Background HLX04 is a proposed biosimilar of bevacizumab. Objective This phase III study aimed to evaluate the efficacy, safety, and immunogenicity of HLX04 compared with reference bevacizumab in combination with XELOX or mFOLFOX6 as first-line treatment for recurrent/metastatic colorectal cancer (CRC). Methods In this double-blind, parallel-group study, patients were randomized 1:1 to receive HLX04 or bevacizumab (7.5 mg/kg every 3 weeks when combined with XELOX; 5 mg/kg every 2 weeks when combined with mFOLFOX6). The primary endpoint was progression-free survival rate at week 36 (PFSR 36w ) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Prespecified equivalence margins of PFSR 36w were set as − 11 to 15% (rate difference) and 0.8 to 1.25 (rate ratio). Secondary endpoints included efficacy, safety, immunogenicity, and pharmacokinetics. Results A total of 677 patients were randomized (HLX04 n = 340; bevacizumab n = 337) between April 2018 and April 2020. PFSR 36w was 46.4% (95% confidence interval [CI] 41.1-51.8) with HLX04 and 50.7% (95% CI 45.4-56.1) with bevacizumab. The rate difference (− 4.2%; 90% CI − 10.6 to 2.1) and rate ratio (0.92; 90% CI 0.80-1.05) both fell within the prespecified equivalence margins. No notable differences were observed between treatment groups in any efficacy endpoints or their subgroup analyses. Safety, immunogenicity, and pharmacokinetic profiles were comparable between the two treatment groups. Conclusions HLX04 demonstrated equivalent efficacy with similar safety and immunogenicity profiles to reference bevacizumab among patients with recurrent/metastatic CRC, thus offering an alternative treatment option to patients.
Abstract. Nasopharyngeal carcinoma (NPC) is a malignancy with an unusually variable incidence rate across the world. Radiotherapy is the primary treatment modality for NPC, but radiation resistance remains a serious obstacle to successful treatment in many cases. To identify the genes involved in this resistance and to find molecular markers for predicting NPC response to radiotherapy, we compare the expression profiles of 12 radiation-resistant patient biopsy specimens and 8 radiationsensitive patient biopsy specimens using DNA microarray, containing 14112 human unigenes. A total of 111 aberrantly expressed genes were identified, of which ZNF608 and CSF1R were up-regulated in the radiation-resistant NPC compared with radiation-sensitive NPC, and the results were confirmed by real-time RT-PCR in 17 independent NPC patient specimens. Biostatistics and bioinformatics analyses were performed to detect the potential pathway underling this resistance, 26 pathways (9 categories) were found probably associated with radiation-resistant NPC, such as cell ion homeostasis, cell proliferation, receptor protein signalling, membrane system, humoral immune response, as well as cytokines and inflammation. We suggest the radiation-resistant capacity of NPC was mostly due to the change of cell Ca 2+ homeostasis promoting anti-apoptosis, DNA repair and rescuing tumour cells under radiation therapy. Cell proliferation promotion induced by extracellular and intracellular factors may maintain tumour size under radiotherapy leading to recurrence after treatment. Our study reveals that at least 2 ectopically expressed genes play important roles in prognosis of NPC radiotherapy and may serve as potential targets for novel radiation therapeutic strategies in the future.
