Ipilimumab and nivolumab

An open-label phase III study (NADINA [NCT04949113]) included patients with resectable macroscopic stage III melanoma. Patients were randomly assigned (1:1) to receive either two cycles of neoadjuvant ipilimumab plus nivolumab every 3 weeks, followed by lymph node dissection/resection of in-transit metastases or lymph node dissection followed by 12 cycles of adjuvant nivolumab every 4 weeks. A total of 423 eligible patients were randomly assigned (212 patients to the neoadjuvant group and 211 to the adjuvant-only group). Adjuvant therapy for patients assigned to the neoadjuvant group was dictated by pathological response. Patients who had a major pathological response (≤10% residual viable tumor) did not receive any adjuvant treatment. Patients who had a pathological partial response (11%–50%) or a pathological nonresponse (>50% residual tumor) received either adjuvant dabrafenib plus trametinib for 46 weeks or an additional 11 cycles of adjuvant nivolumab. The primary end point was EFS in the intention-to-treat population. Events were defined as the time from randomization to the occurrence of progression to unresectable melanoma before surgery, disease recurrence, or death due to melanoma or treatment.[21]

An open-label phase III study (NADINA [NCT04949113]) included patients with resectable macroscopic stage III melanoma. Patients were randomly assigned (1:1) to receive either two cycles of neoadjuvant ipilimumab plus nivolumab every 3 weeks, followed by lymph node dissection/resection of in-transit metastases or lymph node dissection followed by 12 cycles of adjuvant nivolumab every 4 weeks. A total of 423 eligible patients were randomly assigned (212 patients to the neoadjuvant group and 211 to the adjuvant-only group). Adjuvant therapy for patients assigned to the neoadjuvant group was dictated by pathological response. Patients who had a major pathological response (≤10% residual viable tumor) did not receive any adjuvant treatment. Patients who had a pathological partial response (11%–50%) or a pathological nonresponse (>50% residual tumor) received either adjuvant dabrafenib plus trametinib for 46 weeks or an additional 11 cycles of adjuvant nivolumab. The primary end point was EFS in the intention-to-treat population. Events were defined as the time from randomization to the occurrence of progression to unresectable melanoma before surgery, disease recurrence, or death due to melanoma or treatment.[21]

The median duration of follow-up was 10.6 months in both groups. A total of 100 events occurred (28 in the neoadjuvant-adjuvant group and 72 in the adjuvant-only group). EFS was significantly longer in the neoadjuvant group than in the adjuvant-only group. The 12-month EFS rate was 83.7% (95% CI, 73.8%–94.8%) in the neoadjuvant group and 57.2% (95% CI, 45.1%–72.7%) in the adjuvant-alone group.[21][Level of evidence B1] The benefit of neoadjuvant therapy was seen across all subgroups of patients, including those with BRAF pathogenic variants.

An open-label phase III study (NADINA [NCT04949113]) included patients with resectable macroscopic stage III melanoma. Patients were randomly assigned (1:1) to receive either two cycles of neoadjuvant ipilimumab plus nivolumab every 3 weeks, followed by lymph node dissection/resection of in-transit metastases or lymph node dissection followed by 12 cycles of adjuvant nivolumab every 4 weeks. A total of 423 eligible patients were randomly assigned (212 patients to the neoadjuvant group and 211 to the adjuvant-only group). Adjuvant therapy for patients assigned to the neoadjuvant group was dictated by pathological response. Patients who had a major pathological response (≤10% residual viable tumor) did not receive any adjuvant treatment. Patients who had a pathological partial response (11%–50%) or a pathological nonresponse (>50% residual tumor) received either adjuvant dabrafenib plus trametinib for 46 weeks or an additional 11 cycles of adjuvant nivolumab. The primary end point was EFS in the intention-to-treat population. Events were defined as the time from randomization to the occurrence of progression to unresectable melanoma before surgery, disease recurrence, or death due to melanoma or treatment.[21]

Among the 212 patients in the neoadjuvant group who received at least one dose of treatment, 47.2% had at least one grade 3 or 4 adverse event, compared with 34.1% in the adjuvant-only group. No new toxic effects of ipilimumab and nivolumab were observed in either trial group. One patient in the adjuvant group died of pneumonitis caused by treatment. No treatment-related deaths occurred in the neoadjuvant group.