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Introduction: KRAS glycine-to-cysteine substitution at codon 12 (G12C) mutation is a well-recognized and increasingly promising therapeutic target with huge unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study., Methods: Eligible patients with NSCLC with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. The primary endpoint was confirmed objective response rate assessed by an independent radiological review committee (IRRC) as per Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints were safety, IRRC-confirmed disease control rate, duration of response, progression-free survival (PFS), and overall survival., Results: As of December 13, 2023, 116 patients were enrolled (Eastern Cooperative Oncology Group Performance Status 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1 or anti-PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per the IRRC assessment, the confirmed objective response rate was 49.1% (95% confidence interval [CI]: 39.7-58.6), and the disease control rate was 90.5% (95% CI: 83.7-95.2). The median duration of response was not reached whereas disease progression or death events occurred in 22 patients (38.6%), and the median PFS was 9.7 months (95% CI: 5.6-11.0). overall survival data was immature. Treatment-related adverse events (TRAEs) occurred in 107 patients (92.2%) whereas 48 patients (41.4%) had equal to or higher than grade three TRAEs. Common TRAEs were anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%) and presence of protein in urine (25.0%). TRAEs leading to treatment discontinuation occurred in nine patients (7.8%). In biomarker evaluable patients (n = 95), all patients had positive KRAS G12C in tissue whereas 72 patients were blood-positive and 23 were blood-negative for KRAS G12C. Patients with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p < 0.05) and worse PFS (p < 0.05). Tumor mutation profiling identified tumor protein p53 (45.3%), serine/threonine kinase 11 (STK11) (30.5%), and kelch-like ECH-associated protein 1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency equal to or higher than 5%, mutations of six genes (STK11, kelch-like ECH-associated protein 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, DNA polymerase epsilon, SMAD family member 4, and BMP/retinoic acid-inducible neural-specific protein 3) were significantly associated with worse PFS (p < 0.05). Mutation in STK11 was also found to have a significant association with higher tumor burden at baseline and lower response rate (p < 0.05)., Conclusions: IBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC., Competing Interests: Disclosure Prof. Zhou reports honoraria from AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol-Myers Squibb, Hengrui. Prof. Wu reports honoraria from AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol-Myers Squibb, Hengrui; consulting or advisory role from AstraZeneca, Roche, Boehringer Ingelheim, Takeda; and research funding from Boehringer Ingelheim, Roche, Pfizer, Bristol-Myers Squibb. Dr. Huang, Dr. Huang, Dr. Sun, Dr. Zhang, and Dr. Zhou are employees of the sponsor Innovent Biologics (Suzhou) Co., Ltd. The remaining authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: SCT510 is a biosimilar to bevacizumab (Avastin) reference product (RP) that is approved for various metastatic cancers. In this study, we aimed to demonstrate the equivalence of SCT510 and bevacizumab in terms of efficacy, safety, immunogenicity and pharmacokinetics (PK) in patients with advanced non-squamous non-small cell lung cancer (NSCLC)., Methods: Patients with non-squamous NSCLC were randomized equally to the SCT510 group (comprising SCT510, paclitaxel, and carboplatin) and the bevacizumab group (comprising bevacizumab, paclitaxel, and carboplatin) for 4-6 cycles, followed by maintenance monotherapy with SCT510. The primary endpoint was the objective response rate (ORR) at week 12. Secondary endpoints included 18-week ORR, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and 1-year survival rate, as well as assessments of safety, immunogenicity, and multi-dose PK analysis., Results: Between March 29, 2019, and April 27, 2021, 989 patients were screened and 567 eligible patients were randomly assigned to the SCT510 group (285 patients) and the bevacizumab group (282 patients). The ORR at week 12 was 52.6% [95% confidence interval (CI) 46.66-58.55%] in the SCT510 group and 52.5% (95% CI 46.47-58.47%) in the bevacizumab group. The ORR at week 18 was 55.4% (95% CI 49.46-61.30%) for SCT510 and 55.7% (95% CI 49.68-61.62%) for bevacizumab. The ORR risk ratio (RR) at weeks 12 and 18 was 0.99 (90% CI 0.873-1.133) and 0.99 (90% CI 0.872-1.114), respectively, both within the pre-specified equivalence margin of 0.75-1.33. There were no differences between the two groups in relation to other secondary endpoints, specifically DCR, DOR, PFS, OS, and 1-year survival rate. The overall safety findings were similar between the two treatment groups, and both SCT510 and bevacizumab RP exhibited low immunogenicity., Conclusions: SCT510 is similar to bevacizumab in clinical efficacy, safety, immunogenicity, and PK in patients with advanced non-squamous NSCLC. The totality of the evidence supports the clinical equivalence of SCT510 and bevacizumab., Trial Registration: NCT03792074., (© 2024. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Background: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study., Methods: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS)., Results: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed., Conclusions: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases., Trial Registration: ClinicalTrials.gov number, NCT03849768., (© 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat‐sen University Cancer Center.)

