LAUSR

Abstract Background Combination IPI+PD1 immunotherapy has a high initial response rate, but patients can subsequently progress. The best management of this acquired resistance is unknown. We sought to explore the efficacy and safety of rechallenge IPI+PD1 in this setting. Methods Retrospective data from four melanoma centres were reviewed. Demographics, disease characteristics, initial and rechallenge treatment efficacy and toxicity were examined. Results 15 patients (pt) were identified: 60% male, median age 51y, 40% BRAF mutant. 14 pt received IPI+PD1 as 1st line of treatment, 1 received prior BRAFi+MEKi. 9 pt received ipilimumab (I) 3mg/Kg and nivolumab (N) 1mg/kg (I3N1), 5 received I 1mg/kg and pembrolizumab (P) 2mg/kg, 1 patient I 100mg q12w/P200mg q3w, with a median 4 cycles of I. 1 pt had CR, 10 had PR, and 4 prolonged SD (>6 months) to initial treatment. 7 pt (47%) developed significant irAE (4 hepatitis, 2 colitis, 1 pneumonitis), of which 6 (85%) ceased IPI + PD1 and only 1 pt continued PD1 alone. Median time to progression (TTP1) was 11 months (range 5-31 months). After progression, 5 (33%) had no intervening systemic therapy prior to rechallenge IPI+PD1 (of which 3 progressed on while receiving maintenance PD1), 5 had BRAFi/MEKi (33%), 2 (13%) had anti-PD1 monotherapy, 2 (13%) had investigational immunotherapy agents on a trial, and 1 pt had DTIC. At rechallenge, 13 pt received I3N1, 1pt I1N3 and 1 pt I3q12w + N1q2w, with a median 2 cycles of I. Only 1 pt had PR, 1 had SD, while 13 (87%) had PD, with mPFS2 only 2.7 mo (95% CI 2- NA). OS from rechallenge was 7.5 mo (95% CI 6.7- NA). All 7 pt with prior treatment-limiting irAE had the same irAE recur, except for 1 pt who died one week after re-exposure of PD, and 1 pt with prior pneumonitis who remained on 10mg prednisone without recurrence. Conclusions Rechallenge with IPI + PD1 appears to have little efficacy in those with acquired resistance and prior toxicity often recurs. An expanded multi-institutional analysis is under way. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure A. Hepner: Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: Roche. M.S. Carlino: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: AMGEN; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche. D.B. Johnson: Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: BMS; Advisory / Consultancy: Incyte; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Incyte; Travel / Accommodation / Expenses: Genentech. O.A. Michielin: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD. G.V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Mass-Array; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche. A.M. Menzies: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Pierre Fabre. All other authors have declared no conflicts of interest.