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.
In phase 1–2 trials in patients with resectable, macroscopic stage III melanoma, neoadjuvant immunotherapy was more efficacious than adjuvant immunotherapy.
In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival.
A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. 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. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of patients in the neoadjuvant group and in 14.7% in the adjuvant group.
Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)
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.
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.
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