Background: 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., Methods: 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., Findings: 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., Interpretation: 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., Funding: Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer., Competing Interests: Declaration of interests Y-LW reports grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Roche, and personal fees from AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Hengrui, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi, outside of the submitted work. 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: Penpulimab is a novel programmed death (PD)-1 inhibitor. This study aimed to establish the efficacy and safety of first line penpulimab plus chemotherapy for advanced squamous non-small-cell lung cancer., Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 clinical trial enrolled patients with locally advanced or metastatic squamous non-small-cell lung cancer from 74 hospitals in China. Eligible participants were aged 18-75 years, had histologically or cytologically confirmed locally advanced (stage IIIb or IIIc) or metastatic (stage IV) squamous non-small-cell lung cancer, were ineligible to complete surgical resection and concurrent or sequential chemoradiotherapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, did not have previous systemic chemotherapy for locally advanced or metastatic non-small-cell lung cancer, and had one or more measurable lesions according to RECIST (version 1.1). Participants were randomly assigned (1:1) to receive intravenous penpulimab 200 mg or placebo (excipient of penpulimab injection), plus paclitaxel 175 mg/m 2 and carboplatin AUC of 5 intravenously on day 1 every 3 weeks for four cycles, followed by penpulimab or placebo as maintenance therapy. Stratification was done according to the PD-L1 tumour proportion score (<1% vs 1-49% vs ≥50%) and sex (male vs female). The participants, investigators, and other research staff were masked to group assignment. The primary outcome was progression-free survival assessed by the masked Independent Radiology Review Committee in the intention-to-treat population and patients with a PD-L1 tumour proportion score of 1% or more (PD-L1-positive subgroup). The primary analysis was based on the intention-to-treat analysis set (ie, all randomly assigned participants) and the PD-L1-positive subgroup. The safety analysis included all participants who received at least one dose of study drug after enrolment. This trial was registered with ClinicalTrials.gov (NCT03866993)., Findings: Between Dec 20, 2018, and Oct 10, 2020, 485 patients were screened, and 350 participants were randomly assigned (175 in the penpulimab group and 175 in the placebo group). Of 350 participants, 324 (93%) were male and 26 (7%) were female, and 347 (99%) were of Han ethnicity. In the final analysis (June 1, 2022; median follow-up, 24·7 months [IQR 0-41·4]), the penpulimab group showed an improved progression-free survival compared with the placebo group, both in the intention-to-treat population (median 7·6 months, 95% CI 6·8--9·6 vs 4·2 months, 95% CI 4·2-4·3; HR 0·43, 95% CI 0·33-0·56; p<0·0001) and in the PD-L1-positive subgroup (8·1 months, 5·7-9·7 vs 4·2 months, 4·1-4·3; HR 0·37, 0·27-0·52, p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in 120 (69%) 173 patients in the penpulimab group and 119 (68%) of 175 in the placebo group., Interpretation: Penpulimab plus chemotherapy significantly improved progression-free survival in patients with advanced squamous non-small-cell lung cancer compared with chemotherapy alone. The treatment was safe and tolerable. Penpulimab combined with paclitaxel and carboplatin is a new option for first-line treatment in patients with this advanced disease., Funding: The National Natural Science Foundation of China, Shanghai Municipal Health Commission, Chia Tai Tianqing Pharmaceutical, Akeso., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins., Methods: WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing., Findings: Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%])., Interpretation: In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988)., Funding: Dizal Pharmaceutical., Competing Interests: Declaration of interests ZY reports employment by Dizal Pharmaceutical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations. As part of the global, phase 1/2 ARROW trial (NCT03037385), the efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC) were evaluated., Methods: Adult patients with advanced, RET fusion-positive NSCLC with or without prior platinum-based chemotherapy were enrolled into two cohorts receiving 400-mg once-daily oral pralsetinib. Primary end points were objective response rates assessed by blinded independent central review and safety., Results: Of 68 patients enrolled, 37 had received prior platinum-based chemotherapy (48.6% with ≥3 prior systemic regimens) and 31 were treatment-naïve. As of March 4, 2022 (data cutoff), of the patients with measurable lesions at baseline, a confirmed objective response was observed in 22 (66.7%; 95% confidence interval [CI], 48.2-82.0) of 33 pretreated patients, including 1 (3.0%) complete response and 21 (63.6%) partial responses; and in 25 (83.3%; 95% CI, 65.3-94.4) of 30 treatment-naïve patients, including two (6.7%) complete responses and 23 (76.7%) partial responses. Median progression-free survival was 11.7 months (95% CI, 8.7-not estimable) in pretreated patients and 12.7 months (95% CI, 8.9-not estimable) in treatment-naïve patients. The most common grade 3/4 treatment-related adverse events in 68 patients were anemia (35.3%) and decreased neutrophil count (33.8%). Eight (11.8%) patients discontinued pralsetinib because of treatment-related adverse events., Conclusion: Pralsetinib showed robust and durable clinical activity with a well-tolerated safety profile in Chinese patients with RET fusion-positive NSCLC., Clinical Trial Registration: NCT03037385., (© 2023 American Cancer Society.)

One of the most important therapeutic interventions for non-small cell lung cancer is radiotherapy. Ionizing radiation (IR) is classified by traditional radiobiology principles as a direct cytocidal therapeutic agent against cancer, although there is growing recognition of other antitumor immunological responses induced by this modality. The most effective therapeutic combinations to harness radiation-generated antitumor immunity and enhance treatment results for malignancies resistant to existing radiotherapy regimens could be determined by a more sophisticated understanding of the immunological pathways created by radiation. Innate immune signaling is triggered by the activation of cGAS-STING, and this promotes adaptive immune responses to help fight cancer. This identifies a molecular mechanism radiation can use to trigger antitumor immune responses by bridging the DNA-damaging ability of IR with the activation of CD8 + cytotoxic T cell-mediated killing of tumors. We also discuss radiotherapy-related parameters that affect cGAS-STING signaling, negative consequences of cGAS-STING activation, and intriguing treatment options being tested in conjunction with IR to support immune activation by activating STING-signaling. Improved therapeutic outcomes will result from a better understanding of how IR promotes cGAS-STING signaling in immune-based treatment regimens that maximize radiotherapy's anticancer effectiveness., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results., Methods: This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18-75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing)., Findings: Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12·9 months (IQR 8·2-17·8) in the sintilimab plus IBI305 plus chemotherapy group, 15·1 months (8·0-19·5) in the sintilimab plus chemotherapy group, and 14·4 months (9·8-23·8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5·5 months [95% CI 4·5-6·1] vs 4·3 months [4·1-5·3]; hazard ratio [HR] 0·72 [95% CI 0·55-0·94]; two-sided p=0·016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7·2 months [95% CI 6·6-9·3]; HR: 0·51 [0·39-0·67]; two-sided p<0·0001). As of data cutoff (July 4, 2022), the median overall survival was 21·1 months (95% CI 17·5-23·9) for sintilimab plus IBI305 plus chemotherapy (HR 0·98 [0·72-1·34]) and 20·5 months (15·8-25·3) for sintilimab plus chemotherapy group (HR 0·97 [0·71-1·32]) versus 19·2 months (15·8-22·4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0·79 (0·57-1·09) to 0·84 (0·61-1·15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0·78 (0·57-1·08) to 0·84 (0·61-1·16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group., Interpretation: This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up., Funding: National Natural Science Foundation of China, Shanghai Municipal Science & Technology Commission Research Project, and Innovent Biologics., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests SL reports receiving research support from AstraZeneca, Hutchison, Bristol Myers Squibb, Heng Rui Beigene, Roche, and Hansoh; receiving speaker fees from AstraZeneca, Roche, and Hansoh; and serving as an adviser and consultant for AstraZeneca, Pfizer, Hutchison MediPharma, ZaiLab, GenomiCare, Novarti, Yuhan Corporation, Menarini, Mirati Therapeutics Inc, Daiichi Sankyo, D3 Bio, Simcere, Takeda, and Roche. HZ, XS, YS, SW, WZ, and YH are employees of Innovent Biologics. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.)

The randomized, double-blinded, multi-center, phase III GEMSTONE-302 ( NCT03789604 ) study evaluated the efficacy and safety of sugemalimab versus placebo in combination with chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (NSCLC). In this study, 479 treatment-naive patients with stage IV squamous or non-squamous NSCLC without known EGFR sensitizing mutations, ALK, ROS1 or RET fusions were randomized (2:1) to receive 1,200 mg of sugemalimab (n = 320) or placebo (n = 159) every 3 weeks in combination with platinum-based chemotherapy for up to four cycles, followed by maintenance therapy with sugemalimab or placebo for squamous NSCLC and sugemalimab or placebo plus pemetrexed for non-squamous NSCLC. Placebo-treated patients could cross over to receive sugemalimab monotherapy on disease progression. The primary endpoint was investigator-assessed progression-free survival (PFS) and the secondary endpoints included overall survival (OS) and objective response rate. Sugemalimab plus chemotherapy has demonstrated significant PFS prolongation in the primary analysis as reported previously. As of 22 November 2021, the prespecified interim OS analysis showed significant improvement with the addition of sugemalimab to chemotherapy (median OS = 25.4 versus 16.9 months; hazard ratio = 0.65; 95% confidence interval = 0.50-0.84; P = 0.0008). Sugemalimab plus chemotherapy provided superior PFS and OS compared to placebo plus chemotherapy, supporting the use of sugemalimab as a first-line treatment option for metastatic NSCLC., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

KRAS mutation is a common driver in solid tumors, and KRAS-mutated tumors are relatively resistant to radiotherapy. Therefore, we investigated the combined effect of radiation and KRAS-MEK inhibitors (AMG510 and trametinib) in KRAS-mutated tumors. The expression of programmed death-ligand 1 (PD-L1), major histocompatibility complex (MHC) class I molecules, and cytokines in KRAS-mutated cell lines was assessed using flow cytometry, western blot analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. In vivo, tumor growth, T cell infiltration, and gene sequencing analyses were conducted in 2 murine KRAS-mutated models. Both AMG510 and trametinib decreased the radiation-induced increase in PD-L1 expression. Radiation and trametinib additively induced the expression of CXCL10 and CXCL11 cytokines and MHC class I in murine CT26 and LLC cell lines. The combination of trametinib and radiation controlled tumor growth and induced more infiltration of CD4 + and CD8 + T cells in vivo, wherein tumor inhibition function and the survival period of mice could be reduced by CD8 + and/or CD4 + T cell depletion. The expression levels of immune-related genes also increased in the combination therapy group. Our results indicate that KRAS-MEK inhibitors in combination with radiotherapy can enhance antitumor immunity, providing new therapeutic strategies for KRAS-mutated tumors., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Some patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) respond poorly to anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) treatments. Combination