Nivolumab Shows Benefit After Progression in Advanced Melanoma

Treatment of advanced melanoma with the checkpoint inhibitor nivolumab beyond RECIST-defined progression resulted in clinical benefit for selected patients, according to pooled, retrospective data from two phase III trials.

“Our analysis shows that patients treated beyond their first disease progression can experience a tumor response with continued nivolumab treatment, with a safety profile consistent with that observed in patients who did not receive further treatment,” wrote Georgina V. Long, BSc, PhD, MBBS, of the Melanoma Institute Australia, University of Sydney, and colleagues in a study published in JAMA Oncology. “Although patients selected for continued treatment were typically healthier than those who were not selected, it is possible that patients with less favorable clinical characteristics would have also benefited from further nivolumab therapy after progression.”

Data for the analysis were taken from the phase III CheckMate 066 and 067 trials. In both studies, patients could be treated beyond progression at the investigator’s discretion if they were deriving benefit and the drug was well tolerated. Patients who were treated beyond first disease progression (TBP) were defined as having received their last dose of nivolumab more than 6 weeks after progression.

Of the 526 patients in the study, 58% had disease progression. Of those, 28% of patients in the TBP group progressed, and 72% in the group of patients not treated beyond progression (non-TBP) progressed.

“Patients who continued nivolumab therapy were less likely than non-TBP patients to require any subsequent cancer therapy and were more likely to have surgery, which could suggest that nivolumab TBP resulted in tumor shrinkage that allowed for surgical resection or that progression was isolated and not reflective of the total tumor burden,” the researchers wrote.

More than one-quarter (28%) of TBP patients had a target lesion reduction of greater than 30% after progression. These patients were less likely to have poor prognostic features at baseline.

According to the researchers, two theories exist as to the causes of this type of “pseudoprogression.”

“First, patients with relatively high immune suppression within the tumor microenvironment may have a comparatively slow antitumor immune response that is ultimately sufficient to reduce tumor burden, allowing for continued tumor growth of target lesions or the appearance of new lesions in the interim,” they wrote. “Alternatively, treatment may induce a transient immune cell infiltration into the tumor, accompanied by edema, giving the appearance of increased tumor burden on imaging.”

Seventy-six percent of TBP patients and 87% of TBP patients with a 30% tumor reduction were still alive at the time of data analysis; 32% of TBP patients and 46% of TBP with a 30% tumor reduction continued on treatment.

The median time from disease progression to last nivolumab dose was 4.7 months for TBP patients and was 7.6 months for patients with a tumor reduction of at least 30%.  

The researchers concluded that, “The results of this analysis suggest that continued treatment with nivolumab may be an option to achieve further apparent clinical benefit in some patients with advanced melanoma.”