Efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy in potentially resectable stage IIIA/IIIB non-small cell lung cancer: Neo-Pre-IC, a single-arm phase 2 trial.

Background: Some locally advanced (IIIA/IIIB) non-small cell lung cancers (NSCLCs) might have surgical options available. However, information regarding the effectiveness of neoadjuvant immunotherapy for potentially resectable IIIA/IIIB NSCLC is limited. The intent of this investigation was to offer a more favourable alternative to the standard approach of chemoradiotherapy (concurrent or sequential chemoradiotherapy) followed by immunotherapy for potentially resectable stage III NSCLC. Methods: This prospective, single-arm, phase 2 clinical trial (NCT04326153) enrolled treatment-naïve patients with 'potentially resectable' IIIA/IIIB NSCLC who were deemed unsuitable for complete (R0) resection upon initial diagnosis. The study period was between March 20, 2020, and August 20, 2021. Patients underwent neoadjuvant chemoimmunotherapy (sintilimab combined with nab-paclitaxel and carboplatin) for two to three cycles prior to surgical resection of the lung carcinoma and systematic nodal dissection within 30-45 days. The primary endpoint was the 2-year disease-free survival (DFS) rate, with secondary endpoints encompassing major pathological response (MPR) rate, pathological complete response (pCR) rate, overall survival, objective response rate (ORR), downstaging rate, and adverse events (AEs). Tumour immune cell infiltrates, identified via immunohistochemistry, were assessed as biomarkers at baseline and after surgery. Findings: Among 30 patients who received neoadjuvant chemoimmunotherapy, 20 underwent complete resection. The disease control rate was 96.7% (95% CI: 90.3%-99.99%), with an ORR of 55% (95% CI: 37.2%-72.8%) and a downstaging rate of 80% (95% CI: 65.7%-94.3%). In the subgroup of 20 patients who underwent surgery, the MPR rate was 65% (95% CI: 43.3%-82.9%), and the pCR rate was 40% (95% CI: 21.2%-46.3%). The 2-year DFS rate in the surgical group was 75% (95% CI 56%-94%). Notably, the MPR group demonstrated significantly prolonged DFS compared with the non-MPR group (p = 0.00024). A significant increase in pretreatment CD8 expression correlated with improved DFS (p = 0.00019). Three patients (10%) experienced grade 3 or higher immune-related AEs-one case of grade 3 elevated myocardial enzymes, one case of grade 3 interstitial pneumonia, and one case of grade 5 bronchopleural fistula. Interpretation: Neoadjuvant immunotherapy markedly enhanced the rate of pathological response and 2-year DFS in patients with potentially resectable IIIA/IIIB NSCLC. Overexpression of CD8 before treatment (H score≥3) may serve as a potential predictive biomarker for DFS. Consequently, the treatment landscape for potentially resectable IIIA/IIIB NSCLC could undergo changes. Funding: This study did not receive any financial support.

Small cell lung cancer with dermatomyositis: a case report.

Dermatomyositis represents an autoimmune disorder characterized by notable skin and muscular manifestations. The annual incidence of dermatomyositis stands at approximately (5~10)/1 million individuals. Notably, patients with malignant tumors exhibit an elevated risk of developing dermatomyositis compared to the general population. However, in cases where dermatomyositis co-occurs with malignancy, the efficacy of hormone therapy alone tends to be suboptimal. Moreover, reports addressing the correlation between tumor treatment and the management of dermatomyositis are scarce. A 60-year-old male patient presented with dermatomyositis, initially manifesting through symptoms such as rash, muscle weakness, and dysphagia. Despite undergoing standard hormone therapy, there was no discernible improvement in the dermatomyositis symptoms. Considering the patient's concomitant troublesome cough, further investigations were conducted, including CT, PET-CT, and pathological biopsy. These assessments confirmed the diagnosis of limited-stage small cell lung cancer (T1cN3M0 IIIB). Notably, in this patient, dermatomyositis was suspected to be a paraneoplastic syndrome associated with small cell lung cancer. Standard chemotherapy and radiotherapy were employed to treat the small cell lung cancer, resulting in partial remission after two treatment cycles. As the malignancy regressed, a notable improvement in dermatomyositis symptoms was observed, subsequently leading to a gradual reduction in the prescribed hormone dosage. In conclusion, we present a comprehensive case study of dermatomyositis as a paraneoplastic syndrome throughout the treatment process. The response to tumor therapy coincided with the amelioration of dermatomyositis symptoms. Therefore, diligent malignancy screening is imperative for patients diagnosed with dermatomyositis.

