Almost all nsqNSCLC pts harbored EGFR mutation ultimately develop resistance to targeted therapies, with ∼10-20% response rate and tolerance concern to platinum-based salvage treatment. Encouraging clinical data from IMpower150 has demonstrated atezo + beva + chemo are promising strategies. We initiated ML41256 to evaluate the efficacy and safety of atezo + beva, a chemo-free regimen for such pts. ML41256 is an open-label, single-arm, phase II, multicenter study enrolled pts with PD-L1 ≥1%, EGFR+, Stage IIIB/IV nsqNSCLC after treatment failure of EGFR TKIs. All pts received atezo 1200mg and beva 15mg/kg q3w until progressive disease assessed per RECIST v1.1, unacceptable toxicity, or death. The primary efficacy endpoint would be investigator confirmed objective response rate (ORR). Simon's minimax 2-stage design was used. The interim analysis would be performed for futility at the time of 19 pts completing ORR evaluation. Further testing would be halted if responders ≤ 6 in the first evaluable 19 stage 1 pts. By the cutoff date of 16th Jul. 2021, 20 pts were enrolled, and 1 pt without any post-baseline efficacy assessment was excluded from the ORR evaluable population. 8 were males; median age was 63.0 with 75% ECOG PS 1. Metastasis occurred in 100% pts (8 bone metastasis and 5 brain metastasis). Median follow-up was 5.3 m. Of 19 evaluable pts, ORR and disease control rate were 15.8% and 68.4% (3 partial response and 10 stable disease). Median progression-free survival and time to response were 2.8m and 1.4 m. Duration of response and overall survival were immature. Safety was analyzed in all 20 pts. 40% pts experienced grade ≥3 treatment-emergent adverse effect (TEAE). TEAE led to death and drug withdrawn in 1 and 4 pts. All immune-mediated toxicity were grade 1. No new safety signal was observed. Enrollment was stopped due to not meet its preplanned rule for entering stage 2 in the interim analysis. However, atezo + beva was general tolerable and deep response in some pts. Further exploration is needed to identify pts most likely benefit from this chemo-free regimen.

