The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O’Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."
The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.
Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."
And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O’Day added.
As expected, the drug’s adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."
About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.
"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O’Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."
Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O’Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.
Targeted MAP Kinase Therapy: BRAF Inhibitors
The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.
Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).
"We had never seen anything like this in melanoma," Dr. O’Day commented.
Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.
An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.
"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O’Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.
"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.
Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O’Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."
Putting It All Together
"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O’Day said. "I think there is going to need to be a real art to the sequence and combinations."