Tumor microenvironment(TME) and single-source dual-energy CT(ssDECT) on assessment of inconformity between RECIST1.1 and pathological remission in neoadjuvant immunotherapy of NSCLC.

BACKGROUND: The inconformity (IC) between pathological and imaging remissions after neoadjuvant immunotherapy in patients with NSCLC can affect the evaluation of curative effect of neoadjuvant therapy and the decision regarding the chance of surgery. MATERIALS AND METHODS: Patients who achieved disease control(CR/PR/SD) after neoadjuvant chemoimmunotherapy from a clinical trial (NCT04326153) and after neoadjuvant chemotherapy during the same period were enrolled in this study. All patients underwent radical resection and systematic mediastinal lymphadenectomy after neoadjuvant treatments. The pathological remission, immunohistochemistry (CD4, CD8, CD20, CD56, FoxP3, CD68, CD163, CD11b tumor-infiltrating lymphocytes, or macrophages), and single-source dual-energy computed tomography (ssDECT) scans were assessed. The IC between imaging remission by CT and pathological remission was investigated. The underlying cause of IC, the correlation between IC and DFS, and prognostic biomarkers were explored. RESULTS: After neoadjuvant immunotherapy, enhanced immune killing and reduced immunosuppressive performance were observed. 70 % of neoadjuvant chemoimmunotherapy patients were in high/medium IC level. Massive necrosis and repair around and inside the cancer nest were the main pathological changes observed 30-45 days post-treatment with PD1/PD-L1 antibody and were the main causes of IC between the pathology and imaging responses after neoadjuvant immunotherapy. High IC and preoperative CD8 expression (H score ≥ 3) indicate a high pathological response rate and prolonged DFS. Iodine material density ssDECT images showed that the iodine content in the lesion causes hyperattenuation in post-neoadjuvant lesion in PCR patient. CONCLUSIONS: Compared to chemotherapy and targeted therapy, the efficacy of neoadjuvant immunotherapy was underestimated based on the RECIST criteria due to the unique antitumor therapeutic mechanism. Preoperative CD8+ expression and ssDECT predict this IC and evaluate the residual tumor cells. This is of great significance for screening immune beneficiaries and making more accurate judgments about the timing of surgery.

Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib-refractory ALK-positive NSCLC from a phase II study.

BACKGROUND: The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. METHODS: In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. RESULTS: At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. CONCLUSION: Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

Imaging findings can't mean everything in the era of immunotherapy: a case report and literature review.

Immune-checkpoint inhibitors (ICIs) play an important role in the treatment of cancers. However, immunotherapy can also induce atypical response patterns, including pseudoprogression, which is challenging to clinicians. We reported a case of non-small-cell lung cancer showing so-called pseudoprogression during the treatment of pembrolizumab and the patient benefited clinically from continued treatment with ICIs. Therefore, beside imaging evaluation, the assessment of Eastern Cooperative Oncology Group performance status score, numerical rating scale score of cancer pain, tumor markers levels, and neutrophil-to-lymphocyte ratio should be used for response evaluation of tumors in the era of immunotherapy. And more accurate evaluation methods and reliable information are urgently needed to better understand the pseudoprogression.

Sometimes drugs can kill cancer cells but rather than getting smaller, as expected, the tumor size increases. This is called 'pseuoprogression', meaning false progression. Here, we report pseudoprogression in a lung cancer patient receiving immunotherapy. The tumor initially got larger, but with continued treatment, it decreased in size.

Genome-Wide Extrachromosomal Circular DNA Profiling of Paired Hepatocellular Carcinoma and Adjacent Liver Tissues.

