Real-world evidence of immune-related adverse events as predictive factor of response in non-small cell lung cancer.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

Cytoreduction and the Optimization Of Immune Checkpoint Inhibition with Radiation Therapy

Brief Report: First-line Pembrolizumab in Metastatic Non-Small Cell Lung Cancer Habouring MET Exon 14 Skipping Mutation and PD-L1 ≥50% (GFPC 01-20 Study)

Objective To retrospectively evaluate the efficacy in non-small cell lung cancer (NSCLC) patients with brain metastases treated with erlotinib ± whole brain radiotherapy, and observe the adverse events. Methods From March 2012 to January 2015, 56 patients with NSCLC with brain metastases received oral erlotinib, at a dose of 150mg per day till disease progression or intolerable adverse events were developed, including 42 cases who had received brain radiotherapy.The objective response rate (ORR) and disease control rate (DCR) were observed between groups, the progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method with the use of log-rank method.Prognostic factors of the patients were analyzed with univariate and multivariate analysis in Cox regression model.Curative effect was evaluated with response evaluation criteria in solid tumors (RECIST) criteria, and adverse events with National Cancer Institute (NCI) criteria. Results ORR and DCR were 57.1%(32/56), and 82.1%(46/56), respectively. The median PFS was 12.3 months, and the OS was 8.0 months. The 1-, and 2-year PFS rates were 51.0%, and 20.0%, respectively. The 1-, and 2-year year OS rates were 36.0%, and 7.0%, respectively. Men had a higher DRR rate than women (P=0.009). Single brain metastasis patients had higher DCR rate than in multiple brain metastases patients (P=0.044). The non-smokers, less than Karnofsky (KPS) score of 70 and high recursive partitioning analysis (RPA) score groups had higher ORR (P=0.043, P 0.05). Univariate analysis showed that there were higher PFS rate and OS rate in high RPA score group than in low RPA score group (P<0.001, P<0.001), and in KPS score of 70 and more group than in less than score of 70 group (P<0.001, P<0.001), respectively. The non-smokers and patients with adenocarcinoma group had longer OS times. Multivariate analysis showed that KPS score was the independent prognostic factor of PFS and OS (P<0.001, P=0.005), pathological type was the independent prognostic factor of PFS (P=0.001). Conclusions Erlotinib is effective and safe for NSCLC patients with brain metastases. Men and the single brain metastasis patients, non-smokers, high KPS and RPA score groups had higher DCR rates. KPS score is the most important influencing factors for patient's PFS and OS time. Women and the patients with adenocarcinoma have higher PFS rate than those of men and squamous cell carcinoma. Key words: Quinazolines/AD; Radiotherapy; Carcinoma, non-small-cell lung/CO/TH; Brain neoplasms/SC/TH

Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non–small-cell Lung Cancer

Purpose:Gefitinib is a well known therapy for non-small-cell lung cancer (NSCLC). The purpose of this study was to review clinical reports of gefitinib as maintenance therapy after first-line chemotherapy regardless of epidermal growth factor receptor (EGFR) mutation, and assess its efficacy and safety in Chinese patients.Materials and methods:Systematic computerized searches of the following databases were conducted from the start of each database up to July 2012; these include Medline, EMBASE, CNKI and www.clinicaltrials.gov. Terms searched include ‘non-small-cell lung cancer’, ‘NSCLC’, ‘lung cancer’, ‘lung tumor’, ‘gefitinib’, ‘Iressa’, ‘EGFR’ and ‘epidermal growth factor receptor tyrosine kinase inhibitors’. A total of 22 studies were reviewed.Results:In general, the overall response rate (ORR), disease control rate (DCR) and one year survival (OYS) of gefitinib maintenance therapy were 30.89%, 67.5% and 50.6% respectively, in addition, the median overall survival (OS) and median progression free survival (PFS) were 13.09 and 7.88 months respectively. Moreover, ORR, DCR, median survival time (MST) and PFS of female, nonsmoking, lung adenocarcinoma (LAC) patients and patients with rash had higher performance than male, smoking, non-LAC patients and patients without rash (p < 0.05). The adverse events (AEs) were mainly skin rashes and diarrhea, most of which were grades 1 or 2 and were well tolerated.Conclusion:Gefitinib produced encouraging efficacy, safety and survival when delivered as maintenance therapy for NSCLC in Chinese patients after first-line chemotherapy regardless of EGFR mutation, especially for the patients who were female, non-smokers, LAC and with rash. Key limitations of this review include limited subgroup data, small sample sizes, and the lack of EGFR/KRAS data.

