Clinical Benefit With Nivolumab Beyond Progression For Some Advanced Melanoma Patients

Pooled analysis of two phase III trials shows tumour response in a subset of patients with advanced melanoma treated with nivolumab beyond disease progression

medwireNews: Continuing nivolumab treatment beyond conventionally defined disease progression could be a valid option for some patients with advanced melanoma, say researchers.

They pooled data from the nivolumab monotherapy arms of the phase III CheckMate 066 and 067, which allowed participants to remain on the programmed cell death protein 1 inhibitor beyond progression, as defined by the RECIST version 1.1 criteria, provided they were benefitting from and tolerating the drug.

Among 526 patients with stage III or IV malignant melanoma who were randomly allocated to receive frontline, single-agent nivolumab across the two trials, 58% experienced disease progression. And of these 306, 28% were considered for the purpose of the current analysis to have received treatment beyond progression as they received their final dose of nivolumab more than 6 weeks after progression.

Nearly half (42%) of these patients demonstrated a tumour response to continued nivolumab, with 28% achieving at least a 30% reduction in target lesion volume from baseline at a median of 1.4 months from progression.

At the time of analysis, the majority (76%) of the 85 participants treated beyond progression were alive and just under a third (32%) remained on nivolumab therapy. The corresponding rates for the group that achieved a 30% reduction in tumour burden were 87% and 46%.

Median overall survival (OS) from the time of assignment to nivolumab was not reached for participants treated beyond progression and was 10.6 months for the 221 who discontinued nivolumab after progression, with 24-month rates of 59% and 25%, respectively.

Researcher Georgina Long, from Melanoma Institute Australia in Sydney, New South Wales, and co-authors point out, however, that patients who continued nivolumab beyond progression were “typically healthier” than those who did not and were less likely to have poor prognostic features at baseline, such as stage M1c disease and lactate dehydrogenase levels above the upper limit of normal.

Although the incidence of treatment-related select adverse events of any grade was higher among patients who did versus did not receive treatment beyond progression, at 67% versus 44%, the rate of grade 3 or 4 events was comparable, at 6% and 4%, respectively.

In light of these findings, the research team concludes in JAMA Oncology that “[c]ontinued treatment with nivolumab may be an option to achieve further benefit without compromising safety in some patients with advanced melanoma.”

Writing in an accompanying piece, Gideon Blumenthal and colleagues, from the US Food and Drug Administration in Silver Spring, Maryland, say that from an optimistic viewpoint, the strategy of treatment beyond progression deserves further study.

However, “[a] pessimist might argue that in this post hoc subgroup analysis of patients with good prognostic features and potentially more indolent disease, only approximately 5% of the overall population achieved a 30% reduction in tumor burden with [treatment beyond progression]”, they write.

“This suggests that this strategy only benefits a minority of patients, with potential harms: increased risk of toxic effects, increased cost to the patient, and risk of forgoing or delaying switching to an alternative, more effective therapeutic option.”

The editorialists believe that “[g]oing forward, more systematic and uniform data collection is needed to better characterize which patients may ultimately derive benefit from this strategy.”

References

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; Advance online publication 29 June 2017. doi:10.1001/jamaoncol.2017.1588

Blumenthal GM, Theoret MR, Pazdur R. Treatment beyond progressionwith immune checkpoint inhibitors—known unknowns. JAMA Oncol; Advance online publication 29 June 2017. doi:10.1001/jamaoncol.2017.1819

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