More may not always be better. Adjuvant Nivo q2-weeks + Ipi q6-weeks was not better than Nivo q4 weeks in reducing recurrences in fully resected stage III-IV melanoma.
Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma.
In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for ≤ 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup.
At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients.
Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment.
I love this trial in that it advances science but also balances cost. Neoadjuvant therapy with ipilimumab + nivolumab (Ipi+Nivo) x 2 followed by surgery followed by adjuvant nivolumab. Patients with a major pathologic response went on to observation alone. Again, intact tumor-immune interactions are key to maximum treatment effectiveness. Another key to these patients is seeing a medical oncologist before surgery.
10-year survival data from Checkmate 067 on Ipi+Nivo, Nivo and Ipi alone in met-melanoma. The OS was twice as long in the Ipi+Nivo group compared to Nivo alone. Of note this was with Nivo-1 + Ipi-3, and most of us use the more tolerable Nivo-3 + Ipi-1 dosing based on Checkmate 511. This remains the SOC for good PFS met-melanoma in my opinion.
Combination vs. placebo improved PFS, where there was improvement in OS as the risk of death was 20% lower but was not significant, in BRAF V600E, the risk of death was reduced by 25%.
For BRAF V600E, NCCN recommends using this regimen in the adjuvant setting.
This was compared to adjuvant niovolumab for 12 months, patients who did not achieve complete response also received adjuvant nivo. Neoadjuvant therapy was for 2 cycles. 12-month event-free survival was 83.7% in the neoadjuvant group and 57.2% in the adjuvant group. 58% had major pathological response in the neoadjuvant group, less than 5% could not get the surgery. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse.
Interesting study showing a strong difference in EFS with neoadjuvant + adjuvant vs. adjuvant alone for stage III/IV melanoma. All patients had disease that was amenable to surgery; EFS at 24 months was 72% vs. 49% in favor of the neoadjuvant group. The hypothesis is that neoadjuvant therapy functionally inhibits the immune checkpoint before antitumor T-cells are surgically resected. This concept is also developing in other cancers, including NSCLC, breast and bladder cancers. This should affect clinical practice.
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