Squamous Non-small Cell Lung Cancer Research Articles

Analysis of the effects of immunotherapy depending on cancer subtypes on survival - a single center experience

Background: The type of tumor is a huge determinant of survival and treatment outcomes, particularly with immunotherapy, which uses the immune system to target cancer cells. The response to immunotherapy varies depending on tumor types and is influenced by factors such as genetic mutations and the tumor microenvironment. Materials and methods: The present retrospective study analyzed records for 151 patients who underwent immunotherapy at a single center between 2019 and 2023. The cohort included adults diagnosed with solid tumors, primarily NSCLC (non-small cell lung cancer). Immunotherapy agents included pembrolizumab, nivolumab, and others. Data on age, cancer stage, treatment response, adverse events, overall survival (OS), and progression-free survival (PFS) were collected. Statistical analyses, including the Cox proportional hazards model, assessed the impact of tumor types and subtypes on survival outcomes. Results: The median age of the cohort was 69 (SD, 10.3) years, and the majority of the patients were men (64.9%). NSCLC was the predominant tumor type (78.1% of cases). In comparison to adenocarcinoma NSCLC, squamous NSCLC showed a significantly higher hazard ratio (HR) for OS (HR 1.49) and PFS (HR 1.47). Renal cell carcinoma and bladder cancer had lower HRs, suggesting a better prognosis. Conclusions: This study highlights how responses to immunotherapy can differ widely based on tumor type, emphasizing the importance of personalized therapy approaches. These insights underscore the need for further research to tailor immunotherapy more effectively to different cancer types.

Kanglaite alleviates lung squamous cell carcinoma through ferroptosis

Kanglaite, a compound predominantly composed of polyunsaturated fatty acids (PUFAs), has been employed in the clinical treatment of adenocarcinoma non-small cell lung cancer (NSCLC) in China for decades. However, its therapeutic efficacy and specific mechanism in the treatment of squamous NSCLC remains unexplored. In this study, we demonstrate that the co-treatment with ferric ion significantly enhances the cytotoxic effects of kanglaite by inducing ferroptosis in NCL-H1703, a cell line of human lung squamous cell carcinoma. Mechanistic investigations reveal that kanglaite induces mitochondrial dysfunction resulting in reactive oxygen species (ROS) excessive production, which is critical for the induction of ferroptosis. Further analysis shows that kanglaite suppresses the PI3K/AKT signaling pathway, leading to increased IP3 generation. IP3 subsequently binds to and activates IP3R, an endoplasmic reticulum (ER) calcium channel, exacerbating the excessive calcium transfer from the ER to mitochondria. The overloaded mitochondrial calcium contributes to its dysfunction and elevates ROS production. To optimize the synergistic effects of ferric ion and kanglaite, we develop a mesoporous silica-based nanodrug delivery system co-loaded with Kanglaite and Fe3O4, which offers several notable advantages, including reduced drug dosage and a faster therapeutic onset. Finally, in an NCL-H1703 xenograft model, the DMSN/Fe3O4-Kanglaite nanodrug significantly inhibited tumor growth. In conclusion, we identified the function and mechanism of kanglaite in treatment of squamous NSCLC and have developed a DMSN/Fe3O4-Kanglaite nanodrug, providing a superior therapeutic approach for the treatment of squamous NSCLC.

Serum CYFRA 21-1 as a Prognostic Marker in Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors.

Background: A prognostic marker in patients with non-small-cell lung cancer (NSCLC) treated with anti-PD-1/PD-L1 antibodies must be established. This study explored serum cytokeratin fraction 21-1 (CYFRA 21-1), which represents a squamous cell histology, as a prognostic factor in anti-PD-1/PD-L1 antibody treatment, stratifying by histology and treatment regimen. Methods: This study retrospectively evaluated patients with advanced NSCLC without driver mutations receiving anti-PD-1/PD-L1 antibodies between November 2015 and March 2023. Cutoff values for CYFRA 21-1 and carcinoembryonic antigen (CEA) were 3.5 and 5.0 ng/mL, respectively. The Kaplan-Meier method and a log-rank test were conducted. The Cox proportional hazards model was utilized for univariate and multivariate analyses. Results: This study included 258 patients. The squamous NSCLC group demonstrated a shorter overall survival (OS) than the non-squamous NSCLC group (median, 17.8 vs. 23.7 months, p = 0.141). Patients with high serum CYFRA 21-1 and CEA levels exhibited a significantly shorter OS than those with normal levels (median, 11.7 vs. 32.7 months, p < 0.005; 15.8 vs. 29.7 months, p < 0.005). The multivariate analysis identified a performance status (PS) of ≥2, a PD-L1 expression of ≥50%, and a serum CYFRA 21-1 of >3.5 ng/mL as independent prognostic factors. Patients with high serum CYFRA 21-1 levels exhibited a significantly shorter OS even focusing on non-squamous NSCLC, anti-PD-1/PD-L1 antibody and chemotherapy combination therapy, or anti-CTLA-4 antibody combination therapy. Conclusion: Serum CYFRA 21-1 is a poor prognostic marker for patients with NSCLC receiving anti-PD-1/PD-L1 antibody treatment even when stratifying by histology or treatment regimen.

