Summary and Clinical Applicability

This new study supports the previous findings of the earlier study. Compared with those initial results, the 3-year results demonstrated an increase in the objective response rate with nivolumab (40% vs 42.9%, respectively).

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“Nivolumab works regardless [of] PD-L1 expression and BRAF mutation,” Dr Ascierto said.

Dacarbazine, “once a staple of melanoma therapy, essentially has no current role in the treatment of any type or stage of melanoma. That’s been the case for 4 years since the initial publication of the Checkmate 066 results and current updated results confirm that initial assessment.” said Michael Atkins, MD, the deputy director of the Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC. “Its use has primarily been restricted to patients whose disease has not responded to now-standard immunotherapy and, if indicated, targeted therapy approaches, yet are still interested in receiving some form of treatment.”

Dr Ascierto agreed, noting dacarbazine is really used “just as salvage treatment in case of any response to immuno-oncology.”

Study Limitations

Regarding Checkmate 066, there are some limitations to this 3-year analysis, Dr Ascierto noted. For one — and this is a limitation across studies — is the use of subsequent therapies, “which likely affected survival outcomes in the present analysis,” the study authors wrote. The median overall survival (OS) from randomization was longer and 3-year survival rates were higher for nivolumab compared with dacarbazine when either was followed by subsequent therapy that included ipilimumab. These results indicate that patients can benefit from subsequent ipilimumab, regardless of prior therapy. Survival outcomes may also have been affected by the allowance of nivolumab treatment beyond progression in some patients, as suggested by the findings of prior analysis,3 they wrote.

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Finally, in the interval since this study was first published, the field has moved on to other treatment approaches for patients with advanced melanoma.

Nivolumab Followed by Ipilimumab Compared With Nivolumab Plus Ipilimumab

The results of the 3-year analysis of CheckMate 066 “support the use of ipilimumab after nivolumab progression,” Dr Ascierto said. “Patients who are refractory or resistant to treatment can benefit.”

CheckPoint 066 has suggested there may be a benefit from subsequent ipilimumab regardless of prior therapy. For patients who do not respond to nivolumab, Dr Ascierto said treatment should depend on whether the melanoma is refractory (where primary resistance is important) or the patient is someone who relapsed after seeing an early benefit (ie, a patient who developed acquired resistance).

There remains a question of whether one should give nivolumab followed by ipilimumab or nivolumab and ipilimumab in combination.

That’s a “big question” that has been the topic of substantial debate, Dr Atkins said. CheckMate 067 was “a phase 3 trial that examined either the ipilimumab + nivolumab combination or nivolumab monotherapy compared to ipilimumab monotherapy. It was not meant to compare the ipilimumab + nivolumab combination to nivolumab monotherapy, but this is frequently done.” 4

Dr Atkins is of the view that “the activity of the ipilimumab and nivolumab combination is superior to nivolumab monotherapy in terms of response rate, progression-free survival, and tumor shrinkage across all categories of patients. But the toxicity is also greater.”  However, the OS benefits of the ipilimumab plus nivolumab combination relative to the administration of nivolumab followed by ipilimumab is less secure.

“In patients with less-aggressive disease, you could try to start with single-agent nivolumab and if you don’t see a durable response, you could add ipilimumab later and maybe see or recapture the tumor responsiveness and see equivalent survival outcomes. While this might be a valid approach, we don’t have prospective data to support that this will yield an equivalent outcome as the present time,” Dr Atkins said.

“However, until such data [are] available, my view is that ipilimumab should be added to nivolumab in every patient who you think could tolerate the potential treatment toxicity,” he continued. “This is particularly true for patients who are less responsive to nivolumab monotherapy, including patients with brain metastasis, an elevated lactate dehydrogenase (LDH) level, or a mucosal or acral melanoma primary. In addition, the Checkmate 067 study suggests that the ipilimumab + nivolumab combination may produce significantly superior OS for patients with a BRAF-mutant melanoma.”

Dr Atkins further believes that the current combination regimen (approved by the US Food and Drug administration [FDA]) of ipilimumab at the full dose and nivolumab at a reduced dose for 4 doses followed by nivolumab maintenance “is probably not the right regimen for the combination. A combination involving less ipilimumab and more nivolumab was shown in the CheckMate 511 trial,5 to be equally efficacious but half as toxic as the FDA-approved regimen. Such a regimen likely has a higher therapeutic index,” he said.

This view is supported by data presented at the recent Society for Melanoma Research conference, from the Keynote-029 study, which showed that pembrolizumab at full dose with reduced-dose ipilimumab is also very effective, with 73% plateau on the OS curve at 3 years, Dr Atkins noted. 6 “I think we were going to move toward the schedule that involved lower ipilimumab and more nivolumab” as a result, Dr Atkins said.

Meanwhile, Dr Ascierto asserted that “novel combinations under evaluation using anti-PD-1 therapies as their backbone “have the potential to further improve outcomes in patients with advanced melanoma.”1


  1. Ascierto PA, Long GV, Robert C, et al. Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: three-year follow-up of a randomized phase 3 trial [published online October 25, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.4514
  2. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330.
  3. Long GV, Weber JS, Larkin J, et al. Nivolumab for patients with advanced melanoma treated beyond progression: analysis of 2 phase 3 clinical trials. JAMA Oncol. 2017;3(11):1511-1519.
  4. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2017;377(14):1345-1356.
  5. Lebbé  C, Meyer N, Mortier L, et al. Initial results from a phase 3b/4 study evaluating two dosing regimens of nivolumab (NIVO) in combination with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 511). Paper presented at: European Society for Medical Oncology (ESMO) 2018; October 20, 2018; Munich, Germany. LBA47.
  6. Long GV. Long-term follow-up of standard-dose pembrolizumab (pembro) plus reduced-dose ipilimumab (ipi) in 153 patients (pts) with advanced melanoma (MEL): KEYNOTE-029 1B. Paper presented at: Society for Melanoma Research; Oct. 25, 2018: Manchester, England.