Ipilimumab plus nivolumab induced long-lasting tumor shrinkage in advanced melanoma

  • May 31, 2013

Combination therapy with ipilimumab and the investigational antibody nivolumab led to lasting tumor shrinkage in about half of patients with aggressive, advanced melanoma, according to results of a phase 1 study.

Jedd D. Wolchok, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center and a HemOnc Today Editorial Board member, called the complete and near-complete response rates “unprecedented” for an immunotherapy in melanoma.


Jedd D. Wolchok

Ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (BMS-936558, Bristol-Myers Squibb) target immune system checkpoints on immune cells, increasing the immune system’s ability to fight off cancer, according to background information provided by researchers.

For their study, Wolchok and colleagues enrolled patients with inoperable stage III and stage IV metastatic melanoma who underwent up to three prior therapies.

Some patients received concurrent treatment with the two drugs. The regimen consisted of four doses of nivolumab (dose range, 0.3-3 mg/kg) plus ipilimumab (dose range, 1-3 mg/kg) every 3 weeks for four doses, followed by nivolumab alone every 3 weeks for four doses. At week 24, patients resumed combined treatment every 12 weeks for eight doses.

The sequenced cohorts included patients previously treated with ipilimumab outside of the current trial who did not experience significant tumor shrinkage. These patients were treated with nivolumab alone every 2 weeks for 48 doses.

Different doses of nivolumab and ipilimumab were used within both cohorts.

During a press conference intended to highlight select research that will be presented at the ASCO Annual Meeting, Wolchok presented data on 86 patients.

No treatment-associated deaths have been reported in any of the treatment arms, and side effects were managed using standard medication protocols, Wolchok said.

The results indicated objective response rates of 21%, 53% and 50% in the three concurrent treatment arms. The highest response rate was observed in patients treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg, the doses being taken into later-stage trials.

“What was unique in our experience was that most of these responding patients had rapid and deep regressions,” Wolchok said.

Three out of four patients who responded to concurrent treatment demonstrated tumor reduction within 3 months, a rate faster than that observed with ipilimumab alone, Wolchok said. Sixteen of 52 patients (31%) experienced tumor shrinkage of more than 80%.

“When all concurrent cohorts were considered together, 40% had objective responses,” Wolchok said. “If one broadens this to include patients with slow responses, then 65% of patients have the melanoma controlled with this combination.”

Results from the sequenced cohorts indicated responses were noted even in patients who experienced tumor growth or disease progression during prior treatment with ipilimumab.

This suggests that when one immune modulator does not lead to response, patients may still respond to another, Wolchok said.

“My colleague, [Margaret K. Callahan, MD, PhD], will present results of a biomarker study at the upcoming ASCO meeting showing how this combination can overcome some factors which seem to hold back responses to either therapy alone,” he said. “Based on these results, a phase 3 trial will evaluate the efficacy of the concurrent nivolumab and ipilimumab combination vs. nivolumab alone vs. ipilimumab alone in patients with advanced melanoma.”

For more information:

Wolchok JD. Abstract #9012. Scheduled for presentation at: ASCO Annual Meeting; May 31-June 4, 2013; Chicago.

Disclosure: The research was supported by Bristol-Myers Squibb.

Nikhil I. Khushalani, MD

Nikhil Khushalani

  • The combination of two separate immune check-point inhibitors (CTLA-4 and PD-1) in advanced melanoma has sound rationale, as demonstrated in this phase 1 trial. The concurrent use of ipilimumab and nivolumab in a step-wise increase of either drug demonstrated response rates (40% to 53%) that have previously not been seen in the outpatient treatment of metastatic melanoma with immune-targeting agents. Encouragingly, the toxicity of the combination did not appear to be additive from a clinical standpoint and there were no deaths related to therapy, suggesting we are clearly getting better in managing the immune-mediated adverse effects seen with these classes of drugs. It is too early to say if this will be the future of melanoma therapy, and a  trial comparing the combination to either drug alone is the obvious next step. The investigators must be complimented for their rapid conduct of this trial after prior single-agent studies, thus continuing to rapidly reshape the landscape in melanoma therapy.

    • Nikhil Khushalani, MD
    • Section chief of soft tissue and melanoma
      Associate professor or oncology
      Roswell Park Cancer Institute
      Buffalo, N.Y.
  • Disclosures: Khushalani reports grant funding from the National Comprehensive Cancer Network from general research support provided by Allos, Pfizer and Roche; funding for investigator-initiated clinical trials from Merck and Pfizer; a speaker’s bureau role with Prometheus and an advisory board role with Genentech.
Sandra M. Swain, MD

Sandra M. Swain

  • The further exploration of immunotherapy as stand-alone therapy without chemotherapy for a devastating disease such as advanced melanoma is a tremendous advance. We are identifying therapies that appear better together than alone and look promising for more than just a small subset of patients. The extensive tumor shrinkage that was observed in this study is exactly the type of benefit patients and doctors have been hoping for. The combination treatment in this study led to rapid and profound lasting tumor shrinkage. This is truly remarkable, as this kind of response has not been seen with immunotherapy before.

    • Sandra M. Swain, MD, FACP
    • ASCO President
      Medical director, Washington Cancer Institute
      MedStar Washington Hospital Center
  • Disclosures: Swain reports no relevant financial disclosures.