Hepatocellular carcinoma (HCC) develops through multiple mechanisms. While recent studies have shown the presence of extrachromosomal circular DNA (eccDNA) in most cancer types, the eccDNA expression pattern and its association with HCC remain obscure. We aimed to investigate this problem. The genome-wide eccDNA profiles of eight paired HCC and adjacent non-tumor tissue samples were comprehensively elucidated based on Circle-seq, and they were further cross-analyzed with the RNA sequencing data to determine the association between eccDNA expression and transcriptome dysregulation. A total of 60,423 unique eccDNA types were identified. Most of the detected eccDNAs were smaller than 1 kb, with a length up to 182,363 bp and a mean sizes of 674 bp (non-tumor) and 813 bp (tumor), showing a greater association with gene-rich rather than with gene-poor regions. Although there was no statistical difference in length and chromosome distribution, the eccDNA patterns between HCC and adjacent non-tumor tissues showed significant differences at both the chromosomal and single gene levels. Five of the eight HCC tissues showed significantly higher amounts of chromosome 22-derived eccDNA expression compared to the non-tumor tissue. Furthermore, two genes, SLC16A3 and BAIAP2L2, with a higher transcription level in tumor tissues, were related to eccDNAs exclusively detected in three HCC samples and were negatively associated with survival rates in HCC cohorts from public databases. These results indicate the existence and massive heterogeneity of eccDNAs in HCC and adjacent liver tissues, and suggest their potential association with dysregulated gene expression.

Self-polymerized platinum (II)-Polydopamine nanomedicines for photo-chemotherapy of bladder Cancer favoring antitumor immune responses.

Systemic administration of platinum-based drugs has obvious limitations in the treatment of advanced bladder cancer (BC) owing to lower tumor accumulation and uncontrolled release of chemotherapeutics. There is an urgent need for advanced strategies to overcome the current limitations of platinum-based chemotherapy, to achieve maximal therapeutic outcomes with reduced side effects. In this study, self-polymerized platinum (II)-polydopamine nanocomplexes (PtPDs) were tailored for efficient chemo-photoimmunotherapy of BC. PtPDs with high Pt loading content (11.3%) were degradable under the combination of a reductive tumor microenvironment and near-infrared (NIR) light irradiation, thus controlling the release of Pt ions to achieve efficient chemotherapy. In addition, polydopamine promoted stronger photothermal effects to supplement platinum-based chemotherapy. Consequently, PtPDs provided effective chemo-photothermal therapy of MB49 BC in vitro and in vivo, strengthening the immunogenic cell death (ICD) effect and robust anti-tumoral immunity response. When combined with a PD-1 checkpoint blockade, PtPD-based photochemotherapy evoked systemic immune responses that completely suppressed primary and distant tumor growth without inducing systemic toxicities. Our work provides a highly versatile approach through metal-dopamine self-polymerization for the precise delivery of metal-based chemotherapeutic drugs, and may serve as a promising nanomedicine for efficient and safe platinum-based chemotherapy for BC.

A real-world study of the efficacy and safety of furmonertinib for patients with non-small cell lung cancer with EGFR exon 20 insertion mutations.

BACKGROUND: Furmonertinib is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). A phase Ib study (FAVOUR, NCT04858958) initially demonstrated the efficacy of furmonertinib in non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins). This study aimed to investigate the real-world efficacy and safety of furmonertinib in patients with advanced NSCLC with EGFR ex20ins. METHODS: We retrospectively examined patients with advanced NSCLC with EGFR ex20ins having complete follow-up data, who were treated with furmonertinib from April 14, 2021, to March 15, 2022, at our institution and multiple hospitals in China. Objective response rate (ORR), disease control rate (DCR), 6-month progression-free survival (PFS) rates and treatment related adverse events (TRAEs) were assessed. RESULTS: This study included 53 patients with advanced NSCLC with EGFR ex20ins. A767_V769dup (28.3%) and S768_D770dup (11.3%) are the major variants. The ORR and DCR were 37.7% (20/53) and 92.5% (49/53), respectively. The 6-month PFS rate was 69.4% (95% CI 53.7-85.1%). The ORR of patients in the 240 mg once-daily dosage group was higher (42.9%) than that of patients in the 80 mg once-daily (25.0%) and 160 mg once-daily (39.5%) groups, but with no statistically significant difference (P = 0.816). The ORR of furmonertinib is not dependent on insertion location (P = 0.893). Patients with central nervous system (CNS) metastases at baseline responded similarly to those without CNS metastases (ORR: 33.3% vs. 40.6%, P = 0.773). The most common AEs were diarrhea (26.4%) and rash (26.4%). No grade ≥ 3 TRAEs were observed. No statistically significant difference was observed in the incidence of TRAEs between dosage groups (P = 0.271). CONCLUSIONS: Furmonertinib has shown encouraging antitumor activity and CNS activity in patients with advanced NSCLC with EGFR ex20ins. Moreover, furmonertinib had a good safety profile and no dose-dependent toxicity.

