Nivolumab: Promising Survival Signal Coupled With Limited Toxicity Raises Expectations

Decades of research suggesting an association between tumors and immune tolerance have led to the development of an array of immunotherapeutic strategies to reactivate the adoptive and innate immune system against tumor antigens. Understanding of this association has led to the development of multiple immunotherapy approaches, including immune checkpoint inhibition. Emerging clinical data, such as those presented in the article by Topalian et al that accompanies this editorial, introduce the possibility that not only can these immunotherapy treatments be added to treatment regimens, but perhaps they can raise survival curves to new heights. Identified in 1976, interleukin-2 (IL-2) was the first treatment to show promise in advanced melanoma. Although positive outcomes were limited (approximately 20% response rate, with durable complete responses [CRs] of up to 8%), data were sufficient for the US Food and Drug Administration to approve the use of IL-2 in malignant melanoma in 1998. However, the substantial toxicity profile of IL-2 limited its application to select patient populations in specialized treatment centers. For the next 20 years, essentially palliative treatment options, including dacarbazine, temozolomide, and multiple combination drug regimens, resulted in reports of similar response rates, without the durable CRs seen with IL-2. Ipilimumab (Yervoy; Bristol-Myers Squibb, Princeton, NJ), an anti-CTLA-4, immunoglobulin G1 monoclonal antibody, was the first treatment to show improvement in overall survival (OS) in melanoma in randomized trials. Two separate, appropriately powered, randomized controlled trials in previously treated and untreated patients with advanced melanoma suggested a 28% to 34% decrease in mortality for patients receiving ipilimumab and a significant improvement in OS compared with the control arms. This landmark breakthrough for cancer immunotherapy led to US Food and Drug Administration approval of ipilimumab for melanoma in 2011, but also brought a novel group of adverse effects that were presumed to be secondary to host immunologic enhancement. These treatment-emergent, immune-related adverse events (irAE), which were associated with inflammation of nontarget tissues, proved to be reversible by cessation of the drug, with or without the addition of glucocorticoids. In previously treated patients receiving ipilimumab alone or with an active control (gp100 vaccine), OS was 10.1 months and 10.0 months versus 6.4 months for patients receiving the vaccine alone. In this second-line setting, an estimated 21.6% to 23.5% of patients treated with ipilimumab were alive at 24 months versus 13.7% of patients in the control group. In a subsequently reported trial, previously untreated patients had a median OS of 11.2 months versus 9.1 months when treated with ipilimumab with dacarbazine or placebo with dacarbazine, respectively. Approximately 40% of previously untreated patients who received ipilimumab-dacarbazine were still alive at 1 year, compared with 36.3% in the dacarbazine-placebo group. At 3 years, an estimated 20.8% of patients were alive in the ipilimumab-dacarbazine group versus 12.2% of patients in the dacarbazine-placebo arm. Both of these phase III ipilimumab trials had different patient populations. The study by Hodi et al included 676 patients treated with 3 mg/kg of ipilimumab in a second-line setting; 12% of patients had treated brain metastasis and 23% received previous IL-2 therapy. The trial by Robert et al included 502 previously untreated patients, excluded patients with brain metastasis, ocular melanoma, or previous adjuvant therapy, and used ipilimunab 10 mg/kg induction followed by maintenance therapy. In the article that accompanies this editorial, Topalian et al report pooled outcomes for their expansion-dose cohort of patients with melanoma treated with nivolumab, a fully human, immunoglobulin G4 antagonist monoclonal antibody targeting PD-1, an immune checkpoint. Patients had participated in the phase I trial of nivolumab in locally advanced solid malignancies, which was published in 2012. The safety and outcome data cover a maximum follow-up of 4.3 years, the longest available for patients with melanoma treated with an anti-PD-1 agent. Topalian et al included 107 patients from pooled cohorts (62% had received at least two previous therapies), and included patients with ocular melanoma or clinically stable brain metastasis. Patients receiving nivolumab were enrolled in three dose-escalation cohorts, with dose-escalation permitted within the lower-dose groups at disease progression. The authors’ analysis, which was based on findings of durable responses in this patient group, again confirmed noteworthy survival outcomes. Median OS was 16.8 months, with 1and 2-year survival rates of 62% and 43%, respectively, and an estimated median response of 2 years’ duration in patients with confirmed tumor regression (31%). Although the patient populations are different and the currently published data for nivolumab are less than for ipilimumab, the OS signal seen is encouraging. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 10 APRIL 1 2014