Sarcoidosis-like reaction after neoadjuvant pembrolizumab combined with chemotherapy mimicking disease progression of NSCLC induced encouraging discovery of pathological complete response.
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ABSTRACT:
SUBMITTER: Shi Y
PROVIDER: S-EPMC8671890 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In functionally fit patients with localized disease surgical resection remains the treatment of choice. There is also good evidence to support the use of chemotherapy in stages II-III. However, whether to use neoadjuvant or adjuvant therapy has been the topic of much debate. With its strong evidence base, adjuvant chemotherapy has been adopted in the European Society of Medical Oncology clinical practice guidelines for early and locally advanced stages II-III non-small-cell lung cancer (NSCLC), with consideration of adjuvant therapy in those with stage IB but with tumours >4 cm in size. There are fewer trials comparing neoadjuvant therapy plus surgery with surgery alone. Even less has been carried out directly comparing neoadjuvant with adjuvant therapy. The NATCH trial demonstrated no difference in survival between adjuvant and neoadjuvant arms, whilst others have yet to be completed. Meta-analysis also demonstrates no appreciable difference between the two methods. With such a strong body of evidence, however, postoperative delivery of chemotherapy remains the timing of choice in NSCLC.
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Project description:The combination of immune checkpoint inhibitors (ICIs) with chemotherapy (chemoimmunotherapy) in the neoadjuvant setting have achieved favorable clinical benefits in non-small cell lung cancer (NSCLC), but the mechanism of clinical responses remain unclear. We provide a rich resource of 186,477 individual immune cells from 48 samples of four treatment-naive and eight neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients (responders versus non-responders) by single-cell RNA-seq and TCR-seq. We observed the synergistic increase of B cells and CD4+ T cells were associated with a positive therapeutic response of neoadjuvant chemoimmunotherapy. B cell IgG subclasses IgG1 and IgG3 played a critical role in anti-tumor immune response in tumor lesions, and this process was driven by increased IL-21 secreted by infiltrated T follicular helper (Tfh) cells after neoadjuvant chemoimmunotherapy. Furthermore, we uncovered several critical events for positive clinical outcomes, including the diminished activated TNFRSF4+ regulatory T cells (Tregs), increased LAMP3+ dendritic cells (DCs), and the expansion of intratumoral CD4+ T clones and peripheral C3-Cytotoxic CD8+ T clones. A validation cohort of 26 treatment-naive and 30 neoadjuvant chemoimmunotherapy treated IIIA/ IIIB NSCLC patients verified these findings. In total, our comprehensive study of the single-cell profile of immune cells provides insights into mechanisms underlying anti-PD-1-based therapies and identified potential predictive factors and therapeutic targets for improving the efficiency of neoadjuvant chemoimmunotherapy in NSCLC.
| S-EPMC9279493 | biostudies-literature
Project description:Even patients after standard surgery and adjuvant chemotherapy still have a high risk of recurrence and metastasis. With the success of immunotherapy in advanced non-small cell lung cancer (NSCLC), the application of immunotherapy in locally advanced NSCLC has being investigated to reduce the recurrence and metastasis. Pre-clinical studies and several phase II clinical studies had provided theoretical support and clinical evidence for neoadjuvant immunotherapy for NSCLC. This review describes the mechanism of neoadjuvant immuno-chemotherapy, summarizes up-to-date clinical studies, and analyzes efficiency and feasibility of neoadjuvant immune monotherapy or immuno-chemotherapy. Results from four studies (NCT02259621, NEOSTAR, LCMC3 and ChiCTR-OIC-17013726) showed efficiency and feasibility of neoadjuvant anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) monotherapy. Neoadjuvant nivolumab plus ipilimumab achieved higher major pathological response rate than nivolumab monotherapy. However, the combination of nivolumab plus ipilimumab led to more severe adverse events as is seen in the NEOSTAR trial. Results from NCT02716038, SAKK 16/14 and NADIM studies suggest that the pathological response rate of neoadjuvant immune-chemotherapy is higher than neoadjuvant immune checkpoint inhibitor monotherapy. This review also elaborates the mechanism of chemotherapy combined with immunotherapy, and discusses the efficacy evaluation after neoadjuvant immunotherapy.
