Immune Checkpoint Inhibitor Antibody Research Articles

Efficacy and safety of nivolumab monotherapy in metastatic urothelial cancer (mUC): Results from the phase I/II CheckMate 032 study.

4501Background: Minimal antitumor activity of existing therapies and the observation of immune dysfunction in bladder cancer have prompted evaluation of immunotherapy in this malignancy. Nivolumab (fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody) monotherapy has shown survival benefit in patients (pts) with melanoma, lung cancer, and renal cell carcinoma. Here, we report efficacy and safety of nivolumab monotherapy in pts with mUC after ≥1 prior line of platinum-based therapy in an open-label, multicenter phase I/II study (NCT01928394). Methods: Pts (unselected by PD-L1 expression status) with mUC received nivolumab 3 mg/kg intravenously every 2 weeks until progression or discontinuation. Primary endpoint was objective response rate (ORR; RECIST 1.1). Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of 78 treated pts (median age 65.5 years; range, 31–85), 65.4% had received ≥2 prior therapies. At a me...

Advances in immunotherapy for melanoma.

In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients.

Phase II study of nivolumab (ONO-4538/BMS-936558) in patients with esophageal cancer: Preliminary report of overall survival.

TPS175 Background: Patients with esophageal cancer refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a human monoclonal IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced esophageal cancer. We conducted phase II, single-arm, multi-center trial in JAPAN (JapicCTI-No.142422).Methods: The target population was esophageal cancer patients aged ≥ 20 years with ECOG performance status of 0 or 1, who had received one or more previous treatments and not pre-selected by PD-L1 status. Nivolumab (3 mg/kg IV Q2W) was administered to patients until observing unacceptable toxicity or disease progression assessed at 6 week intervals. The primary endpoint was the proportion of patients with a confirmed objective response assessed by independent review committee according to RECIST 1.1. Planned sample size was 60 patients (P0 = 5, P1 = 15, α = 0.025 (one-side), 1-β = 0.8). Data cutoff, 17 May 2015.Results:We enrolled 65 patients with esophageal carcinoma: median age 62.0 years (range, 49-80 years); male/female, 54/11; ECOG PS 0/1, 29/36, Histological type was squamous in all pts. The median prior regimens was 3.0 (range, 1-8); 44 patients (67.7%) were treated with prior esophagectomy and 44 patients (67.7%) with prior radiation therapy. There were 64 evaluable patients for efficacy, and 11(17.2%) of 64 patients had objective response (CR/PR, 1/10). 16 (25.0%) of 64 patients had stable disease. The median overall survival was 12.1 months in 64 evaluable patients. The incidence of drug-related Serious AEs was 11 events (9/65 patients): Lung infection(2[3.1%]), Dehydration(2[3.1%]), Interstitial lung disease (2[3.1%]), etc. The patients with grade 3 pneumonitis improved with supportive care. There was no treatment-related death. We will introduce the updated efficacy and safety data of this trial. Conclusions: Nivolumab has meaningful activity and a manageable safety profile in pretreated esophageal cancer. These data support the assessment of nivolumab in randomized, controlled, phase III studies of second-line treatment. Funding: ONO Pharmaceutical CO.,LTD. Bristol-Myers Squibb Clinical trial information: 142422.

Immune thrombocytopenia exacerbated by nivolumab in a patient with non-small-cell lung cancer

Abstract Introduction Nivolumab is a programmed death 1 (PD-1) immune-checkpoint inhibitor antibody currently approved for second-line therapy of metastatic non-small-cell lung cancer (NSCLC). PD-1 inhibitors including nivolumab are associated with a unique spectrum of immune-related adverse events (irAEs), though hematologic irAEs are rare and have not been previously reported in patients with NSCLC. Presentation of case Here we report a patient who experienced an exacerbation of underlying immune thrombocytopenia (ITP) while receiving nivolumab for NSCLC. The patient's ITP was successfully managed with romiplostim during nivolumab therapy, allowing for 7 months of clinical benefit and a partial tumor response. Discussion Using this case as an example, we provide a brief review of irAEs associated with PD-1 blockade, with particular attention to hematologic events. We also describe our approach to the use of nivolumab in this patient with underlying autoimmune disease. Conclusion Patients with NSCLC and underlying autoimmune disease may experience a flare of the autoimmune condition while receiving immune checkpoint inhibition. As illustrated by this case of ITP exacerbated by nivolumab, careful management of the autoimmune disease may allow for the safe administration of PD-1 directed agents in these patients.

