Search

PURPOSEEffective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product.METHODSWe conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1.RESULTSSixty-six patients received a mean of 3.3 prior therapies (anti–programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti–PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2.CONCLUSIONLifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti–PD-1 or PD-L1 therapy subset.

TPS9594 Background: Patients (pts) with advanced (unresectable or metastatic) cutaneous melanoma and persistent disease after checkpoint inhibitor therapy have poor outcomes and limited treatment options, highlighting a significant unmet medical need (Schadendorf D et al. Lancet. 2018;392:971-984). Investigational autologous TIL cell therapies have shown promise in this population, partly attributable to their intrinsic and patient-specific antitumor activity (Borch TH et al. J Immunother Cancer. 2020;8:e000668). Made from each patient’s digested and cryopreserved tumor, ITIL-168 is an autologous TIL cell therapy manufactured to offer an unrestricted T-cell receptor repertoire. A single-center, compassionate use clinical series demonstrated the feasibility and clinical utility of an earlier version of ITIL-168, with a high overall response rate among pts previously treated with PD-1 inhibitor (PD-1i) therapy (58%, n = 12; Pillai M et al. Ann Oncol. 2021;32[suppl 5]:S882). DELTA-1 (NCT05050006) is a global, multicenter phase 2 study to evaluate efficacy and safety of ITIL-168 in pts with cutaneous melanoma relapsed or refractory to a PD-1i, pts intolerant to a PD-1i, and pts whose current best response to a PD-1i is stable disease. Methods: Pts aged ≥18 years with histologically confirmed advanced cutaneous melanoma, ECOG performance status 0-1, and adequate organ function will be enrolled in 1 of 3 cohorts. Cohort 1 (n≈80) will include pts who relapsed after or were refractory to ≥1 prior line of systemic therapy, including a PD-1i and, if BRAF-mutated, a BRAFi ± MEKi. Cohorts 2 and 3 (n≈25 each) will include pts intolerant to PD-1i and those with stable disease after ≥4 doses of PD-1i, respectively. After tumor resection for TIL harvest, pts must have ≥1 remaining measurable lesion per RECIST 1.1. Pts with uveal, acral, or mucosal melanoma, prior allogeneic transplant or cell therapy, and with central nervous system (CNS) disorder or symptomatic and/or untreated CNS metastases are ineligible. Pts will receive 5 days of lymphodepleting chemotherapy (cyclophosphamide ×2 days overlapping with fludarabine ×5 days) followed by a single ITIL-168 infusion (≥5×109 cells) and supportive short-course, high-dose IL-2. The primary endpoint is objective response rate (ORR) per central review. Secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, TIL persistence, and safety. Hypothesis testing of ORR will be performed for cohort 1. The primary analysis will occur when all pts in the cohort 1 modified intent-to-treat population have been followed for ≥6 months after the first posttreatment disease assessment. DELTA-1 opened for enrollment in September 2021. Updated site information will be given at the time of presentation. Clinical trial information: NCT05050006.

9524 Background: Cutaneous melanoma is characterized by high TMB, which is associated with increased tumor-specific neoantigen expression (Schumacher Science 2015) and an increased response rate to ICI (Yarchoan NEJM 2019). The TMB in tumors that recur/progress after ICI is not well defined. Lifileucel is a one-time, autologous TIL cell therapy under investigation for treatment of patients (pts) with advanced melanoma. We conducted a matched case-control study of prospectively enrolled pts with advanced melanoma treated with lifileucel in the ICI-naïve (IOV-COM-202 trial, Cohort 1A [C1A]) and post-ICI (C-144-01 trial, Cohort 2 [C2]) setting to investigate the potential association between prior ICI therapy, TMB, and response to lifileucel. Methods: All pts had unresectable or metastatic melanoma. Available cases from C1A (ICI-naïve pts receiving lifileucel + pembrolizumab [pembro]) were matched to controls from C2 (pts receiving lifileucel alone after progression on anti–PD-1/PD-L1 therapy); 3 controls per case were matched at least for BRAF status and disease stage at study entry, and if possible, for anatomic site of tumor harvest. Lifileucel regimen was similar in C1A and C2. In C1A, 1 dose of pembro was given after tumor harvest and before nonmyeloablative lymphodepletion and resumed after lifileucel per standard treatment, for up to 2 y. Objective response rate (ORR) was assessed by investigators per RECIST v1.1. TMB of the resected tumor was measured using the ImmunoID NeXT (C1A) or PGDx elio (C2) platform; a validated conversion factor was used to compare TMB between platforms (Vega Ann Oncol 2021). High TMB was defined as ≥10 mut/MB. Results: Seven pts in C1A and 21 in C2 were included in the case-control study and had ORR of 71.4% and 38.1%, respectively. The percentage of pts with high TMB was 57.1% in C1A and 19.0% in C2 ( P = 0.1). ORR in the low and high TMB groups was 66.7% and 75.0%, respectively, in C1A and 41.1% and 25.0% in C2; 60% of responders in C1A and 12.5% in C2 had high TMB. In logistic regression analysis adjusted for cohort, TMB was not associated with response to lifileucel (odds ratio, 1.0; 95% CI, 0.9–1.1; P = 0.8). Data on tumor mutations and neoantigens, T-cell receptor repertoire, and tumor microenvironment profile will be presented. Conclusions: Our preliminary data indicate that the efficacy (ORR) of lifileucel may be independent of TMB, regardless of treatment setting, consistent with its proposed immune checkpoint pathway-independent mechanism of action. The percentage of patients with high TMB tended to be lower in tumors with prior ICI exposure than in those that were ICI-naïve. Clinical trial information: NCT03645928; NCT02360579.