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| S-EPMC8105607 | biostudies-literature
Project description:Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. The expected 5-year survival of stage III NSCLC ranges from 13% to 36% for stage III. Due to the heterogeneity and poor efficacy of stage III patients, there is great controversy on how to optimize the therapy strategy. Immunotherapy is providing better clinical efficacy to more NSCLC patients, and is rapidly extending its range of care from advanced stage to locally advanced stage and early stage NSCLC. Due to the patient's strong treatment intention, drug availability, and a few encouraging results from clinical trials (NADIM, NCT02716038, etc.), the authors observed a case of stage III NSCLC that achieved complete remission after receiving neoadjuvant chemotherapy combined with immunotherapy. In view of such a satisfactory result in neoadjuvant therapy, this article discusses how comprehensive treatment for stage III NSCLC patients may be conducted and the manner in which various therapeutic techniques can be mastered in the era of immunotherapy. Immunotherapy has opened the exploratory space for finding resolutions to numerous challenges of treating stage III NSCLC. Further clinical studies and exploration of personalized treatment, guided by imaging data, and clinical and pathological biomarkers are imperative for the benefit of these patients.
| S-EPMC7653116 | biostudies-literature
Project description:BackgroundStage III Non-small cell lung cancer (NSCLC) is a heterogenous disease with novel treatment options. Recently, immunotherapy has attracted a lot of attention for advanced NSCLC.ObjectiveThe objective of our study was to assess the efficacy and safety of neoadjuvant immuno-chemotherapy for resectable stage III NSCLC.MethodsWe analyzed 11 stage III primary NSCLC surgical cases who had undergone standard lobectomy or bronchial sleeve resection and lymph node dissection between December 2020 and July 2021. The data analyzed included basic clinical features, serum levels of key biomarkers, clinical efficacy in the perioperative period, postoperative pathological results, postoperative complications and the incidence rates of Immune-Related Adverse Events.ResultsEleven patients were enrolled in our study with a mean age of 67.7 ± 4.8 years, and 10 patients being men with former or current smoking history. Squamous carcinoma (10/11, 91.1%) was the most common cancer type. Six patients had stage IIIa, five had stage IIIb. All patients received two or three cycles of neoadjuvant immuno-chemotherapy, with the median duration between the last treatment and surgery being 39 days (range, 32-46 days). All patients underwent R0 resection with ten patients undergoing single-port video-assisted thoracoscopic surgery. The median operative time was 170 min (range, 120-240 min). Only three (3/11, 27.3%) patients experienced mild postoperative complications and the mean hospital stay time was 6.9 days (range, 4-15 days). Nine (9/11, 81.8%) patients experienced major pathological response of which seven (7/11, 63.6%) was complete pathological response in postoperative results. The pathological stage was downgraded in 10 (10/11, 91.1%) patients, and although the incidence of Immune-Related Adverse Events was slightly higher (8/11, 72.7%), most events were grade 1-2 and did not delay surgery.ConclusionOur study demonstrated that neoadjuvant immuno-chemotherapy is feasible and relatively safe for resectable stage III primary NSCLC patients. We hope this new neoadjuvant immuno-chemotherapy model can improve overall survival and open a new era for stage III primary NSCLC patients.
| S-EPMC9018103 | biostudies-literature
Project description:IntroductionPembrolizumab plus chemotherapy significantly improved survival outcomes versus placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC in the randomized, double-blind, phase 3 KEYNOTE-407 study. We present the results of Chinese patients enrolled in the KEYNOTE-407 global and China extension studies.MethodsPatients enrolled from mainland China in the KEYNOTE-407 global (NCT02775435) and China extension studies (NCT03875092) were randomized 1:1 to 35 cycles of pembrolizumab or placebo plus four cycles of carboplatin and paclitaxel or nab-paclitaxel. Dual primary end points were overall survival (OS) and progression-free survival (PFS) (based on the Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review).ResultsA total of 125 patients were randomized (pembrolizumab-chemotherapy, n = 65; placebo-chemotherapy, n = 60). As of September 30, 2020, median (range) study follow-up was 28.1 (25.1‒40.9) months. Pembrolizumab-chemotherapy improved OS (hazard ratio [HR] = 0.44, 95% confidence interval [CI]: 0.28-0.70) and PFS (HR = 0.35, 95% CI: 0.24-0.52) versus placebo-chemotherapy. Two-year OS and PFS rates for pembrolizumab-chemotherapy versus placebo-chemotherapy were 56.9% versus 31.7% and 24.2% versus 3.3%, respectively. Treatment-related grade 3 to 5 adverse events occurred in 81.5% and 81.7%, respectively. Relative to baseline, pembrolizumab-chemotherapy improved global health status/quality of life scores at week 18 versus placebo-chemotherapy (difference in least squares means = 7.6, 95% CI: 1.5-13.7) and prolonged time to deterioration in cough, chest pain, or dyspnea (HR = 0.50, 95% CI: 0.28-0.89).ConclusionsPembrolizumab-chemotherapy prolonged survival versus placebo-chemotherapy with manageable toxicity and preserved or improved health-related quality of life in Chinese patients with metastatic squamous NSCLC. These findings support pembrolizumab-chemotherapy as first-line therapy in this population.
