November 2014, Part 4
New Drugs and Clinical Trial Data: Updates in Cutaneous Malignancies
Immune-targeted therapies and inhibitors of Hedgehog pathway signaling dot the landscape in recent investigations in the treatment of melanoma, BCC, and MCC. A rundown of findings with newly approved therapies and investigational therapies was presented at the Third Annual World Cutaneous Malignancies Congress.
Immune Therapies in Melanoma
In the treatment of advanced melanoma, anti–PD-1 monoclonal antibodies have proven effective as single agents. Pembrolizumab is a humanized high-affinity antibody that exerts dual ligand blockade of PD-1; nivolumab is a fully human monoclonal antibody that is also directed toward PD-1. These anti–PD-1 antibodies represent breakthroughs in extending survival, said Caroline Robert, MD, PhD. They perform similarly in the setting of advanced melanoma, with an objective response rate (ORR) of 32% to 34% and 1-year OS in excess of 60%. “Five years ago, only 25% to 30% of patients were still alive at 1 year,” she said.
In patients with ipilimumab-refractory advanced melanoma, pembrolizumab at 2 or 10 mg/kg was associated with an ORR of 26% and a disease control rate of 50%.
The phase 3 CA209-037 study evaluated nivolumab versus investigator’s choice of chemotherapy (ICC) in 405 patients with advanced melanoma who had progressed despite previous therapies directed against CTLA-4 or BRAF mutation (Weber J, et al. ESMO 2014. Abstract LBA3_PD). Interim efficacy analysis showed a higher ORR in patients who received nivolumab therapy compared with ICC (32% vs 11%), with 3 complete responses in the nivolumab group. Ninety-five percent in the nivolumab group had ongoing response with a minimum of 24 weeks of follow-up, said Robert, head of dermatology, Institut Gustave Roussy, Paris. Responses with nivolumab were observed regardless of pretreatment PD-L1 expression status, BRAF mutation status, or prior benefit from anti–CTLA-4 therapy.
The most recent advancement in the treatment of advanced melanoma is combining ipilimumab and nivolumab. Blocking these pathways represents an immunotherapy strategy that can restore tumor-specific T-cell–mediated immunity. In a phase 1 clinical study, the combination given concurrently was associated with an ORR of 40% and survival of 85% at 1 year and 79% at 2 years. Even better 1-year (94%) and 2-year survival (88%) was achieved when they were given sequentially (Kluger H, et al. ESMO 2014. Abstract 1085O). Treatment responses were independent of BRAF mutation status. Almost two-thirds (64%) of patients had grade 3/4 treatment-related adverse events.
Registry Examining Real-World Management of Advanced Basal Cell Carcinoma
The real-world management of advanced BCC is being examined in the RegiSONIC Disease Registry Study, said Jean Y. Tang, MD, PhD. The goal of RegiSONIC is to learn how clinicians determine and treat advanced BCC in the real world by evaluating the effectiveness, safety, and use of systemic and local treatments in 3 BCC populations: 1) advanced BCC patients who do not have basal cell nevus syndrome (BCNS) and are naive to treatment with a Hedgehog pathway inhibitor; 2) those who were previously enrolled in a trial of the Hedgehog pathway inhibitor vismodegib; and 3) patients who have advanced BCC with BCNS or who have multiple nonadvanced, Hedgehog pathway–naive BCC.
“The study represents the largest planned, prospective, observational cohort study of patients with advanced BCC and BCNS,” said Tang, associate professor of dermatology, Stanford University, CA. It is attempting to provide real-world data that will inform the medical community and improve the care of patients with advanced BCC.
RegiSONIC is a multicenter, prospective, observational cohort study in adult patients with advanced BCC or BCNS and per-protocol follow-up. The determination of advanced BCC is left to the discretion of the study clinician, and treatment, procedures, and clinic visit schedules are left to the clinician’s discretion in accordance with routine practice.
Based on the first 131 locally advanced BCC patients enrolled, locally advanced BCC appears to be determined by using a number of tumor characteristics, including size (74%), extent (61%), and location (62%). Median size of the locally advanced BCC was 20.5 mm at determination, the most frequent location was the nose (19.8%), and the most common histopathology was nodular (58.8%).
The pivotal molecular abnormality in BCC carcinogenesis is inappropriate activation of the Hedgehog signaling pathway. “Essentially all BCC tumors have an overactive Hedgehog signaling pathway, commonly occurring by mutational inactivation of the tumor suppressor PTCH1 gene,” she said.
Vismodegib is a small-molecule inhibitor of the Hedgehog signaling pathway that has been proven effective in the treatment of locally advanced BCC. Significant ORRs with vismodegib are observed in both locally advanced and metastatic BCCs, and the clinical response to vismodegib in responders frequently occurs in a matter of weeks, said Tang.
Vismodegib appears to be an effective chemopreventive agent for BCC. Tang and colleagues showed prevention of new BCCs in patients with BCNS (N Engl J Med. 2012;366:2180-2188). Other data show that in operable BCC, neoadjuvant vismodegib reduces the surgical defect size by 27% at an average of 4 months of treatment. Patients must be on neoadjuvant treatment for at least 3 months to see this effect, said Tang, and they should be counseled about the significant side effects associated with the drug.
Managing Resistance to Hedgehog Inhibitor
More than half of patients with advanced BCCs develop resistance to vismodegib. In these patients, the Hedgehog pathway becomes reactivated; 50% of resistant BCCs contain mutations in the SMO gene of the Hedgehog pathway. Smoothened inhibitors as second-line therapy may be effective when resistance to vismodegib develops, said Tang. Itraconazole reduced Hedgehog pathway signaling by 50% in vismodegib-naive tumors and reduced BCC tumor size by 20% at 1 month of therapy. In the mouse model, “the combination of itraconazole and arsenic trioxide does an even better job of reducing tumor size,” she said. In a small sample of 5 patients, the combination was shown to reduce Hedgehog signaling as well.
Immunotherapy Approaches in Merkel Cell Carcinoma
The use of immunotherapy in MCC is rational, given the increased incidence of the disease and the worse prognosis in immunocompromised patients, “suggesting that the immune system is important in controlling the disease,” said Isaac Brownell, MD, PhD. In addition, prognosis of MCC is improved with the presence of CD8+ tumor-infiltrating lymphocytes. There are documented cases of spontaneous regression of MCC attributed to an antitumor immune response; responses have been observed with immune-stimulating therapies such as dinitrochlorobenzene, tumor necrosis factor-alpha, and interferon; and 80% of MCC patients express non-self Merkel cell polyomavirus viral antigens. Also, the prognosis of MCC is improved with high titers of MCV VP1.
“Similar observations predicted the immune responsiveness of melanoma,” said Brownell, head, Cutaneous Development and Carcinogenesis Section, Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Active immunotherapy trials for MCC include the following agents: anti–PD-L1, adoptive T cells, interleukin (IL)-12 plasmid in vivo electroporation DNA vaccine, glucopyranosyl lipid adjuvant-stable emulsion, F16-IL2 antibody-cytokine fusion with paclitaxel, and adjuvant ipilimumab for excised MCC.
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