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Background: There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations., Methods: In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m 2 on day 1 and either plinabulin (30 mg/m 2 ) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed., Findings: Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group., Interpretation: Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population., Funding: BeyondSpring Pharmaceuticals., Competing Interests: Declaration of interests TF received research funding from BeyondSpring Pharmaceuticals to conduct this trial and is a speaker for Sanofi and Sobi. CH received research funding from BeyondSpring Pharmaceuticals to conduct this trial. GHK is President of Kentucky Society of Oncology and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from BMS, Genentech, AstraZeneca, Regeneron, Guardant, EMD Serono, and Novartis; consulting fees from BMS, Genentech, AstraZeneca, Regeneron, and Guardant; and payment for participation on a data safety monitoring board or advisory board from BMS, Genentech, AstraZeneca, and Regeneron. LB has received research support from Beyondspring and consulting fees from Sanofi, Gilead, Pfizer, Boehringer Ingelheim, Neuvogen, Bayer, BioAtla, Daichi, Summit, Anheart, Merck, Abbvie, Regeneron, Janssen, Genentech, Novocure, InterVenn, Elevation Oncology, Turning Point, and Novartis; and has participated on data safety monitoring board or advisory boards for ORIC Pharmaceuticals. JZ, ZJ, BH, FY, ZL, YSu, and JS have received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from MSD, BeiGene, Roche, and AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Garsorasib (D-1553; InventisBio, Shangai, China), a potent KRAS G12C inhibitor, has shown promising antitumour activity in patients with KRAS G12C -mutated (ie, Gly12Cys) non-small-cell lung cancer (NSCLC) in a phase 1 study. We report results from a phase 2 study conducted to evaluate the efficacy and safety of garsorasib in patients with locally advanced or metastatic KRAS G12C -mutated NSCLC., Methods: This open-label, multicentre, single-arm, phase 2 trial enrolled adult patients with KRAS G12C -mutated NSCLC who had previously been treated with platinum-based chemotherapy and immune checkpoint inhibitors from 43 hospitals in China. Participants received 600 mg garsorasib orally twice per day. Tumour assessments were performed at baseline, at the end of every two cycles (of 21 days) for the first eight cycles, and at the end of every three cycles thereafter. The primary endpoint was objective response rate (ORR) as assessed by an independent review committee (IRC) following the guidelines in Response Evaluation Criteria in Solid Tumours, version 1.1. Efficacy and safety were assessed in all patients who received at least one dose of garsorasib. This trial is registered at ClinicalTrials.gov, NCT05383898, and is active but no longer recruiting., Findings: From June 17, 2022, to May 17, 2023, of 225 patients screened for eligibility, 123 patients were enrolled and treated with garsorasib. Of these 123 participants, the median age was 64 years (IQR 59-68), 108 (88%) were male and 15 (12%) were female. At data cutoff (Nov 17, 2023), the median follow-up duration was 7·9 months (IQR 6·3-10·4), and 82 (67%) of 123 patients had discontinued treatment. The IRC-confirmed ORR was 50% (61 of 123 patients; 95% CI 41-59). 117 (95%) of 123 patients reported treatment-related adverse events, with 61 (50%) experiencing grade 3 or higher events. The most common types of adverse events of grade 3 or higher associated with garsorasib were hepatic and gastrointestinal events, including increased liver enzymes, such as aspartate aminotransferase (21 [17%] of 123 participants), alanine aminotransferase (19 [15%] of 123 participants), and gamma-glutamyltransferase (28 [23%] of 123 participants); nausea (2 [2%] of 123 participants); and vomiting (2 [2%] of 123 participants). No new safety signals were identified, and most of the adverse events were well managed., Interpretation: The results show that garsorasib has a high response rate, long duration of response, and an acceptable and manageable safety profile in patients with previously treated KRAS G12C -mutated NSCLC. Garsorasib potentially provides a promising treatment option for this patient population., Funding: InventisBio., Competing Interests: Declaration of interests ZL has received speaker fees from AstraZeneca, Roche, and Hansoh. SL has received research grants from AstraZeneca, Hutchison, BMS, Heng Rui, and Roche; has received consulting fees from AstraZeneca, Boehringer Ingelheim, Hutchison MediPharma, Simcere, ZaiLab, GenomiCare, and Roche; and has received speaker fees from AstraZeneca, Roche, and Hansoh. LJ, JZ, and PW have received research grants and speaker fees from InventisBio, and have served as advisors and consultants for InventisBio. LinZ is employed by InventisBio and report stocks in InventisBio. All other authors declare no competing interests., (Copyright © 2024 Published by Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) which revealed the systematic and central nervous system (CNS) antitumor activities for EGFR T790M-mutated advanced NSCLC in previous clinical studies and is further analyzed here., Methods: Eligible patients from the previous phase I and phase IIb studies of rezivertinib were included for pooled analysis. Post-progressive patients who received a prescribed dosage (≥180 mg) of