Benefits of Melanoma Combination Therapy Not Diminished by Stopping for Side Effects

F. Stephen Hodi, MD

Discontinuing nivolumab-ipilimumab treatment because of adverse events did not have a detrimental effect on survival among patients with advanced melanoma, follow-up from a randomized trial showed.

Among patients followed for at least 2 years, both the 1-year and 2-year overall survival did not differ between patients who continued randomized treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) and those who discontinued because of adverse effects. Both groups had better survival and progression-free survival as compared with patients randomized to ipilimumab monotherapy.

“Median progression-free survival and median duration of response were not reached at a minimum follow-up of 2 years, indicating durability of nivolumab-ipilimumab efficacy, even in patients who discontinued,” F. Stephen Hodi, MD, director of the melanoma center at Dana-Farber Cancer Institute in Boston, and colleagues concluded in a poster presentation at the 2016 ASCO Annual Meeting.

“In this post-hoc analysis, patients who experienced a treatment-related adverse event leading to discontinuation appeared to derive similar benefit from nivolumab-ipilimumab combination therapy, despite discontinuing early.”

Patients who discontinued the combination had adverse-event profiles similar to those of the overall study population but had more frequent adverse events, the investigators added.

The findings came from the CheckMate 069 trial that compared the combination of the immune checkpoint inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab versus ipilimumab alone in patients with previously untreated, advanced melanoma.

The primary data analysis showed an objective response rate of 61% with the combination versus 11% with ipilimumab alone. Additionally, the combination arm had a 2-year survival of 69%, median survival not yet reached, and complete response rate of 22%, all of which were superior to ipilimumab monotherapy.

Treatment-related adverse events occurred more often with the combination and led to discontinuation of 37% of patients randomized to nivolumab plus ipilimumab. The association between discontinuation for adverse events and clinical outcomes of interest remained a focus of continued follow-up in the trial.

In CheckMate 069, investigators randomized 95 patients 2:1 to the combination or ipilimumab monotherapy. Baseline characteristics did not differ substantially between patients who discontinued the combination and all patients randomized to the combination.

The primary endpoint was objective response rate, and the primary analysis showed an overall response rate of 59% in all patients randomized to combination therapy. The subgroup of patients who discontinued because of adverse events had an overall response rate of 66% and a 69% reduction in tumor burden. Complete and partial response rates were similar between all patients assigned to the combination and those who discontinued, as was the rate of stable disease.

The median time to response (2.8 months) and median duration of response (not yet reached) also did not differ between the patients who discontinued and all patients randomized to the combination. Three fourths of all randomized patients as did the subgroup of patients who discontinued.

An exploratory analysis of survival showed a 2-year overall survival of 71% in patients who discontinued the combination, 64% in all patents randomized to the combination, and 54% in patients assigned to ipilimumab monotherapy. The 2-year PFS was 51-52% in all patients randomized to the combination and those who discontinued, compared with 12% of patients randomized to ipilimumab alone.

Colitis and hepatitis were the most notable adverse events that occurred more frequently among patients who discontinued the combination treatment, said invited poster discussant Steven J. O’Day, MD, director of immune-oncology at the John Wayne Cancer Institute in Santa Monica, Calif. With the exception of endocrine disturbances, 90-100% of adverse events associated with the nivolumab-ipilimumab combination resolved within 4 to 8 weeks.

“This follow-up report from CheckMate 069 shows that early discontinuation of combination therapy with nivolumab and ipilimumab does not impair efficacy,” Dr. O’Day concluded.

Hodi FS, Postow AP, Chesney A, et al. Overall survival in patients with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus ipilimumab (IPI) due to toxicity in a phase II trial (CheckMate 069). Presented at: 2016 ASCO Annual Meeting.J Clin Oncol.34, 2016 (suppl; abstr 9518).