Interim analysis of the efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy (nab-paclitaxel and carboplatin) in potentially resectable stage IIIA/IIIB non-small cell lung cancer: a single-arm, phase 2 trial.

INTRODUCTION: While some clinical studies have shown that PD-1 and PD-L1 can also be an effective neoadjuvant treatment for early-stage non-small cell lung cancer (NSCLC), no evidence has been available for the use of the PD-1 inhibitor sintilimab combined with chemotherapy as a neoadjuvant treatment for potentially resectable NSCLC in the Chinese population. METHODS: This prospective, single-center, single-arm, phase 2 clinical trial (registration number: NCT04326153) included treatment-naive patients with potentially resectable NSCLC (stage IIIA/IIIB) who received sintilimab plus nab-paclitaxel and carboplatin for two to three cycles before systematic nodal dissection 30 to 45 days after neoadjuvant treatment. After surgery, patients needed to complete two cycles of adjuvant chemoimmunotherapy (sintilimab + nab-paclitaxel + carboplatin). The primary endpoint was disease-free survival rate at 24 months, whereas secondary endpoints included major pathological response (MPR) and pathologic complete response (pCR) rates, the proportion of patients who achieved tumor downstaging, overall survival, objective response rate (ORR), and adverse effects. PD-L1 status before and after treatment was also determined. RESULTS: Among the 20 patients who received neoadjuvant chemoimmunotherapy, 16 underwent radical resection. The disease control rate and ORR were 90% and 70%, respectively. Among the 16 patients who underwent surgery, 10 (62.5%) and 5 (31.25%) achieved MPR and pCR, respectively. Squamous cell NSCLC exhibited superior response rates compared to adenocarcinoma (pCR 35.7% vs. 0%). Moreover, 14 patients (70%) experienced grade 1 or 2 neoadjuvant treatment-related adverse events (TRAEs), whereas 6 (30%) experienced grade 3 TRAEs. Bronchopleural fistula (BPF) was found in the current study as an adverse reaction of concern. The rate of BPF was 20% (4/20), of which three patients were in grade 1-2, and one patient died. The occurrence of BPF had no significant correlation with basic disease history, nutritional status, anemia, hypoalbuminemia, surgical procedure, pathological remission, and PD-L1 expression. However, during neoadjuvant treatment, no adverse events prompted dose reduction, treatment discontinuation, surgery delay, or death. Although PD-L1 expression may change after chemoimmunotherapy, no regular pattern was noted. PD-L1 expression, neither at baseline nor after neoadjuvant chemoimmunotherapy, was associated with pathological remission. CONCLUSIONS: The current study found similar ORR, slightly lower MPR and pCR rates, and lower grade 3 TRAEs among patients with potentially resectable stage IIIA/IIIB NSCLC compared to the NADIM trial, as well as a greater ORR, MPR rate, pCR rate, and grade 3 TRAEs compared to Gao's study involving sintilimab for Chinese patients with resectable stage IA-IIIB NSCLC. Though neoadjuvant chemoimmunotherapy had been found to promote a high risk of BPF for patients with stage IIIA/IIIB disease, it offered greater potential for radical cure. Therefore, the current study suggests that neoadjuvant chemoimmunotherapy can be a safe approach in increasing the efficiency of treatment and hopefully improving the prognosis of patients with potentially resectable locally advanced NSCLC.

