3-year relapse-free survival (RFS), overall survival (OS) and long-term toxicity of (neo)adjuvant ipilimumab (IPI) + nivolumab (NIVO) in macroscopic stage III melanoma (OpACIN trial)

abstracts

Annals of Oncology

BMS; Honoraria (self): Illumina; Advisory / Consultancy: GSK; Advisory / Consultancy: Roche/ Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca. M.A. Davies: Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Sanofi Aventis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck; Advisory / Consultancy: Vaccinex. H.A. Tawbi: Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Celegene. All other authors have declared no conflicts of interest.

1313PD

3-year relapse-free survival (RFS), overall survival (OS) and longterm toxicity of (neo)adjuvant ipilimumab (IPI) 1 nivolumab (NIVO) in macroscopic stage III melanoma (OpACIN trial)

C.U. Blank1, J.M. Versluis1, I.L.M. Reijers1, K. Sikorska2, W.J. van Houdt3, J.V. van Thienen1, S. Adriaansz1, H.A. Mallo1, H. van Tinteren2, B.A. van de Wiel4, L.G. Grijpink-Ongering2, A. Bruining5, J.B.A.G. Haanen1, A.C.J. van Akkooi3, T.N. Schumacher6, E.A. Rozeman1 1 Department of Medical Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, Netherlands, 2Department of Biometrics, Netherlands Cancer Institute/Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, Netherlands, 3Department of Surgical Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, Netherlands, 4Department of Pathology, Netherlands Cancer Institute/Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, Netherlands, 5Department of Radiology, Netherlands Cancer Institute/Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, Netherlands, 6Department of Molecular Oncology & Immunology, Netherlands Cancer Institute/Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, Netherlands Background: Outcome of high-risk stage III melanoma patients (pts) was poor with a 5-year OS rate of < 50%. Adjuvant (adj) IPI improved 5-year RFS and OS and adjuvant anti-PD-1 improved RFS further. Preclinical data suggested that neoadjuvant (neoadj) treatment might be more favorable due to broader immune activation. The investigator-initiated OpACIN trial compared neoadj with adj IPI þ NIVO. Neoadj IPI þ NIVO induced a pathologic (path) response in a high percentage of pts (7/9 evaluable pts, 78%). None of the reponders relapsed during the first 2 years, but long-term outcome is pending. Here we present the 3-year landmark safety and survival data. Methods: Between Augustus 2015 and October 2016, 20 stage IIIB/IIIC melanoma pts with palpable nodal disease were included in the phase Ib feasibility OpACIN trial. Pts were randomized to receive IPI 3 mg/kg þ NIVO 1 mg/kg, either adj 4 courses or split 2 courses neoadj and 2 adj. Path response, as reviewed by a blinded pathologist, was defined as < 50% viable tumor cells. Landmark 3-year RFS and OS were estimated using Kaplan Meier method. All efficacy endpoints are descriptive since the study was not powered to compare both arms. Results: After a median FU of 36.7 months (minimum 28.3 months FU of pts alive) none of the 7 pts with a path response in the neoadj arm have relapsed. Both nonresponding pts in the neoadj have relapsed versus 4 pts in the adj arm. One pt has died in the neoadj arm and 3 in the adj arm. The estimated 3-year RFS rate was 80% for the neoadj arm and 60% for the adj arm. The 3-year OS rates were 90% and 67%, respectively. Of the 18 (90%) pts that had developed 1 or more grade 3-4 adverse events all have recovered to  grade 1, except for grade 2 endocrine toxicities needing hormonal supplementation therapy that are ongoing in 8 (50%) of 16 pts alive.

Volume 30 | Supplement 5 | October 2019

Conclusions: OpACIN was the first trial investigating neoadj IPI þ NIVO in pts with macroscopic stage III melanoma, thus having the longest FU. At 3 years FU, no new safety events occurred and none of the pts with a path response have relapsed, suggesting that path response could be considered as surrogate marker for RFS and OS in neoadjuvant checkpoint inhibitor trials. Clinical trial identification: NCT02437279. Legal entity responsible for the study: Netherlands Cancer Institute. Funding: BMS. Disclosure: C.U. Blank: Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab; Advisory / Consultancy: Lilly; Research grant / Funding (institution): NanoString; Advisory / Consultancy: Pierre Fabre. J.V. van Thienen: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis. J.B.A.G. Haanen: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AZ/MedImmune; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Immunocore; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Advisory / Consultancy: Celsius Therapautics; Advisory / Consultancy: Gadet; Advisory / Consultancy: GSK. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: MSD Merck; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy: Scenic Biotech; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck KGaA; Shareholder / Stockholder / Stock options: Neogene Therapeutics; Shareholder / Stockholder / Stock options, Venture partner: Third Rock Venture. E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. All other authors have declared no conflicts of interest.