Abstract C107: Preclinical response of murine syngeneic tumor models to immune checkpoint inhibitor antibodies

Abstract Tumor cell viability and proliferation is regulated by the balance between tumor self-survival and host elimination mechanisms. There are multiple mechanisms whereby tumors successfully evade host immune cell surveillance, permitting continued growth and proliferation. Immunotherapies are aimed at bolstering the host immune system. Delivery of these agents has been shown to actively eliminate disease in a number of patients to date. We evaluated several syngeneic mouse tumor lines for anti-tumor activity with anti-CTLA-4 and/or anti-PD-L1 antibodies, as well as the immunological changes occurring following treatment with these checkpoint inhibitors. The effectiveness of these inhibitors was assessed in the B16.F10 (melanoma), RIF-1 (sarcoma), 4T1-luc (mammary) and CT26 (colon) murine tumor models. Cells or tumor fragments (RIF-1) were implanted SC in the axilla. The anti-CTLA-4 9D9 antibody clone from Bio X Cell (West Lebanon, NH) was employed for responsiveness in each model. All treatments were initiated 3 days post implantation, prior to the appearance of established tumor, at inoculums known to have 100% take rates. The CT26 model was highly responsive with all animals showing tumor regressions and 70% tumor-free survivors at study end. The RIF-1 model was moderately responsive with several mice showing long term progression-free survival and a 56% increase in lifespan vs. the isotype control group. Both the B16.F10 and the 4T1-luc models were non-responsive. Tumor responsiveness to the anti-PD-L1 10F.9G2 antibody clone (Bio X Cell) was also compared in the RIF-1 and CT26 models. In contrast to the anti-CTLA-4 antibody studies, RIF-1 was found to be non-responsive and CT26 was moderately responsive to the anti-PD-L1 antibody. Evaluating immunological endpoints by flow cytometry is critical when assessing the effectiveness of immune checkpoint inhibitors. To this end, the immune profiles of both responsive (CT26) and non-responsive (4T1 and B16.F10) models were examined in the absence or presence of antibody treatments. Initial studies were focused on analysis of T cells (CD4 and CD8) as well as T regulatory cells (Tregs; CD4/CD25/FoxP3) and myeloid derived suppressive cells (MDSC; CD11b/Gr1). The 4T1 model was found to be highly MDSC driven and would be suitable to evaluate agents that target myeloid-derived cell populations. While this model was not very responsive to anti-CTLA-4 treatment, a trend toward decreased MDSCs following treatment was observed with anti-CTLA-4 and not the isotype control antibody. In contrast, the CT26 model was more highly mixed and contained populations of both Tregs and MDSCs. Treatment with anti-CTLA-4 increased the CD8+ T cell population and decreased the Treg cell population with minimal effect on the MSDC population. However, in this same model, anti-PD-L1 treatment increased CD8+ T cells and decreased both Tregs and MDSCs. A more complete mechanistic understanding of how the immune system responds to checkpoint inhibitors permits identification of appropriate models for monotherapy, as well as the rationale for designing drug combination studies. Data enhancing understanding of the above, along with tumor profiling on additional syngeneic models and more flow cytometry multiplexing, is expected from further ongoing research. Citation Format: Maryland Franklin, Matt Thayer, Chris Elders, Dan Saims, Scott Wise. Preclinical response of murine syngeneic tumor models to immune checkpoint inhibitor antibodies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C107.