BackgroundImmune checkpoint inhibitors (ICI) are standard-of-care in the treatment of several types of cancer; however, an unmet medical need exists for early-line combination therapies that are able to provide higher response rates, more durable responses, and manageable long-term safety. Lifileucel (LN-144) and LN-145, adoptive cell therapies using tumor-infiltrating lymphocytes (TIL), have demonstrated encouraging efficacy with acceptable safety in patients with advanced cancer that has failed ICI.1–2 To improve efficacy and safety of early-line treatment options, we explored a combination of TIL and pembrolizumab in patients with ICI-naïve melanoma, head and neck squamous cell carcinoma (HNSCC), and cervical cancer.MethodsIOV-COM-202 (NCT03645928) and C-145-04 (NCT03108495) are ongoing Phase 2 multicenter, multicohort, prospective, open-label studies evaluating TIL cell therapy in ICI-naïve patients with solid tumors. We report efficacy and safety from IOV-COM-202 (Cohort 1A: lifileucel and pembrolizumab in patients with unresectable or metastatic melanoma; Cohort 2A: LN-145 and pembrolizumab in patients with advanced, recurrent, or metastatic HNSCC) and C-145-04 (Cohort 3: LN-145 and pembrolizumab in patients with stage 4b, persistent or recurrent cervical cancer who have not received prior systemic therapy). Eligibility across cohorts included ECOG PS ≤1, ≥1 resectable lesion (diameter ≥1.5 cm post-resection) for TIL manufacturing, and ≥1 measurable lesion for response assessment (by investigator per RECIST v1.1). Lifileucel and LN-145 are cryopreserved TIL infusion products generated at central GMP facilities in a 22-day process. Treatment included tumor resection for TIL manufacturing, followed by 1 dose of pembrolizumab, nonmyeloablative lymphodepletion (cyclophosphamide and fludarabine), TIL infusion, ≤6 interleukin-2 doses (600,000 IU/kg IV), and continued pembrolizumab for ≤24 months.ResultsAs of 09July2021, 32 patients received TIL and pembrolizumab (full-analysis set [FAS]; table 1). Across all cohorts, the objective response rate (ORR) in the FAS was 56.3% (Cohort 1A [melanoma], 87.5%; Cohort 2A [HNSCC], 42.9%; Cohort 3 [cervical], 50.0%; figure 1). Among confirmed responders (n=17), 10 responses (58.8%) were ongoing at data cutoff, with a median study follow-up of 9.7 months. The treatment-emergent adverse-event (TEAE) profile was consistent with the underlying diseases and known profiles of pembrolizumab, nonmyeloablative lymphodepletion, and interleukin-2. The most common (≥30%) Grade ≥3 TEAEs were thrombocytopenia (53.1%), anemia (50.0%), neutropenia (46.9%), and febrile neutropenia (43.8%).ConclusionsThe observed efficacy, including ORR and CR rate, and acceptable safety profile are encouraging and warrant continued investigation of the combination of TIL and pembrolizumab in early-line treatment of patients with advanced cancer. Enrollment is ongoing; updated data will be presented.AcknowledgementsThis study and analysis were funded by Iovance Biotherapeutics, Inc. (San Carlos, CA, USA). Writing support was provided by Amanda Kelly (Iovance); graphics support was provided by Cognition Studio (Seattle, WA, USA).Trial RegistrationNCT03645928 and NCT03108495ReferencesSarnaik AA, et al. J Clin Oncol 2021; doi: 10.1200/JCO.21.00612.Jazaeri AA, et al. J Clin Oncol 2019;37 (suppl; abstract 182).Jimeno A, et al. J Immunother Cancer 2020;8 (suppl; abstract 353).Ethics ApprovalThe IOV-COM-202 study was approved by Advarra Institutional Review Board, approval number Pro00035064; the C-145-04 was approved by WIRB Copernicus Group, approval number 7-1425772-1. All study participants provided written consent via signature of the IRB-approved informed consent form.Abstract 492 Table 1Baseline demographic and clinical characteristics and efficacyAbstract 492 Figure 1Best percentage change from baseline in target lesion sum of diameters for efficacy-evaluable set*

Purpose: KEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) investigated the efficacy and safety of pembrolizumab across multiple cancers. We present results from patients with previously treated advanced well-differentiated neuroendocrine tumors (NET). Patients and Methods: Pembrolizumab 200 mg was administered every 3 weeks for 2 years or until progression, intolerable toxicity, or physician/patient decision. Tumor imaging was performed every 9 weeks for the first year and then every 12 weeks. Endpoints included objective response rate (ORR) per RECIST v1.1 by independent central radiologic review (primary) and duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (secondary). Results: A total of 107 patients with NETs of the lung, appendix, small intestine, colon, rectum, or pancreas were treated. Median age was 59.0 years (range, 29–80), 44.9% had ECOG performance status 1, 40.2% had received ≥3 prior therapies for advanced disease, and 15.9% had PD-L1–positive tumors (combined positive score ≥1). Median follow-up was 24.2 months (range, 0.6–33.4). ORR was 3.7% (95% CI, 1.0–9.3), with zero complete responses and four partial responses (three pancreatic and one rectal) all in patients with PD-L1–negative tumors. Median DOR was not reached, with one of four responses ongoing after ≥21 months follow-up. Median PFS was 4.1 months (95% CI, 3.5–5.4); the 6-month PFS rate was 39.3%. Median OS was 24.2 months (95% CI, 15.8–32.5). Treatment-related adverse events (AE) occurred in 75.7% of patients, 21.5% of whom had grade 3–5 AEs. Conclusions: Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in patients with previously treated advanced well-differentiated NETs.

Background Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented. Methods C-144-01 is a global Phase 2 open-label, multicenter study of the safety and efficacy of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 66) patients with Stage IIIC/IV unresectable melanoma who received lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. All responses were assessed by RECIST 1.1. Results 66 patients had the following baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), relatively high tumor burden (106 mm mean target lesion sum of diameters), 44% with liver and/or brain lesions, median LDH 244 U/L. Objective Response Rate (ORR) by investigator was 36.4% (2 CR, 22 PR, 1 previously confirmed PR is now changed to SD) and Disease Control Rate (DCR) of 80.3%. At a median follow up of 9.7 months, median Duration of Response (DOR) has not been reached. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. The ORR per IRC was 34.8% (2 CR, 21 PR) and DCR was 72.7%. At a median follow up of 6.9 months, the median IRC DOR has not been reached. Overall concordance rate of investigator and IRC read of response was 89.4%. The concordance compares favorably with literature reports in a metastatic disease.1 Conclusions Lifileucel treatment resulted in a 36.4% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who had received prior anti-PD1 and BRAF/MEK inhibitors, if tumor BRAF mutated. The high concordance of 89.4% between investigator and IRC confirms the original assessment of lifileucel efficacy in metastatic melanoma.2 Acknowledgements The authors would like to thank the patients and their families for participation in the study. The authors would also like to acknowledge the support and dedication of all investigators and site team members from all participating clinical trial institutions. Trial Registration ClinicalTrials. gov Identifier: NCT02360579 Ethics Approval Ethics Approval This trial was approved by Western Institutional Review Board - IRB Tracking Number: 20160198. References Ghiorghiu DC, et al. Comparison of central and site review of RECIST data in an open randomised phase II trial in advanced melanoma. 10.1594.ecr 2009/C-075. Sarnaik A, et al. Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1. J Clin Oncol 2019;37:2518–2518.

