Lung cancer is one of the most common malignant tumors in humans and the leading cause of cancer-related deaths worldwide. The microRNA-34 (miR-34) family is dysregulated in various human cancers and ...is an important family of tumor suppressor genes among microRNAs. The miR-34 family is downregulated in lung cancer. It inhibits cell proliferation, metastasis, and invasion, arrests the cell cycle, and induces apoptosis or senescence by negatively regulating many oncogenes. It is commonly used to detect and treat lung cancer. This study describes the regulatory role of the miR-34 family in lung cancer and the associated research advances in treatment.
e21520 Background: Mucosal melanoma therapy remains a formidable challenge especially in Asia. Although several therapies are available for skin type of melanoma, the efficacy of mucosal melanoma is ...not satisfactory. YH003, a humanized agonistic anti-CD40 monoclonal antibody specifically recognizes and agonizes CD40 to enhance immune responses, has demonstrated good safety and promising antitumor activity in Phase I clinical studies in patient with ocular melanoma. Here, we report the results of the phase II study of YH003 in combination with pembrolizumab and nab-paclitaxel in the first-line treatment of patients with unresectable/metastatic mucosal melanoma. Methods: Patients with unresectable/metastatic mucosal melanoma were enrolled and received 0.3 mg/kg YH003, 200 mg pembrolizumab and 200 mg/m 2 of nab-paclitaxel iv, every 21 days. The treatment continued for 12 months if subject was deriving an ongoing clinic benefit. The primary endpoint was overall Response Rate (ORR) by investigator’s assessment per RECIST 1.1. Results: A total of 20 patients were enrolled and had at least 1 evaluable post-treatment tumor assessment, the unconfirmed ORR was observed in 7 patients (35.0%), with 7 partial responses (PR). 7 patients (35.0%) had stable disease (SD), and the Disease Control Rate (DCR) was 70.0%. The mOS was not reached, mPFS was 4.11 months. The grade 3 or above TEAE that occurred in the 20 patients were 30.0% (6/20). There is no significant safety signal from the study. Conclusions: The results of the phase II study have shown that YH003 in combination with pembrolizumab and nab-paclitaxel, as 1L treatment in patients with unresectable/metastatic mucosal melanoma have promising antitumor activity and response durability and well tolerated. Clinical trial information: NCT05420324 .
Conjunctival melanoma (CM) is an ocular malignant tumor arising from the bulbar and palpebral conjunctiva and from the caruncle. The treatment of early-stage CM is wide local excision, followed by ...cryotherapy to the margins and adjuvant therapy postoperatively. Advanced CM has a poor prognosis, and there is no consensus on its management. With the development of precision medicine, the identification of genetic alterations assumes great importance. The genetic characteristics of CM, such as BRAF, NRAS, and NF1 mutations, may provide potential therapeutic targets. For locally advanced tumors and metastatic disease, targeted therapy such as BRAF inhibitors and MEK inhibitors in vitro show therapeutic benefit. Some individual case reports indicate their potential effectiveness in advanced CM. In addition, immune checkpoint inhibitors, such as programmed cell death-1 and cytotoxic T lymphocyte antigen-4 inhibitors, have been successfully used for advanced cutaneous melanoma and may be effective in CM. Limited clinical case reports found immune checkpoint inhibitors effective in advanced CM. More clinical studies are needed.
