ECC 2013: Multiple Studies Validate Long-Term Survival Benefit of Ipilimumab in Melanoma


Key Points

  • In the analysis of 1,861 patients treated in 12 phase II and III trials, median overall survival was 11.4 months and the 3-year overall survival rate was 22%.
  • In the 5-year survival analysis of the phase III trial of ipilimumab plus dacarbazine, 5-year survival was 18.2% with iplimumab/dacarbazine vs 8.8% with dacarbazine alone.
  • In both analyses, a plateau effect emerged at 3 years, and patients who survived to this point were likely to be alive at 5 and 7 years.

There is no longer any doubt that for the treatment of metastatic or locally advanced melanoma, ipilimumab (Yervoy) conveys long-term survival benefits, according to studies presented at the European Cancer Congress 2013.

In the largest survival analysis of the CTLA-4 monoclonal antibody to date (Abstract LBA24), patients receiving ipilimumab in the phase II and III clinical trials had a median overall survival of 11.4 months, and 22% of patients were alive at 3 years, reported F. Stephen Hodi, Jr, MD, Director of the Melanoma Center at the Dana-Farber Cancer Institute, Boston.

“The observed ipilimumab overall survival curve demonstrated greater durability of survival, relative to historical data in the pre-BRAF inhibitor era,” he said. “This analysis adds to the evidence supporting a durable, long-term survival effect of ipilimumab in patients with advanced melanoma.”

The pooled analysis included 1,861 patients from 12 prospective and retrospective trials, and an additional 2,985 patients who were treated with ipilimumab outside of a clinical trial in the expanded access program. The findings are the most precise estimate yet of the benefit of ipilimumab, Dr. Hodi said.

The analysis of the 1,861 patients in trial registries found median overall survival to be 11.4 months, with 254 patients (22%) alive 3 years after initiating treatment. Median overall survival for the whole population, including the 2,985 patients in the expanded access program, was 9.5 months, with 3-year survival in 21% of patients. Dr. Hodi attributed the slightly shorter survival time in this group to limited data and to the possibility that this was a sicker population.

Treatment-naive patients had a median overall survival of 13.5 months vs 10.7 months for previously treated patients, most of whom did not receive a BRAF inhibitor. Three-year survival rates were 26% and 20%, respectively.

Plateau Effect Seen at 3 Years

In both groups, the benefit of the drug appeared to plateau after about 3 years. Beyond 7 years, no deaths were reported, and median 7-year overall survival was 17%. The longest recorded survival was 9.9 years. 

This survival plateau was observed regardless of dose (3 or 10 mg/kg), previous treatment, or the continued use of ipilimumab as maintenance, he said. 

“Around the inflexion point of 3 years, there seems to be a flattening of the tail of the curve,” Dr. Hodi noted. “Going forward, up to 10 years, with lots of censoring, we see a group of patients maintaining a survival advantage long term.”

This plateau effect was also observed in a separate study of long-term survival in the phase III CA184-024 trial of ipilimumab and dacarbazine (Abstract 3704).  The study included 502 treatment-naive patients randomly assigned to ipilimumab at 10 mg/kg plus dacarbazine, or dacarbazine plus placebo, and the 5-year follow-up was presented at the European Cancer 2013 by Michele Maio, MD, PhD, of the University Hospital of Siena in Italy.  

Median 5-year survival was 11.2 months for the ipliumumab arm and 9.1 months in the control arm. The 3-year overall survival was 21.3% and 12.1%, respectively, and 5-year survival was 18.2% and 8.8%.

“The results of this landmark survival analysis, with 5 years of follow-up, continue to demonstrate a long-term survival benefit for patients treated with ipilimumab,” Dr. Maio said. “Consistent with the results of ipilimumab phase II studies in metastatic melanoma, survival rates appear to plateau, beginning at 3 years.”

Few new adverse events were seen in patients alive for at least 5 years who continued to receive maintenance therapy, and the only grade 3 to 4 toxicities were observed in the skin.

Ongoing studies are evaluating outcomes, including overall survival, with ipilimumab at 3 mg/kg (the licensed dose) vs 10 mg/kg.

Metastatic Melanoma Could Become a Chronic Disease

At a press briefing, Dr. Hodi commented on the durability of impilimumab’s effect and what this means for patients. “A few years ago, I could never imagine using the ‘C’ word, or see patients living long term. What we are showing is a great paradigm shift. At least we are turning this disease into a chronic illness. Possibly, in a subset [of patients], we are beginning to consider that this could be a cure. I remain optimistically conservative on that point, but we are headed in the right direction,” he said.

Alexander Eggermont, MD, PhD, General Director of the Institut Gustave Roussy Comprehensive Cancer Center in France and Past President of the European Cancer Organization, commented on the benefit of the new immunotherapies for patients. “This pooled analysis clearly demonstrates that ipilimumab can lead to long-lasting tumor control in metastatic melanoma patients. With a response rate of only 10% to 15%, one can achieve more than 3 to 10 years of survival in 17% to 25% of patients who have received only a few doses of ipilimumab. Thus, patients apparently can keep residual tumors under control for a long time when the immune system is properly ‘reset,’ and the concept of ‘clinical cures’ becomes a reality.”

Dr. Eggermont predicted even more impressive long-term results once novel antibodies targeting the programmed death 1 protein and its ligand (anti-PD1/PD-L1) become available.

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