A phase II study of antiangiogenic therapy (Apatinib) plus chemotherapy as second-line treatment in advanced small cell lung cancer.

INTRODUCTION: Currently, only a few options are available for the treatment of patients with small-cell lung cancer (SCLC) after the failure of first-line platinum-based chemotherapy. The present study aimed to evaluate the efficacy and safety of apatinib plus chemotherapy for second-line treatment of advanced SCLC. PATIENTS AND METHODS: This prospective clinical trial recruited patients treated with apatinib plus second-line chemotherapy until disease progression or intolerable toxicity. Logrank test power analysis was used for calculating samples. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: A total of 29/31 enrolled patients were available for response evaluation until October 2019. The ORR and DCR were 27.59% (8/29) and 96.55% (28/29), respectively. The median PFS and OS were 7.36 months and 14.16 months, respectively, indicating better efficacy compared with the standard second-line chemotherapies. The most common adverse events (AEs) were neutropenia (41.94%, 13/31), followed by leucopenia (35.48%, 11/31) and thrombocytopenia (25.81%, 8/31). The grade 3-4 AEs occurred in 12 (38.71%) patients, of which neutropenia (19.35%, 6/31), leucopenia (9.68%, 3/31), and proteinuria (6.45%, 2/31) were most common. Patients receiving an initial dose of apatinib 250 mg had a better tolerance. CONCLUSION: Antiangiogenic therapy plus chemotherapy had encouraging efficacy in advanced SCLC patients, which provides an insight into the current status of second-line therapy in SCLC.

Sintilimab plus autologous NK cells as second-line treatment for advanced non-small-cell lung cancer previous treated with platinum-containing chemotherapy.

This pilot study (NCT03958097; https://www.clinicaltrials.gov/ct2/show/NCT03958097) was aimed to evaluate the efficacy and safety of PD-1 antibody combined autologous NK cells in the treatment of patients with stage IIIB/IIIC or IV non-small-cell lung cancer (NSCLC) who failed the first-line platinum-based chemotherapy. All patients received both sintilimab 200mg and 3×109 NK cells every 3 weeks. 20 patients were enrolled, median follow up time was 22.6 months. The median PFS was 11.6 months, ORR was 45%. Median OS was 17.7 months, 6-month OS rate and 12-month OS rate was 95.0% and 80.0%. Unexpected adverse events were not observed. 2 patients reported grade 3 adverse events (hypertriglyceridemia, neutropenia and increased creatine kinase). The autologous NK cells did not add extra adverse events to the ICI treatment. Autologous NK plus sintilimab showed promising antitumor activity and an acceptable safety profile in advanced driven-mutation negative NSCLC who failed on the first line treatment.

An open label, safety study of Asian patients with advanced non-small-cell lung cancer receiving second-line nivolumab monotherapy (CheckMate 870).

Background: Nivolumab has been approved in China as second-line treatment for advanced non-small-cell lung cancer (NSCLC) via weight-based infusion, based on the CheckMate 078 study. We investigated the safety and efficacy of 240 mg flat-dose nivolumab in patients with advanced NSCLC, including those with hepatitis B virus (HBV) and epidermal growth factor receptor (EGFR) mutation/ALK receptor tyrosine kinase (ALK) translocation due to high prevalence in China. Methods: CheckMate 870 was a single-arm, open-label, phase IIIb trial in Asian (primarily Chinese) patients with previously treated advanced NSCLC. Patients received flat-dose nivolumab 240 mg every 2 weeks (Q2W) for up to 2 years. The primary endpoint was the incidence and severity of treatment-related select adverse events (TRsAEs) in non-HBV patients; secondary and exploratory endpoints included severity of high-grade TRsAEs in HBV-infected patients, and safety, efficacy and patient-reported outcomes (PROs) in the whole population. Results: Out of 404 patients enrolled, 400 received treatment. Median (standard deviation) age was 60.5 (8.68) years and the majority were male (78.5%). At a median follow-up of 37.6 months, no Grade 5 TRsAEs were reported, and the frequency of Grade 3-4 TRsAEs was low (0.0-5.9%) in non-HBV and HBV NSCLC patients. Median overall survival (OS) and progression-free survival (PFS) in all treated patients were 14.7 (12.3-18.1) and 3.6 (2.3-3.8) months, respectively. Median OS was 14.2 (12.3-18.1) and 22.3 (10.0-NA) months for non-HBV and HBV-infected patients, 19.3 (11.2-31.7) and 13.7 (11.5-18.1) months for EGFR-positive and wild-type subgroups, and 19.3 (12.9-23.5) and 13.3 (10.9-17.7) months for those with programmed death-ligand 1 (PD-L1) expression ⩾1% and <1%, respectively. No notable changes from baseline were observed in PROs throughout the study. Conclusion: Nivolumab 240 mg infusion Q2W was well tolerated, efficacious, and maintained health status and quality of life in Asian patients with previously treated advanced NSCLC regardless of HBV, EGFR, or PD-L1 status.

