A phase I trial of ipilimumab plus bevacizumab in patients with unresectable stage III or stage IV melanoma.

Hodi, F. Stephen; Friedlander, Philip; Atkins, Michael B.; McDermott, David F.; Lawrence, Donald P.; Ibrahim, Nevin F; Wu, Xian; Zhou, J.; Giobbie‐Hurder, Anita; Murphy, Gëorge F.; Velázquez, Elsa F.; Russell, Sara E.; DiPiro, Pamela J.; Yap, Jeffrey T.; Abbeele, Annick D. Van den

doi:10.1200/jco.2011.29.15_suppl.8511

Cited by 49 publications

(40 citation statements)

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“…Early clinical data suggest that combined CTLA-4 and VEGF inhibition can induce durable responses in a substantial proportion of patients with advanced melanoma (81). Furthermore, a durable complete response rate of .…”

Section: Biomarkersmentioning

confidence: 99%

CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients

Ott

Hodi

Robert

2013

Clinical Cancer Research

609

455

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Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is the first agent associated with a documented improved overall survival benefit in this patient population. A striking attribute of CTLA-4 blockade is the durability of objective responses, leading to speculation of a possible cure for some patients. Many tumor responses achieved with PD-1 and PD-L1 inhibition were durable in the phase I trials and were seen in a higher proportion of patients with melanoma than typically observed with ipilimumab. Biomarker development to identify the subset of patients with melanoma who will achieve durable clinical benefit with checkpoint blockade is critical; tumor PD-L1 expression has been promising in early studies. The contrast between unprecedented response rates but limited durability of responses achieved with BRAF and MEK inhibition in BRAF V600 -mutated melanoma and the impressive durability but relatively low rate of response achieved with immune checkpoint blockade is striking. Preclinical data on potential synergies between CTLA-4/PD-1/PD-L1 inhibition and MAPK-targeted therapy is emerging, and combined immune checkpoint blockade and MAPK inhibition are being explored in clinical trials.Other promising approaches to increase the number of patients with melanoma who benefit from durable responses with immune checkpoint blockade include concurrent or sequenced CTLA-4 and PD-1/PD-L1 inhibition and combination with other immunotherapeutic strategies.

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Section: Biomarkersmentioning

confidence: 99%

CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients

Ott

Hodi

Robert

2013

Clinical Cancer Research

609

455

View full text Add to dashboard Cite

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“…Whether the higher incidence of hypophysitis seen in these trials might be attributed to the higher drug dose, to the concomitant administration of vaccine or both, remains to be elucidated. Preliminary results from the only trial evaluating ipilimumab (10 mg/kg) administered in combination with bevacizumab reported high rates of hypophysitis (14%) (43).…”

Section: Anti-ctla4-mabs and Pituitary Dysfunctionmentioning

confidence: 99%

ENDOCRINE SIDE-EFFECTS OF ANTI-CANCER DRUGS: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses

Torino

Barnabei

Paragliola

et al. 2013

European Journal of Endocrinology

108

103

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mAbs are established targeted therapies for several diseases, including hematological and solid malignancies. These agents have shown a favorable toxicity profile, but, despite their high selectivity, new typical side-effects have emerged. In cancer patients, pituitary dysfunction may be mainly due to brain metastases or primary tumors and to related surgery and radiotherapy. Anticancer agents may induce hypopituitarism in patients cured for childhood cancers. These agents infrequently affect pituitary function in adult cancer patients. Notably, hypophysitis, a previously very rare disease, has emerged as a distinctive side-effect of ipilimumab and tremelimumab, two mAbs inhibiting the cytotoxic T-lymphocyte antigen-4 receptor, being occasionally seen with nivolumab, another immune checkpoint inhibitor. Enhanced antitumor immunity is the suggested mechanism of action of these drugs and autoimmunity the presumptive mechanism of their toxicity. Recently, ipilimumab has been licensed for the treatment of patients affected by metastatic melanoma. With the expanding use of these drugs, hypophysitis will be progressively encountered by oncologists and endocrinologists in clinical practice. The optimal management of this potentially life-threatening adverse event needs a rapid and timely diagnostic and therapeutic intervention. Hypopituitarism caused by these agents is rarely reversible, requiring prolonged or lifelong substitutive hormonal treatment. Further studies are needed to clarify several clinical and pathogenic aspects of this new form of secondary pituitary dysfunction.European Journal of Endocrinology 169 R153-R164

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“…In addition, tumor-targeted agents (such as vemurafenib) that significantly reduce tumor burden but alone are insufficient to induce durable regression (17,79) would provide ideal partners for immune therapy such as blockade of PD-L1/ PD-1. Finally, effective tumor-targeted agents that additionally possess immune-enhancing properties could optimally combine with anti-PD-L1/PD-1 to generate durable and adaptable antitumor immunity (6,75,80). …”

Section: Future Directionsmentioning

confidence: 99%

Molecular Pathways: Next-Generation Immunotherapy—Inhibiting Programmed Death-Ligand 1 and Programmed Death-1

Chen

Irving

Hodi

2012

Clinical Cancer Research

563

380

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The aim of T-cell-based immune therapy for cancer has been to generate durable clinical benefit for patients. Following a generation of therapies that largely showed minimal activity, substantial toxicity, and no biomarkers to identify which patients benefit from treatment, early studies are showing signs that programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) inhibitors are highly active. Preclinical and early data from clinical studies suggest that targeting this pathway can induce durable clinical responses in patients in a variety of tumor types, including lung and colon cancer. Furthermore, correlations with tumor PD-L1 expression may enable selection of patients most likely to benefit from treatment. The emerging data not only offer the hope of better cancer therapy but also provide evidence that changes our understanding of how the host immune system interacts with human cancer. Clin Cancer Res; 18(24); 6580-7. Ó2012 AACR.

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A phase I trial of ipilimumab plus bevacizumab in patients with unresectable stage III or stage IV melanoma.

Cited by 49 publications

References 0 publications

CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients

CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients

ENDOCRINE SIDE-EFFECTS OF ANTI-CANCER DRUGS: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses

Molecular Pathways: Next-Generation Immunotherapy—Inhibiting Programmed Death-Ligand 1 and Programmed Death-1

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