BackgroundAt diagnosis, 10%-15% NSCLC patients have brain metastases. BM-NSCLC suffer worse prognosis. For BM-NSCLC, local therapies, e.g., surgery and radiation therapy, are the mainstream of treatment. Immunotherapy combined with or without chemotherapy is first-line standard of care for NSCLC. Immunotherapy showed trends for benefit in BM-NSCLC and a synergistic effect with radiation therapy. However, there is a lack of high-quality evidence on additional immunotherapy on chemotherapy for BM-NSCLC. The present phase III trial aims to confirm camrelizumab, an anti-programmed cell death protein-1 antibody, plus chemotherapy with or without stereotactic or whole brain RT as first-line treatment for BM-NSCLC without driver gene mutation.Trial DesignTreatment-naïve, EGFR/ALK-negative NSCLC aged 18-75 years, with ≥ three brain metastatic lesions or one to two unresectable brain metastatic lesions are eligible. Approximately 200 patients will be randomized (1:1) to receive camrelizumab (200 mg, D1) or placebo plus chemotherapy (D1) for a 21-day cycle. Stereotactic or whole brain RT will be performed at the discretion of investigator, which will be completed within 42 days after first dose of study drugs. Stratification factors include histological type (non-squamous, squamous NSCLC), number of brain metastatic lesions (one to five, ≥ six), and planned radiation therapy (yes, no). The chemotherapy regimens are pemetrexed (500 mg/m2) for non-squamous NSCLC or paclitaxel (175 mg/m2)/albumin-bound paclitaxel (260 mg/m2) for squamous NSCLC plus carboplatin (area under the curve 5)/cisplatin (75 mg/m2). After four to six cycles, camrelizumab or placebo plus pemetrexed, and single-agent camrelizumab or placebo will be administrated as maintenance treatment for non-squamous and squamous NSCLC, respectively. The primary endpoint is intracranial PFS. The secondary endpoints include intracranial ORR, ORR, PFS, OS, duration of response, quality of life, cognitive functioning, and safety. Recruitment began in Apr 2021.Clinical trial identificationNCT04768075.Editorial acknowledgementWe thank the medical writing support from Jiangsu Hengrui Pharmaceuticals Co., Ltd.Legal entity responsible for the studyGuangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences.FundingChinese Thoracic Oncology Group (CTONG).DisclosureAll authors have declared no conflicts of interest. BackgroundAt diagnosis, 10%-15% NSCLC patients have brain metastases. BM-NSCLC suffer worse prognosis. For BM-NSCLC, local therapies, e.g., surgery and radiation therapy, are the mainstream of treatment. Immunotherapy combined with or without chemotherapy is first-line standard of care for NSCLC. Immunotherapy showed trends for benefit in BM-NSCLC and a synergistic effect with radiation therapy. However, there is a lack of high-quality evidence on additional immunotherapy on chemotherapy for BM-NSCLC. The present phase III trial aims to confirm camrelizumab, an anti-programmed cell death protein-1 antibody, plus chemotherapy with or without stereotactic or whole brain RT as first-line treatment for BM-NSCLC without driver gene mutation. At diagnosis, 10%-15% NSCLC patients have brain metastases. BM-NSCLC suffer worse prognosis. For BM-NSCLC, local therapies, e.g., surgery and radiation therapy, are the mainstream of treatment. Immunotherapy combined with or without chemotherapy is first-line standard of care for NSCLC. Immunotherapy showed trends for benefit in BM-NSCLC and a synergistic effect with radiation therapy. However, there is a lack of high-quality evidence on additional immunotherapy on chemotherapy for BM-NSCLC. The present phase III trial aims to confirm camrelizumab, an anti-programmed cell death protein-1 antibody, plus chemotherapy with or without stereotactic or whole brain RT as first-line treatment for BM-NSCLC without driver gene mutation. Trial DesignTreatment-naïve, EGFR/ALK-negative NSCLC aged 18-75 years, with ≥ three brain metastatic lesions or one to two unresectable brain metastatic lesions are eligible. Approximately 200 patients will be randomized (1:1) to receive camrelizumab (200 mg, D1) or placebo plus chemotherapy (D1) for a 21-day cycle. Stereotactic or whole brain RT will be performed at the discretion of investigator, which will be completed within 42 days after first dose of study drugs. Stratification factors include histological type (non-squamous, squamous NSCLC), number of brain metastatic lesions (one to five, ≥ six), and planned radiation therapy (yes, no). The chemotherapy regimens are pemetrexed (500 mg/m2) for non-squamous NSCLC or paclitaxel (175 mg/m2)/albumin-bound paclitaxel (260 mg/m2) for squamous NSCLC plus carboplatin (area under the curve 5)/cisplatin (75 mg/m2). After four to six cycles, camrelizumab or placebo plus pemetrexed, and single-agent camrelizumab or placebo will be administrated as maintenance treatment for non-squamous and squamous NSCLC, respectively. The primary endpoint is intracranial PFS. The secondary endpoints include intracranial ORR, ORR, PFS, OS, duration of response, quality of life, cognitive functioning, and safety. Recruitment began in Apr 2021. Treatment-naïve, EGFR/ALK-negative NSCLC aged 18-75 years, with ≥ three brain metastatic lesions or one to two unresectable brain metastatic lesions are eligible. Approximately 200 patients will be randomized (1:1) to receive camrelizumab (200 mg, D1) or placebo plus chemotherapy (D1) for a 21-day cycle. Stereotactic or whole brain RT will be performed at the discretion of investigator, which will be completed within 42 days after first dose of study drugs. Stratification factors include histological type (non-squamous, squamous NSCLC), number of brain metastatic lesions (one to five, ≥ six), and planned radiation therapy (yes, no). The chemotherapy regimens are pemetrexed (500 mg/m2) for non-squamous NSCLC or paclitaxel (175 mg/m2)/albumin-bound paclitaxel (260 mg/m2) for squamous NSCLC plus carboplatin (area under the curve 5)/cisplatin (75 mg/m2). After four to six cycles, camrelizumab or placebo plus pemetrexed, and single-agent camrelizumab or placebo will be administrated as maintenance treatment for non-squamous and squamous NSCLC, respectively. The primary endpoint is intracranial PFS. The secondary endpoints include intracranial ORR, ORR, PFS, OS, duration of response, quality of life, cognitive functioning, and safety. Recruitment began in Apr 2021. Clinical trial identificationNCT04768075. NCT04768075. Editorial acknowledgementWe thank the medical writing support from Jiangsu Hengrui Pharmaceuticals Co., Ltd. We thank the medical writing support from Jiangsu Hengrui Pharmaceuticals Co., Ltd. Legal entity responsible for the studyGuangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences. Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences. FundingChinese Thoracic Oncology Group (CTONG). Chinese Thoracic Oncology Group (CTONG).