The time window for the reversal of depigmentation from aggravation to recovery in a non-small-cell lung cancer patient with pre-existing vitiligo using anti-programmed cell death-1 therapy: A case report.

Immune checkpoint inhibitors have made remarkable breakthroughs in the treatment of lung cancer, bringing significant survival benefits to the patients. A number of adverse events aggravated by immunotherapy in patients with pre-existing autoimmune diseases have been reported in the past, especially skin toxicity, such as rash, pruritus, erythema, and vitiligo. However, whether the exacerbated autoimmune disease is reversible and when it will return to its original state after immunotherapy discontinuation is still inconclusive. In our report, we described a patient diagnosed with non-small cell lung cancer whose vitiligo was stable for about 10 years. We followed up and observed the patient's skin depigmentation for the complete time window, from aggravation of application anti-programmed cell death-1 receptor antibody (anti-PD-1 antibody) to recovery after the withdrawal. We presented the objective images at particular time points using reflectance confocal microscopy and wood's light. We found that the use of anti-PD-1 antibody aggravated in skin toxicity, but it was reversible, the time window from the beginning to recovery status was approximately 9 months. We used this real case scenario to explain the relationships between immunotherapy and autoimmune diseases.

Efficacy of Immunotherapy Combined with Antiangiogenic Therapy in Treatment-Failure Patients with Advanced Carcinoma Ex Pleomorphic Adenoma of the Submandibular Gland: A Case Report.

Carcinoma ex pleomorphic adenoma (Ca ex PA) is a rare malignant tumor that arises from a primary or recurrent benign pleomorphic adenoma (PA). Ca ex PA has an aggressive behavior and poor prognosis. To date, there are no standardized therapeutic methods. Herein, we reported a case of a 57-year-old Chinese female with Ca ex PA of the submandibular gland. After surgery, cervical lymph nodes recurred, and multiple distant metastases were detected. During the treatment, she received multiple chemotherapies and radiotherapy but suffered from multidrug resistance and repeated disease progression. Hence, PD-1 inhibitor (sintilimab), in combination with anlotinib, was administered, which resulted in better control of pulmonary metastases compared to the other treatment regimens. This provided an alternative treatment option for Ca ex PA of the submandibular gland patients with failed multiple therapies.

Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study.

BACKGROUND: Central nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings. METHODS: In this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Sixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone. CONCLUSIONS: Our study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.

Combined targeting of EGFR and BRAF triggers regression of osimertinib resistance by using osimertinib and vemurafenib concurrently in a patient with heterogeneity between different lesions.

Acquired BRAF V600E mutation can occur in tumors with EGFR mutation and is suspected as a resistance mechanism to third-generation EGFR-tyrosine kinase inhibitors (TKIs). However, the treatment strategy for the coexistence of EGFR and acquired BRAF mutation with heterogeneity in lung cancer has not been systematically established. Here, we report a patient in whom BRAF V600E and EGFR 19del mutation in a metastatic lesion followed by disease progression on osimertinib was detected. Treatment with single-agent vemurafenib was effective for treatment of the metastatic lesion in this patient but the primary lesion progressed. A concurrent combination of vemurafenib and osimertinib was therefore administered and a partial response of both primary and metastatic lesions was achieved with progression-free survival (PFS) of 7 months. The concurrent combination treatment was well tolerated by the patient through dosing modification and supportive medical care. This case highlights the consideration of heterogeneity between different lesions and provides a successful example of the concurrent therapy with vemurafenib and osimertinib for triggering regression of osimertinb resistance induced by BRAF mutation.