Background: Human epidermal growth factor receptor 2 (ERBB2, HER-2) exon 20 insertion (ERBB2ex20ins) remains a refractory oncogenic driver in lung cancer. So far there is limited data showing the co-occurring mutation background of ERBB2ex20ins in Chinese lung cancer and its relationship with response to afatinib. Patients and Methods: A total of 112 Chinese patients with ERBB2ex20ins identified by next-generation sequencing from 17 hospitals were enrolled. The clinical outcomes of 18 patients receiving afatinib treatment were collected. Results: Among the 112 patients, insertion-site subtypes comprised of A775ins (71%; 79/112), G776indel (17%; 19/112), and P780ins (12%; 14/112). There were 66.1% (74/112) of patients carrying TP53 co-mutation and FOXA1 was the most prevalent co-amplified gene (5.5%, 3/55). The co-occurring genomic feature was similar among three insertional-site subtypes and had an overall strong concordance with the western population from the MSKCC cohort (R 2 = 0.74, P < 0.01). For the prognosis, patients with co-occurring mutation in cell-cycle pathway especially TP53 showed shorter OS than patients without [median OS: 14.5 m (95% CI:12.7-16.3 m) vs. 30.3 m (95% CI: not reached), p = 0.04], while the OS was comparable among three subtypes. For Yuan et al. ERBB2 and Afatinib the response to afatinib, ERBB2ex20ins as a subclonal variant was an independent factor relating to shorter PFS [median PFS: 1.2 m (95% CI: 0.8-1.6 m) vs. 4.3 m (95% CI: 3.3-5.3 m), p < 0.05]. Conclusion: Our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, emphasizing the more valuable role of the co-mutation patterns than insertion-site subtypes in predicting prognosis of this group of patients. Moreover, the clonality status of ERBB2ex20ins was identified as a potential indicator for response to afatinib.
2566 Background: Microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) in cells render them susceptible to immune checkpoint blockages. This study aimed to evaluate the efficacy and safety of HLX10, a fully humanized monoclonal antibody against PD-1, in patients with unresectable or metastatic MSI-H/dMMR solid tumors who have progressed on or been intolerant to standard therapies. Methods: In this single-arm, open-label, multicenter, phase 2 study (NCT03941574), patients (18≤ age ≤75 years) with histologically/cytologically confirmed unresectable or metastatic MSI-H/dMMR solid tumors were recruited to receive 3 mg/kg HLX10 every two weeks intravenously for up to 2 years until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was objective response rate (ORR) assessed by IRRC (evaluated every 6 weeks for the first 48 weeks and every 12 weeks thereafter) per RECIST v1.1. Secondary endpoints included ORR assessed by investigators, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. All eligible patients who received at least one dose of HLX10 were included in the safety analyses. Results: As of Jan 9, 2021, 108 patients were enrolled and 68 with locally or centrally confirmed MSI-H were included in the main efficacy analysis population. Among the 68 patients, the median follow-up duration was 7.7 (range: 1.1–16.4) months and the median age was 53.0 (range: 23.0–72.0) years. MSI-H tumor types included colorectal cancer (n = 54), endometrial cancer (n = 5), gastric cancer (n = 4), breast cancer (n = 2), small intestine cancer (n = 2) and fallopian tube cancer (n = 1). IRRC and investigator assessed ORR were 38.2% (95% CI: 26.7–50.8%; 2 complete response) and 35.3% (95% CI: 24.1–47.8%) respectively in the main efficacy analysis population. Median DoR, PFS and OS have not been reached. 105 (97.2%) patients experienced treatment-emergent adverse events (TEAEs), most commonly anemia (34.3%), hypoproteinemia (27.8%) and increased aspartate aminotransferase (25.0%). 53 (49.1%) patients had grade 3 or worse TEAEs, most commonly anemia (8.3%), progressive disease (6.5%), increased γ- glutamyltransferase (5.6%) and intestinal obstruction (5.6%). 52 (48.1%) patients had immune-related adverse events (irAEs) while 10 (9.3%) had grade 3 or worse irAEs. 3 (2.8%) deaths (2 PD and 1 intestinal obstruction) that might be related to the study drug were reported. Conclusions: HLX10 provides encouraging antitumor activity with a manageable safety profile in patients with MSI-H/dMMR solid tumors who have progressed on or been intolerant to standard therapies. As an effective tissue-agnostic treatment, HLX10 possesses the potential to improve patients’ clinical outcomes. Clinical trial information: NCT03941574.
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