P3.12D.09 Trial in Progress: A Phase Ib Study of HMBD-001, An Anti-HER3 Antibody, in Advanced Squamous Non-Small Cell Lung Cancer

P3.12D.09 Trial in Progress: A Phase Ib Study of HMBD-001, An Anti-HER3 Antibody, in Advanced Squamous Non-Small Cell Lung Cancer

Calibrating Observational Health Record Data Against a Randomized Trial

The conditions required for health record data sources to accurately assess treatment effectiveness remain unclear. Emulation of randomized clinical trials (RCTs) with health record data and subsequent calibration of the results can help elucidate this. To pilot an emulation of the KEYNOTE-189 RCT using a commercially available electronic health record (EHR) data source. This retrospective cohort study used an EHR database spanning from April 2007 to February 2023. Follow-up began on treatment initiation and proceeded until an outcome event, loss to follow-up, end of data, or end of study period (640 days). The population-based cohort was ascertained from EHRs provided by 52 health systems across the US. Eligibility criteria were defined as closely as possible to the benchmark RCT. Patients with non-small cell lung cancer initiating first-line treatment for metastatic disease were included. Patients with evidence of squamous non-small cell lung cancer, primary nonlung malignant neoplasms, or identified EGFR/ALK variations were excluded. Data were analyzed from June to October 2023. Initiation of first-line pembrolizumab and chemotherapy and chemotherapy alone. Chemotherapy in both groups was defined as a combination of pemetrexed and platinum-based (carboplatin or cisplatin) therapy. Outcomes of interest were 12-month survival probability and mortality hazard ratio (HR). A total of 1854 patients (mean [SD] age, 63.7 [9.6] years; 971 [52.4%] men) were eligible, including 589 patients who initiated pembrolizumab and chemotherapy and 1265 patients who initiated chemotherapy only. The cohort included 364 Black patients (19.6%) and 1445 White patients (77.9%). The 12-month survival probabilities were 0.60 (95% CI, 0.54-0.65) in the pembrolizumab group and 0.58 (95% CI, 0.55-0.62) in the chemotherapy-only group, compared with 0.69 (95% CI, 0.64-0.74) in the KEYNOTE-189 pembrolizumab group and 0.49 (95% CI, 0.42-0.56) in the KEYNOTE-189 chemotherapy-only group. The mortality HR was 0.95 (95% CI, 0.78-1.16), compared with 0.49 (95% CI, 0.38-0.64) in the KEYNOTE-189 RCT. In this cohort study piloting an RCT emulation, results were incongruous with the benchmark trial. Differences in patient treatment and data capture between the RCT and EHR populations, confounding by indication, treatment crossover, and accuracy of captured diagnoses may explain these findings. Future feasibility assessments will require data sources to have important oncology-specific measures curated.

Metastatic squamous non-small cell lung cancer – complete response following desmocollin-3 targeting immunotherapy as a monotherapy – A case report

Metastatic squamous non-small cell lung cancer – complete response following desmocollin-3 targeting immunotherapy as a monotherapy – A case report

β-glucan combined with Envafolimab and Endostar as immune rechallenge for metastatic non-small cell lung cancer

BackgroundImmune checkpoint inhibitor rechallenge has emerged as a prominent study area in non-small cell lung cancer (NSCLC). β-glucan was reported to reverse resistance to anti-PD-1/PD-L1 inhibitors by regulating the tumor microenvironment. In this self-initiated clinical trial (ChiCTR2100054796), NSCLC participants who have previously failed anti-PD-1 therapy received β-glucan (500 mg, bid, d1-21), Envafolimab (300 mg, d1) and Endostar (210 mg, civ72h) every 3 weeks until disease progression or unacceptable toxicity. The clinical efficacy and adverse events were observed, while serum samples were collected for proteomic analysis.ResultsTwenty Three patients were enrolled from January 2022 to March 2023 (median age, 65 years; male, n = 18 [78.3%]; squamous NSCLC, n = 9 [39.1%]; mutant type, n = 13 [56.5%]). The overall response rate (ORR) was 21.7% and disease control rate (DCR) was 73.9%. Median progression-free survival (mPFS) and median overall survival (mOS) was 4.3 months [95% CI: 2.0–6.6] and 9.8 months [95% CI: 7.2–12.4], respectively. The mPFS between PD-L1 positive and negative subgroup has significant difference (6.3 months vs. 2.3 months, p = 0.002). Treatment-related adverse events (TRAEs) occurred in 52.2% of patients. The most common TRAEs were hypothyroidism (26.1%) and fatigue (26.1%). 2 (8.7%) grade 3 adverse events were reported. No adverse reaction related deaths have been observed. Proteomic analysis revealed that the levels of CASP-8, ARG1, MMP12, CD28 and CXCL5 correlated with resistance to the treatment while the levels of CD40-L and EGF related to the favorable response.Conclusionβ-glucan combined with Envafolimab and Endostar has considerable efficacy and safety for immune rechallenge in metastatic NSCLC patients who failed of anti-PD-1 treatment previously, especially for PD-L1 positive patients.

