Table 4.
Completed trials evaluating neoadjuvant immune checkpoint and targeted molecular therapy for treatment of clinically-evident, resectable stage III melanoma
| Investigator; year | Trial design | Patient #; stage disease | Treatment regimen | Findings |
|---|---|---|---|---|
| Immunotherapy trials | ||||
| Tarhini et al. (2014) | Phase I; single arm | 33; stage IIIB/C | A. Ipilimumab 10 mg/kg every 3 weeks for 2 cycles→surgery at week 6–8→ipilimumab 10 mg/kg every 3 weeks for 2 cycles starting 2-4 weeks after surgery |
∙ 9% RR ∙ 0% pCR ∙ 10.8 month PFS ∙ 42% grade 3 toxicities; no grade 4/5 toxicities ∙ ↑ Tregs and ↓ MDSCs in periphery correlated w/ improved PFS ∙ ≥ threefold ↑ CD3+/CD4+/IFNγ+ T-cells seen only in those with PFS at 6 months |
| Tarhini et al. (2018) | Phase I; double arm | 30; stage IIIB/C |
A. Ipilimumab 3 mg/kg every 3 weeks for 2 cyclesà surgery at week 6–8à Ipilimumab 3 mg/kg every 3 weeks for 2 cycles B. Ipilimumab 10 mg/kg every 3 weeks for 2 cyclesà surgery at week 6–8à Ipilimumab 10 mg/kg every 3 weeks for 2 cycles * Standard HDI given to both groups neoadjuvantly and adjuvantly |
∙ 29% RR with 3 m/kg vs. 43% RR w/ 10 mg/kg ∙ 36% pCR with 3 mg/kg vs. 29% pCR w/ 10 mg/kg ∙ 10/11 patients with pCR or MRD remained disease free at 32 months ∙ More grade 3/4 toxicities with higher ipilimumab dosing; no grade 5 toxicities ∙ ↑ TILs in TME seen with pCR, regardless of ipilimumab dosing ∙ ↑ baseline and post-neoadjuvant TIL clonality correlated w/ improved RFS |
| Amaria et al. (2018) | Phase II; double arm | 23; stage IIIB/C, and oligometastatic stage IV |
A. Nivolumab 3 mg/kg every 2 weeks for 4 cyclesà surgeryà nivolumab 3 mg/kg every 2 weeks for 13 cycles B. Ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 3 weeks for 3à surgeryà nivolumab 3 mg/kg every 2 weeks for 13 cycles |
∙ 25% RR in mono group vs. 73% RR in combo group ∙ 25% pCR in mono group vs. 45% pCR in combo group ∙ PFS, RFS, DMFS, and OS favored combo group ∙ Disease progression prevented surgery in 2 patients in mono group, resulting in early cessation of trial ∙ 73% toxicities and 64% dose delays in combo group ∙ ↑ CD8+ TILs, PD-L1 expression, and TCR clonality in treatment responders |
| Huang et al. (2019) | Phase I; single arm | 29; stage IIIB/C, and oligometastatic stage IV | A. Pembrolizumab 200 mg x1 cycleàsurgery at week 3à pembrolizumab 200 mg every 3 weeks for 1 year |
∙ 29% pCR or near major pathologic response ∙ 63% DFS and 93% OS rate at 2 years; all patients with pathologic response were disease free ∙ No grade 3 or higher toxicities; no surgical delays ∙ ↑ Tex cells in periphery and in tumor at resection associated with improved outcomes ∙ Potential neoadjuvant response signal identified |
| Blank et al. (2018) | Phase I; double arm | 20; stage IIIB/C |
A. Ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 3 weeks for 2 cyclesà surgery at week 6à ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 3 weeks for 2 cycles B. Surgeryà ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 3 weeks for 2 cycles |
∙ 66% pCR or near pCR in neoadjuvant arm ∙ 80% in neoadjuvant vs. 60% in adjuvant group were relapse free at 25.6 months ∙ All patients w/ pathologic response relapse free at 25.6 months ∙ 90% in each group stopped treatment early or had delays due to toxicities ∙ ↓ TILs and ↓ T cell clonality associated w/ relapse ∙ Low baseline IFNγ RNA expression in tumor associated w/ relapse |
| Rozeman et al. (2019) | Phase II; triple arm | 86; stage IIIB/C |
A. Ipilimumab 3 mg/kg + nivolumab 1 mg/kg for 2 cyclesà surgery at 6 weeks B. Ipilimumab 1 mg/kg + nivolumab 3 mg/kg for 2 cyclesà surgery at 6 weeks C. Ipilimumab 3 mg/kg for 2 cyclesà nivolumab 3 mg/kg for 2 cyclesà surgery at 6 weeks |
∙ RR in 63% of arm A, 57% of arm B, and 35% of arm C ∙ Pathologic response in 80% of arm A, 77% of B, and 65% of arm C ∙ No relapse in patients w/ pathologic response ∙ Grade 3/4 toxicities in 40%, 20% and 50% in arms A, B, and C, respectively ∙ Surgery delayed for 1 patient in arm A and 2 in arm C ∙ IFNγ RNA expression level did not correlate w/ outcome |
| Targeted therapy trials | ||||
| Amaria et al. (2018) | Phase II; double arm | 21; stage IIIB/C, and oligometastatic stage IV with BRAF mutation |
A. Dabrafenib 150 mg PO qd + trametinib 2 mg PO qd for 8 weeksà surgeryà Dabrafenib 150 mg PO qd + trametinib 2 mg PO qd for 44 weeks B. Surgeryà standard of care adjuvant therapy |
∙ 71% of standard care arm developed negative survival events by 2 months, prompting early trial cessation ∙ Median event free survival of 19.7 months vs. 2.9 months for neoadjuvant vs. standard of care arms ∙ 85% RR and 75% pathologic response in neoadjuvant arm ∙ Low pERK in baseline tumor specimens associated with pCR ∙ Decreased pre-treatment T cell clonality associated with non-pCR |
| Long et al. (2019) | Phase II; single arm | 35; stage IIIB/C with BRAF mutation | A. Dabrafenib 150 mg PO qd + trametinib 2 mg PO qd for 12 weeksà surgeryà Dabrafenib 150 mg PO qd + trametinib 2 mg PO qd for 40 weeks |
∙ 86% RR ∙ 100% pathologic response with 49% achieving pCR ∙ 57% recurrence rate at 27 months ∙ Median RFS of 30.6 months for pCR vs. 18 months for non-pCR ∙ ↑ CD8+ TILs and PD-L1 expression at baseline associated with pCR ∙ Surgical resection easier in 46% of patients ∙ 29% grade 3/4 toxicities ∙ No correlation between ctDNA and RR or pathologic response |