Immune Checkpoint Inhibitors in Thoracic Malignancies: Review of the Existing Evidence by an IASLC Expert Panel and Recommendations

Remón, Jordi; Passiglia, Francesco; Ahn, Myung Ju; Barlési, Fabrice; Forde, Patrick M.; Garon, Edward B.; Gettinger, Scott; Goldberg, Sarah B.; Herbst, Roy S.; Horn, Leora; Kubota, Keiichi; Lü, Shun; Mezquita, Laura; Paz‐Ares, Luis; Popat, Sanjay; Schalper, Kurt A.; Skoulidis, Ferdinandos; Reck, Martin; Adjei, Alex A.; Scagliotti, Giorgio Vittorio

doi:10.1016/j.jtho.2020.03.006

Cited by 129 publications

(106 citation statements)

References 290 publications

(415 reference statements)

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“…PD-1 pathway blockade has revolutionized the treatment of advanced NSCLC and is now the backbone of all FDA-approved first-line therapies for locally advanced or metastatic NSCLC lacking a targetable driver mutation. 3 …”

Section: Introductionmentioning

confidence: 99%

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer

Reuss

Anagnostou

Cottrell

et al. 2020

J Immunother Cancer

121

101

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BackgroundWe conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab.MethodsPatients with resectable stage IB (≥4 cm)–IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint.ResultsWhile the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations.ConclusionsThough treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

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Section: Introductionmentioning

confidence: 99%

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer

Reuss

Anagnostou

Cottrell

et al. 2020

J Immunother Cancer

121

101

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“…The clinical development of immune-checkpoint inhibitors (ICI) has changed the paradigm of treatment for patients with non-small cell lung cancer (NSCLC) [ 1 ]. However, only a limited part of patients benefits from ICI, rising up the need for affordable biomarkers and different therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

“…However, only a limited part of patients benefits from ICI, rising up the need for affordable biomarkers and different therapeutic strategies. Although evaluating the tumor membrane expression of programmed death-ligand 1 (PD-L1) has become mandatory for newly diagnosed advanced NSCLC [ 2 ], the ICI as single-agent can achieve satisfying responses regardless of the PD-L1 status in the pretreated population [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI)

Giglio

Mezquita

Auclin

et al. 2020

Cancers

Self Cite

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Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms. Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (≥10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications. Results: 413 patients received ICI, 299 were steroids-naïve at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1–12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both p < 0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9–1.5] and mOS [1.9 mo.; 95%CI, 1.5–2.4; p < 0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2–5.6] and OS [HR 4.53; 95% CI, 1.8–11.1], both p < 0.0001. Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms.

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“…The gene modules most upregulated in tumors compared to nlung included genes associated with glycolysis (mod39) and cell cycle (mod38), which were mainly expressed in MoDC cluster 52 ( Figure S2G-I). Frequent upregulation of many monocyte-or MΦ-like modules (7,3,4,6,5,37,10) was consistent with a higher frequency of MoDC compared to cDC in tumors.…”

Section: Resultsmentioning

confidence: 63%

“…Lung cancer is the most common cause of cancer-related death 1 , and the most common subgroup of lung cancer is non-small cell lung cancer (NSCLC) 2 . In recent years, immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has become first-line therapy for a majority of patients with metastatic and locally advanced disease 3 . Though ICB studies have achieved improved overall survival, fewer than half of patients achieve significant clinical benefit, though still may experience physical and financial toxicity.…”

Section: Introductionmentioning

confidence: 99%

CITEseq analysis of non-small-cell lung cancer lesions reveals an axis of immune cell activation associated with tumor antigen load andTP53mutations

Leader

Grout

Chang

et al. 2020

Preprint

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Immunotherapy is becoming a mainstay in the treatment of NSCLC. While tumor mutational burden (TMB) has been shown to correlate with response to immunotherapy, little is known about the relation of the baseline immune response with the tumor genotype. Here, we profiled 35 early stage NSCLC lesions using multiscale single cell sequencing. Unsupervised clustering identified in a subset of patients a key cellular module consisting of PDCD1+ CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). Transcriptional data from two NSCLC cohorts confirmed a subset of patients with LCAMhi enrichment, which was independent of overall immune cell content. The LCAMhi module strongly correlated with TMB, expression of cancer testis antigens, and with TP53 mutations in smokers and non-smokers. These data establish LCAM as a key mode of immune cell activation associated with high tumor antigen load and driver mutations.

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Immune Checkpoint Inhibitors in Thoracic Malignancies: Review of the Existing Evidence by an IASLC Expert Panel and Recommendations

Cited by 129 publications

References 290 publications

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer

Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI)

CITEseq analysis of non-small-cell lung cancer lesions reveals an axis of immune cell activation associated with tumor antigen load andTP53mutations

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