Overall Survival and Long-Term Safety of Nivolumab (Anti–Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer

Gettinger, Scott; Horn, Leora; Gandhi, Leena; Spigel, David R.; Antonia, Scott; Rizvi, Naiyer A.; Powderly, John D.; Heist, Rebecca S.; Carvajal, Richard D.; Jackman, David M.; Sequist, Lecia V.; Smith, David C.; Leming, Philip D.; Carbone, David P.; Pinder-Schenck, Mary; Topalian, Suzanne L.; Hodi, F. Stephen; Sosman, Jeffrey A.; Sznol, Mario; McDermott, David F.; Pardoll, Drew M.; Sankar, Vindira; Ahlers, Christoph M.; Salvati, Mark; Wigginton, Jon M.; Hellmann, Matthew D.; Kollia, Georgia; Gupta, Ashok; Brahmer, Julie R.

doi:10.1200/jco.2014.58.3708

Cited by 1,054 publications

(863 citation statements)

References 38 publications

(10 reference statements)

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“…In tissue biopsies, expression of the biomarker PD-L1 alone is not a prognostic indicator of survival in lung cancer, while RAD50 foci formation has been indicated as positively correlated with survival (14,18,20,24,29,30,32,35,39,40,42). We analyzed the clinical outcomes of patients based on expression of PD-L1, or the average number of RAD50, at both T0 and T1 time points (Fig.…”

Section: Pd-l1 and Rad50 In Circulating Cells As Potential Prognosticmentioning

confidence: 99%

“…PD-L1/PD-1 immune blockade drugs (e.g., nivolumab and pembrolizumab) are potent immune checkpoint inhibitors that have been shown to dramatically shrink and stabilize tumors in approximately 20% of patients with NSCLCs (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). These types of immunotargeted therapeutics specifically alter a patient's stromal interactions by activating the host's immune cell response against the presence of tumor cells (29-36, 41, 42).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

Adams

et al. 2017

Clinical Cancer Research

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Purpose: Evidence suggests that PD-L1 can be induced with radiotherapy and may be an immune escape mechanism in cancer. Monitoring this response is limited, as repetitive biopsies during therapy are impractical, dangerous, and miss tumor stromal cells. Monitoring PD-L1 expression in both circulating tumor cells (CTCs) and circulating stromal cells (CStCs) in blood-based biopsies might be a practical alternative for sequential, noninvasive assessment of changes in tumor and stromal cells.Experimental Design: Peripheral blood was collected before and after radiotherapy from 41 patients with lung cancer, as were primary biopsies. We evaluated the expression of PD-L1 and formation of RAD50 foci in CTCs and a CStC subtype, cancer-associated macrophage-like cells (CAMLs), in response to DNA damage caused by radiotherapy at the tumor site.Results: Only 24% of primary biopsies had sufficient tissue for PD-L1 testing, tested with IHC clones 22c3 and 28-8. A CTC or CAML was detectable in 93% and 100% of samples, prior to and after radiotherapy, respectively. RAD50 foci significantly increased in CTCs (>7Â, P < 0.001) and CAMLs (>10Â, P ¼ 0.001) after radiotherapy, confirming their origin from the radiated site. PD-L1 expression increased overall, 1.6Â in CTCs (P ¼ 0.021) and 1.8Â in CAMLs (P ¼ 0.004): however, individual patient PD-L1 expression varied, consistently low/negative (51%), consistently high (17%), or induced (31%).Conclusions: These data suggest that RAD50 foci formation in CTCs and CAMLs may be used to track cells subjected to radiation occurring at primary tumors, and following PD-L1 expression in circulating cells may be used as a surrogate for tracking adaptive changes in immunotherapeutic targets.

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Section: Pd-l1 and Rad50 In Circulating Cells As Potential Prognosticmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

Adams

et al. 2017

Clinical Cancer Research

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“…The long-term survival and delayed clinical effect observed in multiple cancer immunotherapy phase III clinical trials with timeto-event endpoints (5,6,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) pose unique statistical challenges in study design. Four basic models summarize how the long-term survival and delayed clinical effects affect the study design with time-to-event endpoints (41).…”

Section: Impact Of Survival Kinetics On Study Designmentioning

confidence: 99%

“…11, 12) and the PD-1 ligand, PD-L1 (13), led to the selection of "Cancer Immunotherapy" as the 2013 Breakthrough of the Year by Science (14). Nivolumab, a fully human IgG4 (Immunoglobulin G subclass 4) monoclonal antibody to PD-1, showed promising efficacy in multiple tumor types (15)(16)(17)(18). The significant survival benefit led to decisions by data monitoring committees to discontinue ahead of schedule four randomized phase III nivolumab clinical trials in metastatic melanoma (19), squamous and nonsquamous non-small cell lung cancer (NSCLC; refs.…”