BackgroundPatients with advanced cutaneous melanoma and persistent disease after checkpoint inhibitor therapy have poor outcomes and limited treatment options, highlighting a significant unmet medical need.1 Autologous TIL cell therapies have shown promise in this population attributable, in part, to their intrinsic and patient-specific antitumor activity2; however, no such therapies are approved. Made from each patient‘s digested and cryopreserved tumor, ITIL-168 is an autologous TIL cell therapy manufactured to offer an unrestricted T-cell receptor repertoire. A single-center compassionate use clinical series demonstrated the feasibility and clinical utility of an earlier version of ITIL-168.3 DELTA-1 is a global, multicenter phase 2 study to evaluate efficacy and safety of ITIL-168. DELTA-1 will enroll patients with melanoma relapsed after or refractory to PD-1 inhibitors (PD-1i), patients intolerant to PD-1i, and patients whose best response to PD-1i was stable disease.MethodsPatients aged ≥18 years with histologically confirmed advanced cutaneous melanoma, ECOG performance status 0–1, and adequate organ function will be enrolled in 1 of 3 cohorts. Cohort 1 (n≈80) will include patients who relapsed after or were refractory to ≥1 prior line of systemic therapy, including a PD-1i and, if BRAF-mutated, a BRAFi ± MEKi. Cohorts 2 and 3 (n≈25 each) will include patients intolerant to PD-1i and those with stable disease after ≥4 doses of PD-1i, respectively. After tumor resection for TIL harvest, patients must have ≥1 remaining measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients with uveal, acral, or mucosal melanoma, prior allogeneic transplant or cell therapy, and with central nervous system (CNS) disorder or symptomatic and/or untreated CNS metastases are ineligible. Patients will receive 5 days of lymphodepleting chemotherapy (cyclophosphamide ×2 days overlapping with fludarabine ×5 days) followed by a single ITIL-168 infusion (≥5×109 cells) and supportive short course high-dose IL-2. The primary endpoint is objective response rate (ORR) per central review. Key secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, TIL persistence, and safety. Hypothesis testing of ORR will be performed for cohort 1. Two interim analyses will occur after 20 patients in cohort 1 have been followed for ≥28 days (safety) and evaluated for response ≥3 months after ITIL-168 infusion (futility). The primary analysis will occur when all patients in the cohort 1 modified intent-to-treat population have been followed for ≥6 months after the first posttreatment disease assessment.AcknowledgementsMedical writing support was provided by Christopher Waldapfel, PharmD, of Instil Bio, Inc, and Phylicia Aaron, PhD, of Nexus GG Science, with funding from Instil Bio, Inc.ReferencesSchadendorf D, van Akkoi ACJ, Berking C, et al. Melanoma. Lancet 2018;392(10151):971–984.Borch TH, Anderson R, Ellebaek E, et al. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. J Immunother Cancer 2020;8(2):e000668.Hawkins RE, Jiang Y, Lorigan PC, et al. Clinical feasibility and treatment outcomes with unselected autologous tumor infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma. Cancer Res 2021;81(13):LB150.Ethics ApprovalAll patients will provide written informed consent. The study will be approved by the Institutional Review Board/Independent Ethics Committee at each site and conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation.ConsentN/A; the abstract does not contain sensitive or identifiable patient information.

Background Beneficial treatment options are limited for advanced melanoma patients who progress after or do not respond to immune checkpoint inhibitors (ICI) and targeted therapies. Lifileucel is an adoptive cell therapy using tumor-infiltrating lymphocytes (TIL), that has shown efficacy in patients with advanced melanoma who have progressed on/after anti-PD-1therapy (Sarnaik et al., ASCO 2020). We present the 28-month (mos) follow-up data here. Methods C-144-01 (NCT02360579) is a global Phase 2 open-label, multicenter study of efficacy and safety of lifileucel in patients with unresectable metastatic melanoma who have progressed on anti-PD-1 therapy and BRAF/MEK inhibitors, if BRAF V600 mutant. We report on Cohort 2 (N = 66) patients who have received lifileucel. Tumors were resected at local institutions, processed in central GMP facilities for TIL production, manufactured, cryopreserved and shipped back to sites in a 22-day process. Therapy consisted of one week of nonmyeloablative lymphodepletion using cyclophosphamide (60 mg/kg on Day -7, -6) and fludarabine (25 mg/m2 on Day -5 through -1), a single infusion of lifileucel, and up to six doses of IL-2 doses (600,000 IU/kg/dose). Objective response rate (ORR) was based on RECIST v1.1 as assessed by investigators. Data cutoff was December 14, 2020. Results Baseline characteristics: 3.3 mean prior therapies (100% anti-PD-1; 80% anti-CTLA-4; 23% BRAF/MEK inhibitor), high baseline tumor burden (106 mm mean target lesion sum of diameters), 42% liver/brain lesions, 40.9% had LDH > ULN. Median time from last therapy to tumor harvest was 2.2 mos and 58% of the tumors resected were extra-nodal or non-skin/subcutaneous. ORR by Investigator was 36.4% (3 CR, 21 PR). One patient converted from a PR to CR at 24 mo after lifileucel therapy. Median time to first response was 1.4 mos (range: 1.3-5.6 mos). Median duration of response (mDOR) was still not reached at median follow-up of 28 mos (DOR range: 2.2-35.2 mos). No new safety risks have been identified for lifileucel during the long-term follow-up. Exploratory analyses of product-specific characteristics, including levels of phenotypic markers of T-cell lineage, memory subset, youth, activation/exhaustion, or trafficking did not demonstrate association with response. Conclusions Lifileucel treatment results in a 36.4% ORR and mDOR was not reached at 28 mo of median study follow up in heavily pretreated advanced melanoma patients with high baseline disease burden who progressed on multiple prior therapies, including anti-PD1 and BRAF/MEK inhibitors, if BRAF V600 mutant. Citation Format: Jason Alan Chesney, James M. Larkin, John M. Kirkwood, Jeffrey S. Weber, Nikhil I. Khushalani, Karl Lewis, Theresa M. Medina, Harriet M. Kluger, Sajeve S. Thomas, Evidio Domingo-Musibay, Judit Oláh, Eric D. Whitman, Salvador Martin-Algarra, Philippa G. Corrie, Jose Lutzky, Omid Hamid, Wen Shi, Xiao Wu, Madan Jagasia, Friedrich Graf Finckenstein, Maria Fardis, Amod A. Sarnaik. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT008.