Abstract A89: Istiratumab (MM-141), a bispecific antibody co-targeting IGF-1R and ErbB3, potentiates the activity of immune checkpoint inhibitors

Abstract Purpose: Regulatory T cells (Tregs) help maintain immunological tolerance to cancer cells by suppressing T cell effector function. The depletion of Tregs with the CTLA-4 inhibitor antibody ipilimumab has been proven to be a productive therapeutic strategy in melanoma. Additionally, levels of insulin-like growth factor 1 (IGF-1) are often elevated following chemotherapy treatment and have been associated with poor prognosis in multiple malignances. We demonstrate that IGF-1 can stimulate Treg proliferation. Istiratumab, a tetravalent bispecific antibody that targets both the IGF-1 receptor (IGF-1R) and ErbB3, inhibits IGF-1 signaling by blocking ligand binding and inducing rapid receptor internalization. Based on its mechanism of action, we evaluated the activity of istiratumab on Treg proliferation and in combination with immune checkpoint targeting antibodies in murine models of cancer. Experimental Procedures: Mouse-derived splenocytes were harvested to evaluate the effect of IGF-1 and/or istiratumab treatment on Treg expansion and proliferation in vitro. Flow cytometry studies assessed surface receptor expression of T cell populations isolated from murine splenocytes. Efficacy studies using immunocompetent mice bearing syngeneic murine tumors determined the activity of istiratumab and immune checkpoint targeting antibodies, alone and in combination, on tumor growth alongside isotype-matched controls. Mice whose tumors were eradicated by treatment were maintained and subsequently used in tumor re-challenge studies to assess the development of tumor-specific, immunological, long-term memory. In addition, pharmacodynamic studies analyzed the expression of tumor cell signaling pathway markers, effects on relevant T cell sub-populations and effects on post-treatment cytokine profiles. Data Summary: Our in vitro T cell analyses indicated that sub-populations of murine CD4+ CD25+ FoxP3+ Tregs express IGF-1R, and that istiratumab can reverse IGF-1 driven Treg proliferation in vitro. In addition, istiratumab monotherapy treatment had significant anti-tumor activity in vivo in immunogenic, syngeneic murine tumor models. Moreover, istiratumab potentiated the activity of immune checkpoint targeting antibodies in efficacy studies leading to curative outcomes in a subset of treated animals. These animals developed long-term immunological memory directed against the original tumor cell line. A pharmacodynamic analysis of tumor cell signaling- and immunology-related markers demonstrated that istiratumab impacts tumor cell survival signaling and contributes to overall immunological changes that favor breaking immunological tolerance in relevant syngeneic tumor models, thus enabling the development of an effective and durable anti-tumor immune response. Conclusions: Our in vitro and in vivo pre-clinical studies demonstrate that istiratumab (MM-141) inhibits both tumor cell survival and Treg proliferation in host mice, thereby potentiating the anti-tumor activity of clinically-relevant immune checkpoint inhibitor antibodies. Citation Format: Sharlene Adams, Michael D. Curley, Adam J. Camblin, Sergio Iadevaia, Lin Nie, Gege Tan, Chrystal U. Louis, Alexey A. Lugovskoy. Istiratumab (MM-141), a bispecific antibody co-targeting IGF-1R and ErbB3, potentiates the activity of immune checkpoint inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A89.

Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer

BackgroundNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, disrupts PD-1–mediated signaling and may restore antitumor immunity.MethodsIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non–small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.ResultsOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab versus 39% (95% CI, 33 to 45) with docetaxel. With additional follow-up, the overall survival rate at 18 months was 39% (95% CI, 34 to 45) with nivolumab versus 23% (95% CI, 19 to 28) with docetaxel. The response rate was 19% with nivolumab versus 12% with docetaxel (P=0.02). Although progression-free survival did not favor nivolumab over docetaxel (median, 2.3 months and 4.2 months, respectively), the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel (19% and 8%, respectively). Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (≥1%, ≥5%, and ≥10%) of the PD-1 ligand. Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.ConclusionsAmong patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy, overall survival was longer with nivolumab than with docetaxel. (Funded by Bristol-Myers Squibb; CheckMate 057 ClinicalTrials.gov number, NCT01673867.)

T-cell-based Immunotherapy: Adoptive Cell Transfer and Checkpoint Inhibition.

