Initial stage analysis of tislelizumab in combination with chemotherapy for patients with advanced HIV-positive non-small-cell lung cancer: a comparative clinical trial.

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

238 Meta-analysis on the incidence of hyperprogressive disease during immune checkpoint inhibitor therapy

<div>AbstractPurpose:<p>In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with <i>HER2</i>-amplified non–small cell lung cancer (NSCLC).</p>Patients and Methods:<p>In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with <i>HER2</i> amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety.</p>Results:<p>The enrolled cohort included 27 patients with <i>HER2</i> amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0–69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0–9.6 months), and median OS was 12.5 months (95% CI, 8.2–16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%−40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of <i>HER2</i> amplification was detected upon disease progression.</p>Conclusions:<p>Pyrotinib provided antitumor efficacy with a manageable safety profile in <i>HER2</i>-amplified patients with NSCLC.</p></div>

In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with HER2-amplified non-small cell lung cancer (NSCLC). In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with HER2 amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety. The enrolled cohort included 27 patients with HER2 amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0-69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0-9.6 months), and median OS was 12.5 months (95% CI, 8.2-16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%-40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of HER2 amplification was detected upon disease progression. Pyrotinib provided antitumor efficacy with a manageable safety profile in HER2-amplified patients with NSCLC.

<div>AbstractPurpose:<p>In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with <i>HER2</i>-amplified non–small cell lung cancer (NSCLC).</p>Patients and Methods:<p>In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with <i>HER2</i> amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety.</p>Results:<p>The enrolled cohort included 27 patients with <i>HER2</i> amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0–69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0–9.6 months), and median OS was 12.5 months (95% CI, 8.2–16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%−40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of <i>HER2</i> amplification was detected upon disease progression.</p>Conclusions:<p>Pyrotinib provided antitumor efficacy with a manageable safety profile in <i>HER2</i>-amplified patients with NSCLC.</p></div>

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

Icotinib is the first generation of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) independently developed in China, which has been widely used in the treatment of advanced EGFR mutation-positive nonsmall cell lung cancer (NSCLC). The purpose of this study was to systematically evaluate the efficacy and safety of icotinib in the treatment of advanced EGFR mutation-positive NSCLC and to provide evidence-based evidence for clinical rational drug use. Up to September 30, 2022, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang were searched, and the randomized controlled trials (RCTs) of icotinib (experimental group) versus gefitinib or erlotinib (control group) in the treatment of EGFR-positive advanced NSCLC were included. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included literature. Revman5.4 software was used for meta-analysis. A total of 957 patients were included in 12 studies. The results of meta-analysis showed that the objective response rate (ORR) and disease control rate (DCR) of the experimental group were better than those of the control group (relative risk (RR) = 1.29, 95% confidence interval (CI): 1.10-1.50, P = .001; RR = 1.10, 95%CI: 1.02-1.18, P = .01). There was no significant difference in progression-free survival (PFS) and overall survival between the 2 groups (P > .05). The results of stratified analysis showed that icotinib significantly improved the ORR of EGFR-positive advanced NSCLC patients compared with gefitinib (RR = 1.20, 95%CI: 1.01-1.43, P = .03), but had no significant improvement in DCR (RR = 1.08, 95%CI: 0.99-1.16, P = .07). Compared with erlotinib, icotinib significantly improved ORR and DCR (RR = 1.69, 95%CI: 1.17-2.45, P = .005; RR = 1.21, 95%CI: 1.01-1.44, P = .04). In terms of adverse events of drugs, the incidence of nausea and vomiting in the experimental group was significantly lower than that in the control group (P < .05). Icotinib is safer than gefitinib or erlotinib in the treatment of advanced EGFR-positive NSCLC and seems to bring more clinical benefits to patients. However, there is no obvious advantage in improving the survival rate of patients, and long-term follow-up clinical studies are needed to verify its efficacy.

