Neoadjuvant chemo/immunotherapy for the treatment of stages IIIA resectable non-small cell lung cancer (NSCLC): A phase II multicenter exploratory study—NADIM study-SLCG.

Provencio-Pulla, Mariano; Nadal-Alforja, Ernest; Cobo, Manuel; Insa, Amelia; Rivas, Marinha Costa; Majem, Margarita; Rodríguez-Abreu, Delvys; López-Vivanco, G.; Dómine, Manuel; Morillo, Elvira del Barco; Massutí, Bartomeu; Campelo, Rosario García; Martí, Alejandro; Bernabé, R.; Franco, Fernando; Jové, Maria; Arrabal, Ricardo; Martín, Paloma Leticia; Casal, J.; Calvo, Virginia

doi:10.1200/jco.2018.36.15_suppl.8521

Cited by 61 publications

(52 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PD-1/PD-L1 axis blockade enhances antitumor immunity, induces sustained tumor regression, and extends overall survival in many advanced cancers (1). More recently, neoadjuvant PD-1/PD-L1 pathway blockade in early stage lung cancer has shown clinical efficacy (2,3) while inducing peripheral expansion of mutation-associated neoantigen-specific T-cell clones (3). Neoadjuvant phase III clinical trials incorporating PD-1 blockade are now active across multiple solid tumors (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non–Small Cell Lung Cancer

Zhang

Caushi

et al. 2020

Clinical Cancer Research

119

101

View full text Add to dashboard Cite

Purpose: Neoadjuvant PD-1 blockade is a promising treatment for resectable non-small cell lung cancer (NSCLC), yet immunologic mechanisms contributing to tumor regression and biomarkers of response are unknown. Using paired tumor/blood samples from a phase II clinical trial (NCT02259621), we explored whether the peripheral T-cell clonotypic dynamics can serve as a biomarker for response to neoadjuvant PD-1 blockade. Experimental Design: T-cell receptor (TCR) sequencing was performed on serial peripheral blood, tumor, and normal lung samples from resectable NSCLC patients treated with neoadjuvant PD-1 blockade. We explored the temporal dynamics of the T-cell repertoire in the peripheral and tumoral compartments in response to neoadjuvant PD-1 blockade by using the TCR as a molecular barcode. Results: Higher intratumoral TCR clonality was associated with reduced percent residual tumor at the time of surgery, and the TCR repertoire of tumors with major pathologic response (MPR; <10% residual tumor after neoadjuvant therapy) had a higher clonality and greater sharing of tumor-infiltrating clonotypes with the peripheral blood relative to tumors without MPR. Additionally, the posttreatment tumor bed of patients with MPR was enriched with T-cell clones that had peripherally expanded between weeks 2 and 4 after anti-PD-1 initiation and the intratumoral space occupied by these clonotypes was inversely correlated with percent residual tumor. Conclusions: Our study suggests that exchange of T-cell clones between tumor and blood represents a key correlate of pathologic response to neoadjuvant immunotherapy and shows that the periphery may be a previously underappreciated originating compartment for effective antitumor immunity. See related commentary by XXX, p. XXX

show abstract

Section: Introductionmentioning

confidence: 99%

Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non–Small Cell Lung Cancer

Zhang

Caushi

et al. 2020

Clinical Cancer Research

119

101

View full text Add to dashboard Cite

show abstract

“…The NADIM study, a phase 2 trial examining neoadjuvant chemotherapy plus nivolumab followed by adjuvant nivolumab for 1 year in stage IIIA NSCLC, demonstrated unusually high objective response rates (69.2% complete pathological response). 28 At this interim analysis, there were no delays in surgery, and all tumors were deemed resectable (n ¼ 13). 28 Similarly, interim analysis of the LCMC3 study examining neoadjuvant atezolizumab monotherapy for stage IB-IIIB resectable NSCLC reported a 21% rate of major pathological response and no major delays in surgery.…”

Section: Current Literature and Ongoing Trialsmentioning

confidence: 99%

“…28 At this interim analysis, there were no delays in surgery, and all tumors were deemed resectable (n ¼ 13). 28 Similarly, interim analysis of the LCMC3 study examining neoadjuvant atezolizumab monotherapy for stage IB-IIIB resectable NSCLC reported a 21% rate of major pathological response and no major delays in surgery. 29 In a recent presentation, the NEOSTAR phase 2 trial demonstrated higher rates of major pathological response in patients receiving combination nivolumab plus ipilimumab compared with those receiving nivolumab monotherapy before surgery.…”