Patients treated with immune checkpoint inhibitors (ICIs) often experience unique immune-related adverse events (irAEs), and the previous studies demonstrated an association between irAEs and better ...outcomes in patients with ICI treatment for advanced non-small cell lung cancer (NSCLC). However, the correlation between the occurrence of mild and severe irAEs and prognosis remains unclear. Additionally, little is known regarding the association between the timing of mild and severe irAEs and clinical outcomes. We retrospectively conducted a multicenter study of advanced NSCLC patients treated with ICI monotherapy. Of the 222 patients, 79 patients (35.6%) experienced at least one irAE, and most were of grade 1 or 2 (mild) (26.6%). The most common irAEs were pneumonitis (
n
= 21, 9.5%) and skin-related adverse reactions (
n
= 19, 8.6%). The median progression-free survival of all patients treated with ICIs was 3.2 months. Patients experiencing irAEs had a better prognosis than those without such events (6.5 vs. 2.6 months,
p
= 0.004), and mild irAEs were associated with the best prognosis. The difference in overall survival between mild and severe irAEs was significant (34.3 vs. 17.3 months,
p
= 0.021). We further analyzed differences between patients with irAEs occurring at 3 or 6 weeks, and found that the earlier the occurrence of mild irAEs, the better the prognosis; however, the opposite was true for severe irAEs. In summary, patients with early occurring mild irAEs showed better clinical outcomes, whereas those with early severe irAEs tended to show poorer clinical outcomes.
Here, we revealed the novel role of long non-coding RNAs (lncRNAs) SOX21 antisense RNA 1 (SOX21-AS1)/TSPAN8/GATA6 in progression of lung adenocarcinoma. SOX21-AS1 expression was quantified in lung ...adenocarcinoma tissues and cells by RT-qPCR. Then, gain- and loss-of-function experiments were conducted in lung adenocarcinoma cells. Expression of GATA6, TSPAN8 and extracellular signal-regulated kinase (ERK) signaling pathway-related genes was determined in lung adenocarcinoma cells by western blot analysis. The interaction and relationship among SOX21-AS1, GATA6 and TSPAN8 were predicted and verified respectively by RNA pull down, RIP, ChIP, and dual-luciferase reporter assays. Next, lung adenocarcinoma cell proliferation, colony formation, invasion and migration were assessed by 5-ethynyl-2′-deoxyuridine staining, colony formation assay and Transwell assay. Xenograft tumors were established in nude mice and the tumor growth was observed and recorded. SOX21-AS1 was observed to be highly expressed in lung adenocarcinoma tissues. The overexpression of SOX21-AS1, GATA6 or TSPAN8 obviously enhanced cell biological functions in lung adenocarcinoma. Meanwhile, SOX21-AS1 interacted with GATA6 which bound to TSPAN8 promoter and promoted TSPAN8 expression, which further enhanced cell colony formation, proliferation and invasion, and also activated ERK signaling pathway. Silencing of SOX21-AS1 and inhibiting its binding to GATA6 downregulate TSPAN8 and thereby exert anti-oncogenic effects in lung adenocarcinoma.
Objectives:
To systematically evaluate the effectiveness and safety of neoadjuvant immunotherapy for patients with non–small cell lung cancer (NSCLC).
Methods:
Randomized controlled trials of ...neoadjuvant immunotherapy in treating patients with NSCLC were comprehensively retrieved from electronic databases, eligible studies, previous systematic reviews and meta-analyses, guidelines, and conference abstracts. The meta-analysis was performed by the Stata/SE 12.0 software.
Results:
Eleven randomized controlled trials were eventually included. The results of the meta-analysis showed that neoadjuvant immunochemotherapy significantly improved the objective response rate compared with neoadjuvant chemotherapy (CT; 62.46% vs 41.88%,
P
= 0.003), but the objective response rate of neoadjuvant double-immunotherapy was roughly comparable to that of neoadjuvant single-immunotherapy (15.74% vs 10.45%,
P
= 0.387). Major pathologic response (MPR) rate and pathologic complete response (pCR) rate of neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy were significantly superior to neoadjuvant CT alone and neoadjuvant single-immunotherapy, respectively. Compared with neoadjuvant CT alone, neoadjuvant immunochemotherapy increased the down-staging rate (40.16% vs 26.70%,
P
= 0.060), the surgical resection rate (83.69% vs 73.07%,
P
= 0.231), and R0 resection rate (86.19% vs 77.98%,
P
= 0.502), but there were no statistically significant differences. Neoadjuvant immunochemotherapy did not increase the postoperative complications rate than neoadjuvant CT alone (40.20% vs 41.30%,
P
= 0.920). In terms of safety, neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy did not increase the incidence of treatment-related adverse events (TRAEs) and the grade 3 or higher TRAEs.
