Antitumor Activity of Pembrolizumab (Pembro; Mk-3475) and Correlation with Programmed Death Ligand 1 (Pd-L1) Expression in a Pooled Analysis of Patients (Pts) with Advanced Non–Small Cell Lung Carcinoma (Nsclc)

Garon, Edward B.; Gandhi, Leena; Rizvi, Naiyer A.; Hui, Rina; Balmanoukian, Ani Sarkis; Patnaik, Amita; Eder, Joseph P.; Blumenshein, George; Aggarwal, Charu; Soria, J-C.; Ahn, Myung‐Ju; Gubens, Matthew A.; Ramalingam, Suresh S.; Johnson, Elizabeth A.; Arkenau, Hendrik‐Tobias; Lubiniecki, Gregory M.; Zhang, J.; Rutledge, Ruth Z.; Emancipator, Kenneth; Leighl, Natasha B.

doi:10.1093/annonc/mdu438.51

Cited by 62 publications

(62 citation statements)

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“…Smoking history was associated with an increased ORR to pembrolizumab (48), and this was consistent with an RR of 25% for smokers versus 16% for never smokers seen with MPDL-3270A (47). A similar pattern was observed for active/former smokers treated with nivolumab and MPDL-3280A (41,49); the underlying mechanism remains unknown; however, it is possible that smoking status is a surrogate marker for mutational density (50).…”

Section: Ctla-4 Inhibitorssupporting

confidence: 67%

Cancer Immunotherapy: A Future Paradigm Shift in the Treatment of Non–Small Cell Lung Cancer

Anagnostou

Brahmer

2015

Clinical Cancer Research

208

165

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Emerging evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy even for tumors that were historically considered as nonimmunogenic. Immunotherapy is emerging as a major modality in non-small cell lung cancer (NSCLC) treatment focusing on vaccine approaches to elicit specific immune responses and development of inhibitors of the molecular mediators of cancerinduced immunosuppression (immune checkpoints) to boost antitumor immune responses. Amplification of the host response against evolving tumors through vaccination is being investigated in ongoing clinical trials with tumor cell vaccines; however, the clinical efficacy of these agents has been limited. Blocking inhibitory pathways such as the CTL antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) checkpoint pathways with mAbs has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand 1 (PD-L1) antibodies have shown durable responses in NSCLC, with a favorable safety profile and manageable side effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-na€ ve patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC.

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Section: Ctla-4 Inhibitorssupporting

confidence: 67%

Cancer Immunotherapy: A Future Paradigm Shift in the Treatment of Non–Small Cell Lung Cancer

Anagnostou

Brahmer

2015

Clinical Cancer Research

208

165

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“…20, [33][34][35] Nevertheless, the absence or low expression of PD-L1 does not preclude response to or survival benefit from nivolumab. 19,20,23,36 In this study, equivalent responses were noted across tumor PD-L1 expression levels with no discernible association between PD-L1 expression and PFS or OS.…”

Section: Discussionmentioning

confidence: 99%

Nivolumab in Combination With Platinum‐Based Doublet Chemotherapy for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer

Rizvi

Hellmann

Brahmer

et al. 2016

JCO

397

304

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Purpose Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non–small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC). Patients and Methods Patients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression. Results No dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed death ligand-1 expression. Conclusion The safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.

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“…At present, different companies and academic centers are using different antibodies, and we have little data to help choose the best diagnostic antibody or threshold. Moreover, although initial data obtained in solid tumors suggested that PD-L1 expression on tumor cells was the strongest determinant of response to PD-1 blockade, there is a meaningful response rate even in apparently PD-L1-negative tumors 15,42,43 ; in fact, at least in some cases, the tumor microenvironment may determine response more strongly than PD-L1 tumor expression. 15 It must be remembered that PD-L1 expression on tumor cells is a dynamic process, induced by interferon signaling and other factors.…”

Section: Blockage In Hematologic Malignancies 3395mentioning

confidence: 99%

Immune checkpoint blockade in hematologic malignancies

Armand

2015

Blood

208

136

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Therapeutic blockade of immune checkpoint pathways, in particular cytotoxic T-lymphocyte associated protein 4 and programmed-death 1 (PD-1), has become a paradigm-shifting treatment in solid tumor oncology. Hematologic malignancies (HMs), many of which are known to have clinically exploitable immune sensitivity, are a natural target for this type of treatment. Several clinical trials of checkpoint blockade have been conducted in HM, with preliminary results suggesting the therapeutic usefulness of this approach across several tumor types. In particular, the results of PD-1 blockade in Hodgkin lymphoma (HL) are remarkable, and raise hope that it may alter the treatment landscape in this disease. However, numerous questions remain about the optimal role of checkpoint blockade both in HL and beyond. Those questions are the focus of this review, in the hope that, if we are at the dawn of a new day in HM immunotherapy, we may begin to envision its morning.

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Antitumor Activity of Pembrolizumab (Pembro; Mk-3475) and Correlation with Programmed Death Ligand 1 (Pd-L1) Expression in a Pooled Analysis of Patients (Pts) with Advanced Non–Small Cell Lung Carcinoma (Nsclc)

Cited by 62 publications

References 0 publications

Cancer Immunotherapy: A Future Paradigm Shift in the Treatment of Non–Small Cell Lung Cancer

Cancer Immunotherapy: A Future Paradigm Shift in the Treatment of Non–Small Cell Lung Cancer

Nivolumab in Combination With Platinum‐Based Doublet Chemotherapy for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer

Immune checkpoint blockade in hematologic malignancies

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