Identifying patients who benefit more from perioperative immunotherapy combinations for resectable non-small cell lung cancer based on clinical and molecular characteristics: a meta-analysis of randomized clinical trials.

This study aims to identify patient subgroups who benefit more from perioperative immunotherapy combined with chemotherapy (IO-CT) based on clinical and molecular characteristics in resectable non-small cell lung cancer (NSCLC). Randomized controlled trials (RCTs) on perioperative IO-CT were searched. Beneficial differences of IO-CT regimens across different patient subgroups were assessed by pooling trial-specific ratios in event-free survival (EFS), overall survival (OS), pathological complete response (pCR), and major pathological response (MPR). Six studies (n = 3003) involving five IO-CT regimens were included. Compared to CT alone, all IO-CT regimens significantly improved EFS, OS, MPR, and pCR, but increased toxicity. Toripa-chemo showed the best EFS and nivo-chemo showed the best OS. Patients with PD-L1 ≥ 1% had more EFS benefits compared to those with PD-L1 < 1% (HR [hazard ratio]: 1.55, 95% CI 1.17-2.04). Squamous NSCLC patients had significantly more pCR and MPR benefits than non-squamous NSCLC patients (pCR: OR [odds ratio] 0.68, 95% CI 0.49-0.95; MPR: OR 0.61, 95% CI 0.45-0.82). Former smokers had significantly higher pCR benefits than non-smokers (OR: 2.18; 95% CI 1.21-3.92). Additionally, OS benefit was significantly higher in patients < 65years compared to those ≥ 65years (HR ratio: 0.59, 95% CI 0.36-0.95). For MPR, males benefited significantly more from IO-CT compared to females (OR: 1.69, 95% CI 1.18-2.42). Perioperative IO-CT is more effective but more toxic than CT alone in resectable NSCLC. Patients with PD-L1 ≥ 1%, squamous NSCLC, a history of smoking, age < 65years and male gender may experience greater benefits from perioperative IO-CT.

1225P Perioperative serplulimab and chemotherapy in patients with resectable squamous non-small cell lung cancer: An open-label, single-arm, phase II trial

1225P Perioperative serplulimab and chemotherapy in patients with resectable squamous non-small cell lung cancer: An open-label, single-arm, phase II trial

Registry of Genetic Alterations of Taiwan Non-Small Cell Lung Cancer by Comprehensive Next-Generation Sequencing: A Real-World Cohort Study-Taiwan Cooperative Oncology Group T1521.

Tissue-based next-generation sequencing (NGS) analysis is highly recommended for patients with advanced/metastatic non-small cell lung cancer (NSCLC). We investigated a specific patient population with NSCLC that required tissue-based NGS analysis. We enrolled 500 patients with advanced/metastatic (1) epidermal growth factor receptor (EGFR) mutations or anaplastic large-cell lymphoma kinase (ALK) rearrangement-positive NSCLC who had failed at minimum one line of tyrosine kinase inhibitor (TKI) therapy, (2) EGFR-/ALK-negative nonsquamous, and (3) non- or light-smoker patients with squamous NSCLC who were treatment-naïve or had failed at maximum two lines of systemic treatment. These patients were divided into five cohorts. Comprehensive tissue-based NGS testing (ACTOnco+) was conducted. Cohort 1: EGFR TKI-pretreated EGFR-mutated population (50.0%, n = 250), cohort 2: ALK inhibitor-pretreated ALK-positive population (1.6%, n = 8), cohort 3: treatment-naïve EGFR-/ALK-negative population (28.2%, n = 141), cohort 4: pretreated EGFR-/ALK-negative population (16.8%, n = 84), and cohort 5: squamous cell carcinoma (3.4%, n = 17). In cohort 1, 11.2% (28/250) of the patients had MET amplification, 32.4% (81/250) had been treated with osimertinib, and EGFR C797S was detected in 6.2% (5/81) of these patients. In cohort 2, resistance ALK mutation was detected in 37.5% (3/8) of the patients. In cohorts 3 and 4, targetable genetic alterations, including EGFR mutation (13.3%), ERBB2 mutation (9.3%), MET exon 14 skipping (5.3%), KRAS G12C mutation (4.4%), ROS1 fusion (2.7%), RET fusion (1.8%), and BRAF V600E mutation (1.3%), were detected. In cohort 5, MET exon 14 skipping was detected in 29.4% (5/17) of the patients. This multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

Induction chemotherapy backbone in frail patients with advanced NSCLC treated with chemotherapy plus pembrolizumab: a single institution retrospective audit of dose intensities from modified regimens.

