Neoadjuvant Melanoma Combo Improves RFS in Macroscopic Melanoma


Nivolumab plus ipilimumab showed an improvement in relapse-free survival for this patient population.

Christian Blank, MD

Christian Blank, MD

The neoadjuvant combination of nivolumab (Opdivo) and ipilimumab (Yervoy) continued to demonstrate a benefit in relapse-free survival (RFS) compared with the combination given in the adjuvant setting in patients with stage III macroscopic melanoma, according to 3-year follow-up results of the phase 1b OpACIN trial.1

Updated results of the combination showed that the 3-year RFS rates were 80% versus 60% for patients who received the combination in the neoadjuvant and adjuvant setting versus only the adjuvant setting, respectively. Moreover, at a median follow-up of 36.7 months, the 3-year overall survival (OS) rates were 90% and 70% in the neoadjuvant/adjuvant and adjuvant-only arms, respectively.

Additionally, updated findings from the phase 2 OpACIN-neo trial, which evaluated the optimal dosing schedule of the combination in the neoadjuvant setting for this patient population, showed that at a median follow-up of 17.7 months, relapses were observed in 2% of patients who had a pathologic response to neoadjuvant combination therapy versus 62% of nonresponders.

Results also showed that the estimated 24-month RFS rates were significantly higher for patients who achieved a pathologic response versus those who did not respond, at 97% versus 36%, respectively (P <.001).

The data from both trials suggest that pathologic response is a surrogate marker for RFS, according to lead study author Christian Blank, MD, who discussed the data in a virtual presentation during the meeting.

“The OpACIN trial showed, for the first time, a potential benefit of neoadjuvant ipilimumab/nivolumab versus adjuvant ipilimumab/nivolumab. The subsequent OpACIN-neo trial confirmed the high pathologic response rates that we saw in OpACIN with neoadjuvant ipilimumab/nivolumab,” said Blank, Group Leader of Immunology at the Netherlands Cancer Institute, in Amsterdam, The Netherlands. “The promising RFS rates encourage evaluating neoadjuvant ipilimumab plus nivolumab versus adjuvant nivolumab in a randomized phase 3 trial.”

Patients with stage III melanoma generally have a 5-year OS rate ranging from 30% to 60%. Even with the use of the adjuvant therapy, the RFS remains poor, Blank explained. For example, adjuvant treatment with dabrafenib (Tafinlar) plus trametinib (Mekinist) has 2- and 3-year RFS rates of 67% and 58%, respectively, while adjuvant nivolumab has a 2-year RFS rate of 64% and a 3-year RFS rate of 60%. With both therapies, there are approximately 10% to 20% of screen failures, the majority of which are because of progressive disease.

Blank discussed that neoadjuvant checkpoint inhibition could be superior to adjuvant treatment in this patient population. If T-cell checkpoint blockade is given in a neoadjuvant fashion, Blank hypothesized that the treatment could induce a stronger and broader tumor-specific T-cell response than adjuvant therapy. Moreover, prior data have indicated that the combination of PD-1/CTLA-4 inhibition elicits higher pathologic response rates than neoadjuvant PD-1 inhibition or targeted therapy. Investigators have previously determined that pathologic response can be used as a surrogate outcome marker for RFS and OS, and therefore, neoadjuvant immunotherapy can allow for the identification of biomarkers of response.

In the phase 1b OpACIN trial, investigators randomized patients with macroscopic stage III melanoma to receive standard nivolumab/ipilimumab as either adjuvant therapy (n = 10) or neoadjuvant therapy (n = 10). In the adjuvant arm, ipilimumab was given at 3 mg/kg and nivolumab was given at 1 mg/kg every 3 weeks for 4 cycles; in the neoadjuvant arm, 2 doses of the combination were given prior to surgery and 2 were given after surgery. Initial results showed that the high pathologic response rate was 78%, and the rate of grade 3/4 adverse events (AEs) was 90%, making the standard dose unfeasible for broader testing.2

At a median follow-up of 36.7 months, 4 patients relapsed in the adjuvant arm with local recurrence (n = 1) and distant metastasis (n = 3). In the neoadjuvant arm, 2 patients who had no pathologic response relapsed; 1 patient had local recurrence and the other had distant metastasis. No patients on the neoadjuvant arm who had a pathologic response relapsed.

Additional data showed that 3 patients on the adjuvant arm died versus 1 on the neoadjuvant combination, all of whom had developed distant metastases.

In the 3-arm, phase 2 OpACIN-neo trial, investigators sought to determine the optimal dosing schedule of neoadjuvant nivolumab and ipilimumab. In arm A, patients received 3 mg/kg of ipilimumab plus 1 mg/kg of nivolumab every 3 weeks for 2 cycles (n = 30); arm B comprised patients who received 1 mg/kg of ipilimumab plus 3 mg/kg of nivolumab every 3 weeks for 2 cycles (n = 30), or ipilimumab at 3 mg/kg every 3 weeks for 2 cycles with a sequential 3 mg/kg of nivolumab every 3 weeks for 2 cycles (n = 26).

The pathologic response rates were 80%, 77%, and 65% in arms A, B, and C, respectively, and the grade 3/4 AEs in each arm were 40%, 20%, and 50%, respectively.3 Based on these data, the arm B dosing schedule was identified as the most favorable schedule. Earlier results showed that, at a median follow-up of 8.3 months, no patients who had a pathologic response had relapsed versus 43% of nonresponders.

“Altering the ipilimumab dosing resulted in reduced grade 3/4 toxicity, while preserving the high pathologic response rate,” Blank said.

Updated findings showed that at a median follow-up of 17.7 months, relapses were observed in 2% of patients who had a pathologic response to therapy versus 62% of nonresponders.

Results showed that the 18-month RFS rates were 97% in responders and 47% in nonresponders, respectively. Then, at a median follow-up of 24.6 months, the estimated 2-year RFS and OS rates were 84% and 95%, respectively, for the overall population. Moreover, the 12-month RFS rates were 97% and 47% for responders and nonresponders, respectively.


1. Blank CU, Versluis JM, Rozerman EA, et al. 36-months and 18-months relapse-free survival after (neo)adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma patients—update of the OpACIN and OPACIN-neo trials. Presented at: 2020 AACR Virtual Annual Meeting; June 22-24, 2020; Virtual. Abstract 3412.

2. Blank CU, Rozeman EA, Fanchi LF, et al.Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nature Med. 2018;24:1655-1661. doi:10.1038/s41591-018-0198-0

3. Rozeman EA, Menzies AM, van Akkooi AC, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 2019;20(7):948-960. doi:10.1016/S1470-2045(19)30151-2

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