with other agents may improve the outcomes. This open-label, multicenter, phase 1b trial investigated the combination of sitravatinib, a spectrum-selective tyrosine kinase inhibitor, plus anti-PD-1 antibody tislelizumab., Methods: Patients with locally advanced/metastatic NSCLC were enrolled (Cohorts A, B, F, H, and I; N=22-24 per cohort). Cohorts A and F included patients previously treated with systemic therapy, with anti-PD-(L)1-resistant/refractory non-squamous (cohort A) or squamous (cohort F) disease. Cohort B included patients previously treated with systemic therapy, with anti-PD-(L)1-naïve non-squamous disease. Cohorts H and I included patients without prior systemic therapy for metastatic disease, no prior anti-PD-(L)1/immunotherapy, with PD-L1-positive non-squamous (cohort H) or squamous (cohort I) histology. Patients received sitravatinib 120 mg orally one time per day plus tislelizumab 200 mg intravenously every 3 weeks, until study withdrawal, disease progression, unacceptable toxicity, or death. The primary endpoint was safety/tolerability among all treated patients (N=122). Secondary endpoints included investigator-assessed tumor responses and progression-free survival (PFS)., Results: Median follow-up was 10.9 months (range: 0.4-30.6). Treatment-related adverse events (TRAEs) occurred in 98.4% of the patients, with ≥Grade 3 TRAEs in 51.6%. TRAEs led to discontinuation of either drug in 23.0% of the patients. Overall response rate was 8.7% (n/N: 2/23; 95% CI: 1.1% to 28.0%), 18.2% (4/22; 95% CI: 5.2% to 40.3%), 23.8% (5/21; 95% CI: 8.2% to 47.2%), 57.1% (12/21; 95% CI: 34.0% to 78.2%), and 30.4% (7/23; 95% CI: 13.2% to 52.9%) in cohorts A, F, B, H, and I, respectively. Median duration of response was not reached in cohort A and ranged from 6.9 to 17.9 months across other cohorts. Disease control was achieved in 78.3-90.9% of the patients. Median PFS ranged from 4.2 (cohort A) to 11.1 months (cohort H)., Conclusions: In patients with locally advanced/metastatic NSCLC, sitravatinib plus tislelizumab was tolerable for most patients, with no new safety signals and overall safety profiles consistent with known profiles of these agents. Objective responses were observed in all cohorts, including in patients naïve to systemic and anti-PD-(L)1 treatments, or with anti-PD-(L)1 resistant/refractory disease. Results support further investigation in selected NSCLC populations., Trial Registration Number: NCT03666143., Competing Interests: Competing interests: QZ reports honoraria for lectures/presentations from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. DD reports institutional research funding for clinical trials participation from BeiGene, Bristol-Myers Squibb, EpimAb, Harbour BioMed, Maxinovel, MSD, Olema Pharmaceuticals, Pfizer, PhamAbcine, and Roche. MV reports honoraria from MSD and has served as an advisory board member for AstraZeneca. HL, JZhang, and YP are employees of BeiGene. Y-LW reports institutional grants from AstraZeneca, Bristol-Myers Squibb, and Pfizer; and honoraria for lectures/presentations from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Hengrui, MSD, Pfizer, Roche, and Sanofi. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Rezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) targeting both EGFR-sensitizing mutations and EGFR T790M mutation. This study aimed to evaluate the efficacy and safety of rezivertinib in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC., Methods: Patients with locally advanced or metastatic/recurrent NSCLC with confirmed EGFR T790M mutation who progressed after first-/second-generation EGFR TKI therapy or primary EGFR T790M mutation were enrolled. Patients received rezivertinib at 180 mg orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR) assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival, and safety. This study is registered with Clinical Trials.gov (NCT03812809)., Results: A total of 226 patients were enrolled from July 5, 2019, to January 22, 2020. By the data cutoff date on January 24, 2022, the median duration of follow-up was 23.3 months (95% confidence interval [CI]: 22.8-24.0). The ORR by blinded independent central review was 64.6% (95% CI: 58.0%-70.8%), and DCR was 89.8% (95% CI: 