Guidelines historically recommended mono-chemotherapy for the 1st line treatment of elderly patients with non-small cell lung cancer (NSCLC) and poor performance status (PS). Nowadays, there is no clear indication whether chemo-immunotherapy (chemo-IO) combinations can be effectively delivered in this population. We collected induction chemotherapy data in consecutive patients with advanced NSCLC treated with carboplatin-based chemotherapy regimens plus pembrolizumab, to compute the received dose intensity (RDI) from standard regimens or patient-tailored regimens modified due to age, comorbidities and PS. Comorbidities were stratified according to the comorbidity-polypharmacy score (CPS). The established cut-off of ≥85% for RDI was used to define adequate delivery. 116 pts were treated from Feb-20 to July-23, of whom 96 and 20 with non-squamous and squamous NSCLC, treated with carboplatin-pemetrexed or carboplatin-paclitaxel doublets plus pembrolizumab, respectively. The majority of patients were aged ≥ 70 years (52.6%), the median CPS was 5, with 58.6% having a CPS ≥5, whilst 47.4%, 44.8% and 7.8% had an Eastern Cooperative Oncology Group (ECOG) - PS of 0, 1 and 2, respectively. PD-L1 TPS were <1% in 31.9% and 1-49% in 65.4%. Overall, 47.4% received a priori modified regimens due to poor PS, age, or comorbidities. Among patients with non-squamous NSCLC, median received doses of carboplatin and pemetrexed were 1.37 AUC/week and 138.8 mg/m2/week, with RDIs of 86% and 75% (p < 0.01) for patients treated with standard or modified regimens, respectively. Of note, the RDI was 57.9% among patients with ECOG-PS 2. However, patients treated with modified regimens experienced similar toxicities as those treated with standard regimens, despite being older (p < 0.01), with higher PS (p < 0.01) and more comorbid (p = 0.03). Patients treated with modified regimens achieved a shorter survival (7.1 vs 13.9 months), which is comparable to IO-free historical controls. Among patients with squamous NSCLC, 90% received modified regimens upfront, with median received doses of carboplatin and paclitaxel of 1.19 AUC/week and 40 mg/m2/week, and an overall RDI of 73.5%. Although regimen modifications ensure a safe administration of chemotherapy plus pembrolizumab in frail patients, the RDI seems to be subtherapeutic, especially in those with squamous histology. Dedicated trials are needed to implement combination strategies in this population.

Health and Economic Outcomes of Pembrolizumab in the Treatment of Metastatic Non-small Cell Lung Cancer (mNSCLC) and Melanoma in Italy.

In Italy, the management of metastatic non-small cell lung cancer and melanoma leads to significant healthcare challenges, necessitating cost-effective treatment strategies and offering valuable insights for healthcare policymakers and stakeholders. This study was designed to assess the costs, quality-adjusted life-years (QALYs) and disability-adjusted life-years (DALYs) associated with the health and economic outcomes of (1) pembrolizumab-combined chemotherapy administered as a first-line treatment for metastatic non-squamous and squamous non-small cell lung cancer (NSCLC) where the tumour presents with a programmed death-ligand 1 expression level <50% and of (2) adjuvant pembrolizumab treatment for stage III melanoma. Three cost-effectiveness models developed by MSD were investigated for each treatment indication. A unique model was built to assess the overall effect of pembrolizumab versus chemotherapy or watchful waiting in patients with lung cancer or melanoma, respectively. Theoretical cohorts of patients with metastatic squamous and non-squamous NSCLC were followed over time using a partitioned survival model with weekly cycles. A weekly cycle Markov model was employed for melanoma. The analysis was conducted from the Italian National Health Service perspective, considering a time horizon of 40 years (lifetime). A single closed cohort of treatable patients was followed over time for each indication (4000, 7000 and 900 for NSCLC squamous, non-squamous and melanoma, respectively). The costs evaluated included those for adverse drug events, non-drug disease management, subsequent treatment and terminal care. Drug acquisition and administration costs were excluded. For each treatment indication assessed, pembrolizumab produced downstream direct cost offsets (- €122,498,568, -€133,369,076 and -€32,993,242 for NSCLC squamous, non-squamous and melanoma indications, respectively), increased quality of life (+2088, +5317 and +2307 QALYs for NSCLC squamous, non-squamous and melanoma indications, respectively) and reduced disability (-2658, -7202 and -3029 DALYs for NSCLC squamous, non-squamous and melanoma indications, respectively). Across indications, the total cost offsets of pembrolizumab were -€288,860,885, with 9712 QALYs gained and 12,889 DALYs avoided. The analysis demonstrated that, compared with chemotherapy, pembrolizumab is more cost effective in Italy as a first-line treatment in patients with metastatic squamous or non-squamous NSCLC and, if compared with watchful waiting, as adjuvant treatment in patients with stage III melanoma. The present analysis suggested that pembrolizumab use could lead to important health benefits for patients while offsetting a portion of cancer care costs.

