Befotertinib for patients with pretreated EGFR T790M mutated locally advanced or metastatic NSCLC: Final overall survival results from a phase 2 trial.

BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.

A pooled analysis of clinical outcome in driver-gene negative non-small cell lung cancer patients with MET overexpression treated with gumarontinib.

Background: MET overexpression represents the most MET aberration in advanced non-small-cell lung cancer (NSCLC). However, except MET exon 14 (METex14) skipping mutation was recognized as a clinical biomarker, the role of MET overexpression as a predictive factor to MET inhibitor is not clear. Objectives: The purpose of the pooled analysis is to explore the safety and efficiency of gumarontinib, a highly selective oral MET inhibitor, in drive-gene negative NSCLC patients with MET overexpression. Design and methods: NSCLC patients with MET overexpression [immunohistochemistry (IHC) ⩾3+ as determined by central laboratory] not carrying epidermal growth factor receptor mutation, METex14 skipping mutation or other known drive gene alternations who received Gumarontinib 300 mg QD from two single arm studies were selected and pooled for the analysis. The efficacy [objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS)] and safety [treatment emergent adverse event (TEAE), treatment related AE (TRAE) and serious AE (SAE) were assessed. Results: A total of 32 patients with MET overexpression were included in the analysis, including 12 treatment naïve patients who refused or were unsuitable for chemotherapy, and 20 pre-treated patients who received ⩾1 lines of prior systemic anti-tumour therapies. Overall, the ORR was 37.5% [95% confidence interval (CI): 21.1-56.3%], the DCR was 81.3% (95% CI: 63.6-92.8%), median PFS (mPFS) and median OS (mOS) were 6.9 month (95% CI: 3.6-9.7) and 17.0 month (95% CI: 10.3-not evaluable), respectively. The most common AEs were oedema (59.4%), hypoalbuminaemia (40.6%), alanine aminotransferase increased (31.3%). Conclusion: Gumarontinib showed promising antitumour activity in driver-gene negative locally advanced or metastatic NSCLC patients with MET overexpression, which warranted a further clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT03457532; NCT04270591.

Patient-reported outcomes for the phase 3 FURLONG study of furmonertinib versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer.

Background: Furmonertinib showed superior efficacy compared with gefitinib as first-line therapy in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in the FURLONG study. Here we present prespecified secondary endpoints of patient-reported outcomes (PRO). Methods: In this multicentre, double-blind, double-dummy, randomised phase 3 study, patients were 1:1 randomly assigned to receive furmonertinib 80 mg once daily or gefitinib 250 mg once daily. PROs assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 and Quality-of-Life Questionnaire Lung Cancer 13 were analysed using a mixed model for repeated measures and time-to-event analyses. A difference in score of 10 points or more was deemed clinically relevant. Findings: Three hundred and fifty-seven patients (furmonertinib group, n = 178; gefitinib group, n = 179) received at least one dose of the study drug, all of whom completed at least one PRO assessment. Statistically significant difference of overall score changes from baseline favoured furmonertinib in physical functioning (between-group difference 2.14 [95% CI 0.25-4.04], p = 0.027), nausea/vomiting (-1.56 [95% CI -2.62 to -0.49], p = 0.004), appetite loss (-2.24 [95% CI -4.26 to -0.23], p = 0.029), diarrhoea (-3.36 [95% CI -5.19 to -1.54], p < 0.001), alopecia (-2.62 [95% CI -4.54 to -0.71], p = 0.007), and pain in other parts (-4.55 [95% CI -7.37 to -1.74], p = 0.002), but not reached clinical relevance. Time to deterioration in physical functioning (hazard ratio 0.63 [95% CI 0.42-0.94], p = 0.021), cognitive functioning (0.73 [95% CI 0.54-0.98], p = 0.034), nausea/vomiting (0.64 [95% CI 0.41-0.99], p = 0.042), appetite loss (0.63 [95% CI 0.43-0.92], p = 0.016), diarrhoea (0.63 [95% CI 0.46-0.85], p = 0.002), dyspnoea (0.72 [95% CI 0.53-0.98], p = 0.034), cough (0.67 [95% CI 0.44-1.00], p = 0.049), dysphagia (0.54 [95% CI 0.35-0.83], p = 0.004), and alopecia (0.62 [95% CI 0.42-0.90], p = 0.012) was longer with furmonertinib versus gefitinib. Interpretation: In patients with locally advanced or metastatic EGFR mutation-positive NSCLC, furmonertinib showed improved scores and delayed deterioration in several functioning and symptoms compared to gefitinib. Funding: Shanghai Allist Pharmaceutical Technology Co., Ltd and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Efficacy and safety of MIL62, a novel glycoengineered type â ¡ anti-CD20 monoclonal antibody, combined with lenalidomide in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma: a multicentre, single-arm, phase 1b/2 trial.

