complementary to predicting prognosis.

Efficacy of immunotherapy in KRAS-mutant advanced NSCLC: A real-world study in a Chinese population.

Immunotherapy has improved the clinical outcomes of patients with advanced non-small cell lung cancer (NSCLC). However, in patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, the superior efficacy of immunotherapy has not been elucidated and especially in real-world practice. Our study aimed to use real-world data to assess the efficacy of immunotherapy in KRAS-mutant NSCLC in a Chinese cohort. In this retrospective cohort study, we extracted the clinical, molecular, and pathologic data from the electronic health records of patients with advanced KRAS-mutant NSCLC at Shandong Cancer Hospital between January 2018 and May 2022. Furthermore, we evaluated the progression-free survival (PFS) and overall survival (OS) of the included patients. Between January 2018 and November 2020, 793 patients were identified with stage IIIB-IV NSCLC and a total of 122 patients with KRAS mutations were included in the analysis. The majority of patients were diagnosed with stage IV (82.0%) adenocarcinoma (93.4%), along with a history of smoking (57.4%). Of these, 42% of patients received anti-PD-(L)1 with or without chemotherapy (Immunotherapy-based regimens), while 58.2% of patients received chemotherapy (Chemotherapy-based regimens). The median overall survival (mOS) in this cohort was 22.9 months (95% CI: 14.1-31.7), while the median-progression-free survival (mPFS) was 9.4 months (95% CI: 6.6-12.1). Patients receiving immunotherapy-based regimens displayed better mOS than those receiving chemotherapy-based regimens (45.2 vs. 11.3 months; P=1.81E-05), with no statistical difference observed in the mPFS (10.5 vs. 8.2 months; P=0.706). Patients receiving immunotherapy-based regimens either in the first line (P=0.00038, P=0.010, respectively) or second-line setting (P=0.010, P=0.026, respectively) showed benefits in both PFS and OS. Subgroup analysis indicated that in patients having KRAS G12C or non-KRAS G12C mutant types, immunotherapy showed benefits of better OS (P=0.0037, P=0.020, respectively) than chemotherapy. Moreover, in advanced NSCLCs patients with or without KRAS/TP53 co-mutation the immunotherapy-based regimen achieved longer OS and PFS than chemotherapy-based regimens. In the Chinese population of patients with KRAS-mutant advanced NSCLC, immunotherapy-based regimens achieved longer OS than chemotherapy-based regimens, which was independent of first or second-line setting, as well as KRAS mutational subtypes.

Predicting the efficacy of immune checkpoint inhibitors monotherapy in advanced non-small cell lung cancer: a machine learning method based on multidimensional data.

Immunotherapy has improved the prognosis of patients with advanced non-small cell lung cancer (NSCLC), but only a small subset of patients achieved clinical benefit. The purpose of our study was to integrate multidimensional data using a machine learning method to predict the therapeutic efficacy of immune checkpoint inhibitors (ICIs) monotherapy in patients with advanced NSCLC. We retrospectively enrolled 112 patients with stage IIIB-IV NSCLC receiving ICIs monotherapy. The random forest (RF) algorithm was used to establish efficacy prediction models based on five different input datasets, including precontrast computed tomography (CT) radiomic data, postcontrast CT radiomic data, a combination of the two CT radiomic data, clinical data, and a combination of radiomic and clinical data. The 5-fold cross-validation was used to train and test the random forest classifier. The performance of the models was assessed according to the area under the curve (AUC) in the receiver operating characteristic curve. Survival analysis was performed to determine the difference in progression-free survival (PFS) between the two groups with the prediction label generated by the combined model. The radiomic model based on the combination of precontrast and postcontrast CT radiomic features and the clinical model produced an AUC of 0.92±0.04 and 0.89±0.03, respectively. By integrating radiomic and clinical features together, the combined model had the best performance with an AUC of 0.94±0.02. The survival analysis showed that the two groups had significantly different PFS times (p<0.0001). The baseline multidimensional data including CT radiomic and multiple clinical features were valuable in predicting the efficacy of ICIs monotherapy in patients with advanced NSCLC.