9537 Background: Tumor infiltrating lymphocyte (TIL) cell therapy has demonstrated safety and efficacy in advanced melanoma, both in the pre-immune checkpoint inhibitor (ICI) setting (Goff, JCO 2016) and in patients who have failed anti-PD-1/PD-L1 therapy (Sarnaik, 2020). Combination of TIL and pembrolizumab (pembro) in ICI-naïve patients has demonstrated encouraging efficacy data with acceptable safety in head and neck squamous cell carcinoma (Jimeno, 2020). To improve treatment options in early lines, we explore a combination of LN-144 and pembro in patients with ICI-naïve advanced melanoma. Methods: IOV-COM-202 is a Phase 2 multicenter, multi-cohort, open-label study evaluating TIL cell therapy in multiple settings and indications. We report on Cohort 1A enrolling ICI-naïve advanced melanoma (unresectable or metastatic) patients for treatment with a combination of LN-144 and pembro. Key eligibility criteria include ≤ 3 lines of prior therapy, ECOG < 2, one resectable lesion for lifileucel manufacturing, and ≥ 1 measurable lesion for response assessment. Primary endpoints are objective response rate (ORR) per RECIST 1.1 and safety as measured by incidence of Grade ≥3 treatment-emergent adverse events (TEAE). LN-144 is generated at centralized GMP facilities in a 22-day process. A nonmyeloablative lymphodepletion (NMA-LD) using cyclophosphamide and fludarabine is administered preceding a single LN-144 infusion, followed by < 6 doses of IL-2 (600,000 IU/kg). Pembro is administered after tumor harvest but prior to NMA-LD and continues after lifileucel per label. Results: Seven patients have received lifileucel in combination with pembro as of data extraction date (Feb 14, 2021). Five of the 7 treated patients were treatment-naïve, 1 patient had prior BRAFi + MEKi and 1 had received prior chemotherapy; 71% had liver/brain lesions, 43% had LDH > ULN. Mean SOD for the target lesions was 111 mm, with 86% of patients with > 3 target lesions, representing advanced disease at baseline for this patient group. The TEAE profile was consistent with the underlying disease and known AE profiles of pembro, NMA-LD and IL-2. Six patients had a confirmed objective response with an ORR of 86% (1 CR, 5 PR) and 1 best response of SD. Three of the responding patients have remained off pembro due to pembro related AEs for 3, 4 and 13 months (mos), yet maintaining response. All responding patients remain in response with the longest duration of response being 16.8 mos. Conclusions: Lifileucel can be safely combined with pembro in patients with ICI-naïve advanced melanoma. The ORR of 86% is encouraging when compared to pembro alone in a similar patient population, especially considering the disease burden at baseline and persistence of responses in patients off therapy. Enrollment is ongoing and updated data to be presented. Clinical trial information: NCT03645928.

9505 Background: Immune checkpoint inhibitors (ICI) have become standard of care for treatment of metastatic melanoma. Most patients with advanced melanoma progress on ICI and treatment options are limited for these patients. Progression may be through primary resistance (lack of response) or secondary resistance (initial response then progression). Lifileucel is an adoptive cell therapy using TIL, that has shown efficacy in patients with advanced melanoma who progress on/after an anti-PD-1 (Sarnaik, 2020). We present the 28-month (mos) follow-up data and highlight the impact of prior anti-PD-1 response and duration of exposure on outcome with lifileucel. Methods: C-144-01 is a Phase 2, open-label, multicenter study of efficacy and safety of lifileucel in patients with advanced melanoma who have progressed on anti-PD-1 therapy and BRAFi ± MEKi, if BRAF V600+. We report long-term follow up on Cohort 2 (N = 66). Tumors were resected at local sites, processed in central GMP facilities for TIL production in a 22-day manufacturing process. Therapy consisted of nonmyeloablative lymphodepletion using 2 days of cyclophosphamide and 5 days of fludarabine, a single infusion of lifileucel, and up to six doses of IL-2. Objective response rate (ORR) was assessed by RECIST 1.1. Data cutoff was Dec. 14, 2020. Results: Baseline characteristics: 3.3 mean prior therapies (100% anti-PD-1; 80% anti-CTLA-4; 23% BRAFi/MEKi), high baseline tumor burden (106 mm mean target lesion SOD), 42% liver/brain lesions, 40.9% LDH > ULN. ORR by investigator was 36.4% (3 CR, one new CR developed at 24 mos; 21 PR). Median duration of response (mDOR) was not reached at median follow-up of 28 mos (DOR range: 2.2- 35.2 mos). In responders, the median cumulative duration and median prior lines of anti-PD-1 therapy was 4.4 mos (range: 1.4-22.5 mos), and 1.5 (range: 1-4). Data in Table demonstrates a meaningful increase in DOR to TIL with primary anti-PD-1 resistance and lower duration of time on prior anti-PD-1 therapy. No new safety risks have been identified for lifileucel during long-term follow-up. Conclusions: One-time lifileucel treatment results in a 36.4% ORR, and mDOR was not reached at 28 mos of median study follow up. One PR converted to a new CR at 24 months as responses continue to deepen. DOR is positively associated with primary resistance to prior anti-PD-1 therapy and with shorter cumulative prior duration of anti-PD-1 therapy. Lifileucel may offer a better clinical outcome when used earlier upon detection of progression on prior anti-PD-1 rather than retreatment with anti-PD-1 based regimens. Clinical trial information: NCT02360579. [Table: see text]

