First safety and efficacy results of PRADO: A phase II study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) in resectable stage III melanoma.

Abstract

10002 Background: OpACIN-neo tested 3 dosing schemes of neoadjuvant (neoadj) IPI+NIVO and identified 2 cycles of IPI 1mg/kg + NIVO 3mg/kg (I1N3) as the most favorable with a pathologic (path) response rate (pRR) of 77% and 20% grade 3-4 irAEs. After 17.6 months median FU, 1/64 (2%) patients (pts) with path response vs 13/21 (62%) of the non-responders ( > 50% viable tumor cells; pNR) had relapsed. We hypothesized that therapeutic lymph node dissection (TLND) could be omitted in pts achieving a complete or near-complete path response (≤10% viable tumor cells; major path response, MPR) in the index node (largest LN metastasis: ILN), whereas additional adjuvant (adj) therapy might improve the outcome of pNR pts. Methods: PRADO is an extension cohort of the multi-center phase 2 OpACIN-neo study that aims to confirm the pRR and safety of neoadj I1N3 and to test response-driven subsequent therapy. Pts with RECIST 1.1 measurable clinical stage III melanoma were included to receive 2 cycles of neoadj I1N3 after marker placement in the ILN. ILN resection was planned at wk 6. Pts that achieved MPR in the ILN did not undergo TLND; pts with pPR ( > 10 – ≤50% viable tumor cells) underwent TLND; and pts with pNR underwent TLND and received adj NIVO or targeted therapy (TT) for 52 wks +/- radiotherapy (RT). Primary endpoints were pRR in the ILN and 24-month RFS. Estimated toxicity rates at wk 12 were calculated using a Kaplan Meier based method. Results: Between Nov 16, 2018 and Jan 3, 2020, 99 of 114 screened pts were eligible and enrolled. So far, 86 pts had ≥12 wks FU. 70/99 pts achieved a path response in the ILN (pRR 71%, 95% CI 61% - 79%); 60 (61%) had MPR. TLND was omitted in 58 (97%) of the MPR pts. There were 28 non-responders; 7 developed distant metastasis before ILN resection. To date, 8 of the 21 pNR pts had adj NIVO, 7 had adj TT and 7 had adj RT. The estimated grade 3-4 irAE rate at wk 12 was 24%. Due to toxicity, 10 pts (10%) received only 1 cycle I1N3 and in 3 pts ILN resection was not performed: 2 of these pts underwent TLND at wk 9 and one pt was not evaluated for path response. At data cutoff, the surgery-related grade 1,2 and 3 AE rates were 29%, 10% and 0% in pts who underwent ILN resection only vs 21%, 30% and 9% in pts who underwent subsequent TLND (p = 0.004). At ASCO 2020 all pts will have reached ≥12 wks FU. Conclusions: Neoadj I1N3 treatment induced a high pRR with tolerable toxicity. TLND was omitted in a major subset of pts, reducing surgical morbidity. Longer FU is needed to report safety and RFS when TLND is omitted in MPR pts. Clinical trial information: NCT02977052.

Current Melanoma Treatments: Where Do We Stand?

“…An experimental extension cohort (PRADO; n = 99) of this trial reported that therapeutic lymph node dissection was omitted in 97% of the patients who achieved a complete or near-complete pathological response (≤10% viable tumor cells), therefore reducing surgical morbidity [ 32 ]. The previously reported high-grade toxicity of this trial varied between arms: grade 3–4 adverse events were seen in 40% of patients in arm A, 20% in arm B, and 50% in arm C. The most common grade 3–4 adverse events were elevated liver enzymes in group A (20%) and colitis in group C (19%); in group B, none of the grade 3–4 adverse events were seen in more than one patient.…”

Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

“…As a result of this definition, non-TDLN may sometimes be more proximal to the tumor than TDLN, but due to the fact that tumor-derived factors will diffuse through the lymph basin, be less affected by the tumor, e.g., in terms of immune suppression (9). A growing number of studies are exploring the use of systemically administered immune checkpoint inhibitors (ICI) as neo-adjuvant therapy for patients in earlier (i.e., resectable) cancer stages (10)(11)(12)(13). As in this setting both the primary tumor and TDLN are still in place (rather than surgically removed in the adjuvant setting) this approach will enable simultaneous immune modulation of the TME and of TDLN.…”

Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach

“…The first results show again a high pathologic response rate of 71%, and patients with MPR in whom extensive surgery was omitted had reduced surgical morbidity and higher quality of life scores. 18 The RFS data are still immature with a median follow-up of less than a year.…”