Conclusions:
In summary, neoadjuvant immunochemotherapy had better clinical efficacy than neoadjuvant CT for patients with NSCLC. MPR rate and pCR rate of neoadjuvant immunochemotherapy and neoadjuvant double-immunotherapy were significantly superior to neoadjuvant CT and neoadjuvant single-immunotherapy, respectively, for patients with NSCLC, showing that MPR rate and pCR rate were probably considered as alternative endpoints for survival benefit. TRAEs were comparable between the corresponding groups. The long-term survival outcome of neoadjuvant immunotherapy for patients with NSCLC needs to be further confirmed to better guide clinical practice.
2534 Background: Clinical development of agonistic 4-1BB mAbs is limited by their narrow therapeutic window or unsatisfactory efficacy. Development of novel molecules with improved efficacy and ...restricted 4-1BB activation to tumor microenvironment is crucial. QLF31907 is a BsAb targeting PD-L1 and 4-1BB and showed restricted activation of 4-1BB in preclinical studies. Here we present the results from an ongoing phase 1 study of QLF31907 in patients (pts) with advanced solid tumors and relapsed/refractory (r/r) lymphoma. Methods: This study consisted of dose-escalation and dose-expansion phases. Pts were enrolled if with histologically confirmed solid tumors or r/r lymphoma; failed in or intolerable to standard therapy; and with ≥ 1 measurable lesion. Pts received QLF31907 intravenously once every 2 weeks (Q2W) at 0.026 and 0.1 mg/kg (accelerated titration design), and 0.3, 1, 3, 10, 20, and 30 mg/kg (i3+3 design) in the dose-escalation phase. The DLT evaluation window was 28 days. Pts received QLF31907 10 mg/kg and 20 mg/kg Q2W in the dose-expansion phase. The primary endpoint was dose-limiting toxicity (DLT). Results: As of 30 Nov 2023, 38 pts were enrolled from 5 centers across China. Median age was 58 years and 52.6% patients had an ECOG PS of 1. Five (13.2%) pts had r/r lymphoma. 36 (94.7%) pts had stage IV disease. 31.6% pts previously received ≥3 therapies and 57.9% pts previously received PD-1/PD-L1 therapy. DLTs were observed in 1 pt (20 mg/kg): myalgia and platelet count decreased. All pts experienced TEAEs (treatment-related, 92.1%). The most common TEAE was anemia (73.7%), followed by hypertriglyceridemia (50.0%). Twenty-four (63.2%) pts experienced Gr≥3 TEAEs (treatment-related, 31.6%). The most common Gr≥3 TEAE was pneumonia (13.2%). TEAEs leading to treatment discontinuation occurred in 6 (15.8%) pts (treatment-related, 7.9%). Serious TEAEs occurred in 20 (52.6%) pts (treatment-related, 26.3%). Six (15.8%) pts had PRs and 3 PRs were confirmed. SD was observed in 20 (52.6%) pts. DCR was 60.5% (23/38). PR was observed in 3 patients who previously received PD-1/PD-L1 therapy. The median DoR was not reached and the 6 month DoR rate was 60.0% (95% CI, 12.6-88.2). Two patients had PRs lasting for more than 1 year: 1 with PD-1/PD-L1 naïve cervical cancer (PR>18 months) and 1 with PD-1/PD-L1 treated melanoma (PR>13 months). In the dose range of 0.026-30 mg/kg, the exposure increased proportionally with dose increase. At 10mg/kg Q2W and above, PD-L1 and 4-1BB receptor occupancy indicated by PBMCs stabilized >80% during the treatment period. Conclusions: QLF31907 showed an acceptable safety profile and preliminary clinical activity in heavily pretreated patients with advanced solid tumors and lymphoma. Encouraging clinical activity was observed in patients who have failed PD-1/PD-L1 therapy and further research on the mechanism is ongoing. Clinical trial information: NCT05150405 .