Background: Triple-negative breast cancer (TNBC) comprises about 15% of all breast cancer types, and has a particularly aggressive course. Following first-line therapy, the median PFS is 90% of TNBC, as measured by IHC, we conducted a trial to evaluate the safety and efficacy of a humanized anti-Trop-2 monoclonal antibody conjugated to a high concentration of SN-38, a camptothecin that is a topoisomerase I inhibitor and the active metabolite of the prodrug irinotecan, with 2-3 logs higher potency than the prodrug. Methods: After establishing the optimal repeated dose in a Phase I trial (ClinicalTrials.gov, NCT01631552) involving many different solid cancer types, an expanded Phase II was undertaken in a number of cancers, including TNBC. Patients received 8 or 10 mg/kg IMMU-132 i.v. on days 1 and 8 of 21-day repeated cycles. Assessments of safety and response by RECIST1.1 were made weekly and bimonthly, respectively. Tumor biopsies (archival, at baseline prior to treatment, and at disease progression) were obtained when safe and feasible. Results: As of May 10, 2015, 58 patients with TNBC, with a median of 4 prior therapies (range, 1-11), were treated with IMMU-132. Grade 3-4 toxicities included neutropenia (26%), febrile neutropenia (2%), diarrhea (2%), anemia (4%), and fatigue (4%). No patient developed antibodies to SN-38 or the antibody, and no patient discontinued therapy due to toxicity. Tumor responses were defined as ORR (CR+PR) in 31% of 49 evaluated patients, including 2 with CR, and a clinical benefit ratio (CR+PR+SD>6 mo) of 49% (63% with SD>4 mo; 23 patients continuing treatment after 1st assessment). The current median progression-free survival is 7.3 months with 44% maturity in 50 patients treated at the 8 or 10 mg/kg dose level. Overall survival data are still not mature 20 months after enrollment of first patient. Clinical efficacy correlated to biomarker studies, including Trop-2 expression (target of antibody), topoisomerase-1 expression (target of SN-38), and homologous recombinant deficiency (HRD) assay (marker of DNA repair), is being studied. Immunohistochemistry results in archival specimens currently show 97% positivity of Trop-2 among 34 specimens evaluated, with 79% having high intensity (2+/3+) staining. Conclusions: The Trop-2-targeting IMMU-132, delivering cytotoxic doses of the topoisomerase I inhibitor, SN-38, shows manageable toxicity, and encouraging anti-tumor activity in relapsed/refractory patients with TNBC. This ADC appears to have a high therapeutic index in heavily pretreated patients. Citation Format: Bardia A, Diamond JR, Mayer IA, Starodub AN, Moroose RL, Isakoff SJ, Ocean AJ, Guarino MJ, Berlin JD, Messersmith WA, Thomas SS, O'Shaughnessy JA, Kalinsky K, Maurer M, Chang JC, Forero A, Traina T, Gucalp A, Wilhelm F, Wegener WA, Maliakal P, Sharkey RM, Goldenberg DM, Vahdat LT. Safety and efficacy of anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in heavily pretreated patients with TNBC. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-06.

10006 Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) leverages and enhances the body’s natural defense against cancer and has shown durable responses in heavily pretreated melanoma patients. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of efficacy & safety of lifileucel in patients with unresectable metastatic melanoma who have progressed on checkpoint inhibitors and BRAF/MEK inhibitors, if BRAFv600 mutant. We report on Cohort 2 (N = 66) patients who have received TIL. Tumors were resected at local institutions, processed in central GMP facilities for TIL production, manufactured, cryopreserved & shipped back to sites in a 22-day process. Therapy consisted of one week of lymphodepletion, a single lifileucel infusion, and up to 6 IL-2 doses. ORR was based on RECIST v1.1 by investigator assessment. Data cutoff was Feb 2, 2020. Results: Baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), high baseline tumor burden (106 mm mean target lesion sum of diameters), 44% liver/brain lesions, 40.9% LDH > ULN. ORR by investigator was 36.4% (2 CR, 22 PR) and DCR was 80.3%. Mean time to response was 1.9 months (range: 1.3-5.6). After a median study follow-up of 17.0 months, median DOR (mDOR) was still not reached. Six responders have progressed, 2 have died and 2 started other anti-cancer therapy without progression. The adverse event profile was consistent with the underlying advanced disease and the lymphodepletion and IL-2 regimens. Additional follow-up data will be available for presentation. Conclusions: Lifileucel treatment results in a 36.4% ORR and mDOR was not reached at 17.0 months of median study follow up in a heavily pretreated metastatic melanoma patients with high baseline disease burden who progressed on multiple prior therapies, including anti-PD1 and BRAF/MEK inhibitors, if BRAFv600 mutant. Clinical trial information: NCT02360579.

Purpose: Sacituzumab govitecan (IMMU-132) is an antibody–drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers. Experimental Design: Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed. Results: Twenty-five patients (52–60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (n = 7), 10 (n = 6), 12 (n = 9), and 18 (n = 3) mg/kg. Neutropenia was dose limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done. Conclusions: Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for phase II studies. Clin Cancer Res; 21(17); 3870–8. ©2015 AACR.

2538 Background: There is a high unmet medical need for effective treatments for patients with recurrent, metastatic, or persistent cervical cancer. Most patients are young and survival rates are poor. ORR for second line therapies is between 4 and 14% for chemotherapy and recently approved immunotherapy. Adoptive cell transfer using tumor infiltrating lymphocytes (TIL) have demonstrated durable responses in some patients with recurrent cervical cancer thus offering the potential for long-term disease control. Methods: Study C-145-04 is an ongoing, open-label, multicenter Phase 2 clinical trial evaluating the safety and efficacy of LN-145 TIL therapy in patients with advanced cervical cancer who have undergone at least one prior line of chemotherapy. Prior checkpoint inhibitor therapy is an exclusion criterion. The primary endpoint is ORR per RECIST 1.1; secondary endpoints include duration of response (DOR), disease control rate (DCR), and LN-145 safety. Tumors surgically harvested at local institutions are shipped to central GMP facilities for TIL generation in a 22-day manufacturing process. Final LN-145 TIL product is cryopreserved and shipped to sites. Patients receive one week of preconditioning lymphodepletion (cyclophosphamide, fludarabine), a single LN-145 infusion, followed by up to 6 doses of IL-2 (600,000 IU/kg). Results: As of 4 Feb 2019, 27 efficacy-c patients have received Gen 2 of LN-145, with a mean age of 47 years and 2.6 mean prior lines of therapy. Preliminary efficacy results: ORR was 44% (1 CR, 9 PR, 2 uPR), DCR was 89% at 3.5-month median study follow-up with 11/12 patients maintaining their response. Improved responses were observed in 4 patients with longer follow-up. Mean TIL cells infused was 28x109. Median IL-2 doses administered was 6.0. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. Conclusions: LN-145 results in 44% ORR in previously treated cervical cancer patients with acceptable safety and efficacy profile. LN-145 offers patients a viable therapeutic option warranting further investigation. Clinical trial information: NCT03108495.

