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Bacteremia From an Unlikely Source
An unusual infection caused by contact with a pet reinforces the importance of educating patients about proper postoperative wound care.
The first phase 3 trial investigating ipilimumab randomized previously pretreated patients with advanced melanoma to ipilimumab at a dose of 3 mg/kg with or without the gp100 peptide vaccine. The median OS was 10.0 months among patients receiving ipilimumab plus gp100, compared with 6.4 months among patients receiving gp100 alone. There was no difference in OS between the ipilimumab groups.19 The outcome of this study has led to the approval of ipilimumab at a dose of 3 mg/kg in patients with advanced melanoma by regulatory agencies in the U.S., European Union, and Australia.
For treatment-naive patients, a second phase 3 trial investigating dacarbazine in combination with ipilimumab compared with dacarbazine in combination with placebo also demonstrated improvement of OS in patients treated with dacarbazine in combination with ipilimumab.20 The estimated 1-year, 2-year, and 3-year survival rates were 47.3%, 28.5%, and 20.8%, respectively, in the dacarbazine plus ipilimumab group, compared with 36.3%, 17.9%, and 12.2% in the dacarbazine alone group. This second trial used a higher dose of ipilimumab (10 mg/kg) and though it confirmed ipilimumab’s beneficial effects on OS, ipilimumab is not approved at 10 mg/kg and is not routinely recommended to be used in combination with dacarbazine given hepatic toxicity concerns.
Though the median OS was improved in these phase 3 trials, perhaps the greatest activity of ipilimumab lies in the increased number of patients who can achieve long-term OS. In a recently published updated survival analysis, the 4-year survival rates for previously treated patients who received ipilimumab at 3 or 10 mg/kg were 18.2% and 19.7% to 28.4%. For treatment-naive patients receiving ipilimumab at 10 mg/kg, 4-year survival rates were between 37.7% and 49.5%.22 These values appear superior to historical data from prior chemotherapy trials.
An important consideration in the clinical use of CTLA-4 blocking antibodies is the possible occurrence of toxicities that differ from those associated with traditional chemotherapy. These AEs are termed immune-related AEs (irAEs), and they most commonly manifest as diarrhea, dermatitis, hepatitis, and endocrinopathies but less commonly can involve other organs, resulting in uveitis, nephritis, myopathy, and neuropathy.
In general, the onset of irAEs follows a certain pattern with cutaneous manifestations often presenting early in treatment, followed by gastrointestinal and hepatic events occurring about 2 months into therapy and endocrinopathies appearing even later.23 In rare cases, severe AEs (eg, perforating colitis, toxic epidermal necrolysis) can occur and may require hospitalization.24
Clinicians must be attentive to early signs of these AEs and promptly initiate immunosuppression with steroids or other immunosuppressive medications, which do not appear to diminish the antitumor immune effects.25 Established management algorithms exist to guide clinicians. Given the occasional need for immunosuppression in this patient population, awareness of the possibility of opportunistic or rare infections is also important.
In phase 3 evaluation, the number of patients who had long-term survival exceeded the number of patients who had a classically defined disease response to treatment. Durable stable disease and late responses have been observed clinically and may be responsible for some of the beneficial outcomes.26 If patients are asymptomatic and have minimal radiographic progression, it is reasonable to repeat imaging 1 to 2 months later to confirm progression before considering additional lines of therapy.
Antibodies Blocking the Programmed Death-1 Axis
Programmed death-1 (PD-1) is a receptor on the surface of T cells that is upregulated at later stages of T-cell activation as opposed to the early upregulation of CTLA-4. Normally, engagement of PD-1 attenuates T-cell activity at several phases of an immune response. Tumors are believed to escape immune attack by similarly inhibiting T-cell activity by upregulating one of the ligands of PD-1, PD-L1.27,28 Several antibodies that inhibit PD-1 activity, either by blocking the PD-1 molecule itself or PD-L1, are demonstrating significant promise in ongoing clinical trials.
Nivolumab (previously, BMS-936558) is a fully human monoclonal antibody targeting PD-1. In a large phase 1 study in patients with a variety of malignancies, nivolumab demonstrated a 31% RR in patients with advanced melanoma.29 Subsequent follow-up data indicates these responses are generally durable with a median duration of response of 24 months and a 3-year OS rate of 40%.30 Adverse effects of nivolumab appear less frequently than with CTLA-4 blockade but have included vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis. Unique to PD-1 blockade appears to be the AE of an inflammatory pneumonitis, which can present with a dry cough, dyspnea, and ground-glass opacities and can be potentially lethal.29
On the basis of complementary regulatory roles of CTLA-4 and PD-1 checkpoint inhibition, a trial investigating combined nivolumab and ipilimumab was completed. In the small group of patients treated, a high RR was seen with a generally acceptable safety profile.31 Ongoing phase 2 and 3 trials are assessing nivolumab alone and in combination with other agents for the treatment of advanced melanoma and other malignancies (Table 1).