e20556 Background: The subsequent therapy of elderly non-small cell lung cancer (NSCLC) without driver oncogene has always been a challenge due to the poor performance status and multiple comorbidities, especially in those who acquired resistance to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time which shows a better safety profile, antitumor angiogenesis, and immune modulatory effects compared with traditional chemotherapy. Here we designed an observational study to evaluate the efficacy and safety of PD-1 inhibitors plus metronomic oral vinorelbine(mOV) in elderly pre-treated metastatic NSCLC. Methods: Patients aged 65 years and above who had been histologically or cytologically confirmed unresectable stage III and IV NSCLC were recruited for this study. All the pts had no EGFR mutation, ALK fusions, or ROS1 fusions and received at least one systematic treatment. Pts received PD-1 inhibitors combined with mOV (30mg, TIW1, day 1-3-5 per week) for 6 cycles, followed by PD-1 inhibitors maintenance until disease progression or intolerable toxicities. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: From May 2020 to June 2023, 23 pts were enrolled in the study. The median age was 70 with 18(78%) males. Median follow-up time was 22.8 months (range 3.9months-41.9months). The median PFS was 5.13 months (95%Cl: 3.1 months-7.1 months) and the median OS was 28.1 months (95%Cl: (15.2 months-NA). The ORR and DCR were 13% (95%C1: 1.44%-27.6%) and 69.6% (95%Cl: 49.2%-89.9%), respectively. The PFS (p = 0.459, HR = 0.671 95%CI 0.233-1.932) and OS (p = 0.483, HR = 1.607 95%CI 0.426-6.056) were similar between those pts who previously received immunotherapy (N = 16, 69.5%) and not. PD-L1 TPS didn’t affect the patient’s PFS (&lt;1% vs≥1%, p = 0.078, HR = 2.648 95%CI 0.895-7.835 ) and OS(&lt;1% vs≥1%, p = 0.306, HR = 2.202 95%CI 0.485-9.989). Adverse events (AEs) of any grade were observed in 20(86.9%) pts of which grade III-IV AEs occurred in 4 (17.4%) pts. These grade III-IV events consisted of interstitial pneumonia, pulmonary infection, leukopenia, and neutropenia. Immune-related adverse events (irAEs) occurred in 4 (17.4%) pts, of which grade III irAEs occurred in 2 (8.7%) patients with interstitial pneumonia. No grade 4 irAEs and grade 5 adverse events even occurred. Conclusions: The regimen of PD-1 inhibitors plus mOV for the subsequent therapy showed good overall survival benefits and safety in elderly patients with metastatic NSCLC without driver oncogene which suggests it is worth further exploration.

e14677 Background: Traditional platinum-based combination chemotherapy used as the standard first‐line treatment for advanced NSCLC poses potential safety risk for patients (pts) aged 70 years and above. Moreover, data on immune checkpoint inhibitors treating older pts with lung cancer in the current pivotal trials is limited. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time. Compared with traditional chemotherapy, MCT shows better safety profile and antitumor angiogenesis and immunomodulatory effects. Camrelizumab, an anti-PD-1 inhibitor, demonstrated encouraging efficacy in NSCLC (CameL study and CameL-sq study). Here, we designed a phase II trial to evaluate the efficacy and safety of camrelizumab plus metronomic oral vinorelbine (mOV) as first-line therapy for Chinese older pts with advanced NSCLC. Methods: Key inclusion factors were pts aged 70 years and above, histologically or cytologically confirmed unresectable stage III and IV NSCLC without positive EGFR mutation, ALK fusions or ROS1 fusions, ECOG performance status 0-2, no previous systematic treatment. Pts received camrelizumab (200mg, D1, q3w) combined with mOV (30mg, tiw1, day 1-3-5 per week) for 6 cycles, followed by camrelizumab monotherapy maintenance until disease progression or intolerable side effects. The primary endpoint was progression free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: From March 2021 to November 2022, 12 pts were evaluable for inclusion in the study. The median age was 77 (range: 70-85) with 8 (67%) males. Median follow-up was 7.2 months (range 2.8 months-22.1 months). The median PFS was 9.3 months (95%CI: 3.9 months-14.7 months). The one-year OS rate was 66.3%. The ORR and DCR were 50% (95%CI: 25.4%-74.6%) and 83.3% (95%CI: 50.9%-90.1%), respectively. Pts with positive or negative PD-L1 responded similarly to the treatment (respectively at 5/8 and 1/2 on ORR). The median OS and DoR have not been reached. Adverse events (AEs) with any grade were observed in 10 (83.3%) pts, of which grade III-IV AEs were observed in 2 (16.7%) pts with neutropenia and interstitial pneumonia, respectively. Immune-related adverse events (irAEs) occurred in 3 (25%) pts, of which grade III-IV irAEs occurred in one (8.3%) patient with interstitial pneumonia. No grade 5 adverse event happened. Conclusions: The regimen of camrelizumab plus mOV for the first-line therapy for older NSCLC pts showed initial promising efficacy and safety profile, which suggests it is worth further exploration. Clinical trial information: ChiCTR2100049487 .