TPS2648 Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has demonstrated durable complete responses in immunogenic tumors with high mutational burden in metastatic melanoma patients who had not received prior immune checkpoint inhibitors (ICI); CR rate 24%. Pembrolizumab is an approved agent for the treatment of metastatic melanoma and head & neck cancers, among others. Further, ICI have been reported to potentially enhance the efficacy of TIL therapy. One aim of this study is to improve the efficacy response for early line patients by combining TIL with anti-PD-1 in ICI-naïve patients with metastatic melanoma (Cohort 1) and head & neck cancers (Cohorts 2). In Cohort 3, TIL therapy alone is offered to NSCLC patients who have received prior systemic therapy, including ICI. Methods: IOV-COM-202 is a prospective, Phase 2 multicenter, open-label study in which 36 patients (12 per cohort) are to be enrolled in one of three cohorts; Cohorts 1 and 2: TIL therapy in combination with pembrolizumab, or Cohort 3: TIL therapy alone. Patients will have tumors resected at local centers and shipped to a central GMP facility to undergo a 22-day manufacturing process that yields cryopreserved infusion product (LN-144/LN-145) that is shipped back to treating center. All patients receive TIL therapy consisting of 1 week of preconditioning cyclophosphamide/fludarabine, followed by a single infusion of LN-144/LN-145 (Day 0) and up to 6 doses of IL-2 (600,000 IU/kg). Patients in Cohorts 1 and 2 also receive pembrolizumab on Day -1 and then Q3W for up to 2 years or until disease progression or acceptable toxicity. Co-primary endpoints for each cohort are objective response rate (ORR) per RECIST 1.1, and safety (grade ≥ 3 TEAE). Eligibility criteria: Cohorts 1 (melanoma) and 2 (head & neck): patients must not have received prior ICI (eg, anti-PD-1, anti-CTLA-4) and may have received up to 3 lines of prior systemic therapy, Cohort 3 (NSCLC): patients must have received 1-3 prior lines of systemic therapy including ICI. After tumor resection for TIL manufacturing, patients must have additional measurable disease for assessment per RECIST 1.1. Adequate bone marrow/organ function and ECOG PS of 0 or 1 is required. Clinical trial information: NCT03645928.

2518 Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable long-term responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel (LN-144), a centrally manufactured autologous TIL therapy are presented. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of the efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 55) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. Results: In 55 patients with Stage IIIC/IV unresectable melanoma, 3.1 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 24%), high baseline tumor burden (110 mm mean target lesion sum of diameters), ORR was 38% (2 CR, 18 PR, 1 uPR). Of 21 responders, 4 have progressed to date with median follow up of 7.4 months. Overall disease control was 76%. Improved responses in some patients were observed with longer follow up. Most (54) patients progressed on prior anti-PD1 and those with PD-L1 negative status (TPS < 5%) were among responders. Mean cells infused was 28 x109. Median IL-2 doses administered was 6.0. Adverse events resolved to baseline, 2 weeks post TIL infusion, a potentially important benefit of one-time TIL therapy. Conclusions: Lifileucel treatment results in 38% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who received prior anti-PD1 and BRAF/MEK inhibitor if BRAF mutated. Based on these data, a new Cohort 4 in C-144-01 has been initiated to support lifileucel registration. Clinical trial information: NCT02360579.

136 Background: While immunotherapies including checkpoint inhibitors and targeted therapies (BRAF/MEK inhibitors) are options for patients with metastatic melanoma, many patients still develop progressive disease. These patients have few treatment options available including high dose IL-2 and chemotherapy with reported second line response rates of 4-10%. Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) is recognized as an effective treatment in metastatic melanoma, able to elicit durable and complete responses in even heavily pretreated patients. We provide preliminary data for lifileucel TIL (LN-144) in heavily pre-treated metastatic melanoma patients who progressed on multiple checkpoint and BRAF/MEK inhibitors. Methods: C-144-01 is an ongoing global Phase 2, open-label, multicenter study of efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 47) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed at central GMP facilities in a 22-day manufacturing process. The final product was cryopreserved and shipped to sites. Patients received a one week cyclophosphamide/fludarabine preconditioning lymphodepletion regimen, a single lifileucel infusion, followed by up to 6 doses of iv IL-2 (600,000 IU/kg). Results: Patients with Stage IIIC/IV melanoma had 3.3 mean prior therapies (range: 1-9) and high baseline tumor burden, reflected by a mean sum of diameters of target lesions of 112 mm. Preliminary efficacy results: ORR = 38% (1 CR, 13 PR, 4 uPR), DCR = 77%, and median DOR 6.4 mo (range: 1.3 to 13.7) with median follow-up 6.0 mo. Longer follow-up led to improved responses in some patients including the CR. Frequency of AEs decreased over time, a potentially important benefit of one-time TIL treatment. Conclusions: Preliminary data support lifileucel TIL as an efficacious and well-tolerated therapeutic option for patients with metastatic melanoma who have failed multiple lines of prior therapies including checkpoint inhibitors and BRAF/MEK inhibitors. Clinical trial information: NCT02360579.

190 Background: Data from the KEYNOTE-028 study (NCT02054806) suggested that pembrolizumab (pembro) has clinical activity in a subset of patients (pts) with heavily pretreated neuroendocrine tumors (NET). The KEYNOTE-158 study (NCT02628067) is a phase II basket study investigating the antitumor activity of pembro in 10 specific cancer types. An analysis of the 107 pts included in the NET cohort is presented. Methods: Key eligibility criteria for this cohort included well- and moderately-differentiated NET of the lung, appendix, small intestine, colon, rectum, or pancreas; progression on or intolerance to ≥ 1 line of standard therapy; ECOG PS 0 or 1; and provision of a tumor sample for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 wks for the first 12 mo, and every 12 wks thereafter. PD-L1 positivity, defined as a combined positive score (CPS) ≥ 1, was evaluated retrospectively by IHC. Primary endpoint was ORR assessed per RECIST v1.1 by independent central radiology review. Secondary endpoints included DOR, PFS, OS, and safety. Results: 107 pts were treated. Median age was 59 (range, 29-80) y, 44.9% had ECOG PS 1, and 67.3% received ≥ 2 prior therapies for advanced disease. 15.9% of enrolled pts had PD-L1+ tumors. As of the January 15, 2018 data cutoff, the median follow-up duration was 18.6 (range, 0.2-22.7) mo. ORR was 3.7% (95% CI, 1.0-9.3), with 0 CR and 4 PR (3 pancreatic and 1 gastrointestinal [unknown primary]). 61 pts had SD as best response. The 4 responses were observed in pts with PD-L1 negative tumors. Median DOR had not been reached (range, 4.1-15.9+), with 3 of 4 responses ongoing after ≥ 9 mo follow-up. Median (95% CI) PFS was 4.1 (3.5-5.4) mo, and the 6-mo PFS rate was 38.2%. Median OS (95% CI) had not been reached (18.8-not reached), and the 6-mo OS rate was 84.6%. Treatment-related AEs occurred in 75.7% of pts, and the most common was fatigue (21.5%). 20.6% of pts had treatment-related grade 3-4 AEs. Conclusions: Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in pts with previously treated advanced NET. Clinical trial information: NCT02628067.