Extended use of rh-endostatin improves prognosis in patients with advanced non-small cell lung cancer: an analysis of retrospective study.

Rh-endostatin is a potent inhibitor of angiogenesis approved and widely used for advanced non-small cell lung cancer (NSCLC) in China. While the efficacy and safety of extended use of rh-endostatin with platinum-based chemotherapy during induced and maintenance therapy are still not very clear, and whether extended use of rh-endostatin can improve survival needs further investigation. We performed a retrospective analysis of chemotherapy-naïve patients with stage IIIB-IV or recurrent NSCLC who had been treated with first-line chemotherapy plus rh-endostatin between January 2008 and June 2018. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Cox proportional hazards regression model was used to assess the prognostic importance of risk factors (age, gender, smoking status, Eastern Cooperative Oncology Group (ECOG) performance score, stage, pathology, previous thoracic surgery, and rh-endostatin treatment cycles). A total of 105 patients, with a median of 4 cycles of chemotherapy with rh-endostatin, were eligible for analysis. The median [95% confidence interval (CI)] PFS and OS for patients with extended use of rh-endostatin (≥4 cycles) and nonextended use were 8.2 (4.2-12.3) vs. 3.2 (1.3-5.0) months [hazard ratio (HR) =0.50, P=0.002] and 25.1 (20.5-29.7) vs. 14.0 (9.2-18.8) months (HR =0.50, P=0.003), respectively. The objective response rate (ORR) and disease control rate (DCR) were 23.2% and 92.9%, respectively. Extended use of rh-endostatin (≥4 cycles) was significantly correlated with better PFS and OS in multivariate analysis. Patients with squamous cell cancers significantly benefited from the extended use of rh-endostatin (≥4 cycles) (n=56, P=0.001) but not adenocarcinoma (n=49, P=0.378). Hematologic and gastrointestinal toxicities occurred more frequently in the extended group compared with those in the nonextended group but without any significant differences. In patients with advanced NSCLC, the extended use of rh-endostatin (≥4 cycles) could provide additional survival benefits and satisfactory toxicity profiles, especially for those with squamous cell cancer, which merits further evaluation in a prospective randomized study in the future.

Long-term survival analysis of patients with stage IIIB-IV non-small cell lung cancer complicated by type 2 diabetes mellitus: A retrospective propensity score matching analysis.

This study aimed to determine the effect of type 2 diabetes mellitus (T2DM) on overall survival (OS) of patients with stage IIIB-IV non-small cell lung cancer (NSCLC). We retrospectively analyzed patients with stage IIIB-IV NSCLC from January 2015 to December 2018 in the Department of Oncology at the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models were used to describe the effect of T2DM on the OS of patients with stage IIIB-IV NSCLC. This study collected data on 76 patients with NSCLC and T2DM (group A) and 214 NSCLC patients without T2DM (group B). After propensity score matching (PSM) analysis, 74 patients were included in each group. The mean OS of all patients was 17 months (range, 11-31 months). The mean OS of group A was 15 months (range, 8-25 months) and the mean OS of group B was 20 months (range, 14-39 months). The mean OS of group B was longer than group A, and the difference was statistically significant. Univariate analysis of the clinical data showed that T2DM and complications were significantly correlated with the prognosis of patients with stage IIIB-IV NSCLC (p=0.003 and p=0.034). Multivariate Cox model analysis showed that T2DM and complications were independent prognostic factors for patients with stage IIIB-IV NSCLC (p=0.002 and p=0.024, respectively). Stage IIIB-IV NSCLC patients without T2DM have an increased OS compared to patients with stage IIIB-IV NSCLE and T2DM.