Section: Current Literature and Ongoing Trialsmentioning

confidence: 99%

The immunotherapeutic landscape in non–small cell lung cancer and its surgical horizons

Rhodin

Rucker

Ready

et al. 2020

The Journal of Thoracic and Cardiovascular Surgery

View full text Add to dashboard Cite

Lung cancer continues to be a leading cause of cancer-related death worldwide. Despite tremendous advances in surgical technique, chemotherapy regimens, radiation, and targeted therapies, survival is <50% at 5 years. Immunotherapy, specifically immune checkpoint inhibitors (ICIs), demonstrates promise as a solution to this clinical problem. Several agents have been Food and Drug Administration-approved for locally advanced and metastatic non-small cell lung cancer (NSCLC). Further studies are now exploring the use of these agents in the neoadjuvant and adjuvant settings. Although ICIs have demonstrated meaningful efficacy in NSCLC and other advanced malignancies, they are not without adverse toxicities. Furthermore, there are minimal data on their use in the perioperative period. Here we discuss the current domain of ICIs and their surgical implications in NSCLC.

show abstract

“…Pathologically, tumour regression was accompanied by marked signs of local immune activity including the influx of lymphocytes and macrophages, and the creation of tertiary lymphoid structures, along with tumour-cell death (18). Subsequently, preliminary outcomes of further early phase trials of neoadjuvant nivolumab or atezolizumab (antibody blocking PD1-Ligand 1, PD-L1) with or without chemotherapy have been reported, with these therapies proving well-tolerated and with considerable evidence of clinical efficacy (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Pharmacodynamics of Pre-Operative PD1 Checkpoint Blockade and Receptor Activator of NFkB Ligand (RANKL) Inhibition in Non-Small Cell Lung Cancer (NSCLC): study protocol for a multicentre open-label phase 1B/2 translational trial (POPCORN)

Ahern

Cubitt

Ballard

et al. 2019

Preprint

View full text Add to dashboard Cite

Background Neoadjuvant immunotherapy targeting the immune checkpoint programmed death-1 (PD-1) is under investigation in various tumour settings including non-small-cell lung cancer (NSCLC). Preclinical models demonstrate the superior power of immunotherapy given in the neoadjuvant (pre-operative) compared with adjuvant (post-operative) setting to eradicate metastatic disease and induce long-lasting antigen-specific immunity. Novel effective immunotherapy combinations are widely sought in the oncology field, targeting non-redundant mechanisms of immune evasion. A promising combination partner with anti-PD1 in NSCLC is denosumab, a monoclonal antibody blocking Receptor Activator of NF-κB Ligand (RANKL). In preclinical cancer models, and a large retrospective case series in NSCLC, anti-cancer activity of combination immune checkpoint inhibition (ICI) and denosumab has been reported. Furthermore, clinical trials of ICI and denosumab are underway in advanced melanoma and clear-cell renal cell carcinoma. However, the mechanism of action of combination anti-PD1 and anti-RANKL is poorly defined. Methods This open-label multicentre trial will randomise by minimisation 30 patients with resectable stage IA (primary > 2cm) to IIIA NSCLC to a neoadjuvant treatment regime of either two doses of nivolumab (3 mg/kg every 2 weeks) or two doses of nivolumab (same regimen) plus denosumab (120 mg every 2 weeks, following nivolumab). Each treatment arm is of equal size, and be approximately balanced with respect to histology (squamous vs. non-squamous) and clinical stage (I-II vs IIIA). All patients will receive surgery for their tumour two weeks after the final dose of neoadjuvant therapy. The primary outcome will be translational research to define the tumour-immune correlates of combination therapy compared with monotherapy. Key secondary outcomes will include a comparison of rates of the following between each arm: toxicity, response (pathological and radiological), and microscopically complete resection. Discussion The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer. Trial registration Prospectively registered on Australian New Zealand Clinical Trials Registry (ACTRN12618001121257) on 06/07/2018.

show abstract

Neoadjuvant chemo/immunotherapy for the treatment of stages IIIA resectable non-small cell lung cancer (NSCLC): A phase II multicenter exploratory study—NADIM study-SLCG.

Cited by 61 publications

References 0 publications

Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non–Small Cell Lung Cancer

Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non–Small Cell Lung Cancer

The immunotherapeutic landscape in non–small cell lung cancer and its surgical horizons

Pharmacodynamics of Pre-Operative PD1 Checkpoint Blockade and Receptor Activator of NFkB Ligand (RANKL) Inhibition in Non-Small Cell Lung Cancer (NSCLC): study protocol for a multicentre open-label phase 1B/2 translational trial (POPCORN)

Contact Info

Product

Resources

About