Ipilimumab/Nivolumab Combo Boosts Long-Term Survival in Advanced Melanoma

CHICAGO-Long-term follow-up results from an expanded phase I study demonstrate that concurrent treatment with the anti-CTLA-4 antibody ipilimumab and the PD-1 antibody nivolumab led to an unprecedented median survival of roughly three and a half years (40 months) for patients with advanced melanoma (Late Breaking Abstract 9002). That is nearly double the median overall survival (OS) found in previous studies of either agent alone, reported lead investigator Mario Sznol, MD, professor of medical oncology at Yale University School of Medicine, New Haven, Conn. Findings were reported at the 2014 annual meeting of American Society of Clinical Oncology (ASCO).

“Just a few years ago, median survival for patients diagnosed with advanced melanoma was as little as a year or less, and only approximately 20% to 25% percent survived 2 years,” said Sznol. “It’s truly remarkable that we’re seeing a median survival over 3 years in this trial. Even in the latest era of targeted and immunotherapy agents, the median survival is on average only about 16 to 18 months with any new treatment alone.”

Although the findings are encouraging, Sznol cautioned, “This trial was small. It will be important to validate our initial results in a randomized phase III trial.” In the present study, 94 patients with inoperable stage III or IV melanoma who had undergone up to three prior systemic therapies received concurrent treatment with ipilimumab and nivolumab. Approximately 53% of patients had very advanced disease (stage M1c), and 55% percent had no prior systemic treatments.

Sznol presented long-term follow-up data on the 53 patients enrolled in the initial four concurrent dosing cohorts. Patients received ipilimumab and nivolumab every 3 weeks for 4 cycles, followed by nivolumab alone every 3 weeks for 4 cycles. At week 24, patients who did not have disease progression or severe side effects could continue nivolumab plus ipilimumab every 12 weeks for 8 cycles. 

Overall, 22 of 53 patients (41%) responded to the treatment, and nine (17%) experienced complete remissions. Tumor shrinkage was rapid and extensive: 42% percent of patients had greater than 80% tumor reduction by week 36. Responses were durable, with 18 of 22 responses (82%) ongoing at time of analysis.

Across doses, the 1-year and 2-year median OS rates were 85% and 79%, respectively, and the median survival duration was 39.7 months. At the doses currently being tested in an ongoing phase II/III trial (nivolumab 1 mg/kg and ipilimumab 3 mg/kg) 1-year and 2-year OS rates were 94% and 88%, respectively.

The rate of side effects related to induction of immune reactivity against normal tissues was higher than previously observed for either single agent, but Sznol said side effects were “manageable and reversible” in almost all patients. Clinical responses were seen across all dose levels regardless of tumor BRAF mutation status or PD-L1 status. Activity of the combination in the PD-L1 negative subgroup was higher than observed in prior trials of nivolumab alone, which the investigators say supports the observation that the combination is more effective than nivolumab alone.

In addition, the authors stated, if the activity is validated in the phase III trial, patients with melanomas that test positive for a BRAF mutation would have an even more effective immunotherapy option in addition to targeted therapy for treatment of their disease.

The researchers will continue following patients in all cohorts of the study, including a separate cohort composed of 41 patients who received the combination treatment every 3 weeks for 4 cycles, followed by nivolumab alone every 2 weeks for up to 2 years.

A separate, ongoing phase III study is evaluating nivolumab plus ipilimumab vs nivolumab or ipilimumab alone, and a phase II randomized study is comparing nivolumab plus ipilimumab to ipilimumab alone.

Impressive findings were also reported from a large phase I study of another PD-1 targeting antibody, MK-3475. In what was described by investigators as the largest study to date of an investigational anti-PD-1 agent in advanced melanoma--MK-3475 achieved long-term responses in a high percentage of the 411 patients evaluated (Late Breaking Abstract 9000). Results were reported by lead author Antoni Ribas, MD, PhD, professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles.

In the study, the 1-year OS was 69% across all patient subgroups, and responses were ongoing in 88% of patients at analysis after a median follow-up of 12 months. Responses occurred across all dose regimens and in various subgroups of patients, including those whose disease progressed following ipilimumab therapy, for whom there are currently no effective treatment options. “This is probably the biggest phase I trial ever conducted in oncology,” said Ribas.  “We were excited to see that MK- 3475 was effective in previously untreated patients, as well as in those who had multiple prior therapies, including ipilimumab. These are early data,” he acknowledged, “but they tell us we are on to something really important.”

The study enrolled 221 patients with prior ipilimumab treatment and 190 patients who had not previously received ipilimumab. All patients had advanced melanoma that had spread to the skin, lungs, or other major organs.

Three different MK-3475 dose schedules as a single agent were tested. Overall, 34% of patients experienced tumor response, including 40% of patients not previously treated with ipilimumab and 28% of patients whose disease progressed on prior ipilimumab. Responses were durable with 88% ongoing at the time of analysis. Activity was observed across all dose levels and patient subgroups, irrespective of prior ipilimumab therapy, performance status, LDH levels, BRAF mutation status, tumor stage, and number and type of prior therapies.

The estimated 1-year survival rate was 69% and median OS duration was not reached. The estimated 1-year survival rate was 74% in patients not previously treated with ipilimumab and 65% in those patients who received prior ipilimumab.

Overall, 8% of patients experienced serious treatment-related side effects and 4% discontinued treatment due to a drug-related side effect.

Ongoing randomized controlled studies are assessing the efficacy and safety of MK-3475 in advanced melanoma patients not previously treated with ipilimumab, as well as in those who progressed on or after ipilimumab.

“I think the future of melanoma research over the next 3 to 5 years is going to continue to focus on targeted therapy and immunotherapy,” commented Lynn M. Schuchter, MD, professor of hematology-oncology at the University of Pennsylvania. “We’ve already seen advances made in the new targeted therapies with BRAF and MEK inhibitors. We’re going to be building upon those results. At the same time there have been tremendous advances in immunotherapy.”

Various targeted therapy/immunotherapy combinations and approaches are already being investigated. “This is the future,” said Axel Hauschild, MD, of the Skin Cancer Center, University of Kiel, Kiel Germany, discussant at a symposium on targeted and immunotherapies as front-line approaches for BRAF-mutated advanced melanomas. “And there is a lot of work to do” as companies compete “in the run for new single-agent or combination-drug standards.”

Both nivolumab and iplimumab are marketed by Bristol-Myers Squibb; MK-3475 is marketed by Merck.