ENDOLUNG trial. A phase 1/2 study of the Akt/mTOR inhibitor and autophagy inducer Ibrilatazar (ABTL0812) in combination with paclitaxel/carboplatin in patients with advanced/recurrent endometrial cancer

BackgroundCarboplatin and paclitaxel (CP) have been the standard of care for advanced/recurrent endometrial cancer (EC) for many years. However, this chemotherapy combination shows limited efficacy and recurrences often occur in less than 12 months. ABTL0812 is a novel drug that selectively kill cancer cells by cytotoxic autophagy and has shown anticancer efficacy in preclinical models of EC in combination with CP.MethodsENDOLUNG was an open-label, phase 1/2 clinical trial designed to determine the safety and efficacy of Ibrilatazar (ABTL0812) with CP in patients with advanced/recurrent EC and non-irradiable stage III and IV squamous non-small cell lung cancer (sq-NSCLC). The phase 1 part consisted of a 3 + 3 de-escalation design followed by an expansion cohort with 12 patients. The primary endpoint was safety. ABTL0812 starting dose was 1300 mg tid combined with carboplatin at area under the curve (AUC) 5 and paclitaxel at 175 mg/m2 both administered every 21 days for up to 8 cycles. The phase 2 part included a total of 51 patients. The primary endpoint was overall response rate (ORR) and the secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS).ResultsDuring the phase 1 only one dose limiting toxicity (DLT), a grade 4 neutropenia, was observed in 1 out of 6 patients, thus no de-escalation was applied. One additional DLT, a grade 3 febrile neutropenia, was observed in the expansion cohort, thus the recommended phase 2 dose (RP2D) for ABTL0812 was established at 1300 mg tid. Most frequent hematological adverse events (AE) of the combination were neutropenia (52.9%), anemia (37.3%) and thrombocytopenia (19.6%). Nausea (66.7%), asthenia (66.7%), diarrhea (54.9%) and vomiting (54.9%) were the most frequent non-hematological adverse events (AEs). The combination of ABTL0812 plus CP showed an ORR of 65.8% (13.2% complete response and 52.6% partial response) with a median DOR of 7.4 months (95% CI: 6.3–10.8 months). Median PFS was 9.8 months (95% CI: 6.6–10.6) and median OS 23.6 months (95% CI 6.4-ND). Pharmacokinetic parameters were compatible with target engagement observed in preclinical studies, and blood pharmacodynamic biomarkers indicated sustained target regulation during, at least, 28 days after starting the treatment.ConclusionsThis study suggests that the combination of ABTL0812 with CP is safe and feasible with an encouraging activity in patients with advanced/recurrent EC. Our data warrant further confirmation in prospective randomized trials.Trial registrationEU Clinical Trial Register, EudraCT number 2016-001352-21 and National Clinical Trials Number, NCT03366480. Registration on 19 September 2016.

Comparison of Nivolumab with Docetaxel in the Treatment of Advanced Squamous Cell Non-small Cell Lung Cancer

Lung squamous-cell carcinoma poses a significant global health challenge with limited treatment options available. Immune checkpoint inhibitors, particularly nivolumab, have revolutionized cancer therapy, especially in non-small cell lung cancer (NSCLC). Nivolumab, targeting the PD-1 protein, exhibits promise in treating advanced squamous-cell NSCLC. This article critically examines nivolumab’s development and compares its efficacy with docetaxel in this context. Nivolumab’s effectiveness lies in its ability to block the PD-1/PD-L1 immune checkpoint pathway, reinvigorating the immune response against cancer cells. Clinical trials reveal higher overall survival rates and fewer adverse events (AEs) with nivolumab compared to docetaxel, alongside improvements in patient-reported outcomes and mental well-being. However, limitations exist, primarily stemming from clinical trial data’s potential mismatch with real-world scenarios. Short trial durations hinder long-term outcome analysis and delay AE evaluations. Furthermore, the comparison is restricted to nivolumab and docetaxel, overlooking other Food and Drug Administration-approved monoclonal antibodies. Addressing these limitations are crucial for enhancing the utility of these evaluations in clinical decision-making and guiding future research in advanced squamous-cell NSCLC management. Nivolumab emerges as a promising treatment option, offering superior efficacy and safety over traditional chemotherapy, yet its real-world efficacy warrants further exploration.