Dapsone (4,4′-diaminodiphenylsulfone; DDS) is a sulfone antimicrobial used to treat leprosy, malaria, and inflammatory dermatoses and to prevent and treat opportunistic infections in immunocompromised patients, particularly those who cannot tolerate sulfonamide antimicrobials.1 However, dapsone can lead to dose-dependent hematologic toxicity and is the most commonly recognized cause of acquired methemoglobinemia in human patients.2 The hydroxylamine metabolite of dapsone oxidizes the iron moiety of hemoglobin,3 which leads to increased levels of methemoglobin, impaired oxygen delivery, and cyanosis. Dapsone hydroxylamine is generated by CYP2C9 and CYP2C19, with minor contributions from other P450s.4,5 A rapid activity variant for CYP2C19 (CYP2C19*17) has been reported6 but not for CYP2C9. Dapsone hydroxylamine is detoxified by cytochrome b5 (b5) and its electron donor, cytochrome b5 reductase (b5R),7 which are expressed in blood, liver, and other tissues. This reduction pathway converts the hydroxylamine back to the parent dapsone. Dapsone itself is inactivated and eliminated following N-acetylation by the enzyme NAT2 in the liver,8 and impaired N-acetylation activity is a risk factor for hematologic and neurologic toxicity from dapsone.9,10 However, genotypic analysis of the CYP2C19, NAT2, and b5/b5R pathways has not been performed in the setting of dapsone-associated methemoglobinemia. This report describes a patient who developed methemoglobinemia at prophylactic dosages of dapsone, for which we characterized wild-type alleles at the CYP2C19*17 loci, but low activity of the b5/b5R pathway along with low expression of the CYB5A gene encoding b5, and a homozygous slow NAT2*5B haplotype, both of which may have contributed to defective dapsone detoxification.

Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TIL) has been employed for years in hundreds of patients with metastatic melanoma and other solid tumors, demonstrating durable and complete responses, even in heavily pretreated patients. Despite the approvals of checkpoint-directed therapies, metastatic melanoma remains an unmet need due to progression subsequent to administration of checkpoints, as well as due to intolerance. The C-144-01 study will enroll metastatic melanoma patients who progressed on anti-PD-1 and BRAF inhibitors if BRAF mutation positive. This phase II trial utilizes a central GMP facility for the manufacture of LN-144 in either a non-cryopreserved generation-1 (Gen-1), or cryopreserved generation-2 (Gen-2) investigational TIL infusion product. The Gen-2 manufacturing process reduces the time required for manufacture of TIL product to 22 days. The process development of cryopreservation for the final LN-144 infusion product incorporates dramatic improvements in the flexibility of scheduling, distribution and delivery required for commercial use. C-144-01 (NCT02360579) is a global phase 2 multicenter, open-label study evaluating the efficacy and safety of autologous TIL (LN-144) therapy for the treatment of patients with advanced metastatic melanoma. The study consists of three treatment cohorts: 30 patients in Cohort 1 will receive a single dose of Gen-1, non-cryopreserved LN-144; 30 patients in Cohort 2 will receive a single dose of Gen-2, cryopreserved LN-144; and up to 10 eligible patients from either Cohort 1 or Cohort 2 may enter a third cohort (Cohort 3) for re-treatment with a second dose of LN-144. The investigational LN-144 TIL infusion product for all cohorts is prepared at the central GMP facility using lymphocytes that are extracted from a surgically-resected sample of patient tumor. LN-144 infusion is preceded by a non-myeloablative lymphodepletion regimen of cyclophosphamide and fludarabine and followed by IL-2 for up to 6 doses. Patients ≥ 18 years of age must have progressive, unresectable metastatic melanoma (Stage IIIc or Stage IV) following ≥1 line of prior systemic therapy including immune checkpoint inhibitors and BRAF-targeted therapy (if BRAF mutation-positive). A minimum of 2 tumor lesions are required: 1 for resection and TIL manufacture and 1 for assessment of response by RECIST 1.1 criteria. Other major eligibility criteria include: adequate bone marrow, cardiac, liver, pulmonary, and renal function; ECOG PS of 0 or 1. Efficacy is being assessed as a function of ORR, CR rate, DOR, DCR, and PFS per RECIST 1.1 and OS. Assessment of safety data will be descriptive and based on the summarization of TEAEs, SAEs, AEs leading to discontinuation from treatment and the study, vital signs, physical examinations, and clinical laboratory tests. Citation Format: Amod Sarnaik, Brendan Curti, Diwakar Davar, Omid Hamid, Jose Lutzky, Melissa Wilson, Harriet Kluger, Jason Chesney, Kevin Kim, Giao Phan, Sajeve Thomas, Eric Whitman, Bente Larsen, Sam Suzuki, Nancy Samberg, Igor Gorbatchevsky, Maria Fardis, John M. Kirkwood. A phase II, multicenter study to assess the efficacy and safety of autologous tumor infiltrating lymphocytes (LN-144) for treatment of patients with metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT169.

TPS9595Background: Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) is recognized as an effective treatment in metastatic melanoma and other solid tumors elliciting durable and ...

TPS9601Background: Immunotherapy and targeted therapies have significantly changed the treatment landscape for advanced melanoma over the past few years. However, despite the addition of these new ...

8559Background: Sacituzumab govitecan (IMMU-132) is a novel ADC comprising SN-38, the active metabolite of the topoisomerase inhibitor, irinotecan, conjugated to an anti-Trop-2 humanized antibody. ...

