Yervoy paves the way in adjuvant melanoma
| Jun 3, 2014
By Mara Jeffress and Stephanie Hawthorne
Yervoy® (ipilimumab, Bristol-Myers Squibb) was an exciting and welcomed breakthrough in the treatment of advanced/metastatic melanoma when it was first launched in 2011. The agent not only improved the median overall survival (OS) in patients irrespective of BRAF status; it also showed a plateau in the survival curve, indicating that a subset of patients derive long-term benefit from Yervoy. Given the poor prognosis of metastatic disease, however, could Yervoy have a greater impact on survival outcomes if used earlier in the course of the disease? It has long been speculated that immunotherapies would be most active in lower tumor burden disease by allowing the immune system enough time to mount and maintain an effective response to the tumor cells. The activity of interferons in this setting (albeit somewhat controversial given the conflicting level of evidence to date) suggests that locally advanced melanoma could benefit from effective immunotherapies.
Yervoy is the first of the modern immunotherapies to be studied in a randomized trial (EORTC 18071; NCT00636168) in completely resected high-risk Stage II/III melanoma patients. The data from this trial was presented Monday at the American Society for Clinical Oncology (ASCO) meeting in Chicago. Patients were randomized to receive Yervoy (10 mg/kg every 21 days for four cycles, then maintenance every 12 weeks starting at Week 24 for up to three years) (n=475) or placebo (n=476). The primary endpoint of recurrence-free survival (RFS) was significantly improved: in the intent-to-treat population, median RFS was 26.1 months in the Yervoy arm versus 17.1 months in the placebo arm (HR=0.75, p=0.0013), and the three-year RFS rate was 46.5% versus 34.8%. The RFS benefit remained significant across all subpopulations but was more pronounced in patients with microscopic lymph node metastases (as opposed to macroscopic or palpable metastases), in patients with ulcerated tumors, and in patients with Stage III disease. The secondary endpoints of OS, metastasis-free survival and quality-of-life-adjusted survival were not reported.
Toxicity was significant, with 49% of patients discontinuing Yervoy due to adverse events (AEs). This discontinuation often occurred early in the course of treatment, with 39% discontinuing in the first 12 weeks, where the majority of AEs occurred. Another troubling result is that five (1.1%) patients died due to drug-related AEs. As expected, the most common Grade 3/4 adverse events were immune-related affecting the gastrointestinal (16.0% vs. 0.8%), hepatic (10.7% vs. 0.2%) and endocrine (8.5% vs. 0%) systems. The majority of immune-related AEs did resolve by ceasing treatment and following standard protocols of management, with the notable exception of hypophysitis (18.7% all grade, including 4.7% Grade 3 and 0.4% Grade 4), which was noted with concern. Although this type of safety profile may be acceptable in the metastatic setting, there is typically a higher standard for tolerability in patients with earlier-stage disease who have been rendered disease-free by surgical resection. It’s also interesting to wonder whether the efficacy benefit that was reported might have been even greater if patients had been able to tolerate the drug rather than discontinue prematurely.
In general, the outlook for immunotherapy in melanoma is promising based on these results. The strength of RFS benefit with Yervoy in high-risk patients with resected disease are encouraging and may eventually lead to approval in the adjuvant setting, but mature OS data will likely be required. However, the use of Yervoy may hinge on several elements of its risk-to-benefit analysis. Could the toxicity profile prove unacceptable to physicians and/or patients? Will this safety profile limit its use to only those Stage III patients at highest risk of recurrence, or will physicians prescribe the drug more broadly for Stage III disease? Finally, how will the cost of therapy affect its utilization in this setting? Notably, this trial evaluated the high dose of Yervoy (10 mg/kg, which is rarely used in clinical practice in favor of the approved 3 mg/kg dose) – at this dose and the administration schedule used in the study, this amounts to a price tag in excess of $500,000 for the first year and over $1 million for the full three-year course of therapy. This is certainly a topic that would fit well with the “Value in Cancer Care” series that has been running in this week’s ASCO Daily News.
Cost of therapy aside, the data from EORTC 18071 remain important for advancing care in adjuvant melanoma, but it may just be the beginning, opening the door for other agents in this setting. In fact, Yervoy, Zelboraf®(vemurafenib, Genentech/Roche) and the combination of Tafinlar®(dabrafenib, GSK) and Mekinist® (trametinib, GSK) are all attempting to move into the adjuvant setting and all have ongoing Phase III trials. In addition, another adjuvant Yervoy trial is ongoing and has nearly completed enrollment. This additional three-arm Phase III trial compares 3 mg/kg Yervoy to 10 mg/kg Yervoy to IFN-alpha-2b in completely resected Stage IIIb/IIIc/IV melanoma (NCT01274338; ECOG 1609). If successful, this second trial could act as confirmation, resolve the dosing/cost issue mentioned above, and provide stronger evidence for approval and adoption given the use of an active comparator. Whether or not Yervoy becomes the next drug to market in the adjuvant setting, it is paving the way for other agents in this setting.