Single-drug Chemotherapy Plus Immunotherapy as First-line Treatment for Stage Ⅳ Non-small Cell Lung Cancer Elderly Patients: A Phase II Clinical Trial UNICORN Study

IntroductionLung cancer remains the most common malignancy and the leading cancer-related death among the elderly in China, which deserves more research attention. Immunotherapy combined with platinum-based doublet chemotherapy has been approved as the standard treatment for advanced non-small cell lung cancer (NSCLC) patients who are devoid of specific gene mutations or fusions. Given that patients with NSCLC over the age of 65 typically exhibit declining organ function and physical condition, they often showed reduced tolerance for this rigorous treatment regimen. However, the KEYNOTE-042 study illuminated a promising pathway: in patients testing positive for programmed death-ligand 1 (PD-L1), immunotherapy alone has demonstrated a superior overall survival (OS) compared to platinum-based doublet chemotherapy. This suggests that moderating the intensity of chemotherapy and prioritizing immunotherapy may be a gentler alternative in elderly demographic. Patients and MethodsThis multicenter phase II clinical trial named UNICORN aimed to enroll 49 patients aged 65 and older, utilizing paclitaxel or nab-paclitaxel for those with squamous NSCLC, and pemetrexed for those diagnosed with lung adenocarcinoma. The treatment protocol entails 4 cycles of serplulimab plus chemotherapy followed by an extended regimen of serplulimab maintenance, spanning a total of 35 cycles. Primary endpoints of this study are progression-free survival (PFS), disease control rate (DCR) and the secondary endpoints are OS, objective control rate (ORR) and safety metrics. ConclusionThis is the first study to evaluate the efficacy and safety of serplulimab combined with either paclitaxel or pemetrexed in elderly treatment-naïve patients with stage IV NSCLC whose PD-L1 are positive.

Evaluating Safety and Clinical Activity of Front-line Treatment with Cadonilimab plus Chemotherapy in Advanced/Metastatic Nonsmall Cell Lung Cancer Harboring STK11 Genetic Aberration: A Protocol of Phase II Study

BackgroundCadonilimab is a first-in-class bispecific PD-1/CTLA-4 antibody. Serine/threonine kinase (STK11) mutation was shown to be related to low PD-L1 expression and objective response rate (ORR) in nonsmall cell lung cancer (NSCLC), resulting in poor progression-free survival (PFS) and overall survival (OS). Herein, we hypothesized that combining cadonilimab with chemotherapy could enhance antitumor immunity and extend survival in these patients. Consequently, we designed this study to explore the clinical activity and safety of cadonilimab combined with chemotherapy in patients with advanced/metastatic NSCLC harboring STK11 alteration. Trial designThis single-center, open-label, single-arm phase II trial is conducted at the first affiliated hospital of Guangzhou Medical University. Treatment-naïve advanced/metastatic NSCLC patients harboring STK11 mutation will be enrolled in this study. Eligible patients will receive either cadonilimab (10mg/kg on Day 1) plus pemetrexed (500 mg/m2) and carboplatin (AUC = 5) for nonsquamous NSCLC or abraxane (100 mg/m2) and carboplatin (AUC = 5) for squamous NSCLC for 4 cycles, followed by maintenance therapy (cadonilimab plus pemetrexed or abraxane). The treatment will be discontinued when disease progression, intolerability to cadonilimab, and/or chemotherapy occurs. Measurable lesions were assessed according to the Response Evaluation Criteria in Solid Tumors (1.1). The main endpoint is ORR and safety. Subordinate endpoints include PFS, disease control rate, and duration of response. ResultsThe study commenced enrolment in September 2023, with preliminary findings regarding the primary endpoint anticipated by January 2025.

