Ipilimumab plus dacarbazine improved survival in metastatic melanoma

2011 ASCO Annual Meeting

CHICAGO — Adding ipilimumab to dacarbazine significantly improved OS in patients with metastatic melanoma, according to data presented here today.

“This is the second randomized, phase 3 study in melanoma to show a statistically significant survival improvement with the use of ipilimumab,” Jedd D. Wolchok, MD, director of immunotherapy clinical trials and associate attending physician at Memorial Sloan-Kettering Cancer Center, said during his presentation.

Patients with unresectable, stage III or IV melanoma were enrolled (n=502), regardless of their BRAF mutation status or immune HLA type. They were randomly assigned in a 1:1 blinded fashion to a standard schedule of dacarbazine (850 mg/m²) plus ipilimumab (10 mg/kg) or dacarbazine (850 mg/m²) plus placebo at weeks 1, 3, 7 and 10 followed by dacarbazine every 3 weeks through week 22.

Dacarbazine plus ipilimumab was associated with a 28% reduction in the risk for death (HR=0.72; P<.0009), and higher estimated OS compared with dacarbazine plus placebo at 1 (47.3 months vs. 36.3 months), 2 (28.5 months vs. 17.9 months) and 3 years (20.8 months vs. 12.2 months).

According to Wolchok, median PFS for both groups occurred around the same time of the first set of tumor assessments, but the combination of ipilimumab and dacarbazine was associated with a statistically significant improvement (HR=0.76; P<.006). The best overall response rate was higher in the combination arm compared with the dacarbazine alone arm: 15.2% vs. 10.3%. In addition, the duration of response with the combination was 19.3 months compared with 8.1 months for dacarbazine alone. The sustained response is characteristic of ipilimumab as an immunotherapy, Wolchok said.

The total number of adverse events was similar, but grade 3 and 4 events occurred more often in the combination group (56.3% vs. 27.5%). Higher grade events included elevated ALT (22% vs. 1%), diarrhea (4% vs. 0%) and rash (1% vs. 0%); there were no reports of intestinal perforation or hypophysitis.

“I think these results really form the foundation for the development of combination regimens in the future, and we really look forward to pursuing those studies.” – by Stacey L. Fisher

For more information:

• Wolchok JD. #LBA5. Presented at: 2011 ASCO Annual Meeting; Chicago; June 3-7, 2011.

Disclosure: Dr. Wolchok holds a consultant/advisory role at Bristol-Myers Squibb.

As we celebrate 40 years of progress in cancer, I think melanoma is a wonderful example that once you finally understand what’s driving it — understanding new immunological approaches, understanding what’s driving the disease — we can develop more therapies that are more effective. This is a really exciting time for our patients and we think now the future is going to be built upon this success, so efforts to combine a BRAF inhibitor with immunotherapy is going to be a great example. We see that these patients have a dramatic response, but patients do develop resistance to these therapies, so over time the therapies stop working, the cancer cells outwit us (they’re brilliant) and figure out other pathways. So going forward, to combine targeted therapies is going to be the wave of the future to really identify which patients should receive which therapy.

- Lynn Schuchter, MD
C. Willard Robinson Professor of Hematology-Oncology,
Division Chief of Hematology-Oncology, Abramson Cancer Center, University of Pennsylvania

Wen-Jen Hwu, MD, PhD

Major breakthroughs in the treatment of metastatic melanoma were reported in the 2011 ASCO Plenary Session. Considerable excitement has been generated by two new antitumor agents, vemurafenib and ipilimumab. In patients with late-stage melanoma, vemurafenib demonstrated dramatic clinical responses and ipilimumab showed significantly improved survival as a single agent or in combination with chemotherapy (dacarbazine). Both agents were developed to target relevant molecular targets, either in the signal transduction pathway (vemurafenib) or tumor immunity barriers (ipilimumab). These major breakthroughs result from the great success in translational research from bench to bedside. Small-molecule vemurafenib targeting BRAF V600E mutation was developed based on the identification of genetic mutations of various components of signal pathways involving melanoma initiation and progression. Humanized monoclonal antibody ipilimumab targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) was developed based on the emerging insights into the mechanisms of activation and regulation of tumor immunity.

The treatment of metastatic melanoma is changing rapidly due to the new targeted therapy approach. However, there are many hurdles to overcome in order to optimize the targeted therapy. The mechanisms of rapid development of drug resistance to vemurafenib remain largely unknown. The safety and management of serious autoimmune toxicities induced by ipilimumab require intense education and training of oncologists. Thus, further improvement in the targeted therapy and translational research from bedside to bench is warranted.

- Wen-Jen Hwu, MD, PhD
HemOnc Today Editorial Board member

Follow HemOncToday.com on Twitter.