Clinical outcome, long-term survival and tolerability of sequential therapy of first-line crizotinib followed by alectinib in advanced ALK+NSCLC: A multicenter retrospective analysis in China.

BACKGROUND: There is limited data on the clinical outcome, long-term survival and tolerability of sequential therapy of first-line crizotinib followed by alectinib in a real-world setting for Chinese patients with advanced ALK+ NSCLC. METHODS: The medical records of patients who received sequential therapy with first-line crizotinib followed by alectinib (no intermittent systemic therapy was allowed between the two ALK-TKIs) were collected from six centers in China. Combined time treatment to failure (C-TTF) was defined as the period from the start of crizotinib to the complete discontinuation of alectinib due to any cause. RESULTS: A total of 61 patients were included in our study. Fifty-two patients were switched to alectinib due to disease progression, seven as a result of toxicity, and two due to patient preference. At the time of data cutoff, alectinib treatment was discontinued in 31 patients on account of disease progression while severe adverse events resulted in cessation of alectinib in another two patients. Rebiopsy was conducted in 21 patients following disease progression on alectinib in whom ALK secondary mutation was found in 13 patients. Patients with ALK secondary mutation demonstrated better PFS during treatment with subsequent ALK-TKIs compared with those without (10.4 vs. 3.1 m, p = 0.0018, HR = 0.08). With a median follow-up of 34.3 months, C-TTF was 39.2 months and estimated 5-year OS was 68.6% in the overall population. CONCLUSION: Sequential therapy with first-line crizotinib followed by alectinib demonstrated long-term benefits. Different efficacy in subsequent ALK-TKI between patients with or without ALK secondary mutation further emphasized the importance of rebiopsy to guide targeted therapy more precisely.

Alectinib as first-line treatment for advanced ALK-positive non-small cell lung cancer in the real-world setting: preliminary analysis in a Chinese cohort.

Background: Tyrosine kinase inhibitors (TKIs) have been a major advance in the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) which have been substantiated in clinical trials. However, real-world data on first-line alectinib in a Chinese patient population are limited. Methods: We enrolled patients diagnosed with advanced ALK-positive NSCLC treated with first-line alectinib at 8 centers in China, including cases with symptomatic or active CNS metastases. Continuation of alectinib was permitted after local or gradual progression at the treating clinician's discretion. Time-to-treatment failure (TTF) was defined as the period from the start of alectinib to discontinuation for any cause including disease progression, death, adverse events and patient's preference. We defined longer EML4-ALK variants as containing EML4 fusions to at least exon 13 and shorter variants had EML4 fusions up to exon 6. Results: Of the 110 patients included, 26.4% had Eastern Cooperative Oncology Group Performance Status (ECOG) ≥2 points. The objective response rate (ORR) was 88.5% [95% confidence interval (CI): 79.9-94.3%] and median tumor shrinkage rate was 60% (range, 0-100%) in patients with target lesions. For patients with measurable central nervous system (CNS) metastases, the CNS-ORR was 92.9% (95% CI: 66.1-99.8%), additionally, 80% (8/10) of patients experienced significant improvement in CNS-related symptoms following alectinib treatment. With a median follow-up of 18.3 months, the estimated 2-year progression-free survival (PFS) rate and 2-year treatment failure-free rate were 81.1% (95% CI: 71.5-87.7%) and 81.0% (95% CI: 70.6-88.0%) respectively. Grade 3-4 adverse events occurred in 6.4% and only 2 patients (1.8%) permanently discontinued alectinib due to adverse events. Multivariate analysis indicated that patients with metastases in ≥3 distant organs and a tumor reduction rate ≤50% demonstrated more unfavorable mPFS than their counterparts. Furthermore, patients carrying longer variants showed superior mPFS to those with shorter variants (not reached vs. 24.2 months, hazard ratio =0.17, 95% CI: 0.04-0.68, P=0.004). Conclusions: Alectinib showed substantial efficacy and an excellent safety profile in a real-world setting of Chinese patients. Clinical outcomes and long-term survival still require longer follow-up. Tumors with shorter EML4 fusion variants, more extensive metastases and less reduction in tumor lesions may require more aggressive strategies.