Current status of PD-(L)1 inhibitor usage in advanced or metastatic non-small cell lung cancer: A national survey of oncologists in China.

e20559 Background: The aim of the present study conducted by Chinese Society of Clinical Oncology Expert Committee on Immunotherapy was to obtain real-world information on the use of PD-(L)1 inhibitors for non-small cell lung cancer (NSCLC) in different regions of China via a national questionnaire survey for oncologists. Methods: This survey was distributed online to cancer-related medical departments in 202 first-tier to fourth-tier cities of China between March to April 2023. The national survey consisted of four sections regarding oncologists’ concerns about immunotherapy as follows: treatment choice, response assessment, treatment duration, and management of immune-related adverse events (irAEs). Results: A total of 2,018 oncologists completed this survey. For advanced squamous (SQ) and non-squamous (NSQ) NSCLC without targetable genetic alterations, PD-(L)1 inhibitor-based regimens were the most widely used first-line treatment regimen (SQ: 52%, NSQ: 46%), followed by chemotherapy alone (SQ: 37%, NSQ: 37%) and other regimens (SQ: 11%, NSQ: 17%). The average treatment duration of 1L PD-(L)1 inhibitor-based regimens in SQ NSCLC and NSQ NSCLC were 6.4 and 6.2 cycles, respectively. 67% of oncologists may discontinue immunotherapy or change regimens when the first radiographic tumor assessment was SD per RECIST 1.1. Other reasons for early discontinuation of PD-(L)1 inhibitors before PD or unacceptable toxicity included economic reasons (78%) and patients’ low willingness to continue immunotherapy even they reached CR/PR (62%). Oncologists in the second-tier cities and below were more likely to discontinue immunotherapy when the tumors were stable, with shorter treatment duration of 5.7 cycles versus 7.1 cycles in the first-tier cities. The most common irAEs included dermatologic, endocrine, pulmonary, gastrointestinal, and hepatic toxicities. Conclusions: PD-(L)1 inhibitor-based regimens have become the priority choice for advanced NSCLC in China, however, the status of standardized continuous use of immunotherapy is obviously insufficient. There is a gap between clinical practice and clinical trials regarding PD-(L)1 inhibitor usage, which need more attention. [Table: see text]

Surufatinib monotherapy or combined with vinorelbine as a late-line therapy in patients with refractory advanced non–small cell lung cancer (NSCLC).

e20543 Background: Surufatinib (S, a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) has shown synergy mechanism with vinorelbine (V) in lung cancer cell lines (A549 cells and PC9 cells) and nude mice experiment. Here, we evaluated the efficacy and safety of surufatinib with or without vinorelbine in refractory advanced NSCLC patients (pts). Methods: This single center, open label, phase Ⅱ study (NCT04922658) has two cohorts. Eligible pts with stage IIIb/IV NSCLC who progressed after at least two lines of previous therapies were assigned to cohort 1 (S, 250 mg qd, po, q3w plus V, 20 mg, po, once every 2 days, q3w) or cohort 2 (S, 300mg qd, po, q3w). Treatment continued until disease progression, intolerable toxicity, or study withdrawal. Primary endpoint was PFS. Secondary endpoints included ORR, DCR, OS, and safety. Results: Up to Jan 15, 2024, 17 pts were enrolled in cohort 1 (median age 62 years, male 76.47%, TNM stage IV 70.59%, ECOG PS 1 94.12%). 32 pts were assigned to cohort 2 (median age 55 years, male 65.62%, TNM stage IV 87.5%, 71.88% pts failing with at least three lines of previous therapies). In cohort 1, 12 pts had received at least one post-baseline tumor assessment (evaluable), among which ORR was 16.7%, DCR was 100 %. 75% pts had stable or shrinking tumors (based on best of response). Median PFS was not reached in cohort 1. In cohort 2, 32 pts were evaluable, ORR was 3.1%, DCR was 87.5%. 62.5% pts had stable or shrinking tumors. Median PFS was 5.4m (95% CI 3.4, 7.4). In subgroup analysis, compared with pts with distant metastases (mainly bone, liver, and brain metastases), pts without above metastases showed significantly longer PFS (6.9m vs 4.1m, p = 0.0071). Additionally, PFS was significantly prolonged in pts who were anti-angiogenic drugs naïve, in contrast with those who received anti-angiogenic therapies before (8.3m vs 4.1m, p = 0.004). Similar result was observed in pts with enlargement tumors versus stable or shrinking tumors (2.8m vs 6.9m, p&lt;0.0001). Longer PFS was observed in pts with squamous NSCLC (sq vs non-sq, 8.3m vs 4.1m, p = 0.0655) or those who received two lines of previous therapies vs at least three lines (6.2m vs 4.8m, p = 0.0728). The most common treatment-emergent adverse events (Total, Grade≥3) in cohort 1 were proteinuria (25.0%, 0), hypothyroidism (16.67%, 0), and diarrhea (8.33%, 8.33%). The most common adverse events (Total, Grade≥3) in cohort 2 were proteinuria (50.0%, 14.7%), hypothyroidism (44.1%, 0), and hypoproteinemia (35.3%, 5.9%). Conclusions: Surufatinib, or combined with vinorelbine, showed encouraging survival benefits and promising anti-tumor activity with acceptable toxicity in the late-line treatment of refractory advanced NSCLC, especially in patients without distant metastases, never using anti-angiogenic drugs, or with squamous NSCLC. The results warrant further investigations in a large cohort. Clinical trial information: NCT04922658 .