rezivertinib orally once daily were included in full analysis set (FAS), while those with stable, asymptomatic CNS lesions, including measurable and non-measurable ones at baseline were included in CNS full analysis set (cFAS). Patients with measurable CNS lesions were included in CNS evaluable for response set (cEFR). BICR-assessed CNS objective response rate (CNS-ORR), CNS disease control rate (CNS-DCR), CNS duration of response (CNS-DoR), CNS progression-free survival (CNS-PFS), and CNS depth of response (CNS-DepOR) were evaluated., Results: 355 patients were included in FAS, among whom 150 and 45 patients were included in cFAS and cEFR. This pooled analysis showed the CNS-ORR was 32.0% (48/150; 95% CI: 24.6-40.1%) and the CNS-DCR was 42.0% (63/150; 95% CI: 34.0-50.3%) in cFAS, while that in cEFR were 68.9% (31/45; 95% CI: 53.4-81.8%) and 100% (45/45; 95% CI: 92.1-100.0%). In cEFR, the median CNS-DepOR and the mean of CNS-DepOR were -52.0% (range: -100.0 to 16.1%) and -46.8% (95% CI: -55.5 to -38.1%). In cFAS, the median CNS-DoR and CNS-PFS were 13.8 (95% CI: 9.6-not calculable [NC]) and 16.5 (95% CI: 13.7-NC) months., Conclusions: Rezivertinib demonstrated encouraging clinical CNS efficacy among advanced NSCLC patients with EGFR T790M mutation and CNS metastases., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael Greco, Tingting Wang, and Anqi Zhou are employees of Beta Pharma, and all other authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients., Methods: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR)., Results: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively., Conclusions: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population., Trial Registration: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020., (© 2023. The Author(s).)

Background: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This phase IIa study was part of a phase I/IIa study (NCT03386955), aimed to evaluate the efficacy and safety of rezivertinib as the first-line treatment for patients with locally advanced or metastatic/recurrent EGFR mutated non-small cell lung cancer (NSCLC)., Methods: Patients received the first-line treatment of 180 mg rezivertinib orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety., Results: From Jun 12, 2019, to Oct 17, 2019, 43 patients were enrolled. At the data cutoff date on Dec 23, 2021, the ORR by BICR was 83.7% (95% CI: 69.3-93.2%). The median DoR was 19.3 (95% CI: 15.8-25.0) months. The median PFS by BICR was 20.7 (95% CI: 13.8-24.8) months and 22.0 (95% CI: 16.8-26.3) months by investigators. Data on OS was immature. Totally, 40 (93.0%) patients had at least one treatment-related adverse event while 4 (9.3%) of them were grade ≥ 3., Conclusions: Rezivertinib (BPI-7711) showed promising efficacy and a favorable safety profile for the treatment among the locally advanced or metastatic/recurrent NSCLC patients with EGFR mutation in the first-line setting., Trial Registration: ClinicalTrials.gov, NCT03386955., (© 2022. The Author(s).)

Introduction: Rezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M mutations. This study was designed to evaluate the safety, efficacy, and pharmacokinetics of rezivertinib for patients having advanced NSCLC with EGFR T790M mutation., Methods: This phase 1 study (NCT03386955) was conducted across 20 sites in the People's Republic of China. Patients received rezivertinib at six oral dose levels (30 mg, 60 mg, 120 mg, 180 mg, 240 mg, 300 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were safety for the dose-escalation phase and objective response rate by the blinded independent central review for the total study population., Results: A total of 19 patients in dose-escalation phase using the standard 3 + 3 design principle and 153 patients in dose-expansion phase were enrolled from September 11, 2017, to August 23, 2019. The data cutoff date was on June 15, 2020. No dose-limiting toxicity occurred in the dose-escalation phase. The treatment-related adverse events were observed in 82.0% (141 of 172) of patients, and 17.4% (30 of 172) had grade greater than or equal to 3, among which decreased neutrophil count (2.9%), leukopenia (2.9%), and pneumonia (2.9%) were the most common. The overall blinded independent central review-evaluated objective response rate was 59.3% (102 of 172, 95% confidence interval: 51.6-66.7), and the median progression-free survival was 9.7 (95% confidence interval: 8.3-11.1) months., Conclusions: Rezivertinib was found to have promising efficacy with a manageable safety profile in patients with EGFR T790M-mutated advanced NSCLC. Further study is warranted., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not reached. Overall, 140 of the 152 (92%) patients experienced treatment-related adverse events (TRAEs) and 35 of the 152 (23%) patients had TRAEs ≥grade 3. The overall ORR was 59.3% (32 of 54) for the dose-escalation phase and 56.6% (56 of 99) for the dose-expansion phase. For patients who were ALK-rearranged and ALK TKI naive, the ORR were 81.0% (17 of 21) in the dose-escalation phase and 76.3% (29 of 38) in the dose-expansion phase, and for patients who previously received crizotinib as the only ALK TKI, the ORR were 38.1% (8 of 21) and 45.7% (21 of 46) for the two phases, respectively. For patients who were ROS1-rearranged, the ORR were 30.0% (3 of 10) in the dose-escalation phase and 44.4% (4 of 9) in the dose-expansion phase. WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement., (© 2022. The Author(s).)

