July 2015, Vol. 2, No. 4
Checkpoint Blockade: Durable Responses in Lung and Kidney Cancers and Metastatic Melanoma
A new guideline from the National Comprehensive Cancer Network (NCCN) incorporates nivolumab as subsequent therapy for metastatic squamous non–small cell lung cancer (NSCLC) following its recent FDA approval.
In 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 NCCN 20th Annual Conference, presenters provided an update of immunotherapy for the treatment of melanoma and lung and kidney cancers.
Lung Cancer: Nivolumab Recently Approved
The experience with immunotherapy in lung cancer is minimal, said Gregory A. Otterson, MD, The Ohio State University Comprehensive Cancer Center, Columbus. Checkpoint blockade (humanized antibodies against programmed death-1 [PD-1] or its ligand [PD-L1]) appears to offer a better immunotherapy strategy than an anti–CTLA-4 antibody (ipilimumab) in lung cancer. Nivolumab given as second- to fifth-line treatment produced an overall response rate (ORR) of 18% in 76 evaluable patients with NSCLC, and survival in this patient population treated with nivolumab was 42% at 1 year and 24% at 2 years, and toxicity was quite mild, with all grade 3 or grade 4 events being 1% or less, said Otterson.
A single-arm phase 2 study of nivolumab in the third-line setting in squamous NSCLC reported a 15% ORR, a median overall survival (OS) of 8.2 months, and a 1-year OS of 41%. This study led to a phase 3 trial comparing nivolumab versus docetaxel in previously treated patients with advanced squamous NSCLC. This study was stopped early when at the planned analysis in January 2015, OS was 9.2 months in the nivolumab arm versus 6 months in the docetaxel arm (hazard ratio, 0.59; P = .00025). The FDA recently approved nivolumab for this indication, and on this basis, in March 2015, the NCCN recommended nivolumab as subsequent therapy for metastatic squamous cell NSCLC.
RCC: 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, MD Anderson Cancer Center, Houston, TX.
High-dose interleukin-2 (IL-2) is an option in a select group of individuals who have good performance status, clear cell RCC, and low-grade disease. “It’s the one cytokine, or immunotherapy, currently approved for RCC,” he 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. Retrospective measurement of tumor PD-L1 expression was successful as a marker of response in high-dose IL-2 recipients, and further study of this biomarker is warranted.
A number of vaccine strategies have been tried or are being tested in RCC, including vitespen, a heat shock protein (gp96)–peptide complex purified from resected autologous tumors. Vitespen, however, did not improve recurrence-free survival in an adjuvant setting. A multipeptide cancer vaccine is currently under study in patients receiving sunitinib 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 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, Clinical Pharmacology, Fox Chase Cancer Center, Philadelphia, PA. Interferon remains the only adjuvant systemic option for patients at risk, 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 analysis of OS is awaited.
Ipilimumab is currently indicated for the treatment of unresectable or metastatic melanoma. Anti–PD-1 therapy (pembrolizumab, nivolumab) is indicated for the treatment of unresectable/metastatic melanoma and for disease progression following ipilimumab therapy, 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 setting for metastatic melanoma. In the second-line setting, “some of these patients have been followed for over 10 years without relapse for metastatic melanoma,” said Olszanski.
Anti–PD-1 treatment with nivolumab was recently shown to be superior to dacarbazine as first-line 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,” he said. In this study, the superior OS with nivolumab was irrespective of PD-L1 tumor status, Olszanski noted.
Although vaccines are not yet a standard procedure in the therapeutic management of patients with NSCLC, they may play an important role in the future Therapeutic cancer vaccines are classified as either whole-cell vaccines (such as the belagenpumatucel-L vaccine, developed from 4 different NSCLC cell lines) or vaccines that target [ Read More ]
Numerous clinical studies are under way investigating the blockade of inhibitory “checkpoint pathways” to enhance the antitumor immune response One promising approach to treating lung cancer involves augmenting the existing antitumor immune responses through blockade of inhibitory checkpoint pathways (ie, natural mechanisms that serve to limit the immune response).1 Checkpoint [ Read More ]