Immune checkpoint inhibitors (ICIs) of programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) have revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The combination of ICIs with chemotherapy is an approved first-line treatment for advanced NSCLC, resulting in improved patient survival compared with chemotherapy alone. However, the utility of a combined ICI-chemotherapy regimen as second-line treatment is still unclear. This retrospective study was conducted to determine the efficacy and safety of toripalimab combined with chemotherapy in the treatment of advanced NSCLC patients following first-line chemotherapy. In total, 79 patients diagnosed with advanced or metastatic NSCLC with PD-L1 expression >50% were analyzed. After first-line chemotherapy, patients received toripalimab combined with chemotherapy at the Affiliated Hospital of Qingdao University between May 2019 and January 2020. The objective response rate (ORR) was the primary endpoint while secondary endpoints included progression-free survival (PFS), disease control rate (DCR) and safety. Patient median age was 62.1 years (38-79], 25 (31.6%) were female, 8 (10.1%) were former or current smokers, 49 (62.0%) had non-squamous NSCLC and 21 (26.6%) had undergone prior surgery. As of April 2021, the median follow-up was 13.8 months (6.5-17.3) with median OS not yet reached. ORR and DCR for evaluable patients were 39.24% and 96.2%, respectively. The overall median PFS was 8.13 months (95%CI 6.38–10.62), with median PFS of adenocarcinoma and squamous cell carcinoma patients being 9.6 months (95%CI 3.1-15.8) and 7.1 months (95%CI 3.5-11.6), respectively. Grade 1-2 treatment-related adverse events (TRAEs) were most common including anemia (83.6%), decreased appetite (62.0%), fever (3.8%), neutropenia (26.6%) and pneumonia (32.9%). Only one patient developed grade 3 TRAE (pneumonia) and no grade 4/5 TRAEs occurred. Toripalimab combined with chemotherapy as second-line treatment of advanced NSCLC patients demonstrates favorable therapeutic activity and safety.

MIL60 is a biosimilar of bevacizumab (BEV) which can bind and inhibit vascular endothelial growth factor. We compared the efficacy, safety, popular pharmacokinetics (PoP PK) and immunogenicity of MIL60 with BEV in patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC).

Platinum-based chemotherapy is still the backbone of advanced squamous non–small-cell lung cancer (NSCLC). Paclitaxel (PTX) liposome is the only PTX liposomal formulation on the market for the treatment of lung, ovarian and breast cancer since 2006 in China. The purpose of this study was to compare the clinical efficacy and safety between PTX liposome/cisplatin and gemcitabine/cisplatin as first-line treatment of patients with staged IIIB/IV squamous NSCLC.