Objectives: This prospective trial was performed to verify whether microwave ablation (MWA) in combination with chemotherapy could provide superior survival benefit compared with chemotherapy alone., Materials and Methods: From March 1, 2015, to June 20, 2017, treatment-naïve patients with pathologically verified advanced or recurrent non-small cell lung cancer (NSCLC) were randomly assigned to MWA plus chemotherapy group or chemotherapy group. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS), time to local progression (TTLP), and objective response rate (ORR). The complications and adverse events were also reported., Results: A total of 293 patients were randomly assigned into the two groups. One hundred forty-eight patients with 117 stage IV tumors were included in the MWA plus chemotherapy group. One hundred forty-five patients with 113 stage IV tumors were included in the chemotherapy group. The median follow-up period was 13.1 months and 12.4 months, respectively. Median PFS was 10.3 months (95% CI 8.0-13.0) in the MWA plus chemotherapy group and 4.9 months (95% CI 4.2-5.7) in the chemotherapy group (HR = 0.44, 95% CI 0.28-0.53; p < 0.0001). Median OS was not reached in the MWA plus chemotherapy group and 12.6 months (95% CI 10.6-14.6) in the chemotherapy group (HR = 0.38, 95% CI 0.27-0.53; p < 0.0001) using Kaplan-Meier analyses with log-rank test. The median TTLP was 24.5 months, and the ORR was 32% in both groups. The adverse event rate was not significantly different in the two groups., Conclusions: In patients with advanced NSCLC, longer PFS and OS can be achieved with the treatment of combined MWA and chemotherapy than chemotherapy alone., Key Points: • Patients treated with MWA plus chemotherapy had superior PFS and OS over those treated with chemotherapy alone. • The ORR of patients treated with MWA plus chemotherapy was similar to that of those treated with chemotherapy alone. • Complications associated with MWA were common but tolerable and manageable.

Background: Tyrosine kinase inhibitors (TKIs) can significantly prolong overall survival for patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-mutation or anaplastic lymphoma kinase (ALK)-rearrangement. However, the real-world evaluation status of ALK/EGFR in China remains unclear., Methods: We conducted a prospective study including 1134 patients with cytologically or histologically confirmed advanced NSCLC (stage IIIb-IV) at 12 Chinese hospitals., Results: The most common evaluation methods were amplification-refractory mutation system for EGFR status and immunohistochemistry targeting D5F3 for ALK status. Among patients with non-squamous, the EGFR mutation rate was 44.1% and the ALK rearrangement rate was 10.0%. Among patients with squamous cell carcinoma, the EGFR mutation rate was 8.3% and the ALK rearrangement rate was 3.7%. Among all patients, gender (HR = 1.7, 95%CI = 1.2-2.4, P = 0.006), smoking history (HR = 1.8, 95%CI = 1.3-2.7, P = 0.001), histology (HR = 5.0, 95%CI = 2.4-10.1, P < 0.001), and brain metastases (HR = 1.5, 95%CI = 1.1-2.2, P = 0.017) were independent predictors of EGFR mutation, while age (HR = 2.6, 95%CI = 1.7-4.1, P < 0.001) was an independent predictor of ALK rearrangement. The median time from tumor diagnosis to EGFR or ALK status confirmation was 7 and 5 days, respectively. Targeted therapy rate was 73.8% in EGFR-positive patients and 51.4% in ALK-positive patients. There was a negative correlation between the first-line targeted therapy rate and the EGFR mutation detection period (r = -0.152, P = 0.02), while no significant correlation among patients with ALK rearrangement (r = -0.179, P = 0.076)., Conclusion: Squamous NSCLC patients should also be routinely tested to determine their EGFR/ALK statuses. The first-line targeted therapy rate remains low in Chinese patients with NSCLC., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)