e14636 Background: Alterations of SMARCA4 or SMARCB1 (SMARCA4/B1) proteins have been identified in various aggressive cancers. Recent studies show that tumors harboring deleterious SMARCA4/B1 ...alterations express PD-L1 and respond to immune checkpoint inhibitor (ICI) therapies. Current ongoing immunotherapy-based clinical trials for cancers deficient in SMARCA4/B1 include combinations of atezolizumab and the TIGIT antibody tiragolumab (Phase II), as well as nivolumab and the CTLA-4 antibody ipilimumab (Phases II & III). Here we present a comprehensive analysis of the pan-cancer landscape of SMARCA4/B1 alterations, based on real-world data from a large cohort of Chinese patients. Methods: From 2021 to 2023, we collected genomic information from 16,113 cancer patients, spanning more than 40 different cancer types. These patients had undergone targeted next-generation sequencing (NGS) through the Med1CDx panel, which targets 601 cancer-associated genes. After excluding 1,034 samples of unidentified tumor origins, 15,079 samples were analyzed further. The analysis included somatic and germline pathogenic/likely pathogenic (P/LP) single-nucleotide variants, insertions/deletions, and copy number alteration in SMARCA4/B1. Results: We identified 421/15079 (2.8%) patients with SMARCA4/B1 alterations, with a median age of 63 years (range 13-90). Cancer types with a higher frequency of SMARCA4/CB1 mutations include: endometrial cancer (9.8%), thyroid cancer (6.9%), gastric cancer (6.2%), cholangiocarcinoma (5.7%), and lung cancer (4.4%). The predominant mutation type is variants of uncertain significance (VUS) gene mutations, constituting 72% (302/421) of the spectrum, with nearly all being missense mutations. These are mainly observed in lung cancer, thyroid cancer, and colorectal cancer. The frequency of pathogenic/likely pathogenic mutations is 28% (119/421), mainly distributed in lung cancer and liver cancer. Q201L, P222L, and E1364del are the most common mutations in SMARCA4, with a mutation rate of approximately 4.1%, occurring across over five cancer types. The most common co-mutations of SMARCA4/B1 were TP53 (47.3%), EGFR (25.4%), KRAS (15.9%), STK11 (7.1%) and CDKN2A (7.4%). Clinicopathological feature of age showed no significant differences between SMARCA4/B1 mutant and wild-type groups. Tissues with SMARCA4/B1 mutations exhibited a higher tumor mutational burden (TMB) (median=8.3) than wild-type tissues (median=4.2) (P < 0.001). Conclusions: Elevated TMB levels in patients with SMARCA4/B1 mutations suggest a significant potential benefit from immunotherapy. The presence of co-mutations may also aid in predicting the efficacy of combination immunotherapy treatments. Furthermore, the high prevalence of VUS emphasizes the need for additional research to determine their clinical relevance.
•Dacomitinib is a potent, irreversible and pan-HER tyrosine kinase inhibitor.•Fourteen EGFR mutant NSCLC patients with brain metastasis received Dacomitinib.•Dacomitinib with both 45 mg and 30 mg ...starting dose induces response.•Intracranial response to dacomitinib was observed in NSCLC patients.
Dacomitinib is a potent, irreversible and pan-HER tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). Currently, evidence of its activity on brain metastasis is lacking.