Background: MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively. Methods: This multicentre, single-arm, phase 1b/2 trial aimed to explore the efficacy, pharmacokinetics, and safety of MIL62 combined with lenalidomide in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Eligible patients included those who had histopathologically confirmed CD20 positive FL (grade 1-3a) or MZL and failed to be treated with rituximab. Patients received intravenously infused MIL62 1000 mg (cycle 1: day 1, 15; cycles 2-8: day 1, cycles 10 and 12: day 1) combined with oral lenalidomide (once a day, days 2-22, the initial dose was 10 mg, and the maximum dose was 20 mg) for 12 cycles, 28 days as a cycle. The primary endpoint was objective response rate (ORR) assessed by investigator per Lugano 2014 criteria every 3 cycles. This study was registered in ClinicalTrials.gov (NCT04110301). Findings: Between November 22, 2019 and December 22, 2020, 54 patients were enrolled from 11 hospitals in China and received study treatment. Fifty patients were included in the efficacy analysis set, and 43 patients (86%, 95% CI: 73, 94) achieved objective response, meeting the pre-specified primary endpoint. Disease control rate was 96% (48/50, 95% CI: 86, 100), proportion of patients with duration of response (DoR) > 6 months was 77% (33/43). The median follow-up for survival was 12.3 months (IQR 12.0-12.6). The 1-year progression-free survival rate was 72% (95% CI: 57, 83), 9-month DoR rate was 74% (95% CI: 58, 85), and 1-year overall survival rate was 98% (95% CI: 85, 100). Most common TRAEs were neutropenia (93%, 50/54), leukopenia (85% 46/54), thrombocytopenia (61% 33/54), lymphopenia (32% 17/54), and alanine aminotransferase increased (20% 11/54). Interpretation: MIL62 combined with lenalidomide showed promising efficacy in patients with R/R FL and MZL. A multicentre, randomized, open-label, phase Ⅲ trial of MIL62 combined with lenalidomide versus lenalidomide in anti-CD20 monoclonal antibody refractory FL patients is ongoing (NCT04834024). Funding: Beijing Mabworks Biotech Co. Ltd, Beijing China and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors.

Objective: The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Methods: Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Results: Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Conclusions: Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study.

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.

Plasma proteome profiling reveals dynamic of cholesterol marker after dual blocker therapy.

Dual blocker therapy (DBT) has the enhanced antitumor benefits than the monotherapy. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the DBT longitudinal plasma proteome profiling including 113 longitudinal samples from 22 patients who received anti-PD1 and anti-CTLA4 DBT therapy. The results show the immune response and cholesterol metabolism are upregulated after the first DBT cycle. Notably, the cholesterol metabolism is activated in the disease non-progressive group (DNP) during the therapy. Correspondingly, the clinical indicator prealbumin (PA), free triiodothyronine (FT3) and triiodothyronine (T3) show significantly positive association with the cholesterol metabolism. Furthermore, by integrating proteome and radiology approach, we observe the high-density lipoprotein partial remodeling are activated in DNP group and identify a candidate biomarker APOC3 that can reflect DBT response. Above, we establish a machine learning model to predict the DBT response and the model performance is validated by an independent cohort with balanced accuracy is 0.96. Thus, the plasma proteome profiling strategy evaluates the alteration of cholesterol metabolism and identifies a panel of biomarkers in DBT.