Objective To compare the effectiveness of concurrent chemoradiotherapy and sequential chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC).Methods From March 2002 to October 2012,121 patients with stage Ⅲ NSCLC in Peking Union Medical College Hospital were enrolled into concurrent chemoradiotherapy group and sequential chemoradiotherapy group.Objective response rate (ORR),overall survival (OS),and progression-free survival (PFS) were compared between two groups.Enumeration data were analyzed by Chi-Square test,the mean of samples by t-test,and OS and PFS by Kaplan-Meier test.Results Among 121 patients with stage Ⅲ NSCLC,66 patients received concurrent chemoradiotherapy and 55 patients received sequential chemoradiotherapy.The median OS and PFS of the whole group were 23.1 and 10.7 months.In concurrent chemoradiotherapy group and sequential chemoradiotherapy group,ORR was 45.5％ and 16.4％,the disease control rate (DCR) was 84.8％ and 61.8％,the median OS was 33.4 and 19.7 months,and the median PFS was 12.7 and 9.8 months,there were significant differences between two groups (x2 =10.128,P ＜0.05).In concurrent chemoradiotherapy group,ten patients received surgery after chemoradiotherapy.The median OS and PFS did not arrival.Conclusions Compared with sequential chemoradiotherapy,concurrent chemoradiotherapy can significantly increase the ORR,DCR,OS,and PFS for patients with locally advanced NSCLC.Surgery after concurrent chemoradiotherapy may prolong the survival in carefully selected patients. Key words: Locally advanced non-small cell lung cancer; Concurrent chemoradiotherapy; Sequential chemoradiotherapy

PurposeNivolumab plus ipilimumab (Nivo-Ipi) combination therapy is an effective first-line treatment for advanced non-small cell lung cancer (NSCLC). However, its effectiveness and feasibility in elderly patients (aged ≥ 75 years) remain unclear. This study aimed to investigate the efficacy and safety of first-line Nivo-Ipi therapy in elderly patients with NSCLC.MethodsThis retrospective study included 57 patients with NSCLC (52 men and 5 women), aged ≥ 75 years (range: 75–86) who received first-line Nivo-Ipi therapy from December 2020 to November 2022 at four institutes in Japan. Patient characteristics, therapeutic efficacy, and the incidence and severity of adverse events (AE) were assessed.ResultsThe overall response rate was 42.1%, the disease control rate was 73.6%, the median progression-free survival (PFS) was 7.1 months, and the median overall survival (OS) was 14.1 months. Common Grade ≥ 3 AEs included pneumonitis, elevated aspartate transaminase, elevated alanine transaminase, adrenal insufficiency, and colitis. No treatment-related deaths were reported. PFS and OS were longer in patients who experienced treatment-related AEs. Patients with and without AEs had a median PFS of 11.7 and 2.8 months, respectively. Similarly, the median OS of patients with and without AEs was 20.4 and 9.0 months, respectively.ConclusionFirst-line Nivo-Ipi therapy is effective in elderly patients with NSCLC. Although there was an increased incidence of pneumonitis, the treatment was manageable and presented as a viable treatment option. Notably, the occurrence of treatment-related AEs was associated with improved clinical outcomes, suggesting a potential prognostic value of AEs in this population.