NSCLC patients diagnosed at Hunan Cancer Hospital between July, 2019 and July, 2020 with enhanced MRI-detected brain metastasis prior to treatment and laboratory-confirmed EGFR mutations were reviewed. In total, 14 EGFR-mutant NSCLC patients with brain metastasis were treated with first-line dacomitinib. The first radiographic review of chest CT and brain MRI was after one month and thereafter every 2 months. The objective response rate (ORR) and the depth of the brain metastasis response were determined via RECIST 1.1 and RANO-LM criteria.
In total, 14 of 59 EGFR-mutant advanced NSCLC patients who received first-line dacomitinib therapy had brain metastasis before treatment. Among these patients, 5 were given a dacomitinib starting dose of 45 mg once daily, while 9 received 30 mg daily until disease progression or unbearable toxicity. Eight patients harbored EGFR 19del, 5 had EGFR L858R, and one patient had EGFR G719A and I706 T co-mutations. The median duration of follow-up was 4.5 months. All patients received at least one review. The ORR was 92.9 % (13/14) and the disease control rate (DCR) was 100 %. A measurable response of the intracranial metastases was observed in 12 of 14 patients (85.7 %), including 12 of 13 (92.3 %) with brain parenchymal metastasis, but the one patient with meningeal metastasis did not respond well. All patients (100 %) had grade 1–2 adverse effects, but none discontinued treatment or required a dosage adjustment.
This case series study of 14 patients has shown that dacomitinib has potent efficacy for central nervous system (CNS) metastasis in EGFR-positive NSCLC. More data are required to confirm its advantages and optimize its clinical application.
9541
Background: Initial safety and efficacy data of LBL-007 plus toripalimab in patients with advanced melanoma (Part A) have been reported in 2022 ASCO (Abstract 9538). Here we present the updated ...results of part A and the preliminary results of part B (LBL-007 plus toripalimab with axitinib). Median follow-up was 9.7 months at cut-off data (January 11, 2023). Methods: Patients with advanced melanoma with or without prior therapy were enrolled during Jan 2021 - Aug 2022. This trial comprised 2 parts: Part A, patients received LBL-007 (0.25 - 10 mg/kg for dose escalation; 3 or 6 mg/kg for dose expansion) plus toripalimab at 3 mg/kg (both i.v. Q2W); and Part B, patients received LBL-007 at 3 or 6 mg/kg plus toripalimab at 3 mg/kg (both i.v. Q2W) and axitinib at 5 mg BID. The primary objective was safety, the second objectives were pharmacokinetics, pharmacodynamics and efficacy (per RECIST v.1.1). Results: In part A, 68 patients in total (57 treatment-naïve) were enrolled including 20 patients in dose escalation and 48 patients in dose expansion, and among which, 31 additional patients have been enrolled since 2022 ASCO report. Nineteen (27.9%) patients occurred grade ≥3 TEAEs, the common grade ≥3 TEAEs was anaemia (11.8%). No new safety signals were detected. Among 55 efficacy evaluable treatment-naïve patients (41 with acral, 7 mucosal, 7 others), ORR was 23.6%, DCR was 58.2%, and mPFS was 5.7 months (95% CI: 3.7, 9.5). In part B, 11 patients (10 mucosal, 1 acral) were enrolled. No DLT was observed. Five patients (45.5%) occurred grade ≥3 TEAEs, the common grade ≥3 TEAEs included blood pressure increased (18.2%) and transaminases increased (18.2%). One (9.1%) patient discontinued treatment due to TEAEs. ORR was 45.4% (including 4 mucosal and 1 acral), DCR was 72.7%, and mPFS was 5.5 months (95% CI: 1.8, 9.1). Conclusions: LBL-007 plus toripalimab continued to show promising antitumor activity and manageable safety profile in patients with treatment-naïve melanoma, which support further development in this indication. LBL-007/toripalimab/axitinib combination demonstrated acceptable safety profile and encouraging antitumor activity in patients with mucosal melanoma. Acknowledgements: Junshi Biosciences. Clinical trial information: NCT04640545 .
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