85.1%-93.4%). The median duration of response was 12.5 months (95% CI: 10.0-13.9), and median PFS was 12.2 months (95% CI: 9.6-13.9). The median overall survival was 23.9 months (95% CI: 20.0-not calculated [NC]). Among 91 (40.3%) patients with central nervous system (CNS) metastases, the median CNS PFS was 16.6 months (95% CI: 11.1-NC). In 29 patients with more than or equal to one brain target lesion at baseline, the CNS ORR and CNS DCR were 69.0% (95% CI: 49.2%-84.7%) and 100% (95% CI: 88.1%-100%), respectively. Time to progression of CNS was 16.5 months (95% CI: 9.7-NC). Of 226 patients, 188 (83.2%) had at least one treatment-related adverse event, whereas grade more than or equal to 3 occurred in 45 (19.9%) patients. No interstitial lung disease was reported., Conclusions: Rezivertinib was found to have promising efficacy and favorable safety profile for patients with locally advanced or metastatic/recurrent NSCLC with EGFR T790M mutation., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR -mutated non-small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768)., Methods: Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment., Results: A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively., Conclusion: Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR -mutant NSCLC in the first-line setting.

Background: VEGF inhibitors can enhance the efficacy of immunotherapy. However, despite high initial response rates, almost all patients eventually develop treatment resistance to EGFR tyrosine-kinase inhibitors. We aimed to evaluate the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin, compared with pemetrexed and cisplatin alone, for the treatment of patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) who had disease progression after receiving EGFR tyrosine-kinase inhibitor therapy., Methods: This randomised, double-blind, multicentre, phase 3 trial was conducted at 52 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC and EGFR mut who progressed after receiving a EGFR tyrosine-kinase inhibitor, had an Eastern Cooperative Oncology Group performance status of 0 or 1 with at least one measurable lesion, and an estimated life expectancy of at least 3 months. Participants were randomly assigned (1:1:1) to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ), sintilimab plus pemetrexed and cisplatin, or pemetrexed and cisplatin (chemotherapy alone) using block randomisation with stratification according to sex and presence or absence of brain metastases. All study drugs were administered intravenously on day 1 of each cycle, once every 3 weeks. Except for cisplatin, which was only given in the first four cycles, treatment was given for 24 months or until disease progression, intolerable toxic effects, withdrawal of consent, death, or other protocol-specified conditions, whichever occurred first. The primary endpoint was progression-free survival in the intention-to-treat population. We herein report the first planned interim analysis, with progression-free survival results for the comparison between sintilimab plus IBI305 plus chemotherapy versus chemotherapy alone. The progression-free survival results for the sintilimab plus pemetrexed and cisplatin group are immature and not reported here. This study is registered with ClinicalTrials.gov, NCT03802240 (recruiting)., Findings: Between July 11, 2019, and July 31, 2021, 936 patients were screened and 444 were randomly assigned (148 to the sintilimab plus IBI305 plus chemotherapy group, 145 to the sintilimab plus chemotherapy group, and 151 to the chemotherapy alone group). Data cutoff for this interim analysis was July 31, 2021. After a median follow-up of 9·8 months (IQR 4·4-13·3), progression-free survival was significantly longer in the sintilimab plus IBI305 plus chemotherapy group versus the chemotherapy alone group (median 6·9 months [95% CI 6·0-9.3] vs 4·3 months [4·1-5·4]; hazard ratio 0·46 [0·34-0·64]; p<0·0001). