Thu-Oanh Dang

PURPOSE: Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF). PATIENTS AND METHODS: We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival. RESULTS: Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids. CONCLUSION: IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.

OBJECTIVE: To provide the clinician with an update and the current status and future direction of approved immune checkpoint inhibitors (ICIs) in oncology. DATA SOURCES: A PubMed search from January 1, 1966 to March 13, 2015 was performed using the key terms ipilimumab, pembrolizumab, lambrolizumab, nivolumab, immune checkpoint inhibitor, MDX-010, MDX-101, BMS-734016, MK-3475, SCH 900475, MDX-1106, BMS-936558, ONO-4538, CTLA-4, PD-1, or PD-L1 and cancer, oncology, or neoplasm. Additional references were identified from the investigators(') personal files, recent oncology meetings, review articles, clinical guidelines, and package inserts. STUDY SELECTION AND DATA EXTRACTION: All English-language clinical trials assessing the safety and efficacy of ipilimumab, nivolumab, and pembrolizumab in cancer were considered. The PubMed search resulted in 215 trials; 33 met inclusion criteria. A further 28 trials were identified from the above sources; 61 trials from 2005 to 2015 were included. We consolidated and clarified treatment recommendations for the management of immune-related adverse events (irAEs), assessed response criteria, and calculated the clinical utility of leading tumor profiling options. DATA SYNTHESIS: Ipilimumab and nivolumab, but not pembrolizumab, have an overall survival (OS) advantage over chemotherapy first line in unresectable/metastatic melanoma. Nivolumab has an OS advantage versus chemotherapy in second-line squamous non-small-cell lung cancer. Data in other settings are promising. Nivolumab and pembrolizumab are better tolerated than ipilimumab. Further validation of response criteria is needed. Tumor profiling to predict clinical benefit is premature but promising. CONCLUSIONS: The treatment landscape in oncology is quickly evolving with the advent of ICIs.

Indini et al state that immune-related adverse events (irAEs) are associated with improved response to immunotherapy. Although some small early trials with ipilimumab suggested that patients with irAEs were more likely to respond, this observation has not been confirmed in later, larger series with ipilimumab or nivolumab. Therefore, the impact of this association is not clear. Regarding this, Indini et al ask whether patients who experience severe irAEs had a different prognosis. As we discuss in our article, the Common Terminology Criteria for Adverse Events grading system does not adequately identify clinically significant ipilimumab immune-related toxicities. As such, we defined severe irAEs on the basis of whether the treating physician believed the patient required systemic corticosteroids. In this case, our Figures 3B and 3D address their question and show that patients experiencing irAEs severe enough to require systemic corticosteroids had similar time-to-treatment failure and overall survival compared with patients who did not require corticosteroids. They ask about the dose and timing of the systemic corticosteroids our patients received to treat irAEs. In most cases, patients received 0.5 to 1 mg/kg/d of intravenous methylprednisolone or the equivalent dose of oral prednisone. The proportion of patients who received systemic corticosteroids after each dose of ipilimumab is shown in Figure 1. Finally, Indini et al inquire if patients achieved a response before starting corticosteroids. As we explain in our article, we did not assess patients for tumor response. Even so, the majority of irAEs occurred before week 12, when a formal response would have been assessed. We decided not to assess tumor responses on the basis of the low response rate to ipilimumab and the general understanding that clinical benefit to ipilimumab does not necessarily require a response as measured by RECIST. It is worth noting that neither theWHO criteria nor RECIST were meant to play a role in making decisions about individual patient care and, in fact, have not generally correlated well with overall survival. In the penultimate sentence of their letter, Indini et al suggest that immunotherapy “should be continued even if patients experience irAEs.” Although in selected cases, immunotherapy might be continued after resolution of low-grade or asymptomatic irAEs, in most cases, we would not give additional doses of ipilimumab to patients who had required systemic immunosuppression for irAEs.