Investigating treatment response and immune profile in association with pattern identification in NSCLC patients scheduled for immune checkpoint inhibitor monotherapy (HARMONY study)

Immune checkpoint inhibitors (ICI) considerably improve overall survival of advanced nonsmall cell lung cancer (NSCLC) patients. However, it has certain limitations, such as low response rates. Although programmed death-ligand 1 (PD-L1) expression is currently used as a representative predictive biomarker, it cannot robustly predict response; thus, identifying other dynamic biomarkers to ensure better selection of patients susceptible for ICI therapy is required. Pattern identification is a diagnostic system used in oriental medicine and is performed through collecting and analyzing a series of symptoms and characteristic signs. We intended to analyze the association between survival, treatment response, and immune profile evaluated on every visit according to different pattern identifications and determine how pattern identification changes during the course of NSCLC treated with ICI. Across 10 academic hospitals, 200 patients diagnosed with stage Ⅲb-Ⅳ NSCLC and scheduled for ICI monotherapy (pembrolizumab or atezolizumab) as second-line or more treatment following platinum-based first-line treatment for NSCLC will be recruited. Throughout the study, participants are expected to exhibit different immune profiles according to pattern identification in association with treatment response and survival. The primary endpoint is progression-free survival (PFS), while secondary endpoints are overall survival (OS), objective response rate (ORR), and immune profile, all of which will be analyzed in association with pattern identification. Approximately 10 mL blood samples will be obtained from each patient. Results from the analysis of immune cells and cytokines will be analyzed together with pattern identification. Results from the analysis of differences in survival, treatment response, and immune profile, together with pattern identification for NSCLC patients during ICI therapy, will have significant scientific and medical contributions, and will provide comprehensive data to identify pattern identification-based immune biomarkers for predicting survival and treatment response of ICI therapy for NSCLC patients. Ethical approval has been obtained from the medical ethics committees of 10 academic hospitals. All amendments to the research protocol were submitted and approved. This trial is registered in Clinical Research Information Service (CRIS) of the Republic of Korea with the number KCT0005173. Registration date: July 22, 2020 (version 3.0).

Platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios are associated with the efficacy of immunotherapy in stage III/IV non-small cell lung cancer.

Peripheral serological indicators are novel markers associated with prognosis in multiple malignant tumors. In the present study, platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) were selected to construct a model that predicts long-term survival of patients with stage IIIB-IV non-small cell lung cancer (NSCLC) who received treatment with an anti-programmed cell death protein-1 (PD-1) monoclonal antibody. A total of 133 patients were eligible for the present retrospective study (January 2019-February 2021). The area under the receiver operating characteristic curve was used to compare the diagnostic value of PLR and NLR, and combined PLR and NLR. The objective response rate and disease control rate of each group were obtained and the differences were compared using the χ2 test. The prognostic value of these indicators was assessed using the Kaplan-Meier method. Cox regression analysis was used to evaluate risk factors associated with long-term survival. Statistically significant parameters were included in the nomogram. Based on the median PLR and NLR values, the patients were divided into high PLR (H-PLR) (PLR >200.00, 67 patients) and low PLR (L-PLR) (PLR ≤200.00, 66 patients), and high NLR (H-NLR) (NLR >3.56, 65 patients) and low NLR (L-NLR) (NLR ≤3.56, 68 patients) groups. Immune-related adverse events (irAEs) occurred in 22 patients (16.5%) during the observation period, including 18 grade 2–3 irAEs and 4 grade 4 cases. H-NLR and H-PLR were associated with poor progression-free (PFS) and overall survival (OS) in the present study. NLR was an independent prognostic factor for PFS [hazard ratio (HR): 0.201, 95% confidence interval (CI): 0.060-0.670; P=0.009) and OS (HR: 0.413, 95% CI: 0.226-0.754; P=0.004) in this patient group. Therefore, NLR may be used in the prognostication of patients with stage IIIB-IV NSCLC treated with PD-1 inhibitors. These serological markers may be used in combination with established immunomarkers to help predict outcomes.

Correlation of psychological distress with quality of life and efficacy of immune checkpoint inhibitors in patients with newly diagnosed stage IIIB-IV NSCLC.