Regorafenib monotherapy or combined with an immune-checkpoint inhibitor as later-line treatment for metastatic colorectal cancer: a multicenter, real-world retrospective study in China.

OBJECTIVE: To evaluate the efficacy and safety of regorafenib monotherapy or in combination with immune-checkpoint inhibitor while treating Chinese patients with metastatic colorectal cancer (mCRC): a real-world study. METHODS: The data of patients with metastatic colorectal cancer who received regorafenib-containing regimen as the third or later line treatment at ten Chinese hospitals from Aug 2017 to Jun 2020 were retrospectively analyzed, including dosing details, survival data as well as adverse events. Survival analysis was further performed for patients administrated with regorafenib monotherapy and combined with an immune-checkpoint inhibitor based on Kaplan-Meier and Cox regression methods. The primary endpoint was overall survival. RESULTS: A total of 537 patients were included with a median age of 61, among whom 376 received regorafenib monotherapy and 245 received regorafenib combined with immune-checkpoint inhibitors. The clinicopathological characteristics of the two groups at baseline were mainly balanced. No significant difference in progression-free survival (PFS) was observed in patients receiving regorafenib monotherapy or combination therapy (3.8 vs. 5.5 months, p = 0.170). In contrast, patients receiving combination therapy had a more prolonged overall survival (OS) than those receiving regorafenib monotherapy (13.5 vs. 10.0 months, p = 0.001). The treatment regimen and regorafenib dosage were significant prognostic factors in the multivariate analysis. Significant benefits in PFS and OS were achieved in KRAS mutant and anti-angiogenesis treatment-naïve subgroups receiving combination therapy compared to monotherapy. No apparent increase was recorded in treatment-related adverse events in patients receiving combination therapy. CONCLUSION: Regorafenib plus an immune-checkpoint inhibitor has already been a widely adopted strategy in the later-line treatment for mCRC in the real world. The combination therapy yielded a significantly prolonged overall survival than regorafenib alone, with a manageable safety profile in Chinese patients, and warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04835324. Registered 6th April 2021.

A phase Ib study evaluating the safety and efficacy of IBI310 plus sintilimab in patients with advanced non-small-cell lung cancer who have progressed after anti-PD-1/L1 therapy.

BACKGROUND: The development of immune checkpoint inhibitors has made a significant breakthrough in the treatment of non-small-cell lung cancer (NSCLC). However, there remains a huge unmet clinical need for patients with acquired resistance after initial treatment response. METHODS: This study evaluated the combination of IBI310 (an anti-cytotoxic T lymphocyte-associated antigen-4 [CTLA-4] antibody) and sintilimab (an anti-programmed death 1 [PD-1]) antibody) in NSCLC patients who have previously been treated with anti-PD-1/ligand (L)1 and acquired resistance. The patients were randomly assigned to receive either a lower dose of IBI310 (1 mg/kg Q3W, cohort A) or a higher dose of IBI310 (3 mg/kg Q3W, cohort B) in combination with sintilimab (200 mg Q3W). The primary endpoints of the study were objective response rate (ORR) assessed by RECISTv1.1 and safety, while secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: As of November 2, 2023, the study had enrolled 30 patients, with 15 patients in each cohort. The ORR was 13.3% (2/15, 95% confidence interval [CI], 1.7-40.5) in cohort B. DCR were 46.7% (95% CI, 21.3-73.4) and 66.7% (95% CI, 38.4-88.2) in cohorts A and B, respectively. In cohorts A and B of this trial, the median follow-up times were 4.2 and 5.6 months, respectively. Median PFS was 1.45 (95% CI, 1.35-2.73) versus 2.73 (95% CI, 1.41-4.90) months for cohort A versus B; the median OS was 7.03 (95% CI, 3.09-not calculable [NC]) months in cohort A and 8.90 (95% CI, 5.13-NC) months in cohort B. Of the 30 patients, 86.7% in both cohorts experienced treatment-related adverse events (TRAEs) with Grade ≥3 TRAEs occurring in 40% and 53.3% of patients in cohorts A and B, respectively. CONCLUSION: IBI310 3 mg/kg Q3W plus sintilimab was effective in a small number of previously treated anti-PD-1/L1-resistant NSCLC patients.