A phase I/II, first-in-human study of VLS-1488, an oral KIF18A inhibitor, in patients with advanced cancer.

TPS3181 Background: Chromosomal instability (CIN) is a hallmark of cancer characterized by high rates of chromosomal segregation errors during mitosis. This creates structural and numerical changes to chromosomes, driving genetic heterogeneity and cancer evolution. KIF18A is a mitotic kinesin protein shown to be important for successful division of cancer cells with CIN but not required for mitosis in normal diploid cells. Pre-clinical studies demonstrated that treatment of chromosomally unstable cancer cells in vitro and in xenograft models (HCC15 and OVCAR-3) with a KIF18A inhibitor resulted in failure of chromosomal congression, mitotic arrest, cell death and dose-dependent inhibition of tumor growth. VLS-1488 is an oral small molecule inhibitor of KIF18A that is being examined in an open-label, phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity in advanced solid tumors with high prevalence of CIN. Methods: Key eligibility criteria include specific histologically confirmed metastatic or advanced tumor types with at least one site of measurable disease per RECIST 1.1, adequate organ function, and mismatch repair proficient/microsatellite stable.Eligible tumor types include high grade serous ovarian/fallopian tube/primary peritoneal cancer, squamous non-small cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, gastroesophageal cancer, esophageal cancer, colorectal adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian or uterine carcinosarcoma, and uterine serous carcinoma. Subjects will receive VLS-1488 monotherapy continuously for 28-day cycles once daily. The study consists of two parts, Dose Escalation and Dose Expansion. Utilizing a Bayesian Optimal Interval (BOIN) design, Dose Escalation will examine the safety and tolerability of VLS-1488 at various dose levels (DLs) to identify the Maximum Tolerated Dose (MTD) and to select DLs for Dose Expansion. Dose Expansion may commence after the MTD or DLs of interest are identified. Dose Expansion will examine the safety, tolerability, preliminary efficacy and preliminary drug-drug interaction (DDI) and food effect risk of VLS-1488 in selected tumor types. Subjects enrolled to specific tumor type cohorts may be randomized to DLs of interest. Enrollment to Dose Escalation began in September 2023 and is ongoing. Clinical trial information: NCT05902988 .

A phase 2 study of EIK1001, a Toll-like receptor 7/8 (TLR7/8) agonist, in combination with pembrolizumab and chemotherapy in patients with stage 4 non-small cell lung cancer.

TPS8667 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response. Significant advances for the treatment of non-small cell lung cancer (NSCLC) have been made using the ICI pembrolizumab in combination with chemotherapy, which confers significant clinical benefit relative to chemotherapy and placebo. Not all patients benefit, however, and some become refractory. As a result, there remains a critical unmet need to develop therapies for the treatment of NSCLC. EIK1001 is a TLR7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study EIK1001-005 is a multicenter, Phase 2, open-label study of EIK1001 in combination with pembrolizumab and chemotherapy – carboplatin plus either pemetrexed or paclitaxel – in participants (pts) with histologically confirmed Stage 4 nonsquamous or squamous NSCLC, respectively. This study includes a safety run-in period for pts enrolled in each NSCLC cohort. If &lt; 2 dose-limiting toxicities occur, an expansion phase for each NSCLC cohort will be conducted at the target dose to evaluate the tolerability and efficacy of EIK1001 (QW) in combination with pembrolizumab and chemotherapy (administered Q3W per label). Key eligibility criteria include pts ≥ 18 years of age with a life expectancy of at least 3 months, histologically or cytologically confirmed Stage 4 NSCLC (nonsquamous or squamous) without prior therapy for advanced NSCLC, confirmation that mutation-directed therapy is not indicated as first-line, and at least 1 measurable lesion at Baseline according to RECIST 1.1. The primary objective of this study is to determine the safety and tolerability of EIK1001 in combination with pembrolizumab and chemotherapy. The secondary objectives are evaluation of antitumor activity by objective response rate (ORR; defined as the proportion of pts who have a confirmed complete response [CR] or partial response [PR] per RECIST 1.1) and duration of response (DOR) by RECIST 1.1. Other exploratory objectives include evaluation of anti-tumor activity (ORR/DOR) by immune-related RECIST 1.1, overall survival, progression-free survival, investigation of the relationship between treatment with EIK1001 in combination with pembrolizumab/chemotherapy and biomarkers predictive of response, and the pharmacokinetic parameters of EIK1001. This study opened on 29 Jan 2024. Clinical trial information: NCT06246110 .