12001 Background: Psychological distress is common among cancer patients and leads to activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) and continuous production of distress hormones, which may contribute to a highly immunosuppressive tumor microenvironment (TME). Meanwhile, preclinical studies have shown that psychological distress could undermine cancer therapies. Therefore, we investigate the prevalence of psychological distress in non-small-cell lung cancer (NSCLC) patients, identify its impact on quality of life (QoL) and efficacy of immune checkpoint inhibitors (ICIs), and explore the possible neuro-endocrinological mechanisms. Methods: Patients with newly diagnosed stage ⅢB-Ⅳ NSCLC received ICIs as first-line treatment were included. The assessments of psychological distress including depression and anxiety symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), respectively. The QoL was measured by Short Form Health Survey 36 (SF-36). Stress hormones including serum cortisol, adrenocorticotropic hormone (ACTH), plasma epinephrine (Epi), and norepinephrine (NE) were determined by ELISA kit before treatment. Objective response rates (ORR) and Median progression-free (PFS) were estimated using the Chi-square test, Kaplan-Meier, and Cox regression method. Results: 77 NSCLC patients with a mean age of 60.9 years were enrolled. Stage distribution included 50 (64.9%) stage ⅢB/C and 27 (35.1%) stage Ⅳ. 44(57.1%) patients were present psychological distress. Psychological distress was associated with poorer QoL (P&lt;0.001). The median follow-up time was 16.2 months. Compared with non-psychological distress patients, psychological distress patients had a significant lower ORR (35.9% vs 63.64%; P=0.033) and shorter PFS (median 12.63 vs 14.60 months; 95% CI: 0.36 to 1.98; P=0.026). Moreover, psychological distress was the only independent predictor for PFS (HR:2.71, 95%CI: 1.06～6.90; P=0.037) in multivariate Cox regression analyses. The patients with psychological distress had higher levels of serum cortisol ( P=0.040) and plasma Epi ( P=0.023). Additionally, the serum cortisol ( P=0.043) and plasma Epi ( P=0.025) concentrations were associated with inferior ICIs response. Conclusions: Psychological distress is common within stage ⅢB-Ⅳ NSCLC patients. Patients with psychological distress are associated with worse QoL and inferior outcomes to ICIs and discover the potential mechanisms of neuro-endocrinological hormones in resistance to ICIs therapy.

Efficacy and safety of pyrotinib in advanced lung adenocarcinoma with HER2 mutations: a multicenter, single-arm, phase II trial

BackgroundThere is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations.MethodsIn this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored.ResultsSeventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2–60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2–30.0), with median PFS of 5.6 months (95% CI, 2.8–8.4), and median OS of 10.5 months (95% CI, 8.7–12.3). The median duration of response was 9.9 months (95% CI, 6.2–13.6). All treatment-related adverse events (TRAEs) were grade 1–3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression.ConclusionsPyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation.Trial registrationChinese Clinical Trial Registry Identifier: ChiCTR1800020262

Are older patients with non-small cell lung cancer receiving optimal care? A population-based study

Background Results from studies addressing age-related patterns of cancer care have found evidence of unjustified differences in management between younger and older patients. Methods We examined associations between age and clinical presentation, management and mortality in patients diagnosed with non-small cell lung cancer (NSCLC) between 2002 and 2016. Analyses were adjusted for comorbidity and other factors that may have affected management decisions and outcomes. Results The study population encompassed 40,026 patients with NSCLC. Stage at diagnosis did not differ between age groups ≤ 84. The diagnostic intensity was similar in age groups <80 years. In patients with stage IA–IIB disease and PS 0–2, surgery was more common in the youngest age groups and decreased with increasing age, and was rarely performed in those ≥ 85 years. The use of stereotactic body radiotherapy (SBRT) increased with age (≤69 years 5.4%; ≥85 years 35.8%). In patients with stage IIIA disease and PS 0–2, concurrent chemoradiotherapy was more common in younger patients (≤69 years 55.3%; ≥85 years 2.2%). In stage IA–IIIA disease, no major differences in treatment-related mortality was observed. In stage IIIB–IV and PS 0–2, chemotherapy was more common in patients <80 years. However, 58.1% of patients 80–84 years and 30.3% ≥ 85 years received treatment. In stage IA–IIIA, overall and cause-specific survival decreased with increasing age. No age-differences in survival were observed in patients with stage IIIB-IV NSCLC. Conclusion Treatments were readily given to older patients with metastatic disease, but to a lesser degree to those with early stage disease. Significant differences in cause specific survival were observed in early, but not late stage disease. Our findings underscore the importance of individualized assessment of health status and life expectancy. Our results indicate that older patients with early stage lung cancer to a higher extent should be considered for curative treatment.

