Effective treatment options for melanoma after immune checkpoint blockade failure are limited. RP1 (vusolimogene oderparepvec) is a herpes simplex virus type 1–based oncolytic immunotherapy, here evaluated in combination with nivolumab in anti–PD-1–failed melanoma.
Patients had advanced melanoma that had confirmed progression on anti–PD-1 (≥8 weeks, last prior treatment). RP1 was administered intratumorally (≤8 doses, ≤10 mL/dose; additional doses allowed) with nivolumab (≤2 years). The objective response rate (ORR) was assessed by independent central review using Response Evaluation Criteria in Solid Tumors version 1.1.
Of 140 patients enrolled, 48.6% had stage IVM1b/c/d disease, 65.7% had primary anti–PD-1 resistance, 56.4% were PD-L1 negative, and 46.4% received prior anti–PD-1 and anti–cytotoxic T-lymphocyte antigen-4 therapy (43.6% in combination and 2.9% sequentially). Confirmed ORR (95% CI) was 32.9% (95% CI, 25.2% to 41.3%; 15.0% complete response). Responses occurred with similar frequency, depth, duration, and kinetics for injected and noninjected, including visceral lesions. The median (95% CI) duration of response was 33.7 (95% CI, 14.1 to not reached) months. Overall survival rates (95% CI) 1 and 2 years were 75.3% (95% CI, 66.9% to 81.9%) and 63.3% (95% CI, 53.6% to 71.5%), respectively. Biomarker analysis demonstrated broad immune activation associated with response, including increased CD8+ T-cell infiltration and PD-L1 expression. Treatment-related adverse event rates were 77.1% grade 1/2, 9.3% grade 3, 3.6% grade 4, and no grade 5 events.
RP1 combined with nivolumab provided deep and durable systemic responses in patients with anti–PD-1–failed melanoma, including those with poor prognostic factors. The safety profile was favorable, with mostly grade 1/2 adverse events.
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.