| S-EPMC8503629 | biostudies-literature
Project description:IntroductionEvidence supports the addition of immunotherapy to definitive chemoradiation for unresectable stage IIIA NSCLC. Adding pembrolizumab to neoadjuvant chemoradiation in patients with resectable stage IIIA NSCLC requires study for safety and feasibility.MethodsPatients with resectable stage IIIA NSCLC received neoadjuvant cisplatin, etoposide, and pembrolizumab concurrently with thoracic radiotherapy of 45 Gy in 25 fractions. Patients without progression underwent resection followed by 6 months of consolidation pembrolizumab. Safety and feasibility were defined as less than or equal to 30% grade 3 or higher pulmonary toxicity or any grade 4 or 5 nonhematologic toxicity. A total of 10 patients were to be enrolled initially. If less than or equal to two patients had events, another 10 were to be enrolled.ResultsThe study closed after enrolling nine patients. The median age was 66 (range: 49-76) years. A total of 67% were female. Median follow-up was 38.3 months. Serious adverse events occurred in seven patients, including two grade 5 events: one sudden cardiac arrest in the neoadjuvant phase and one fatal pneumocystis pneumonia after resection. Eight patients were assessable for response. The overall response rate was 67%. Six underwent complete resection. Four achieved pathologic complete response, whereas one additional patient had complete nodal clearance. Median progression-free survival has not been reached. The 3-year overall survival was 64%.ConclusionsAdding pembrolizumab to neoadjuvant concurrent cisplatin, etoposide, and radiotherapy in resectable stage IIIA NSCLC resulted in an encouraging pathologic complete response rate. Higher-than-expected toxicities necessitated trial closure after meeting the rule for infeasibility. The relationship of grade 5 events to the addition of pembrolizumab is unclear.
| S-EPMC9257414 | biostudies-literature
Project description:BackgroundNeoadjuvant immunotherapy, the focus of current research and treatment modality for long-term survival, has become one of the main options in supporting primary treatment interventions in early NSCLC.MethodsThis was a retrospective analysis of patients with locally resectable NSCLC who received the neoadjuvant drug pembrolizumab combined with chemotherapy and underwent surgical resection. Pathological responses, PFS and OS in the whole sample and subgroups were analyzed.ResultsOf the 61 patients included in this retrospective analysis, 31 (50.82%) achieved a pCR, and 38 (62.30%) obtained an MPR. Patients with a pCR had significantly higher OS than the non-pCR group (HR = 0.093, P = 0.0227); patients with an MPR also had significantly elevated OS compared with the non-MPR group (HR = 0.05357, P = 0.0169). Patients with lymph node metastasis after surgery had significantly reduced OS (HR = 0.01607, p = 0.0004) and PFS (HR = 0.08757, p = 0.0004) than those without lymph node metastasis. There was no significant difference in OS and PFS between squamous cell carcinomas (SCC) group and adenocarcinomas (AD) group. No significant differences in OS and PFS were found between patients administered 2 and 3 cycles of neoadjuvant therapy before surgery, between those administered ≤5 and > 5 cycles of adjuvant therapy post-surgery, and between patients with TPS <50% and ≥50% (all P > 0.05).ConclusionNeoadjuvant immunochemotherapy with pembrolizumab plus chemotherapy in non-small cell lung cancer is safe and tolerable. Both pCR and MPR were closely associated with OS and PFS, reflecting a good response of tumor tissues to drug therapy. Lymph node metastasis after surgery was a poor prognostic factor, reducing OS and PFS.
