Small Study Evaluates Neoadjuvant vs Adjuvant Nivolumab Plus Ipilimumab in Stage III Melanoma

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The neoadjuvant combination of nivolumab and ipilimumab yielded a continued benefit in relapse-free survival vs adjuvant use of the same combination therapy in 20 patients with stage III macroscopic melanoma. This finding is based on 3-year follow-up results of the phase Ib OpACIN trial, presented during the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II.1

Updated results of the trial demonstrated 3-year relapse-free survival rates of 80% (8 of 10) in the neoadjuvant setting vs 60% (6 of 10) in the adjuvant setting. At a median follow-up of 36.7 months, the 3-year overall survival rates were 90% and 70% in the neoadjuvant/adjuvant and adjuvant-alone arms, respectively.

In addition, updated findings from the follow-up phase II OpACIN-neo trial, with a median follow-up of 17.7 months, found that patients who had a pathologic response to neoadjuvant therapy had a 2% relapse rate vs 62% in nonresponders. The estimated 24-month relapse-free survival rates were significantly higher for patients who achieved a pathologic response vs those who did not: 97% vs 36%, respectively (P <.001).

Christian U. Blank, MD

Christian U. Blank, MD

“The OpACIN trial showed, for the first time, a potential benefit of neoadjuvant vs adjuvant ipilimumab/nivolumab. The subsequent OpACIN-neo trial confirmed the high pathologic response rates seen in OpACIN with neoadjuvant ipilimumab/nivolumab. The promising relapse-free survival rates support evaluating neoadjuvant ipilimumab plus nivolumab vs adjuvant nivolumab in a randomized phase III trial,” said lead author Christian U. Blank, MD, group leader of immunology at the Netherlands Cancer Institute, Amsterdam.

According to Dr. Blank, as well as other investigators, results from both trials suggest that pathologic response may be used as a surrogate marker for relapse-free survival.

The 5-year survival for stage III melanoma ranges from 30% to 60%, and relapse-free survival remains poor with adjuvant therapy. Dr. Blank and coauthors hypothesized that giving neoadjuvant nivolumab/ipilimumab could induce a stronger immune response than adjuvant therapy with the same combination.

OpACIN Trials

The phase Ib OpACIN trial randomly assigned patients with macroscopic stage III melanoma to receive standard nivolumab/ipilimumab as either adjuvant therapy (n = 10) or the same combination as neoadjuvant therapy (n = 10).

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


  • Early evidence from the OpACIN trials suggests that nivolumab/ipilimumab may be used as neoadjuvant therapy for stage III melanoma.
  • The combination will be studied further in the neoadjuvant setting.
  • Although the number of study patients is too small to draw firm conclusions, these early findings are worthy of further investigation.

Deaths due to distant metastasis were reported in three patients in the adjuvant arm and one patient in the neoadjuvant arm.

The three-arm, phase II OpACIN-neo trial was conducted to determine the optimal dosing schedule of neoadjuvant nivolu-mab/ipilimumab. The arm B dosing schedule with a reduced dose of ipilimumab (ie,1 mg/kg of ipilimumab plus 3 mg/kg of nivolumab every 3 weeks for two cycles) was identified as the most favorable schedule.

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

DISCLOSURE: Dr. Blank owns stock and other ownership interests in Forty Seven and Neon Therapeutics; has served as an institutional consultant or advisor to AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Third Rock Ventures; has received research funding from Bristol-Myers Squibb, NanoString Technologies, and Novartis; and has received travel, accommodations, and expenses from Bristol-Myers Squibb.


1. Blank CU, Versluis JM, Rozeman 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. 2020 AACR Virtual Annual Meeting II. Abstract 3412.

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