LUMINOS-102: Lerapolturev with and without α-PD- 1 in unresectable α-PD- 1 refractory melanoma

Lerapolturev (lera, formerly PVSRIPO) is a novel poliovirus based intratumoral immunotherapy that infects both cancer cells and antigen-presenting cells (APCs) via CD155, the poliovirus receptor. Lera has direct anticancer effects while also generating type I/III interferon-dominated inflammation and anti-tumor T-cell priming and activation via infection of local APCs. LUMINOS-102 (NCT04577807) is a multi-center, open-label, two-arm randomized Phase 2 study investigating the efficacy and safety of lera ± α-PD- 1 in patients with unresectable melanoma who failed prior α-PD- 1 therapy. Cross-over to the α-PD- 1 arm is permitted after progression, PR for ≥6 mo or 6 mo on treatment with SD. The maximum initial lera dose was 6x108 TCID50 /visit every 3 or 4 weeks (Q3/4 W). As of March 2022, the maximum lera dose was increased to 1.6 x 109 TCID50/visit, every week (QW) for 7 weeks (induction), followed by Q3/4 W dosing (maintenance). As of 20-Jun- 2022, 21 participants (10 male, 11 female, median 64 yrs) received lera (n = 14 at initial dose, Q3/4 W; n = 4 at increased dose, Q3/4 W; n = 3 at increased dose, QW) ± αPD-1. Five patients are currently on treatment. With the initial regimen, no objective responses and a CBR of 7% were observed. However, with the higher dose regimen, 1 complete response and a CBR of 71% (5/7) has been observed. Two of 4 participants with stable disease have evidence of response (1 with resolution of uninjected lung metastasis, 1 with decreased PET signal in injected and uninjected lesions receiving combination therapy). The only treatment related AE in \u3e1 pt was fatigue (19%, all grade 1 or 2). No dose-limiting toxicities or treatment-related SAEs were reported. Multiplex-IF analysis of on-treatment tumor biopsies will be presented. Lera ± αPD-1 is well tolerated, with early signs of efficacy at the higher dose level. Enrollment and randomization are ongoing

Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update

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

Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study

PurposeKEYNOTE-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 methodsPembrolizumab 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).ResultsA 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.ConclusionsPembrolizumab monotherapy showed limited antitumor activity and manageable safety in patients with previously treated advanced well-differentiated NETs

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

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 x10 9 . 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

Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients previously treated with at least one prior systemic therapy

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

Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced melanoma: Evaluation of impact of prior anti-PD-1 therapy

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

Abstract CT008: 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 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