| S-EPMC10559199 | biostudies-literature
Project description:Objective To compare the cost-effectiveness of the combination of pembrolizumab and chemotherapy (Pembro+Chemo) versus pembrolizumab monotherapy (Pembro) as the first-line treatment for metastatic non-squamous and squamous non-small-cell lung cancer (NSCLC) with PD-L1expression ≥50%, respectively, from a US health care perspective. Material and Methods A comprehensive Makrov model were designed to compare the health costs and outcomes associated with first-line Pembro+Chemo and first-line Pembro over a 20-years time horizon. Health states consisted of three main states: progression-free survival (PFS), progressive disease (PD) and death, among which the PFS health state was divided into two substates: PFS while receiving first-line therapy and PFS with discontinued first-line therapy. Two scenario analyses were performed to explore satisfactory long-term survival modeling. Results In base case analysis, for non-squamous NSCLC patients, Pembro+Chemo was associated with a significantly longer life expectancy [3.24 vs 2.16 quality-adjusted life-years (QALYs)] and a substantially greater healthcare cost ($341,237 vs $159,055) compared with Pembro, resulting in an ICER of $169,335/QALY; for squamous NSCLC patients, Pembro+Chemo was associated with a slightly extended life expectancy of 0.22 QALYs and a marginal incremental cost of $3,449 compared with Pembro, resulting in an ICER of $15,613/QALY. Our results were particularly sensitive to parameters that determine QALYs. The first scenario analysis yielded lower ICERs than our base case results. The second scenario analysis founded Pembro+Chemo was dominated by Pembro. Conclusion For metastatic non-squamous NSCLC patients with PD-L1 expression ≥50%, first-line Pembro+Chemo was not cost-effective when compared with first-line Pembro. In contrast, for the squamous NSCLC patient population, our results supported the first-line Pembro+Chemo as a cost-effective treatment. Although there are multiple approaches that are used for extrapolating long-term survival, the optimal method has yet to be determined.
| S-EPMC8784520 | biostudies-literature
Project description:The purpose of the present study was to investigate the association of glutathione S-transferase P1 (GSTP1) expression with resistance to neoadjuvant paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide (P-FEC) in human breast cancers. The relationship of GSTP1 expression and GSTP1 promoter hypermethylation with intrinsic subtypes was also investigated. In this study, primary breast cancer patients (n = 123, stage II-III) treated with neoadjuvant P-FEC were analyzed. Tumor samples were obtained by vacuum-assisted core biopsy before P-FEC. GSTP1 expression was determined using immunohistochemistry, GSTP1 promoter methylation index (MI) using bisulfite methylation assay and intrinsic subtypes using DNA microarray. The pathological complete response (pCR) rate was significantly higher in GSTP1-negative tumors (80.0%) than GSTP1-positive tumors (30.6%) (P = 0.009) among estrogen receptor (ER)-negative tumors but not among ER-positive tumors (P = 0.267). Multivariate analysis showed that GSTP1 was the only predictive factor for pCR (P = 0.013) among ER-negative tumors. Luminal A, luminal B and HER2-enriched tumors showed a significantly lower GSTP1 positivity than basal-like tumors (P = 0.002, P < 0.001 and P = 0.009, respectively), while luminal A, luminal B and HER2-enriched tumors showed a higher GSTP1 MI than basal-like tumors (P = 0.076, P < 0.001 and P < 0.001, respectively). In conclusion, these results suggest the possibility that GSTP1 expression can predict pathological response to P-FEC in ER-negative tumors but not in ER-positive tumors. Additionally, GSTP1 promoter hypermethylation might be implicated more importantly in the pathogenesis of luminal A, luminal B and HER2-enriched tumors than basal-like tumors. Fresh frozen tumor samples obtained by vacuum-assisted core biopsy from one hundred and fifteen patients were subjected to RNA extraction and hybridization on Affymetrix microarrays.
2012-03-20 | E-GEOD-32646 | biostudies-arrayexpress