Tumor immunotherapy has had demonstrable efficacy in patients with cancer. The most promising results have been with T-cell-based therapies. These include adoptive cell transfer of tumor-infiltrating lymphocytes, genetically engineered T cells, and immune checkpoint inhibitor antibodies. In this review, we describe the different T-cell-based strategies currently in clinical trials and put their applications, present and future, into perspective.

Development of an automated PD-L1 immunohistochemistry (IHC) assay for non-small cell lung cancer.

Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune checkpoint inhibitor antibody, developed by Bristol-Myers Squibb Inc., has activity across non-small cell lung cancer (NSCLC) histologies and is Food and Drug Administration approved for treatment of metastatic squamous NSCLC with progression on or after platinum-based chemotherapy. PD-L1 has been investigated as a potential biomarker to predict clinical response to nivolumab in clinical settings. We report an automated PD-L1 immunohistochemistry (IHC) assay, which was developed to detect cell surface PD-L1 in formalin-fixed paraffin-embedded human tumor tissue specimens using Dako's Autostainer Link 48. The primary antibody for this assay is a rabbit monoclonal anti-human PD-L1 antibody, clone 28-8. The specificity of 28-8 for PD-L1 was demonstrated by antigen competition and genetic deletion of PD-L1 in tumor cell lines. The specificity of the PD-L1 IHC assay was further evaluated in a collection of 30 normal human tissues. The PD-L1 IHC assay was optimized for high sensitivity and precision in routine application. A pathology scoring and interpretation method specific to nivolumab clinical studies was adopted for the assay. The analytical performance of the assay was validated for application in the determination of PD-L1 status in human NSCLC specimens. The clinical application of the assay and scoring method was further validated in 3 Clinical Laboratory Improvement Amendments certified labs. The assay is currently being investigated in a variety of clinical studies for use as an in vitro diagnostic to select and stratify patients for treatment with the anti-PD-1 therapeutic antibody, nivolumab.

Abstract 2855: Immunomodulatory activity of nivolumab monotherapy in patients with advanced melanoma

Abstract Background: Nivolumab, a fully human anti-programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has shown encouraging clinical activity in melanoma. We evaluated the pharmacodynamic effects of nivolumab on immune endpoints in patients (pts) with advanced melanoma in an exploratory phase 1 study (NCT01621490). Methods: 85 pts (41 and 44 anti-CTLA-4 therapy-naïve and refractory, respectively) received nivolumab 3 mg/kg IV Q2W in 56-day cycles. Tumor biopsies were obtained at baseline (B/L) and on treatment during Cycle 1, Week 4 (C1Wk4). Response was assessed during the last week of each cycle. The primary objective was to evaluate the pharmacodynamic activity of nivolumab on immune biomarkers, including circulating T-cell subsets (by multiparametric flow cytometry), serum interferon (IFN) and IFN-induced factors (by multiplex immunoassay), and T-cell infiltration in the tumor microenvironment (by immunohistochemistry for CD3, CD4, CD8, PD-1 and FOXP3). Secondary objectives included safety, efficacy, and the association between tumor PD ligand-1 (PD-L1) expression and clinical responses. Results: Across all 85 pts, the objective response rate was 25%, with 2 pts having a confirmed complete response. The safety profile was consistent with prior nivolumab monotherapy trials. Of 85 pts, 34 had evaluable biopsies at B/L and C1Wk4. Increases in tumor infiltrating lymphocytes (TILs) at C1Wk4 relative to B/L were seen in most pts; 65% of pts had an increase in CD3+ T cells. Expression of other TIL markers CD4, CD8, FOXP3 and PD-1, correlated well with one another and CD3 after treatment (C1Wk4; r = 0.69-0.93, P<0.0001). Increased TIL, in particular CD3+ and CD8+, was associated with response; 100%/88% of responders had elevated CD3+/CD8+ TILs compared with 54%/58% of non-responders. PD-L1 expression was not consistently modulated between B/L and C1Wk4 (30 matched samples); however, highest PD-L1 expression (C1Wk4) was accompanied by highest TIL levels (C1Wk4). No consistent change in the frequency of activated peripheral T-cell subsets (HLA-DR+ or ICOS+, CD4 and CD8 T cells) was seen with nivolumab treatment, but peripheral increases in serum IFN-γ-stimulated cytokines were observed. Mean concentrations of serum CXCL9 and CXCL10 increased 2.2- and 1.1-fold from B/L, respectively, 43 days after initial dose; no association was apparent between the increases and response. Conclusions: Nivolumab monotherapy is marked by increased TIL, inclusive of cytotoxic CD8 T cells, and FOXP3+ T regulatory cells and these increases are associated with response. Unlike ipilimumab, nivolumab treatment does not demonstrate consistent increases in circulating activated T cells. However, increases in peripheral IFN-γ-stimulated cytokines, CXCL9 and CXCL10 are observed, presumably derived from the tumor microenvironment. Further characterization of the effects of nivolumab on the tumor microenvironment is ongoing. Citation Format: Walter J. Urba, Salvador Martín-Algarra, Margaret Callahan, Jedd D. Wolchok, William H. Sharfman, Jeffrey A. Sosman, Shailender Bhatia, Wen-Jen Hwu, Thomas F. Gajewski, Craig L. Slingluff, Yun Shen, Christine E. Horak, F Stephen Hodi. Immunomodulatory activity of nivolumab monotherapy in patients with advanced melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2855. doi:10.1158/1538-7445.AM2015-2855