A global phase 3 study of serplulimab plus chemotherapy as first-line treatment for advanced squamous non-small-cell lung cancer (ASTRUM-004).

Combining immunotherapy with chemotherapy can provide improved survival in advanced squamous non-small-cell lung cancer (NSCLC) patients without targetable gene alterations. 537 previously untreated patients with stage IIIB/IIIC or IV squamous NSCLC without targetable gene alterations were enrolled and randomized (2:1) to receive serplulimab 4.5 mg/kg or placebo, both in combination with nab-paclitaxel and carboplatin, intravenously in 3-week cycles. The primary endpoint of progression-free survival (PFS) was met at the first interim analysis. At the second interim analysis, PFS benefit was maintained in serplulimab-chemotherapy group (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.42-0.67). At the final analysis, serplulimab-chemotherapy significantly improved median OS compared to placebo-chemotherapy (HR 0.73, 95% CI 0.58-0.93; p = 0.010). Grade ≥3 serplulimab or placebo-related adverse events occurred in 126 (35.2%) and 58 (32.4%) patients, respectively. Our results demonstrate that adding serplulimab to chemotherapy significantly improves survival in advanced squamous NSCLC patients, with manageable safety.

Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial.

The combination of immune-checkpoint blockade with chemotherapy for the first-line treatment of advanced triple-negative breast cancer (TNBC) has generated mixed results. TORCHLIGHT is a randomized, double-blinded phase 3 trial evaluating the efficacy and safety of first-line toripalimab and nab-paclitaxel (nab-P) (n = 353; experimental arm) versus placebo and nab-P (n = 178; control arm) for the treatment of women with metastatic or recurrent TNBC. The primary end point was progression-free survival (PFS) assessed by a blinded independent central review in the PD-L1-positive and intention-to-treat populations. The secondary end points included overall survival and safety. Overall, 200 and 100 patients, in the toripalimab and placebo arm respectively had PD-L1-positive TNBC. At the prespecified interim analysis, a statistically significant improvement in PFS assessed by a blinded independent central review was demonstrated in the experimental arm in the PD-L1-positive population (median PFS 8.4 versus 5.6 months; hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.470-0.906, P = 0.0102). The median overall survival was 32.8 versus 19.5 months (HR = 0.62, 95% CI 0.414-0.914, P = 0.0148). Similar incidences of treatment-emergent adverse events (AEs) (99.2% versus 98.9%), grade ≥3 treatment-emergent AEs (56.4% versus 54.3%) and fatal AEs (0.6% versus 3.4%) occurred in the experimental and control arms. The addition of toripalimab to nab-P provided a significant improvement in PFS for PD-L1-positive patients with metastatic or recurrent TNBC with an acceptable safety profile. ClinicalTrial.gov identifier NCT03777579 .

Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study.