1314PD

Cell phenotypes associated with response and toxicity defined by high resolution flow cytometry in melanoma patients receiving checkpoint inhibition

J.S. Weber1, S. Hodi2, M. Wind-Rotolo3, D. Woods1, A. Winter1, P. Chattopadhyay1, A. Laino1 1 Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA, 2 Melanoma Center and Center for Immuno-Oncology, Dana Farber Cancer Institute, Boston, MA, USA, 3Medical Oncology, Bristol-Myers Squibb, Princeton, NJ, USA Background: Peripheral blood T cell and myeloid-derived suppressor cells (MDSC), as well as myeloid and macrophage subsets, have been associated with a poor clinical outcome in a variety of cancers. We analyzed circulating cells from patients (pts) that received either nivolumab (NIVO) then ipilimumab (IPI) (cohort A, 16 pts) or IPI then NIVO (cohort B, 17 pts) in a randomized clinical trial to determine if peripheral blood phenotypes were associated either at baseline or on treatment with outcome. Methods: Frozen peripheral blood mononuclear cells (PBMC) from the ChekMate 064 study were assessed at baseline and on treatment at week 13 for circulating cell subsets by 28-color, high-dimensional flow cytometry with CytoBrute, a rapid computational platform that performs high-parameter Boolean analysis. Correlations with response and survival as well as toxicity were evaluated using the machine learning algorithm ElasticNet. Results: In cohort B pts the frequency of resting Ki67-, long-lived memory CD45þ/ CD45ROþ/CD127þ T cells was reduced (p ¼ 0.005), and dividing Ki-67þ CD4þ/ CD45ROþ/CD95þ T cells susceptible to apoptosis were increased after IPI (p ¼ 0.007), but were associated at baseline with a poor outcome with cohort A (p ¼ 0.0002). Subsets of myeloid cells that were CD66bþ/CD33þ/41-BBþ/CD86þ at baseline were associated with survival in cohort B (p ¼ 0.0006). A macrophage subset that was PD-L2þ/CD163þ/41-BBLþ/CD40þ was associated with survival for cohort A (p ¼ 0.0001). Additional phenotypes were associated with grade 1 compared with grades 2-4 toxicity that differentiated side effects from either IPI or NIVO, and other phenotypes distinguished normals and pts (AUC¼0.96). Conclusions: A circulating CD4þ/CD45ROþ/CD95þ proliferating memory T cell phenotype signature is augmented after IPI and is associated at baseline with poor survival with NIVO in CheckMate 064. We discriminated pts and healthy controls with great specificity and sensitivity at baseline, and demonstrated new phenotypes associated with immune-related toxicity. Peripheral blood immune monitoring may be of value in selecting melanoma pts to be treated with immunotherapy. Clinical trial identification: NCT01783938. Legal entity responsible for the study: BMS. Funding: Perlmutter Cancer Center. Disclosure: J.S. Weber: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Hoffmann-La Roche. S. Hodi: Honoraria (self), Advisory / Consultancy: BMS. M. Wind-Rotolo: Full / Part-time employment: BMS. D. Woods: Shareholder / Stockholder / Stock options: BMS. All other authors have declared no conflicts of interest.

doi:10.1093/annonc/mdz255 | v535

Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz255.003/5578142 by guest on 24 October 2019

there are multicentered trials ongoing evaluating this combinatorial approach for pts with untreated MM, there are no approved therapies for pts after TT and IMT failure. Notably, patients with untreated brain metastases (BM) are often excluded from such trials. We hypothesized that N in combination with DT is safe and will demonstrate clinical activity in BRAF-mutated pts refractory to PD1 therapy and in pts with BM. Methods: We report a single arm phase II study (NCT02910700) of NDT in pts with BRAF-mutated, unresectable stage III or stage IV MM. Prior IMT is allowed, but pts who have received BRAF/MEKi are ineligible. Pts with untreated BM and asymptomatic or mildly symptomatic/requiring stable or decreasing steroids (up to PO dexamethasone of 8 mg or equivalent) are also allowed. Pts received 3mg/kg Q2wks of N (later amended to 480 mg q4wks), 150mg BID of D and 2mg QD of T, all starting on Day 1. The primary objective of this study is to determine safety and efficacy (ORR by RECIST 1.1) of the NDT combination. This study is continuously monitored for safety and futility. Tissue and blood-based samples to assess for correlative studies are also collected. Results: Following a 6 pts safety run-in which no DLTs were observed, 24 patients in total have received NDT – 18 of which were PD1 refractory. 6 pts have discontinued due to toxicities. 7 of the 18 PD1 refractory pts had untreated BM. Of the 19 total evaluable pts, 15 achieved PR and 2 CR (ORR 89%). 12 PD1 refractory were evaluable for response; 2 achieved CR and 10 PR (ORR 67%). Conclusions: NDT is well-tolerated and shows promising clinical activity in pts with IMT refractory disease and with BM. Further investigation into the correlatives and mechanisms of action is warranted. Clinical trial identification: NCT02910700. Legal entity responsible for the study: The University of Texas, MD Anderson Cancer Center. Funding: Bristol-Myers Squibb. Disclosure: R.N. Amaria: Research grant / Funding (institution): Merck. J. Wargo: Honoraria (self):