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Immune Checkpoint Blockade Shows Durable Responses in Lung and Kidney Cancers, Metastatic Melanoma

TOP - August 2015, Vol 8, No 3

Hollywood, FL—The National Com­prehensive Cancer Network (NCCN) now recommends nivolumab (Opdivo) as subsequent therapy for metastatic squamous non–small-cell lung cancer (NSCLC) after its recent FDA approval.

In patients with advanced renal-cell carcinoma (RCC), immune checkpoint blockade may provide a new approach to treat this disease, with durable responses achieved in some patients in a phase 2 clinical trial.

At the 2015 NCCN annual conference, presenters provided an update of immunotherapy for the treatment of melanoma as well as lung and kidney cancers.

Lung Cancer: Nivolumab Now FDA Approved

The experience with immunotherapy in lung cancer is minimal, said Gregory A. Otterson, MD, Professor of Internal Medicine, Ohio State Uni­versity Comprehensive Cancer Center, Columbus. Checkpoint blockade (humanized antibodies against PD-1 or its ligand 1 [PD-L1]) with nivolumab offers a better immunotherapy strategy than the anti–CTLA-4 antibody ipilimumab (Yervoy) in patients with lung cancer. Nivolumab given as a second-line to fifth-line treatment produced an overall response rate of 18% in 76 evaluable patients, “and of the responses, 20 of 31 lasted more than a year, and toxicity was quite mild, with all grade 3 or 4 events being 1% or less,” said Dr Otterson.

A single-arm phase 2 study of nivolu­mab in the third-line setting in squamous-cell NSCLC demonstrated a 15% overall response rate, a median overall survival (OS) of 8.2 months, and a 1-year OS rate of 41%. This study led to a phase 3 trial comparing nivolumab versus docetaxel (Taxotere) in previously treated patients with advanced squamous-cell NSCLC.

The study was stopped early when, at the planned analysis in January 2015, the OS was 9.2 months in the nivolumab arm versus 6 months in the docetaxel arm, for a hazard ratio of 0.59 (P = .002). The FDA recently approved nivolumab for advanced squamous-cell NSCLC, and on this basis, in March 2015, the NCCN recommended nivolumab as subsequent therapy for metastatic squamous cell NSCLC.

Renal-Cell Carcinoma: Anti–PD-1 Promising

“As a field, renal-cell carcinoma is probably 3 or 4 years behind” in immunotherapy, said Eric Jonasch, MD, Associate Professor, Department of Geni­tourinary Medical Oncology, M.D. Anderson Cancer Center, Houston, TX.

High-dose interleukin (IL)-2 is an option in a select group of patients who have good performance status, clear-cell RCC, and low-grade disease. “It’s the one cytokine, or immunotherapy, currently approved for RCC,” Dr Jonasch said. High-dose IL-2 is associated with better response rates than interferon, but no survival advantage has been shown with high-dose IL-2 in randomized clinical trials. Carbonic anhydrase IX failed as a biomarker to improve the selection criteria for high-dose IL-2.

The retrospective measurement of tumor PD-L1 expression was successful as a marker of response in recipients of high-dose IL-2, and further study of this biomarker is warranted.

A number of vaccine strategies have been tried or are being tested in RCC, including vitespen, an autologous heat shock 90 protein plus peptide extract. Vitespen, however, did not improve recurrence-free survival in an adjuvant setting. A multipeptide cancer vaccine is currently under study in patients receiving sunitinib (Sutent) for advanced RCC.

Checkpoint blockade using a CTLA-4 inhibitor and an anti–PD-1 antibody is in ongoing clinical studies in patients with previously treated metastatic RCC. The PD-1 checkpoint inhibitor nivolumab was associated with an OS as long as 25 months in patients with previously refractory RCC, said Dr Jonasch, and a subset of patients had durable response to nivolumab.

Metastatic Melanoma: Durable Disease Control with Nivolumab

To date, no vaccine therapy has been found useful as adjuvant therapy for melanoma, said Anthony J. Olszanski, MD, RPh, Director, Medical Oncology Melanoma Program, Fox Chase Cancer Center, Philadelphia. Interferon remains the only adjuvant systemic option for patients at risk for melanoma, with the choice being high-dose interferon or pegylated interferon, which is easier to tolerate. Although anti–CTLA-4 therapy extends recurrence-free survival in this setting, the rate of adverse events is high, and an OS analysis is awaited.

Ipilimumab is currently indicated for the treatment of unresectable or metastatic melanoma. Anti–PD-1 therapy (ie, pembrolizumab [Keytruda], nivolumab) is indicated for the treatment of patients with unresectable or metastatic melanoma and for patients with disease progression after therapy with ipilimumab, and in combination with a BRAF inhibitor if the patient has a BRAF mutation.

CTLA-4 inhibitors are associated with durable disease control in the first- and second-line settings for metastatic melanoma. In patients receiving CTLA-4 inhibitors in the second-line setting, “some of these patients have been followed for over 10 years without relapse for metastatic melanoma,” said Dr Olszanski.

Anti–PD-1 treatment with nivo­lumab was recently shown to be superior to dacarbazine as first-line therapy for the treatment of metastatic melanoma, with a 1-year OS rate of 72.9% in the nivolu­mab group versus 42.1% for dacarbazine. “The median survival for nivolumab has not been met,” Dr Olszanski said. In this study, the superior OS with nivolumab was irrespective of PD-L1 tumor status, he noted.

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