Selective Role for Single-Agent Ipilimumab After Anti-PD-1 Failure in Melanoma

Patients with wild-type metastatic melanoma that progressed on frontline PD-1 inhibition had almost a 2-year median overall survival (OS) when treated with single-agent ipilimumab (Yervoy), a small retrospective case review showed.

Median OS with post-progression ipilimumab was 23.2 months in patients with no targetable biologic markers versus 5.3 months and 4.5 months, respectively, for BRAF-mutated and NRAS-mutated tumors. Multivariate analysis showed that brain metastasis and BRAF or NRAS mutation were independent predictors of mortality.

“Despite the small sample size [N=44], our results indicate that a careful evaluation should be performed by clinicians when prescribing ipilimumab as treatment after the failure of therapy with iPD-1 [PD-1 inhibitors],” concluded Maria Luigia Carbone, MD, of the Istituto Dermopatico dellʹImmacolata in Rome, and co-authors in Cancers. “The balance between the benefits and detrimental effects of ipilimumab therapy should be particularly defined in patients with activating BRAF mutations who have been pretreated with BRAF or MEK inhibitors, as well as in NRAS-mutated patients. Special care should be adopted when a patient with brain metastases is to be treated.”

“Instead, ipilimumab treatment could be of great value in patients with BRAF/NRAS wild-type melanoma and without brain metastases, with several benefits to long-term survival, although a larger dataset is needed for a more precise indication.”

Although ipilimumab paved the way for treatment of advanced melanoma with immune checkpoint inhibitors, PD-1/L1 inhibitors rapidly emerged as the preferred frontline therapy in the absence of actionable mutations. About 40% of patients with metastatic melanoma respond to PD-1/L1 inhibition, creating a substantial need for effective therapies in second line and beyond.

For patients without activating mutations, the National Comprehensive Cancer Network recommends single-agent pembrolizumab (Keytruda) or nivolumab (Opdivo), combination therapy with a PD-1 inhibitor plus ipilimumab, and single-agent ipilimumab. Targeted combination therapy is recommended for progressive/refractory melanoma that has activating mutations.

Several studies have shown efficacy with single-agent ipilimumab after failure of anti-PD-1 therapy, Carbone and co-authors noted. In one example, ipilimumab after progression/failure of pembrolizumab led to a median OS of 19.6 months. A small randomized trial compared single-agent ipilimumab and combination of ipilimumab and nivolumab after anti-PD-1 failure. The results showed a 16% response rate with ipilimumab and a 12-month survival of 54%. Another small comparative trial showed similar disease control rates with single-agent ipilimumab and the nivolumab-ipilimumab combination after first-line PD-1/L1 inhibition.

NRAS mutation, occurring in 15-20% of advanced melanomas, appears to confer a worse prognosis as compared with BRAF or BRAF/NRAS wild-type, Carbone and colleagues continued. Whether NRAS is predictive for immunotherapy efficacy is uncertain, as recent studies have yielded conflicting data.

Given the background information, the authors performed a retrospective, single-center study to evaluate the predictive role of NRAS/BRAF mutations in patients treated with single-agent ipilimumab after failure of frontline PD-1 inhibition. The analysis included 44 consecutive adults with unresectable/metastatic melanoma treated from July 2017 to May 2023. The primary outcome was OS, defined as the time from initiation of ipilimumab until death.

The study population had a median age of 68, and men accounted for 62% of the total. The 44 patients consisted of 28 with BRAF wild-type tumors, nine with BRAF-mutated tumors, and seven with NRAS-mutated tumors. About half (21/44) of the patients had one or two metastatic sites, and the remainder had three or more.

Nine patients had received BRAF/MEK inhibitors and five had received chemotherapy, in addition to anti-PD-1 therapy. Four patients had brain metastases, and two had received cranial irradiation.

The entire study population had a median OS of 14 months, and the 23.2-month median for BRAF wild-type patients proved to be significantly better versus patients with mutated tumors (P=0.017). Median OS was 14 months for patients without brain metastases versus 3.2 months for those with brain metastases (P=0.006).

Patients with mutated tumors had a more than three-fold greater mortality risk as compared with patients who had wild-type tumors (HR 3.3, 95% CI 1.1-9.3, P=0.027), and patients with brain metastases had more than a fourfold greater risk (HR 4.5, 95% CI 1.0-19.1, P=0.037).

Analysis of progression-free survival (PFS) showed only a small difference between patients with wild-type tumors (median PFS of 3.3 months) compared with the pooled subgroup with mutated tumors (2.4 months), although the difference did achieve statistical significance. Patients with brain metastases had a median PFS of 1.1 months versus 3.2 months for those without (P<0.001).

Given the somewhat discrepant results for OS and PFS, investigators examined post-progression survival (PPS) to estimate “the true significance of the impact of PFS on OS.” The analysis showed a median PPS of 11.7 months for patients with wild-type tumors versus 2.1 months for the pooled subgroup with mutated tumors (P=0.002).

Objective responses occurred in eight (28.5%) patients with wild-type tumors, and two others (7.1%) had stable disease. That compared with a single partial response in patients with BRAF-mutated tumors (11.1%), and two responses (one complete) in the NRAS-mutated subgroup (14.3% each).

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