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophil count (30 [20%] in the sintilimab plus IBI305 plus chemotherapy group vs 26 [18%] in the sintilimab plus chemotherapy group vs 27 [18%] in the chemotherapy alone group), decreased white blood cell count (17 [11%] vs 12 [8%] vs 13 [9%]), and anaemia (18 [12%] vs ten [7%] vs 15 [10%]). Potentially treatment-related deaths occurred in six patients (intestinal obstruction, gastrointestinal haemorrhage, and myelosuppression in one patient each, and three deaths of unknown cause) in the sintilimab plus IBI305 plus chemotherapy group, and in one patient in the chemotherapy alone group (unknown cause)., Interpretation: In this interim analysis, sintilimab plus IBI305 plus cisplatin and pemetrexed was generally efficacious and well tolerated in patients with EGFR-mutated NSCLC who progressed after receiving EGFR tyrosine-kinase inhibitor therapy., Funding: Innovent Biologics and the National Natural Science Foundation of China., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests SL reports research support from AstraZeneca, Hutchison, BMS, Hengrui Therapeutics, Beigene, Roche, Hansoh, and Lilly Suzhou Pharmaceutical; speaker fees from AstraZeneca, Roche, Hansoh, and Hengrui Therapeutics; and is an adviser and consultant for AstraZeneca, Pfizer, Boehringer Ingelheim, Hutchison MediPharma, ZaiLab, GenomiCare, Yuhan Corporation, Menarini, InventisBio, and Roche. LW reports research support from AstraZeneca, Bristol-Myers Squibb, and Hengrui Therapeutics. HZ, XS, SW, WZ, and CZ are employees of Innovent. DF and YL are employees of Eli Lilly and Company, a global partner of Innovent. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Increasing evidence indicates that human forkhead box C1 (FOXC1) plays important roles in tumor development and metastasis. However, the underlying molecular mechanism of FOXC1 in non-small cell lung cancer (NSCLC) metastasis remains unclear. Here, we identified FOXC1 as an independent prognostic factor in NSCLC and showed clear biological implications in invasion and metastasis. FOXC1 overexpression enhanced the proliferation, migration and invasion of NSCLC cells, whereas FOXC1 silencing impaired the effects both in vitro and in vivo. Importantly, we found a positive correlation between FOXC1 expression and lysyl oxidase (LOX) expression in NSCLC cells and patient samples. Downregulation of LOX or LOX activity inhibition in NSCLC cells inhibited the FOXC1-driven effects on cellular migration and invasion. Xenograft models showed that inhibition of LOX activity by β-aminopropionitrile monofumarate decreased the number of lung metastases. Mechanistically, we demonstrated a novel FOXC1-LOX mechanism that was involved in the invasion and metastasis of NSCLC. Dual-luciferase assay and ChIP identified that FOXC1 bound directly in the LOX promoter region and activated its transcription. Collectively, the present study offered new insight into FOXC1 in the mediation of NSCLC metastasis through interaction with the LOX promoter and further revealed that targeted inhibition of LOX protein activity could prevent lung metastasis in murine xenograft models. These data implicated FOXC1 as a potential therapeutic strategy for the treatment of NSCLC metastasis., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: There is no definitive conclusion so far on the predictive values of ERCC1 polymorphisms for clinical outcomes of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). We updated this meta-analysis with an expectation to obtain some statistical advancement on this issue., Methods: Relevant studies were identified by searching MEDLINE, EMBASE databases from inception to April 2015. Primary outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). All analyses were performed using the Review Manager version 5.3 and the Stata version 12.0., Results: A total of 33 studies including 5373 patients were identified. ERCC1 C118T and C8092A could predict both ORR and OS for platinum-based chemotherapy in Asian NSCLC patients (CT + TT versus CC, ORR: OR = 0.80, 95% CI = 0.67-0.94; OS: HR = 1.24, 95% CI = 1.01-1.53) (CA + AA versus CC, ORR: OR = 0.76, 95% CI = 0.60-0.96; OS: HR = 1.37, 95% CI = 1.06-1.75)., Conclusions: Current evidence strongly indicated the prospect of ERCC1 C118T and C8092A as predictive biomarkers for platinum-based chemotherapy in Asian NSCLC patients. However, the results should be interpreted with caution and large prospective studies are still required to further investigate these findings.