Abstract 5522: Combination of a supramolecular nanotherapeutic targeting MEK and immune checkpoint inhibitor exerts a synergistic antitumor outcome

Abstract The use of targeted therapeutics, such as BRAF inhibitors, and breakthrough immunotherapy treatments such as immune checkpoint inhibitors, are two emerging paradigms in treatment of chemotherapy-resistant melanoma. However, the treatment responses with targeted therapies are short lived mainly because the patients develop resistance, and also the treatment leads to severe toxicities. Higher concentrations of drug in tumor and sustained inhibition of the kinase signaling pathway for longer period of time is required to achieve better therapeutic efficacy. Similarly, immunotherapy results in lower response rates and the response takes longer time. We envision a new paradigm where a quick as well as durable objective response could be achieved by novel supramolecular nanotherapeutic that targets MEK, downstream of BRAF, in combination with immune checkpoint inhibitor antibody PD-L1. A supramolecular nanotherapeutic is engineered from self-assembly due to supramolecular interactions of molecular building blocks designed using an in silico model based on large scale all atomistic explicit water molecular dynamic simulations. The molecular building blocks were engineered using selumetinib as a template, and rationally re-engineering these molecules by conjugating it to cholesterol to enable supramolecular nanoassembly. The supramolecular nanostructures were stable for over a month as measured by changes in size and zeta potential at different time points. Drug release kinetics profiles showed sustained activation into selumetinib in cell lysate conditions. In vitro cytotoxicity studies in multiple cell lines including Breast Cancer (MDA-MB-231), Lung Cancer (A549) and Melanoma (B16F10) cells showed that supramolecular nanotherapeutics were as effective as selumetinib, and resulted in a sustained inhibition of the MAPK pathway. In vivo studies using a B16/F10 melanoma model revealed that supramolecular nanotherapeutics alone exerted significant tumor growth inhibition as compared to selumetinib. Furthermore, the combination of supramolecular nanotherapeutics and PD-L1 antibody resulted in superior antitumor efficacy, as well as significantly increased number of tumor infiltrating lymphocytes, compared to selumetinib + PD-L1 antibody or PD-L1 antibody alone treatments. This study shows that a successful strategy to improve chemotherapy outcome could be devised by synergistic combinations of supramolecular nanoparticles that target oncogenic signaling pathway with immune checkpoint inhibitors. Citation Format: Ashish A. Kulkarni, Venkata Sabbisetti, Prithvi Raj Pandey, Shiladitya Sengupta. Combination of a supramolecular nanotherapeutic targeting MEK and immune checkpoint inhibitor exerts a synergistic antitumor outcome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5522. doi:10.1158/1538-7445.AM2015-5522

Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer

BackgroundPatients with advanced squamous-cell non–small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, as compared with docetaxel in this patient population.MethodsWe randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.ResultsThe median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group.ConclusionsAmong patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.)

Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC).

LBA109 Background: Options for advanced non-SQ NSCLC patients (pts) who progress after platinum-based doublet chemotherapy (PT-DC) are limited, with minimal improvement in overall survival (OS). We report results from a randomized, global phase III study of NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC and tyrosine kinase inhibitor, if eligible. Methods: Pts were randomized to NIVO 3 mg/kg Q2W (n=292) or DOC 75 mg/m2 Q3W (n=290) until progression or discontinuation due to toxicity/other reasons. Primary objective was OS; Secondary objectives were investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression, quality of life, and safety. Results: NIVO demonstrated superior OS (HR=0.73; 96% CI: 0.59, 0.89; P=0.00155) and improved ORR (19.2% vs 12.4%; P=0.0235). HR for PFS was 0.92 (95% CI: 0.77, 1.11; P=0.393). PD-L1 expression was associated with benefit from NIVO (Table). In PD-L1+ pts, NIVO showed improved efficacy across all endpoints at predefined 1%, 5%, and 10% cut- points. Grade 3–5 drug-related AEs occurred in 10.5% (30/287) of NIVO and 53.7% (144/268) of DOC pts. No deaths were related to NIVO vs 1 DOC-related death. After discontinuation, 42.1% of NIVO and 49.7% of DOC pts received subsequent systemic therapy. Conclusions: NIVO demonstrated superior OS vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC. The safety profile of NIVO 3 mg/kg Q2W was favorable vs DOC. NIVO demonstrated survival benefit across histologies in two randomized phase III trials. Clinical trial information: NCT01673867. [Table: see text]

An ongoing phase IIIb/IV safety trial of nivolumab (NIVO) in patients (pts) with advanced or metastatic non-small-cell lung cancer (NSCLC) who progressed after receiving 1 or more prior systemic regimens.

3013 Background: NIVO, a fully human IgG4 programmed death-1 (PD-1), immune checkpoint inhibitor antibody, has demonstrated durable responses and tolerability in heavily pretreated pts with advance...

First-line monotherapy with nivolumab (NIVO; anti-programmed death-1 [PD-1]) in advanced non-small cell lung cancer (NSCLC): Safety, efficacy and correlation of outcomes with PD-1 ligand (PD-L1) expression.

8025 Background: NIVO, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has demonstrated durable responses and tolerability in heavily pretreated patients (pts) with advanced NSCLC. Th...

Expanded cohort results from CheckMate 016: A phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC).

4516 Background: Nivolumab (N), a fully human IgG4 immune checkpoint inhibitor antibody, has shown durable response and encouraging overall survival (OS) in mRCC. Previously in CheckMate 016, N + i...

Phase II studies of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients with advanced squamous (sq) or nonsquamous (non-sq) non-small cell lung cancer (NSCLC).

8027 Background: Nivolumab, a fully human IgG4, PD-1 immune-checkpoint inhibitor antibody, has shown durable clinical activity in phase I and II trials in several tumor types. Recently, a phase III...

Nivolumab: targeting PD-1 to bolster antitumor immunity.

Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, blocks PD-1 and can restore anticancer immune responses by abrogating PD-1 pathway-mediated T-cell inhibition. Nivolumab is approved in Japan and the USA for the treatment of patients with advanced melanoma. A Phase I trial reported overall objective response rates of 17, 32 and 29% in patients with advanced non-small-cell lung cancer, melanoma and renal cell carcinoma, respectively, which included many heavily pretreated patients. 1-/2-year overall survival rates were 42%/24%, 63%/48% and 70%/50% for non-small-cell lung cancer, melanoma and renal cell carcinoma, respectively. Nivolumab significantly improved survival versus dacarbazine in previously untreated patients with metastatic melanoma in a Phase III trial. Nivolumab is associated with a manageable adverse event profile. Numerous clinical trials are investigating nivolumab alone or in combination with other therapies in multiple cancer settings. This article summarizes the development of nivolumab as of November 2014.

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial

Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746. Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. Bristol-Myers Squibb.

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial

Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Bristol-Myers Squibb.