BackgroundSynergistic anti-tumor effects were observed in vivo and in vitro when immune checkpoint inhibitors (ICIs) were combined with denosumab. However, the clinical benefit and safety of this synergy have not been adequately evaluated in non-small cell lung cancer (NSCLC).MethodsConsecutive charts of NSCLC patients with bone metastases between December 2020 and December 2021 in the Chinese National Cancer Center were reviewed. The entire cohort was divided into one experimental group (denosumab + ICIs [DI]) and three control groups (denosumab + non-ICIs [DnI], phosphates + ICIs [PI], phosphates + non-ICIs [PnI]). Real-world objective response rates (ORRs), median progression-free survival (mPFS), skeletal-related events (SREs), and adverse events (AEs) were compared between groups.ResultsA total of 171/410 (41.7%) patients with advanced or recurrent NSCLC carrying bone metastases who received bone-targeted therapy were eligible for analysis. Although the DI group showed a better benefit trend, differences were not statistically significant concerning the therapeutic efficacy among the DI group (n = 40), PI group (n = 74), DnI group (n = 15), and PnI group (n = 42) (ORRs: 47.5%, 43.2%, 33.3%, and 40.5%, respectively, p = 0.799; and mPFS: 378, 190, 170, and 172 days, respectively, p = 0.115; SREs: 5%, 10.8%, 13.3%, and 11.9%, respectively, p = 0.733). Nevertheless, further analysis in the NON-DRIVER cohort revealed a greater benefit for the DI group (p = 0.045). Additionally, the AEs of the DI group were not significantly different from those of the PI, DnI, and PnI groups (AEs: 27.5%, 39.2%, 26.7%, and 28.6%, respectively, p = 0.742). Furthermore, the multivariate analysis revealed the independent prognostic role of DI treatment for PFS in the overall cohort. Within the DI group, we did not observe differences in benefit among different mutational subgroups (p = 0.814), but patients with single-site bone metastasis (p = 0.319) and high PD-L1 expression (p = 0.100) appeared to benefit more, though no significant differences were observed.ConclusionsDenosumab exhibited synergistic antitumor efficacy without increasing toxicity when used concomitantly with ICIs in patients with advanced non-small cell lung cancer carrying bone metastases.

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

Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer.

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.

Objective: The objective was to study the effectiveness and safety of super-selective bronchial arterial infusion (SBAI) chemotherapy in the treatment of advanced stage non-small cell lung cancer (NSCLC). Methods: The clinical data of 120 advanced NSCLC patients were retrospectively analyzed. Among them, 60 NSCLC patients were treated with SBAI method, another 60 NSCLC patients received systemic intravenous chemotherapy as the control group. The efficacy and safety between two groups of patients were compared. Results: The objective response rate and disease control rate of NSCLC patients treated with SBAI were significantly higher than those of the control group (p < 0.05). The 3-month progression-free survival (PFS) rate (96.67%) and 6-month PFS rate (86.67%) of the SBAI group were significantly higher than those of the control group (73.33% and 56.67%) (p < 0.01). After treatment, the FACT-L scores of patients in the SBAI group were significantly higher than those of the control group (p < 0.05). The scores of all the 13 core symptom items and six symptom interference items of NSCLC patients in the SBAI group were lower than those of the control group (p < 0.05). The adverse reactions rate in the SBAI group were significantly lower than those in the control group (p < 0.05). Conclusion: The short-term efficacy of SBAI chemotherapy for advanced NSCLC is significantly higher than that of traditional peripheral intravenous chemotherapy, and it can significantly improve patients’ quality of life and reduce the incidence of adverse reactions.