Section: Introductionmentioning

confidence: 99%

Statistical Challenges in the Design of Late-Stage Cancer Immunotherapy Studies

Mick

Chen

2015

Cancer Immunology Research

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The past several years have witnessed a revival of interest in cancer immunology and immunotherapy owing to striking immunologic and clinical responses to immune-directed anticancer therapies and leading to the selection of "Cancer Immunotherapy" as the 2013 Breakthrough of the Year by Science. But statistical challenges exist at all phases of clinical development. In phase III trials of immunotherapies, survival curves have been shown to demonstrate delayed clinical effects, as well as long-term survival. These unique survival kinetics could lead to loss of statistical power and prolongation of study duration. Statistical assumptions that form the foundations for conventional statistical inference in the design and analysis of phase III trials, such as exponential survival and proportional hazards, require careful considerations. In this article, we describe how the unique characteristics of patient response to cancer immunotherapies will impact our strategies on statistical design and analysis in late-stage drug development.

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“…Clinical trials have also suggested that clinical response rates strongly correlate with PD-L1 expression status. This was first demonstrated in a phase I study of nivolumab in solid tumors (CA209-003) 24 . Of 46 patients with melanoma, NSCLC, or RCC, 25 tumors were positive and 21 were negative for PD-L1.…”

mentioning

confidence: 92%

PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness

Qu¹,

Chang²,

Dai³

et al. 2017

European Urology Supplements

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Programmed death ligand-1 (PD-L1), a promising antitumor target, has proven clinical value against many malignancies. However, the PD-L1 content of Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) and its correlation with clinical outcomes remain unclear. This study aimed to investigate PD-L1 expression in Xp11.2 RCC and to assess its prognostic value. Formalin-fixed paraffin-embedded specimens from 36 adult patients that were histologically confirmed (by fluorescence in situ hybridization) were subjected to immunohistochemical analysis. Of the 36 Xp11.2 RCC patients, 9 (25.0%) had tumors with positive PD-L1 expression and 27 (75.0%) had tumors with negative PD-L1 expression. Positive PD-L1 expression correlated with advanced tumor stage (P = 0.001), regional lymph node metastasis (P < 0.001), and distant metastasis (P < 0.001). A multivariate analysis identified positive PD-L1 expression was an independent adverse prognostic factor for both progression free survival (hazard ratio: 3.7, P = 0.018) and overall survival (hazard ratio: 4.5, P = 0.034). Renal cell carcinoma (RCC) is widely recognized as a heterogeneous disease with various histological subtypes. The most common histopathological subtypes are clear cell (60%-75%), papillary (10%-15%), chromophobe (5%), and collecting duct carcinomas 1 . Xp11.2 translocation RCC (Xp11.2 RCC) is a rare subtype that was recognized as a distinctive pathological entity in the 2004 World Health Organization renal tumor classification 2, 3 . Xp11.2 RCC is characterized by several translocations on chromosome Xp11.2, resulting in gene fusion between TFE3 and at least six possible partners [4][5][6] .As it is a rare RCC subtype, the best treatment for Xp11.2 RCC has not been defined. Surgery is the optimal treatment for localized Xp11.2 RCC patients, including those with positive regional lymph nodes 7 . However, previous studies indicate that Xp11.2 RCC presents at an advanced stage with a rapid clinical course 8,9 . As a result, systematic treatment may be indispensable for most patients. Anti-VEGF drugs are reported to have activity against metastatic Xp11.2 RCC 10, 11 . However, Xp11.2 RCC has poor prognosis regardless of treatment 12,13 . Therefore, new, effective treatments are desperately needed for patients with this tumor type.Monoclonal antibodies (mAbs) targeting the programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) pathway have achieved impressive response rates in patients with melanoma, non-small cell lung cancer, and bladder cancer, and PD-L1 has been validated as a predictive biomarker for the outcome of mAb therapy in many studies [14][15][16] . However, its prognostic and clinical value in patients with Xp11.2 RCC subtypes is unknown. In this study, we sought to investigate the levels of PD-L1 expression and its correlation with clinical outcome in a series of patients with Xp11.2 RCC that was histologically confirmed using TFE3 break-apart fluorescence in situ hybridization (FISH).

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Overall Survival and Long-Term Safety of Nivolumab (Anti–Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer

Abstract: Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.

Cited by 1,054 publications

References 38 publications

Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

Statistical Challenges in the Design of Late-Stage Cancer Immunotherapy Studies

PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness

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