Background: QL1101 is a biosimilar molecule of bevacizumab (BEV, Avastin), a monoclonal antibody (mAb) that binds and inhibits vascular endothelial growth factor (VEGF). The main purpose of the study was to evaluate whether the effectiveness of QL1101 is equivalent to that of Avastin; the secondary purpose is safety and immunogenicity. Methods: The study (NCT03169335) planned to recruit 512 patients with locally metastatic or recurrent non-squamous cell non-small cell lung cancer to QL1101 (test group) or Avastin (control group) in combination with paclitaxel/carboplatin (paclitaxel 175mg/m2, carboplatin AUC=5) at a 1:1 ratio. QL1101 or Avastin (15mg/kg, respectively) combined with chemotherapy, every 3 weeks as one treatment cycle for 6 cycles, followed by QL1101 single-drug maintenance treatment until disease progression, intolerable toxicity, initiation of other treatment, loss to follow-up or death. The primary endpoint was the best objective response rate (ORR) evaluated by the blind independent imaging review committee at week 18. Results: A total of 675 subjects were screened and 532 were eventually treated, including 266 in the trial group and 266 in the control group. At week 18, the ORR of the QL1101 group and Avastin group, evaluated by the blind independent imaging review committee, was 52.26% (CR:0, PR:139) and 56.02% (1 cases CR, 148 PR), respectively. Risk ratio (RR) value was 0.917 (90% CI, 0.807-1.043), which met the prespecified equivalence margins (0.75-1.33). The incidence of treatment-related adverse events and immunogenicity of the two groups was similar, and no neutralizing antibodies were detected. Conclusions: QL1101 and Avastin are equivalent in clinical efficacy in non-squamous cell non-small cell lung cancer patients, and the safety profile (including immunogenicity) is similar. There are no unexpected serious adverse reactions. Clinical trial identification: NCT03169335. Legal entity responsible for the study: Professor Baohui Han. Funding: Qilu Pharmaceutical Co., Ltd. Disclosure: All authors have declared no conflicts of interest.

Conclusion: Pemetrexed-Carboplatin is not superior to Paclitaxel (weekly) -Carboplatin as first-line regimen in advanced ns-NSCLC in terms of 6 months PFS rates.

2% - 7% NSCLC patients were detected to have ALK mutation. At present, two or more generations ALK inhibitors have been used for ALK positive NSCLC treatment which including crizotinib, alectinib, ceritinib, brigatinib and so on. Although, most of the adverse events (AEs) of ALK inhibitors are grade 1 to grade 2 and can be generally well tolerated, the serious adverse events (SAEs) of ALK inhibitors are lack of huge data analysis as we know and the lung toxicity of ALK inhibitors is needed to be payed attention to. Thus, we performed meta-analysis to evaluate the safety of ALK inhibitors and especially the SAEs. 16 studies from 4 database (Pubmed, Science Direct, ClinicalTrials.gov and Cochrane Library) were included in this meta-analysis. All statistical analyses in this meta analysis were performed by STATA 14.0 software. We analyzed the incidence of pooled AEs, the incidence of pooled SAEs and the incidences of common types of SAEs of ALK inhibitors. The pooled AEs of ALK inhibitors almost occurred in all participates and the pooled SAEs occurred in over 20% participates. Especially ceritinib and brigatinib, of which the SAEs occurred in over 40% participates. It is likely that alectinib is safest ALK inhibitors of the two generations ALK inhibitors. Generally, ALK inhibitors shows significant lung toxicity. In conclusion, the ALK related SAEs should draw our attention especially the lung toxicity. According to this meta-analysis, alectinib seems to be the safest ALK inhibitor. Physicians should focus on the related SAEs when using ALK inhibitors.

Apatinib, a specific tyrosine kinase inhibitor targeting VEGFR-2, shows anti-angiogenesis effects in multiple solid tumors including lung cancer. Correlation between cavitation formation and outcome of some anti-angiogenic drugs is evaluated in patients with pulmonary cancer. However, the onset of cavitation in lung metastases in solid tumor patients following apatinib treatment has not been mentioned yet. The clinical data of solid tumor patients with lung metastasis treated with apatinib in the Affiliated Hospital of Qiingdao University between 4/1/2015 and 6/17/2017 were collected from medical records, and chest imaging findings were documented. Survival data were analyzed with Kaplan-Meier estimates and compared with log-rank test. Sixty-four eligible patients were identified (Table). The main primary tumor sites were stomach (n=23, 35.9%), colorectum (n=14, 21.9%) and liver (n=10, 15.6%). 93.8% patients received 250 mg/day of apatinib orally. Tumor cavitation formation in lung metastases occurred in 20 (31.3%) patients. None of these patients had preexisting cavity, which demonstrated that all cavitary lesions were developed during apatinib administration. There was no significant difference in age, gender, primary tumor site, histology and stage of lung metastases, history of pulmonary surgery and typical adverse events of apatinib between patients developed cavity or not. Compared with those without cavitary lesions, patients with cavitary showed higher rate of temporary increase in CEA (85.0% vs. 34.1%, P=0.0002) and longer progression-free survival (PFS; 15.44 [95% CI, 12.12-20.65] months vs. 6.71 [95% CI, 6.11-8.13] months, P<0.0001). However, patients with temporary increase in CEA showed longer but not significant PFS (11.15 [95% CI, 6.71-15.44] vs. 8.13 [95% CI, 6.31-15.57] months; P=0.3047). Cavitation development in lung metastases is accompanied with temporary elevation of CEA in patients treated with apatinib, and might be used as a potential biomarker for survival free of progression.

