Ipilimumab (Ipi) Alone Or In Combination With Anti-Pd-1 (Ipi+Pd1) In Patients (Pts) With Metastatic Melanoma (Mm) Resistant To Pd1 Monotherapy.

10005 Background: PD1 induces long-term responses in approximately 30% of MM pts, however 2/3 are resistant (innate or acquired) and will require further treatment. A subset of these pts will benefit from IPI or IPI+PD1, but these pts are yet to be identified. We sought to determine; i) response rate (RR) and survival to IPI+/-PD1 after PD1 progression, and ii) clinical predictors of response and survival to IPI+/-PD1. Methods: MM pts resistant to PD1 and then treated with IPI+/-PD1 were studied. Demographics, disease characteristics and baseline blood parameters were examined. Univariate, multivariate and backward elimination technique analyses were performed to create predictive models of response and overall survival (OS). Results: Of 330 MM pts resistant to PD1 (median time to prog 2.9 months [0.5 – 42.3], 12% adjuvant, 88% metastatic; 70% innate, 30% acquired), 161 (49%) had subsequent IPI and 169 (51%) had IPI+PD1. Characteristics at start of IPI+/-PD1 were similar in IPI vs IPI+PD1 groups (stage M1D 27% vs 34%; elevated LDH 38% vs 40%), except IPI group had more ECOG ≥1 (60% vs 34%) and less BRAF mutation (mut) (21% vs 37%). Median follow-up from start of IPI+/-PD1 was 22.3 months (19.8 - 25.8); RR was 22%, higher in IPI+PD1 (31%) vs IPI (12%) (p < 0.01). PFS and OS at 1 year were 20% and 48%, respectively; better with IPI+PD1 (27%/57%) vs IPI (13%/38%) (p < 0.01). PD1 setting (adjuvant/metastatic) and response did not impact response to IPI+/-PD1. Most pts progressing on adjuvant PD1 had IPI+PD1 (88%) and RR was 33%. Neither the interval between PD1 and IPI+/-PD1 nor use of other drugs affected response to IPI+/-PD1. RR was similar in BRAF WT (23%) vs BRAF mut (RR 21%) pts. In BRAF WT pts, RR was higher with IPI+PD1 vs IPI (38% vs 9%, p < 0.01), while RR was similar with IPI (24%) or IPI+PD1 (19%) in BRAF mut pts. One third of BRAF mut pts had BRAF inhibitors (BRAFi) prior to IPI+/-PD1 and lower RR (13%) vs those without BRAFi (RR = 25%, p > 0.05). High grade (≥G3) toxicity (tox) was similar with IPI+PD1 (30%) or IPI (34%, p = 0.48), and was not associated with response. Stage III/M1A/M1B, normal LDH and treatment with IPI+PD1 were the best predictors of response (AUC = 0.69). These factors, in addition to sex (male), ECOG PS = 0, BRAF mut, progressed/recurred > 3 months on PD1, and absence of bone mets were the best predictors of longer OS (AUC = 0.74). Conclusions: In pts resistant to PD1, IPI+PD1 has higher RR, longer survival, yet similar high grade tox than IPI alone. Predictive models of response & survival will help select pts for IPI+/-PD1 after progressing on PD1.