ObjectiveThe potential of immune-related adverse events (irAEs) in predicting the efficacy of PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) has rarely been assessed. This study investigated the associations between irAEs and the clinical efficacy of PD-1 inhibitors combination therapy in patients with advanced NSCLC.MethodsA retrospective analysis was conducted of 73 patients with advanced NSCLC receiving PD-1 inhibitors combination therapy from January 2022 and July 2023. Patients were divided into two cohorts: patients with irAEs and patients without irAEs. We conducted an analysis to investigate the impact of irAEs on these different clinical outcomes.ResultsThere were no significant differences observed in clinical characteristics between the two cohorts, except for smoking status (P = 0.011).The cohort with irAEs exhibited a higher objective response rate (ORR) and disease control rate (DCR) compared to the cohort without irAEs (ORR: 32.5% vs 12.1%, P = 0.040; DCR: 80.0% vs 48.5%, P = 0.010).Moreover, the median progression-free survival (PFS) and overall survival (OS) were significantly better in the cohort with irAEs compared to the cohort without irAEs (PFS: 12.4 months vs 6.8 months, P = 0.009; OS: not reached vs 18.3 months, P = 0.024). Additionally, the multivariate COX regression analysis revealed that mild irAEs (PFS: HR = 0.386, 95% CI: 0.199–0.748, P = 0.005; OS: HR = 0.300, 95% CI: 0.105–0.855, P = 0.024) and single-system irAEs (PFS: HR = 0.401, 95% CI: 0.208–0.772, P = 0.006; OS: HR = 0.264, 95% CI: 0.090–0.776, P = 0.015) were identified as independent prognostic factors for both PFS and OS.ConclusionsIrAEs, especially thyroid irAEs, as well as mild or single-system irAEs, may serve as predictors of improved efficacy in advanced NSCLC patients receiving PD-1 inhibitors combination therapy.

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

e21600 Background: PD-1/PD-L1 inhibitor monotherapy has been approved as second line therapy in advanced non-small-cell lung cancer (NSCLC). The study aims to compare clinical outcome of PD-1 inhibitor plus chemotherapy with PD-1/PD-L1 inhibitor monotherapy as 2nd/subsequent line therapy in advanced NSCLC. Methods: The clinical data of NSCLC patients who received PD-1/PD-L1 inhibitor as 2nd/subsequent line therapy were retrospectively collected in our study. According to the therapy modality, patients were assigned to PD-1/PD-L1 inhibitor monotherapy group and PD-1 inhibitor plus chemotherapy group. Disease control rates (DCRs), progression free survival (PFS) and overall survival (OS) were evaluated between the 2 groups. The prognostic role of derived neutrophils-to-lymphocyte ratio (dNLR) on the outcomes was also evaluated at the same time. Results: From April 2017 to October 2019, a total of 84 patients were enrolled in the current study. Twenty-six patients were allocated to the PD-1/PD-L1 inhibitor monotherapy group and fifty-eight patients were allocated to PD-1 inhibitor plus chemotherapy group. Chemotherapy regimens were detailed as follow: liposome paclitaxel (n = 15), nab-paclitaxel(n = 12), docetaxel(n = 9), pemetrexed(n = 6), and others(n = 16). Disease control rates (DCRs) and overall survival (OS) were not significantly different between the two groups. Progression free survival (PFS) in the PD-1/PD-L1 inhibitor monotherapy was longer(median PFS: NR vs 4.4 months, p = 0.02). Univariate and multivariate analyses suggested that derived neutrophils-to-lymphocyte ratio (dNLR) was independent prognostic factor of OS and gender was independent prognostic factor of PFS. In the second-line therapy subgroup of 38 patients, OS and PFS were not significantly different in the two groups. In the subgroup of 46 patients of over 2nd line, PD-1/PD-L1 inhibitor monotherapy group had longer PFS (median PFS: NR vs 4.0 months, p = 0.01).The incidence of any grade adverse events (AEs) was no significant difference in the two groups. One patient in the PD-1 inhibitor plus chemotherapy group died of immune-related pneumonitis. Conclusions: The addition of chemotherapy to PD-1 inhibitor as 2nd/subsequent line therapy had similar clinical outcomes compared with PD-1/PD-L1 inhibitor monotherapy of advanced NSCLC patients.