BACKGROUND: Befotertinib (D-0316) is a novel, selective oral third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor. This phase 3 trial compared the efficacy and safety of befotertinib with icotinib as a first-line treatment for patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This study was a multicentre, open-label, randomised, controlled phase 3 study at 39 hospitals in China. Eligible patients were 18 years of age or older, had histologically confirmed locally advanced or metastatic stage IIIB, IIIC, or IV unresectable NSCLC, and had confirmed exon 19 deletions or exon 21 Leu858Arg mutation. Patients were randomly assigned (1:1) via an interactive web response system to receive either oral befotertinib (75-100 mg once daily) or oral icotinib (125 mg three times per day) in 21-day cycles until disease progression or withdrawal criteria were met. Randomisation was stratified by type of EGFR mutation, CNS metastasis status, and gender, and participants, investigators, and data analysts were not masked to treatment allocation. The primary endpoint was independent review committee (IRC)-assessed progression-free survival in the full analysis set, which comprised all randomly assigned patients. All patients who received at least one dose of the study drug were included in safety analyses. This study was registered with ClinicalTrials.gov, NCT04206072, and the overall survival follow-up is still in progress. FINDINGS: Between Dec 24, 2019, and Dec 18, 2020, 568 patients were screened, of whom 362 were randomly assigned to the befotertinib (n=182) or icotinib (n=180) group; all 362 patients were included in the full analysis set. Median follow-up was 20·7 months (IQR 10·2-23·5) in the befotertinib group and 19·4 months (10·3-23·5) in the icotinib group. Median IRC-assessed progression-free survival was 22·1 months (95% CI 17·9-not estimable) in the befotertinib group and 13·8 months (12·4-15·2) in the icotinib group (hazard ratio 0·49 [95% CI 0·36-0·68], p<0·0001). Grade 3 or higher treatment-related adverse events occurred in 55 (30%) of 182 patients in the befotertinib group and in 14 (8%) of 180 patients in the icotinib group. Treatment-related serious adverse events were reported in 37 (20%) patients in the befotertinib group and in five (3%) patients in the icotinib group. Two (1%) patients in the befotertinib group and one (1%) patient in the icotinib group died due to treatment-related adverse events. INTERPRETATION: Befotertinib demonstrated superior efficacy compared with icotinib in first-line treatment for patients with EGFR mutation-positive NSCLC. Although serious adverse events were more common in the befotertinib than the icotinib arm, the safety profile of befotertinib was manageable overall. FUNDING: Betta Pharmaceuticals (China). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors.

BACKGROUND: QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. METHODS: In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. RESULTS: Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3-not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. CONCLUSIONS: QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Gumarontinib in patients with non-small-cell lung cancer harbouring MET exon 14 skipping mutations: a multicentre, single-arm, open-label, phase 1b/2 trial.

Background: Approximately 3-4% of patients with non-small-cell lung cancer (NSCLC) have MET exon 14 (METex14) skipping mutations. We report primary results from the phase 2 stage of a phase 1b/2 study of gumarontinib, a selective, potent, oral MET inhibitor, in patients with METex14 skipping mutation-positive (METex14-positive) NSCLC. Methods: The single-arm, multicentre, open-label, phase 2 stage of the GLORY study was conducted at 42 centres across China and Japan. Adults with locally advanced or metastatic METex14-positive NSCLC received oral gumarontinib 300 mg once daily in continuous 21-day cycles until disease progression, intolerable toxicity, or withdrawal of consent. Eligible patients had failed one or two prior lines of therapy (not including a MET inhibitor), were ineligible for/refused chemotherapy, and had no genetic alterations targetable with standard therapies. The primary endpoint was objective response rate in patients with a valid baseline tumour assessment, by blinded independent review. The study was registered at ClinicalTrials.gov (NCT04270591). Findings: Between Aug 2, 2019 and Apr 28, 2021, 84 patients were enrolled and received gumarontinib (median follow-up 13.5 months [IQR 8.7-17.1]), at data cut-off (Apr 28, 2022) five patients whose METex14 status could not be confirmed by a central laboratory were excluded from the efficacy analysis. The objective response rate was 66% (95% CI 54-76) overall (n = 79), 71% (95% CI 55-83) in treatment-naïve patients (n = 44), and 60% (95% CI 42-76) in previously-treated patients (n = 35). The most common treatment-related adverse events (any grade) were oedema (67/84 patients, 80%) and hypoalbuminuria (32/84, 38%). Grade ≥3 treatment-emergent adverse events occurred in 45 (54%) patients. Treatment-related adverse events leading to permanent discontinuation occurred in 8% (7/84) of patients. Interpretation: Gumarontinib monotherapy had durable antitumour activity with manageable toxicity in patients with locally advanced or metastatic METex14-positive NSCLC when used in first line or later. Funding: Haihe Biopharma Co., Ltd. Supported in part by grants from the National Science and Technology Major Project of China for "Clinical Research of Gumarontinib, a highly selective MET inhibitor" (2018ZX09711002-011-003); the National Natural Science Foundation of China (82030045 to S.L. and 82172633 to YF.Y); Shanghai Municipal Science & Technology Commission Research Project (19411950500 to S.L.); Shanghai Shenkang Action Plan (16CR3005A to S.L.) and Shanghai Chest Hospital Project of Collaborative Innovation (YJXT20190105 to S.L.).