BackgroundSome studies imply a strong correlation between smoking history and the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC). Hence, a systematic review and meta-analysis was conducted to comprehensively investigate this correlation.MethodsThree online databases including PubMed, Embase and Cochrane Library were searched. s and presentations from European Society of Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) were also reviewed. The deadline of search was Nov 9, 2019. Randomized clinical trials (RCT) of ICIs that reported hazard ratio (HR) for overall survival (OS) or progressive-free survival (PFS) by the smoking status of NSCLC patients were eligible for our study. We focused on publications issued in English. A random effects model was implemented in the synthesis, and a two-step interaction test was used to investigate the difference of ICIs efficacy among patients with different smoking histories.ResultsTwelve RCTs involving 6,497 NACLC patients [5,569 (85.72%) current/former smokers and 928 (114.28%) never smokers] were eligible for our systematic review and meta-analysis. The pooled HRs [95% confidential interval (CI)] of OS and PFS were 0.74 (0.67, 0.81) and 0.72 (0.59, 0.88) respectively for current/former smokers in the experimental group with ICIs versus those in the control group. The pooled HRs (95% CI) of OS and PFS were 0.81 (0.60, 1.08) and 0.92 (0.55, 1.54) respectively for never smokers in the experimental group with ICIs compared with those in the control group. The difference of ICIs efficacy in terms of OS between current/former and never smokers was insignificant [interaction HR (95% CI), 0.77 (0.69, 0.86), I2=25.4%, P_hetero=0.21].ConclusionsThe efficacy of ICIs in patients with smoking history is seemingly superior over patients without smoking history, but insignificantly. The difference can be explained by several factors such as insufficient sample size of non-smokers, and confounding factors. We suggest that smoking history cannot be recognized as a predictor of immune therapy in advanced NSCLC.

e21079 Background: Although the administration of immune checkpoint inhibitors (ICIs) and antiangiogenic agents in advanced non–small-cell lung cancer (NSCLC) has been well established, evidence supporting the combination of immune checkpoint inhibitors plus antiangiogenic drugs in previous treatment patients with advanced NSCLC is insufficient. We aimed to investigate the efficacy and safety of nivolumab combined with recombinant human endostatin (rh-Endostatin) as second-line or later treatment for advanced NSCLC. Methods: In this prospective and multicentre phase 2 trial we enrolled patients with advanced NSCLC who had not responded to standardized first-line treatment regimen from two cancer centres in China. Eligible patients were those aged 18-75 years without ICIs in first-line treatment who received nivolumab (3mg/kg, intravenous drip, day 1) every 2 weeks and rh-Endostatin (30 mg, 24-hour continous intravenous infusion，day 1–7) every 4 weeks till disease progression or discontinuation. The primary end points were objective response rate and safety. This study is registered with Chinese Clinical Trial Registry, number ChiCTR1900023664. Results: A total of 35 patients (median age, 60 years; range, 37-72 years) received nivolumab and rh-Endostatin. Median previous treated line of eligible patients was 2 lines (range, 1-7 lines). Patients received a median of 2 cycles of therapy (range, 1-14 cycles). Eleven of 33 evaluable patients achieved confirmed partial response with an objective response rate of 33.3% (11/33, 95% confidence interval [CI]: 17.2% – 49.4%) and disease control rate of 60.6% (20/33,95%CI:43.9%–77.3%). Median follow-up was 8.2 months (range: 0.9 –17.1). Median progression-free survival was 7.1 months (95% CI: 1.2m–13.0m), median overall survival was not reached and the 6-month overall survival rate was 54.5% (95% CI:37.6%–71.4%). The predominant grade 1-2 adverse events were thyroiditis, arrhythmia, hypertension. The grade 3 treatment-related adverse events were pneumonitis (3/35, 8.6%), hypertension (1/35, 2.9%) and atrial fibrillation (1/35, 2.9%), respectively. No grade 4 or 5 treatment-related adverse events were observed. Conclusions: To the best of our knowledge, this is the first prospective study that assessed nivolumab combined with rh-Endostatin as second-line or later treatment in pretreated patients with advanced NSCLC. In view of its encouraging efficacy and safety profile, nivolumab plus rh-Endostatin represents a promising treatment regimen in this patient population. Clinical trial information: ChiCTR1900023664.

Durvalumab Consolidation Should Be the Standard Therapy in Stage III EGFR-Mutant NSCLC After Chemoradiation