It is difficult to identify tumor driving genes in advanced non-small cell lung cancer (NSCLC) patients especially for those who were unable to obtain cancer tissue samples and had developed treatment resistance. Circulating tumor DNA (ctDNA) has garnered much excitement over the past few years for its potential clinical utility as a tumor therapy monitoring tool. Our study aims to evaluate the usefulness of ctDNA for serial monitoring actionable genetic alterations in NSCLC patients. 34 pairs of matched cancer tissue and plasma samples were collected from patients with advanced NSCLC and applied to capture-based next generation sequencing (NGS) using the lung panel, consisting of critical exons and introns of 168 genes. Additional, serial monitoring of ctDNA was conducted in 11 NSCLC patients with actionable genetic alterations using the above NGS assay. ctDNA yielded a close agreement of 85.3% (29/34) on actionable genetic alteration status when compared to cancer tissue at baseline in this study. Analysis of ctDNA at different time points showed a strong correlation to treatment efficacy. Interestingly, secondary genetic alterations such as EGFR mutation T790M were detected in 45.5% (5/11) of the patients during monitoring. ctDNA may be a potential alternative to conventional primary tissue based NGS assay. ctDNA assay by NGS could be clinically used to monitor the efficiency of personalized target therapy for NSCLC patients.

Although previous studies demonstrated that the PFS of geftinib, erlotinib and afatinib as first line treatment is superior to chemotherapy in advanced NSCLC patients harboring activating EGFR mutation, the efficacy of icotinib therapy as first line therapy has not yet been elucidated. Patients with IIIB/IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R substitution) received oral icotinib (125 mg, three times per day) until disease progression or unacceptable toxic effects. The primary outcome was overall survival (OS), and the second endpoint were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR). 1615 patients with advanced NSCLC receiving icotinib from Oct. 2012 to Apr. 2016 were screened in four cancer centers in Qingdao city, P R. China, and 79 patients with intact follow-up data received icotinib in first-line setting and were enrolled. Of them, the number of women and men were 51 (64.56/%) and 28 (35.44/%) respectively. 27 (34.18%) patients were with EGFR exon 19 deletion, and 52(65.82%) patients with exon 21 L858R mutation. The median follow-up period at the time of analysis was 24.50 months. The objective response rate (ORR) was 45.57% (36/79), and the disease control rate(DCR) reached 89.87%(71/79). One (1.27%) patient had CR, and 35(44.30%) patients had PR, 35(44.30%) patients had SD, 8(10.13%) patients with PD. The median PFS and OS were 13.61 months and 31.11 months respectively of overall population. The median PFS was 12.30 months in EGFR exon 19 mutation subgroup and 14.00 months in exon 21 mutation subgroup respectively(p=0.441). The exon 19 mutation group had a significantly longer median overall survival than exon 21 mutation group (34.72 months, vs. 28.66 months, log-rank p=0.006, hazard ratio, 0.31 95% CI, 0.13 to 0.71). Meanwhile, there is significant difference of overall survival during different ECOG PS subgroups (ECOG PS 0-1 versus ECOG PS 2-3, 32.59 months versus 20.59 months, p=0.002,HR 3.09,95%CI, 1.46 to 6.52). The study illustrates that icotinib is effective as first-line treatment for patients with advanced NSCLC and sensitive EGFR mutation. The patients harboring EGFR exon 19 deletion mutations yield similar PFS, but longer OS compared to those harboring exon 21 L858R mutations.