ObjectiveProgrammed cell death 1 (PD-1) inhibitor has been in the market in China for several years, which lacks sufficient domestic evidence regarding its application in lung cancer. Thus, this study intended to assess the treatment outcome and tolerance of PD-1 inhibitor plus chemotherapy in advanced, driver-gene-negative, nonsquamous, non-small-cell lung cancer (NSCLC) patients in a real clinical setting.MethodsThis retrospective cohort study analyzed 68 advanced driver-gene-negative nonsquamous NSCLC patients, among which 38 cases received PD-1 inhibitor plus chemotherapy and 30 cases adopted chemotherapy alone. Disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were reviewed.ResultsGenerally, PD-1 inhibitor plus chemotherapy achieved a more satisfying ORR compared with chemotherapy alone (52.6% vs. 30.0%, P = 0.061), while the DCR did not vary between PD-1 inhibitor plus chemotherapy and chemotherapy (84.2% vs. 73.3%, P = 0.271). Patients receiving PD-1 inhibitor plus chemotherapy exhibited favorable PFS (median: 10.1 vs. 7.1 months, P = 0.040) and OS (median: 17.4 vs. 13.9 months, P = 0.049) than patients adopting chemotherapy alone. Additionally, after adjustment using multivariable Cox's analyses, PD-1 inhibitor plus chemotherapy (vs. chemotherapy) could independently realize prolonged PFS (P = 0.020) and OS (P = 0.029). Moreover, the majority of adverse events were manageable; meanwhile, grade 3–4 adverse events included leukopenia (13.2%), neutropenia (13.2%), nausea and vomiting (7.9%), anemia (5.3%), elevated transaminase (5.3%), thrombopenia (2.6%), anorexia (2.6%), peripheral neuropathy (2.6%), and rash (2.6%).ConclusionPD-1 inhibitor plus chemotherapy exhibits a better efficacy and equal tolerance compared with chemotherapy alone in advanced driver-gene-negative nonsquamous NSCLC patients.

e21073 Background: Anlotinib, a multi-target tyrosine kinase inhibitor antiangiogenic drug, had been recommended by guideline for the 3 lines or more treatment of non-small cell lung cancer (NSCLC) in China. However, data of anlotinib based combination in the first-line treatment remains unknown. Therefore, this study aims to evaluate efficacy and safety of the combination of erlotinib, chemotherapy or sintilimab with anlotinib respectively, in Chinese patients with locally advanced or metastatic NSCLC. Methods: In this open-label, three arms, prospective study, locally advanced or metastatic NSCLC patients with EGFR mutation (exon 19 deletion or L858R) (Cohort A) receive anlotinib (10 mg QD from day 1 to 14 of a 21-day cycle) and erlotinib (150 mg once daily) until disease progression or treatment intolerance. For patients with EGFR mutation negative, the treatment regimen was anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) in combination with chemotherapy (Cohort B) or sintilimab (Cohort C) according to investigator. The primary outcome was objective response (ORR), the secondary outcomes were progression free survival (PFS), disease control rate (DCR), overall survival (OS) and safety. Results: A total of 80 patients were enrolled with 30 patients in Cohort A, 28 patients in Cohort B, and 22 patients in Cohort C. Among these patients, 16 (57.1%), 7 (23.3%) and 1(4.5%) were female in Cohort A, B, and C, respectively. And 9 (32.1%) and 4 (18.2%) of them had brain metastasis in Cohort A and C, respectively. Till December 2020, all the patients received tumor assessment at least once. In Cohort A, 26 patients achieved confirmed PR, the ORR was 92.9%, and DCR was 96.4%. Median PFS was 20.53 months, and the 12-month PFS rate was 81.5%. In Cohort B, 17 patients achieved PR, the ORR was 60.0%, while DCR was 96.7%. Median PFS was 13.3 months, and the 12-month PFS rate was 55.5%. In Cohort C, medium PFS was 15.6 months. The 18- and 24-month PFS rate was 45.9% and 26.2%, respectively. The most common grade 3 adverse events (AEs) were rash (17.2%), oral mucositis (10.3%), diarrhea (6.9%) and proteinuria (6.9%) in Cohort A, and a grade 4 hypertension was observed. In Cohort B, the most common grade 3 AEs were platelet count decreased (20.0%), leucopenia (16.7%), hand-foot-skin reaction (10.0%), hypertriglyceridemia (10.0%), oral mucositis (6.7%) and thrombus (6.7%). Grade 4 platelet count decreased occurred in three patients (10.0%). Safety data of Cohort C had been published elsewhere. Conclusions: This study suggest that anlotinib-based combination treatment for patients with advanced non-small cell lung cancer might be new first-line therapy strategy. For EGFR-mutated positive patients, anlotinib plus erlotinib shows good efficacy and well tolerability. For EGFR-mutated negative patients, anlotinib combines with chemotherapy or sintilimab also may be a promising first-line treatment. Clinical trial information: NCT03628521.