Safety and effectiveness of apatinib in elderly patients with metastatic gastric cancer: a sub-analysis from the large-scale, prospective observational study of apatinib for gastric cancer treatment in a real-world clinical setting (AHEAD-G202).

Background: Apatinib was shown to improve the survival of Chinese patients with refractory metastatic gastric cancer (mGC). As an orally administered drug, it has been widely used in elderly patients because the dosing schedule can be adjusted flexibly. However, data on the efficacy and safety of apatinib in elderly patients is scarce. The aim of this study was to evaluate the toxicity and effectiveness of apatinib for elderly patients with mGC in a real-world setting. Methods: Data from the sub-population of patients who were ≥65 years enrolled in the AHEAD-G202 trial were analyzed. Patients with mGC were prospectively registered and initially received ≤850 mg oral apatinib daily combined or not combined with chemotherapy, at the investigator's discretion. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results: A total of 117 patients were included. There were 51 (43.59%) patients in the low-dose (250 mg) group, 60 (51.28%) patients in the mid-dose (425 to 500 mg) group, and 6 (5.13%) patients in the high-dose (850 mg) group according to the initial daily doses. Hypertension (6.84%) was the only grade 3-4 adverse event (AE) with a prevalence of more than 5% and across the low-dose (11.76%), mid-dose (3.33%) and high-dose group (0%). The median OS and PFS were 7.13 months (95% CI: 5.04 to 9.22 months) and 4.27 months (95% CI: 3.24 to 5.29 months), respectively. The OS and PFS were similar among the 65-74 and ≥75 years groups (χ2=1.406, P=0.306; χ2=0.378, P=0.066, respectively). The OS and PFS were also comparable among the 3 dose groups. Conclusions: Elderly patients with mGC can tolerate and benefit from apatinib therapy. A lower initial daily dosing strategy may be a suitable choice for elderly patients in clinical practice.

Central Nervous System Efficacy of Furmonertinib (AST2818) Versus Gefitinib as First-Line Treatment for EGFR-Mutated NSCLC: Results From the FURLONG Study.

INTRODUCTION: Furmonertinib (AST2818) is a pan-EGFR tyrosine kinase inhibitor with central nervous system (CNS) antitumor activity. We report the CNS efficacy of furmonertinib compared with gefitinib in untreated EGFR-sensitizing mutation-positive NSCLC from the FURLONG study. METHODS: FURLONG was a randomized, double-blind, phase 3 study conducted in 55 hospitals in the People's Republic of China. Patients 1:1 randomly received furmonertinib 80 mg once daily or gefitinib 250 mg once daily treatment. At screening, all the patients underwent brain imaging examination. Patients with asymptomatic steady CNS metastases at baseline constituted this preplanned CNS subgroup analysis. RESULTS: A total of 358 patients were enrolled in the FURLONG study. In the 133 (37%) patients who had measurable or nonmeasurable CNS lesions, CNS progression-free survival was 20.8 months (95% confidence interval [CI]: 15.2-25.3) in the furmonertinib group and 9.8 months (95% CI: 7.2-18.0) in the gefitinib group (hazard ratio = 0.40 [95% CI: 0.23-0.71], p = 0.0011). In the 60 patients (17%) who had measurable CNS lesions, CNS objective response rate was 91% (95% CI: 72-99) with furmonertinib and 65% (95% CI: 48-80) with gefitinib (OR = 6.82 [95% CI: 1.23-37.67], p = 0.0277). The least-square mean of CNS depth of response was 62% (95% CI: 51-72) in the furmonertinib group and 39% (95% CI: 30-47) in the gefitinib group, the mean difference was 23% (95% CI: 10-37, p = 0.0011). CONCLUSIONS: Furmonertinib first-line treatment was found to have superior efficacy in CNS progression-free survival, CNS objective response rate, and CNS depth of response compared with gefitinib in patients with EGFR-mutated NSCLC with CNS metastases.