Correlation of circulating tumor DNA EGFR mutation levels with clinical outcomes in patients with advanced lung adenocarcinoma.

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising biomarker for non-invasive epidermal growth factor receptor mutations (EGFRm) detection in lung cancer patients, but existing methods have limitations in sensitivity and availability. In this study, we used the ΔCt value (mutant cycle threshold [Ct] value-internal control Ct value) generated during the polymerase chain reaction (PCR) assay to convert super-amplification-refractory mutation system (superARMS) from a qualitative method to a semi-quantitative method named reformed-superARMS (R-superARMS), and evaluated its performance in detecting EGFRm in plasma ctDNA in patients with advanced lung adenocarcinoma. METHODS: A total of 41 pairs of tissues and plasma samples were obtained from lung adenocarcinoma patients who had known EGFRm in tumor tissue and were previously untreated. EGFRm in ctDNA was identified by using superARMS. Through making use of ΔCt value generated during the detection process of superARMS, we indirectly transform this qualitative detection method into a semi-quantitative PCR detection method, named R-superARMS. Both qualitative and quantitative analyses of the data were performed. Kaplan-Meier analysis was performed to estimate the progression-free survival (PFS) and overall survival (OS). Fisher exact test was used for categorical variables. RESULTS: The concordance rate of EGFRm in tumor tissues and matched plasma samples was 68.3% (28/41). At baseline, EGFRm-positive patients were divided into two groups according to the cut-off ΔCt value of EGFRm set at 8.11. A significant difference in the median OS (mOS) between the two groups was observed (EGFRm ΔCt ≤8.11 vs. >8.11: not reached vs. 11.0 months; log-rank P = 0.024). Patients were divided into mutation clearance (MC) group and mutation incomplete clearance (MIC) group according to whether the ΔCt value of EGFRm test turned negative after 1 month of treatment. We found that there was also a significant difference in mOS (not reached vs. 10.4 months; log-rank P = 0.021) between MC group and MIC group. Although there was no significant difference in PFS between the two groups, the two curves were separated and the PFS of MC group tended to be higher than the MIC group (not reached vs. 27.5 months; log-rank P = 0.088). Furthermore, EGFRm-positive patients were divided into two groups according to the cut-off of the changes in ΔCt value of EGFRm after 1 month of treatment, which was set at 4.89. A significant difference in the mOS between the two groups was observed (change value of ΔCt >4.89 vs. ≤4.89: not reached vs. 11.0 months; log-rank P = 0.014). CONCLUSIONS: Detecting EGFRm in ctDNA using R-superARMS can identify patients who are more likely sensitive to targeted therapy, reflect the molecular load of patients, and predict the therapeutic efficacy and clinical outcomes of patients.

Neoadjuvant Therapy in Lung Cancer: What Is Most Important: Objective Response Rate or Major Pathological Response?

Lung cancer is the most fatal and frequently diagnosed malignant tumor. Neoadjuvant therapy is a promising approach for prolonging survival and increasing the chance of cure rates for patients with potentially resectable disease. Currently, many therapeutic alternatives, including chemotherapy, targeted therapy, and immunotherapy, are continually being explored to enrich the content of neoadjuvant therapy. However, neoadjuvant therapy remains to have no unified evaluation standards. Overall survival (OS) is the "gold standard" for evaluating the clinical benefit of cancer treatment, but it needs years for a reliable evaluation. Hence, researchers need to identify surrogate endpoints that can predict OS accurately and reliably without long follow-up periods. In this review, we describe the research progress of different neoadjuvant therapies and explore their response evaluation, aiming to identify stronger predictors of OS.