Abstract 9514: Olson DJ, Luke JJ, Hallmeyer S et al. Phase II trial of pembolizumab (pembro) plus 1 mg/kg ipilumumab (ipi) immediately following progression on anti-PD-1 Ab in melanoma (mel).

Background: Immunotherapy with anti-PD-1 + CTLA-4 Abs improves response rates over anti-PD-1 Ab alone; however, the utility of this combination after first line anti-PD-1 is unknown. We report the first prospective data evaluating pembro + low dose ipi immediately following progression on anti-PD-1 (NCT02743819). 

Methods: Patients (pts) with mel and measurable disease, no autoimmunity, and no prior anti-CTLA-4 who had progressed immediately prior on an anti-PD-1 (or non-CTLA4 combination) were eligible. Prior BRAF inhibitor was allowed (none received it). Pts received pembro 200 mg + ipi 1 mg/kg Q3W for 4 doses, then pembro alone. The primary endpoint was response rate (RR) as assessed by irRECIST. An optimal Simon two-stage design was employed to test the null hypothesis of a 10% RR vs 30% alternative (1-sided alpha 0.10, 90% power, ≥2/12 RR to continue to total of ≥6/35). The data analysis cutoff date was January 2, 2018. 

Results: 22 patients have been accrued with 17 evaluable for the primary endpoint (4 have not yet had their first imaging evaluation and 1 was not enrolled). Prior treatment included 21 on anti-PD-1 alone and 1 on combination with IDO inhibitor. Median length of treatment on prior anti-PD-1 was 5.6 months among all 22 pts. The study met its interim efficacy analysis with 5/12 responses to move to stage 2. Among the 17 response-evaluable pts there were 2 CR, 6 PR (47% RR), and 5 SD for disease control rate (DCR) of 76% and rejection of the null hypothesis. Progression-free survival at 6 months was 75% (CI 47%-90%). All responses are ongoing. At last follow-up, 8 pts have gone off treatment with 14/22 (64%) having any drug-related and 3/22 (14%) ≥ grade 3-4 drug-related AE (hyperglycemia, acute kidney injury and skin tissue disorder, diarrhea and rash acneiform). Among 11 response-evaluable pts with staining results currently available, RR and DCR were 67% and 100% in PD-L1+ (n = 3) and 50% and 88% in PD-L1 negative (n = 8) tumors. Further biomarker analysis is underway. 

Conclusions: Pembro + 1 mg/kg ipi is tolerable and has antitumor activity in pts with mel who have progressed immediately prior on an anti-PD-1 Ab. The trial sample size has been expanded to further explore this regimen. Clinical trial information: NCT02743819.

Abstract TPS9602: Rohaan MW, van den Berg J, Gomez-Eerland R et al. Multicenter phase I/IIa study using T cell receptor gene therapy in metastatic melanoma.

Background: Since the introduction of targeted therapy and checkpoint inhibitors, the historically poor prognosis of patients with unresectable stage IIIc/IV melanoma has greatly improved, with now known 2-year survival rates of 46-64%. However, a substantial group of patients, for example those with metastatic uveal melanoma, have poor response rates upon these therapies with no alternative approved therapy yet available. Adoptive transfer of T cell receptor (TCR) gene modified T cells is a modality to create a large pool of tumor reactive T cells. Responses of clinical significance have been seen in preclinical and clinical trials when targeting the melanocyte differentiation antigens gp100 and MART-1. The primary aim of our study is to explore the feasibility, safety and objective response rate of the adoptive transfer of autologous T cells modified with a MART-1 specific TCR, preceded by non-myeloablative (NMA) chemotherapy. 

Methods: In this phase I/IIa study, a total of 25 patients ≥ 18 years of age, with irresectable stage IIIc/IV melanoma (cutaneous, melanoma of unknown primary, mucosal and uveal melanoma) who have failed previous standard treatments, are HLA-A2 positive and have MART-1 and MHC class I expressing tumors, will be included. Patients will undergo leukapheresis to isolate autologous T cells, which will be transduced with a retroviral vector encoding the 1D3HMCys MART-1 TCR and expanded ex vivo. Patients will receive NMA chemotherapy and a single intravenous infusion with MART-1 TCR transduced T cells in a dose escalating regimen after evaluation of toxicity and efficacy. Primary endpoints are the feasibility of MART-1 specific TCR therapy in terms of delivery of this sequence of treatment in metastatic melanoma patients, safety according to CTCAE 4.0 and objective response rate according to RECIST 1.1. Secondary endpoints are the 1-year progression free survival, median overall survival and the efficacy of induction of tumor specific T cell responses measured in peripheral blood and tumor biopsies. Enrollment started in March 2012 in The Netherlands Cancer Institute and will be continued in a 2-stage Simon design. Clinical trial information: NCT02654821.

Abstract TPS9597: Vanderwalde AM, Latkovic-Taber M, Hu-Lieskovan S et al. Combining ipilimumab (ipi) and nivolumab (nivo) in advanced melanoma following progression on a PD-1 inhibitor (SWOG S1616).

Background: We hypothesize that patients with advanced melanoma who progress on anti-PD-1 therapy upfront may respond to the addition of the CTLA-4 inhibitor ipi to continue PD-1 inhibition (with nivo), and that responses would occur at a rate higher than would be expected from switching to ipi alone. We surmise that this would occur because melanomas primarily refractory to PD-1 antibodies may not have a sufficient pre-existing T cell infiltrate, which can be corrected by adding treatment with ipi, as CTLA-4 blockade increases new intratumoral T cell infiltration. 

Methods: This is a Phase 2, prospective open-label study of ipi +/- nivo in patients with advanced melanoma refractory to a PD-1 inhibitor. The primary endpoint of the study is progression free survival. Secondary objectives include the difference in T-cell infiltrate in biopsies of patients with response and no-response to therapy; objective response rate; overall survival; and toxicity. Key eligibility criteria include unresectable melanoma; disease progression while on prior PD-1 agents or after stopping with no intervening therapy; no confirmed partial or complete response to prior anti-PD1 agents; no prior receipt of CTLA-4 inhibitor; Zubrod performance status 0-2; no active brain metastases; no history of autoimmune pneumonitis or colitis requiring steroids or interruption of therapy; and adequate organ function. Prior receipt of BRAF/MEK inhibitors is permitted. Subjects are randomized 1:3 to ipi 3mg/kg q3wk x4 doses or ipi with nivo 1mg/kg q3wk x4 doses followed by nivo 240mg q2wk (21 planned on ipi; 63 on ipi+nivo). Tumor biopsy and blood for correlative studies are taken prior to enrollment and at Day 28-35 on study. Tumor assessments are performed every 12 weeks for 1 year and treatment is continued while clinical benefit persists with a final survival follow-up at 2 years. The combination will be considered superior to single-agent ipi if PFS is doubled from 3 to 6 months with one-sided alpha of 0.1 and power of 0.9. As of January 2018, 5 of 84 planned subjects have enrolled. Clinical trial information: NCT03033576.