Efficacy and safety of camrelizumab plus apatinib in previously treated patients with advanced non-small cell lung cancer harboring EGFR or ALK genetic aberration.

Background: Camrelizumab plus apatinib shows encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced non-small cell lung cancer (NSCLC); however, clinical benefits from this combination regimen in NSCLC patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) have not been reported. We assessed the efficacy and safety of this combined regimen in pretreated patients with advanced NSCLC and defined EGFR/ALK status (EGFR+/ALK+) in a phase 1b/2 trial. Methods: Previously treated patients with advanced EGFR+/ALK+ NSCLC were enrolled and given camrelizumab 200 mg intravenously every 2 weeks plus apatinib at the recommended dose of 250 mg orally once daily. Patients harboring sensitive EGFR mutations or ALK fusion genes had received at least one EGFR/ALK TKI and a platinum-based chemotherapy regimen before the enrollment. The primary endpoint was objective response rate (ORR). Results: All 43 enrolled patients comprised the efficacy and safety analysis population. The confirmed ORR was 18.6% (95% CI: 8.4-33.4%) and the clinical benefit response rate was 27.9% (95% CI: 15.3-43.7%). Median progression-free survival (PFS) was 2.8 months (95% CI: 1.9-5.5 months) and median overall survival was not reached (95% CI: 7.3 months-not reached), with a median follow-up period of 15.7 months (range, 0.5-24.4 months). The most common grade ≥3 treatment-related adverse events (TRAEs) were hypertension (16.3%), proteinuria (11.6%) and palmar-plantar erythrodysaesthesia syndrome (9.3%). No unexpected adverse events were recorded. Conclusions: Camrelizumab plus apatinib showed moderate antitumor activity and acceptable safety profile in previously treated patients with advanced NSCLC and EGFR or ALK genetic aberrations, which warranted further validation. Trial Registration: ClinicalTrials.gov identifier: NCT03083041. Registered March 17, 2017.

Two case reports of non-small cell lung cancer patients harboring acquired EGFR T790M-cis-C797S benefit from immune checkpoint inhibitor combined with platinum-based doublet chemotherapy.

Background: Acquired resistance is inevitable in non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The emergence of EGFR exon 20 C797S is one of the major resistance mechanisms to osimertinib as a third-generation EGFR-TKI. To date, there is no standard of care for NSCLC patients after acquiring EGFR C797S. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various types of cancers in the last decade. Whether NSCLC patients with acquired EGFR C797S could benefit from ICIs remains elusive. Case Description: Herein, we reported two cases of EGFR-mutant NSCLC patients who acquired a tertiary EGFR mutation C797S benefited from ICIs. A 28-year-old woman presented with anepithymia and nausea. Chest computed tomography (CT) revealed a mass in the right lung. She was diagnosed with stage IV lung adenocarcinoma (LUAD) with EGFR exon 19 deletion (19del) based on imaging and next-generation sequencing (NGS) findings. She received icotinib followed by osimertinib, then acquired EGFR T790M-cis-C797S. She had low tumor mutation burden (TMB) and achieved partial response (PR) to a programmed cell death-1 (PD-1) inhibitor sintilimab combined with platinum-based doublet chemotherapy as late-line treatment lasting more than 5 months. A 66-year-old man complained with chest tightness, hemoptysis, and back pain. CT scans revealed a mass in the right lung and metastases to the bilateral lungs, liver, adrenal gland, mediastinal lymph nodes, and bone. He was also diagnosed with EGFR 19del-positive LUAD and treated with icotinib followed by osimertinib. He also acquired EGFR T790M-cis-C797S. The patient had low TMB also and benefited from a PD-1 inhibitor camrelizumab combined with platinum-based doublet chemotherapy as late-line treatment with a progression-free survival (PFS) of 8 months. Two cases had no treatment-related adverse events leading to discontinuation of PD-1 inhibitors. Conclusions: Our study provides the first clinical evidence that ICIs combined with platinum-based doublet chemotherapy may be effective treatment options for overcoming resistance mediated by EGFR T790M-cis-C797S. Clinical trials are needed to evaluate the efficacy and safety of PD-1 inhibitors in the treatment of NSCLC patients harboring EGFR T790M-cis-C797S.

