September 2011 ASCO 2011 Wolchok JD

Background

A phase III study of ipilimumab monotherapy in previously treated, unresectable or metastatic melanoma patients showed improved overall survival (OS).1 Additional background is provided by phase II data suggesting that the combination of ipilimumab with dacarbazine (DTIC) provided durable objective responses, as well as adverse events (AEs) consistent with other ipilimumab studies.2 Ongoing studies in the treatment of first-line metastatic melanoma include evaluation of combination of therapy with DTIC, a global standard of care, plus ipilimumab.

At ASCO 2011 Wolchok and colleagues presented the results of a phase III randomized study of ipilimumab plus DTIC versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma.3

Study design

  • The trial was a double-blind, phase III study of metastatic melanoma patients 18 years or older, with an ECOG performance status of 0–1, and no prior therapy for advanced disease.
  • Patients with brain metastases or symptomatic autoimmune disease were excluded.
  • During the induction phase, patients were randomized in a one-to-one ratio to ipilimumab (10 mg/kg) plus DTIC (850 mg/m2), or placebo plus DTIC (850 mg/m2) once every three weeks for four cycles, followed by DTIC every three weeks through week 24.
  • During the maintenance phase, eligible patients received blinded ipilimumab or placebo every 12 weeks.
  • The primary endpoint was originally progression-free survival (PFS); but it was changed to overall survival (OS) after it was learned that OS was the most accurate way to measure the efficacy of ipilimumab.

Key findings

  • Of 502 patients from 24 countries, more than 50% of patients were poor prognosis with stage M1c disease (representing patients with visceral disease and/or elevated lactate dehydrogenase [LDH]) and 26% of patients had received adjuvant therapy.
  • 37.2% of patients in the ipilimumab plus DTIC arm and 66.0% of patients in the DTIC alone arm received four induction doses.
    • Approximately 20% of all patients received at least one dose of maintenance therapy.
  • A significant improvement was seen in OS (hazard ratio [HR] = 0.72; p = 0.0009) indicating a 28% reduction in the risk of death, and higher estimated one, two and three-year survival rates were seen with combination therapy.
    • The median OS was 9.1 months for DTIC alone versus 11.2 months in the ipilimumab plus DTIC arm. (Figure 1)
  • The combination therapy arm had a statistically significant improvement in PFS, with a hazard ratio of 0.76 (p = 0.006), compared with DTIC alone. (Figure 2)
  • Disease control rates did not differ between the two study groups.
  • The duration of response was 19.3 months in the ipilimumab plus DTIC arm versus 8.1 months in the placebo plus DTIC arm, and the duration of response was sustained. (Figure 3)
  • 56.3% of patients in the combination therapy arm (n = 247) and 27.5% of patients in the DTIC alone arm (n = 251) had grade 3/4 adverse events (AEs) including:
    • Elevated alanine aminotransferase (ALT) (21.9% versus 0.8%)
    • Elevated aspartate aminotransferase (AST) (18.2% versus 1.2%)
    • Diarrhea (4% versus 0%)
    • Rash (1.2% versus 0%)
  • No intestinal perforations or hypophysitis were noted in either group.
  • There were no drug-related deaths in the combination therapy arm, and one in the DTIC alone arm (which was due to gastrointestinal hemorrhage).

Key conclusions

  • Combination therapy with ipilimumab (at a dose of 10 mg/kg) plus DTIC significantly prolongs OS in the first-line treatment of metastatic melanoma versus DTIC alone.
  • Ipilimumab, when combined with DTIC, provides durable responses.
  • AEs were consistent with those noted in prior ipilimumab studies, and primarily affected the skin, gastrointestinal tract, liver and endocrine system.
    • The AEs were immune-based, and managed with established guidelines.
    • The rates of high-grade events differed from those seen in phase II trials, with a higher rate of transaminitis, and rates of diarrhea/colitis/ gastrointestinal perforation were lower than expected.
  • No drug-related deaths were noted with ipilimumab.
  • This phase III randomized trial confirms that ipilimumab provides OS benefit in treatment-naïve metastatic melanoma patients.

References: 1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–723. 2. Wolchok JD, Neyns B, Linette G,et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010:11;155–164. 3. Wolchok JD, Thomas L, Bondarenko IN, et al. Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma. J Clin Oncol (ASCO Annual Meeting Abstracts) 2011;29:LBA5.