Background: Sacituzumab govitecan (IMMU-132) is a new ADC comprising SN-38, the active metabolite of the topoisomerase inhibitor, camptothecin (irinotecan), conjugated to an anti-Trop-2 antibody. In vitro and in vivo preclinical data suggest that IMMU-132 is a unique ADC, being most efficacious at a high drug-antibody ratio (DAR) of 7.6, and capable of delivering up to 135-fold more SN-38 than its parental drug, irinotecan, in a human cancer xenograft. In vitro studies also demonstrate specific double-stranded DNA breaks by the internalizing ADC. Methods: IMMU-132 is completing a phase I/II clinical trial with phase II expansion after MTD determination (ClinicalTrials.gov.NCT01631552) in patients with advanced cancers that typically express high levels of Trop-2, at doses of 8 and 10 mg/kg on days 1 and 8 of 21-day repeated cycles. Efficacy (N = 91) and safety (N = 130) results are provided. Results: The% of grades 3/4 AEs for both dose levels are neutropenia (16/4), febrile neutropenia (4/4), anemia (4/0), diarrhea (4/0), and fatigue (4/0) (Table 1). No patient discontinued therapy due to toxicity, and no patient showed immunogenicity despite repeated therapy. Patient dose reductions were 15-16%, and dose delays after first 2 cycles were 3-4%. Conclusions: IMMU-132 shows activity in patients with diverse cancers, even when they no longer responded to a topoisomerase inhibitor. It appears to have a manageable toxicity profile, with promising efficacy at a high therapeutic index in patients with heavily-pretreated metastatic cancers, especially TNBC, SCLC, and NSCLC. Based on these results, this ADC carrying a moderately-toxic drug that is the active metabolite of a currently-used camptothecin analogue represents a novel cancer therapeutic that challenges the current dogma of requiring ultratoxic drugs conjugated at low DARs for ADC therapy. Tumor typeORR (CR+PR)Disease stabilization (CR+PR+SD)Clinical benefit (CR+PR+ SD > 6 moMedian TPP (mo)TNBC (N = 31)TNBC (N = 31)23%71%39%3.7+NSCLC (N = 15)27%73%42%3.3+SCLC (N = 19)26%53%29%2.8+CRC (N = 26)4%58%24%3.7 Citation Format: Alexander N. Starodub, Allyson J. Ocean, Aditya Bardia, Michael J. Guarino, Wells Messersmith, Jordan Berlin, Vincent J. Picozzi, Sajeve S. Thomas, Gregory Masters, Linda T. Vahdat, Ingrid A. Mayer, Rebecca Moroose, Jennifer S. Diamond, Scott T. Tagawa, Manish A. Shah, Francois Wilhelm, William A. Wegener, Pius Maliakal, Robert M. Sharkey, David M. Goldenberg. Advanced solid cancer therapy with a novel antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): key preclinical and clinical results. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT236. doi:10.1158/1538-7445.AM2015-CT236

9633 Background: Considerable evidence demonstrates the benefits of exercise for cancer survivors, but few studies focus on those living with advanced disease. We conducted a randomized trial of a ...

2504 Background: Sacituzumab govitecan (IMMU-132) is a new ADC comprising SN-38, the active metabolite of the topoisomerase inhibitor, camptothecin (irinotecan), conjugated to an anti-Trop-2 antibo...

3546 Background: Sacituzumab govitecan (IMMU-132) is a conjugate of a humanized anti-Trop-2 (trophoblast cell-surface antigen) coupled site-specifically to SN-38 (7.6 moles SN-38/IgG), an active me...

1016 Background: Patients with metastatic TNBC have an aggressive disease with limited therapy options. The duration of response with standard chemotherapy is usually short, with median PFS of abou...

703 Background: Trop-2 is a tumor-associated glycoprotein highly expressed in many epithelial cancers. Elevated expression has been linked to more aggressive disease and a poorer prognosis. IMMU-132 is an ADC comprising a humanized mAb binding to Trop-2 and conjugated to SN-38 (drug: Ab ratio = 7.6), the active metabolite of irinotecan. After finding potent activity in human tumor xenografts, a phase I/II trial was undertaken (NCT01631552). Methods: Pts with relapsed/refractory metastatic cancers were enrolled, starting at a dose of 8 mg/kg given on days 1 and 8 of a 3-week cycle. Dose levels of 8 and 10 mg/kg were chosen for phase II (N=47). Results: Sixty pts with advanced GI cancers were enrolled in phase I/II. Neutropenia was the principal dose-limiting toxicity, with fatigue, diarrhea, nausea, and vomiting as other reported toxicities. In the phase II pts with median prior therapies of 3 (range 1-7), the following moderate/severe drug-related toxicities occurred: neutropenia (Gr 3, 18.8%; Gr 4, 10.4%); fatigue (Gr 3, 14.6%; Gr 4, 0%), anemia (Gr 3, 10.4%; Gr 4, 0%); diarrhea (Gr 3, 4.2%; Gr 4, 0%). Of 29 CRC pts (10 mg/kg [N=9], 8 mg/kg [N=20]), 1 had a PR and 14 had SD as the best response by RECIST, with a time to progression (TTP) of 11.5+ months (mo) for the PR (65% shrinkage) and a median of 4.8+ mo for the SD pts (5 ongoing). This is a disease control rate (DCR) of 51.7%. Thirteen CRC pts had KRAS mutations, 7 with SD (median TTP = 4.4+ mo [range, 2.8-7.8 mo; 3 ongoing]). Of 15 pts with pancreatic ca, 8 had SD as best RECIST response (median TTP = 3.4 mo); DCR=53.3%. Among 11 pts with esophageal ca, 7 had CT assessments with 1 PR (TTP, 6.9+ mo), and 4 SD (TTP, 4.0+, 5.0, 6.0, and 6.9 mo) as best response; DCR=62.5%. Of 5 gastric ca pts, only 3 had post-baseline CT assessments, all with SD (1 with 19% target lesion reduction and an ongoing TTP of 6.7+ mo). Conclusions: IMMU-132 is a novel anti-cancer therapeutic, conjugating a topoisomerase I inhibitor to an internalizing, cancer-selective mAb. This ADC can be given safely and repeatedly over many months to heavily pretreated patients. Encouraging activity in pts with several metastatic gastrointestinal tumors has been observed. Clinical trial information: NCT01631552.

3032 Background: IMMU-132 is an ADC of the internalizing, humanized, anti-Trop-2 antibody, hRS7, conjugated by a pH-sensitive linker, to SN-38, the active metabolite of CPT-11 (mean drug-antibody r...