Furmonertinib (AST2818) versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer (FURLONG): a multicentre, double-blind, randomised phase 3 study.

BACKGROUND: Furmonertinib (AST2818) is an irreversible, selective, third-generation EGFR tyrosine-kinase inhibitor. We aimed to investigate the efficacy and safety of furmonertinib versus the first-generation EGFR tyrosine-kinase inhibitor gefitinib as first-line treatment in patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: The FURLONG study is a multicentre, double-blind, randomised, phase 3 study done in 55 hospitals across mainland China. We enrolled patients who were aged 18 years or older and had histologically confirmed, locally advanced or metastatic, stage IIIB, IIIC, or IV unresectable NSCLC with EGFR exon 19 deletions or exon 21 Leu858Arg mutation on tissue biopsy confirmed by a central laboratory. Eligible patients were stratified according to EGFR mutation (exon 19 deletions or exon 21 Leu858Arg) and CNS metastases (with or without) and randomly assigned (1:1) to receive either oral furmonertinib (80 mg/day) or oral gefitinib (250 mg/day) in 21-day cycles until disease progression, the occurrence of intolerable toxicities, withdrawal of consent, or other discontinuation reasons judged by the investigators. Investigators, clinicians, participants, independent review centre (IRC) members, the sponsor, and those analysing the data were all masked to treatment allocation. The primary endpoint was IRC-assessed progression-free survival and, along with safety, was analysed in the full analysis set, which comprised all randomly assigned patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03787992, and is ongoing for survival follow-up. FINDINGS: Between May 30, 2019, and Dec 5, 2019, 750 patients were screened, of whom 358 were randomly assigned to receive either furmonertinib and gefitinib-matching placebo (n=178) or gefitinib and furmonertinib-matching placebo (n=180). 178 patients randomly assigned to furmonertinib and 179 patients randomly assigned to gefitinib were treated and were included in the full analysis set. Median follow-up was 21·0 months (IQR 18·0-23·5) in the furmonertinib group and 21·0 months (18·0-23·5) in the gefitinib group. Median IRC-assessed progression-free survival was 20·8 months (95% CI 17·8-23·5) in the furmonertinib group and 11·1 months (9·7-12·5) in the gefitinib group (hazard ratio 0·44, 95% CI 0·34-0·58; p<0·0001). Treatment-related adverse events of a grade 3 or more occurred in 20 (11%) of 178 patients in the furmonertinib group and in 32 (18%) of 179 patients in the gefitinib group. Treatment-related serious adverse events were reported in ten (6%) patients in the furmonertinib group and in 11 (6%) patients in the gefitinib group. Ten (6%) patients in the furmonertinib group and three (2%) patients in the gefitinib group died due to adverse events, which were all judged to be possibly unrelated to study treatment by the investigators. INTERPRETATION: Furmonertinib showed superior efficacy compared with gefitinib as first-line therapy in Chinese patients with EGFR mutation-positive NSCLC, along with an acceptable safety profile without new signals. Furmonertinib is a new potential treatment option for this population. FUNDING: Shanghai Allist Pharmaceuticals and the China National Major Project for New Drug Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study.

INTRODUCTION: Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. METHODS: This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. RESULTS: A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. CONCLUSIONS: Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).