Mefatinib as first-line treatment of patients with advanced EGFR-mutant non-small-cell lung cancer: a phase Ib/II efficacy and biomarker study

EGFR inhibitors have revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). Mefatinib is a novel, bioavailable, second-generation, irreversible pan-EGFR inhibitor. This phase Ib/II open-label, single-arm, multi-center study investigated the efficacy, safety, biomarker, and resistance mechanisms of mefatinib in the first-line treatment of patients with advanced EGFR-mutant NSCLC. This study included 106 patients with EGFR-mutant stage IIIB-IV NSCLC who received first-line mefatinib at a daily dose of either 60 mg (n = 51) or 80 mg (n = 55). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The cohort achieved an ORR of 84.9% and DCR of 97.2%. The median PFS was 15.4 months and the median OS was 31.6 months. Brain metastasis was detected in 29% of patients (n = 31) at diagnosis and demonstrated an ORR of 87.1%, PFS of 12.8 months, and OS of 25.2 months. Adverse events primarily involved skin and gastrointestinal toxicities, which were well-tolerated and manageable. Analyses of mutation profiles were performed using targeted sequencing of plasma samples at baseline, first follow-up 6 weeks from starting mefatinib therapy (F1), and at progression. Patients with concurrent TP53 mutations had comparable PFS as wild-type TP53 (14.0 vs 15.4 months; p = 0.315). Furthermore, circulating tumor DNA clearance was associated with longer PFS (p = 0.040) and OS (p = 0.002). EGFR T790M was the predominant molecular mechanism of mefatinib resistance (42.1%, 16/38). First-line mefatinib provides durable PFS and an acceptable toxicity profile in patients with advanced EGFR-mutant NSCLC.

Efficacy and Prognosis of First-Line EGFR-Tyrosine Kinase Inhibitor Treatment in Older Adults Including Poor Performance Status Patients with EGFR-Mutated Non-Small-Cell Lung Cancer.

IntroductionEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line treatments for advanced EGFR-mutated non-small-cell lung cancer (NSCLC) patients. The efficacy of EGFR-TKIs in older patients including poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) is seldom investigated.MethodsWe enrolled patients 65 years or older with EGFR-mutated Stage IIIB–IV NSCLC and evaluated the efficacy and prognosis of first-line EGFR-TKI treatment. Clinical and demographic characteristics were reviewed and analyzed, including age, sex, PS, smoking history, EGFR mutation type, treatment regimen, progression-free survival (PFS), and overall survival (OS).ResultsFrom January 2015 to December 2019, a total of 237 patients were included, 205 of whom were eligible for efficacy and outcome analyses. Among them, 91 (44.4%) were categorized as poor PS (2–4). Compared with patients categorized as good PS (0–1), those with poor PS were older (79 versus 75 years), had a higher proportion of brain metastases (41.8% versus 25.4%), more comorbidities (74.7% versus 54.4%), and more likely to be treated with first-generation TKIs (74.7% versus 57.0%). The PFS and OS were 17.1 and 26.7 months respectively in patients with good PS and 12.7 and 18.2 months in those with poor PS (both p < 0.001). In the multivariate analysis, good PS, <3 metastatic sites, and first-line treatment with afatinib compared with erlotinib and gefitinib were associated with longer PFS. A relatively younger age, good PS, < 3 metastatic sites, and no brain metastasis at diagnosis were associated with better OS.ConclusionIn older patients with EGFR-mutated NSCLC and receive EGFR-TKI treatment, a good PS and <3 metastatic sites at diagnosis were associated with a longer PFS and OS. In addition, afatinib as first-line treatment was associated with a longer PFS whereas a relatively younger age and no brain metastasis at diagnosis were associated with better OS.