Safety and efficacy of lifileucel (LN-144), an autologous, tumor infiltrating lymphocyte cell therapy in combination with pembrolizumab for immune checkpoint inhibitor naïve patients with advanced melanoma.

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.

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A phase II open-label study of cabozantinib in patients with advanced or unresectable renal cell carcinoma pretreated with one immune-checkpoint inhibitor: The BREAKPOINT trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.tps685 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. TPS685-TPS685 ◽

Cited By ~ 1

Author(s):

Elena Verzoni ◽

Alessandra Bearz ◽

Ugo De Giorgi ◽

Franco Nole ◽

Camillo Porta ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitor ◽

Kinase Inhibitors ◽

Checkpoint Inhibitor ◽

Objective Response ◽

First Line ◽

Open Label

TPS685 Background: First-line treatment landscape of metastatic renal cell carcinoma (mRCC) is evolving with strong evidence in favour of PD-1/PD-L1 combinations over tyrosine kinase inhibitors (TKIs). No prospective data about efficacy of TKIs post immune-checkpoint inhibitor (CPI) combinations are available. Among TKIs, cabozantinib has demonstrated progression-free survival (PFS) and overall survival (OS) benefit over everolimus in pre-treated mRCC patients (pts). Methods: Overall 49 mRCC pts who received a previous CPI (anti PD-1/PD-L1) will be treated with cabozantinib. Pts will be stratified according to Heng prognostic group, duration of first-line and type of previous therapy received (CPI+CPI or CPI+TKI or CPI+anti-VEGF or CPI monotherapy). Key inclusion criteria include: one previous treatment with a PD-1/PD-L1 inhibitor in first-line and histological diagnosis of clear-cell RCC. The primary endpoint is to assess the efficacy of cabozantinib based on PFS. Secondary endpoints include evaluation of OS, objective response rate and safety profile of the drug. Exploratory endpoints include evaluation of PD-L1 levels by immunohistochemistry in tumor samples; the analysis of the immunological signature/profile of tumor cells; the state of circulating immune cells, as well as the modulating activity of cabozantinib on systemic tumor immunity; the evaluation of bone formation and reabsorption markers in pts with or without bone involvement. Cabozantinib will be administered orally at a dose of 60 mg/day continuously until evidence of disease progression or onset of unacceptable toxicity. Statistical design: By the methodology of Brookmeyer and Crowley, assuming an accrual period of 18 months and a minimum follow-up of 10 months (mos), 49 pts are necessary to detect an increment of the median PFS time from 3.8 mos to 7.4 mos with a power of 90% and one-sided alpha of 5%. The large sample critical value detecting the increment of the PFS median survival time will be 5.54 mos. To date, 2 pts have been enrolled. Clinical trial information: NCT03463681.

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Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9503 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9503-9503

Author(s):

Evan J. Lipson ◽

Hussein Abdul-Hassan Tawbi ◽

Dirk Schadendorf ◽

Paolo Antonio Ascierto ◽

Luis Matamala ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Objective Response ◽

Cell Activity ◽

Advanced Melanoma ◽

Phase Iii ◽

Fixed Dose ◽

First Line ◽

Programmed Death

9503 Background: Immune checkpoint inhibitor therapy has revolutionized the treatment of patients with advanced melanoma. However, novel combinations are needed to optimize the benefit-risk profile. Lymphocyte-activation gene 3 (LAG-3) regulates an immune checkpoint pathway, which inhibits T-cell activity, and is upregulated in many tumor types including melanoma. Relatlimab (RELA), a human IgG4 LAG-3-blocking antibody, restores effector function of exhausted T cells. RELA in combination with nivolumab (NIVO; anti-programmed death [PD]-1) modulates potentially synergistic immune checkpoint pathways and can enhance antitumor immune responses. RELATIVITY-047 is a global, randomized, double-blind, phase II/III study evaluating a novel immune checkpoint inhibitor combination of RELA+NIVO as a fixed-dose combination (FDC) treatment in first-line advanced melanoma. Methods: Patients with previously untreated advanced melanoma were randomized 1:1 to receive RELA 160 mg + NIVO 480 mg FDC intravenously (IV) every 4 weeks (Q4W) or NIVO monotherapy 480 mg IV Q4W, stratified by LAG-3 expression, programmed death ligand 1 expression, BRAF mutation status, and AJCC (v8) M stage. The primary endpoint was progression-free survival (PFS) per RECIST v1.1 as assessed by blinded independent central review. Secondary endpoints were overall survival and objective response rate. PFS in prespecified subgroups and safety were additional objectives. Results: 714 patients were randomized to RELA+NIVO FDC (n = 355) or NIVO (n = 359). Patient characteristics were well balanced between treatment groups. Median follow-up was 13.2 months. Median PFS in the RELA+NIVO FDC group (10.1 months [95% CI, 6.4–15.7]) was significantly longer than in the NIVO group (4.6 months [95% CI, 3.4–5.6]; hazard ratio, 0.75 [95% CI, 0.6–0.9]; P = 0.0055). PFS rates at 12 months were 47.7% (95% CI, 41.8–53.2) and 36.0% (95% CI, 30.5–41.6) for RELA+NIVO FDC and NIVO, respectively. PFS favored RELA+NIVO FDC across key prespecified subgroups. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was higher in the RELA+NIVO FDC group (18.9%) versus NIVO (9.7%). There were 3 treatment-related deaths with RELA+NIVO FDC and 2 with NIVO. TRAEs (any grade) led to treatment discontinuation in 14.6% and 6.7% of patients in the RELA+NIVO FDC and NIVO groups, respectively. Conclusions: First-line treatment with RELA+NIVO FDC demonstrated a statistically significant PFS benefit compared to NIVO monotherapy in patients with advanced melanoma. RELA+NIVO FDC was well tolerated with a manageable safety profile and without unexpected safety signals. This is the first phase III study of a novel FDC to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways. Clinical trial information: NCT03470922.

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353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0353 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A378-A378

Author(s):

Antonio Jimeno ◽

Sophie Papa ◽

Missak Haigentz ◽

Juan Rodríguez-Moreno ◽

Julian Schardt ◽

...

Keyword(s):

Cell Therapy ◽

Checkpoint Inhibitors ◽

Adoptive Cell Therapy ◽

Single Agent ◽

Objective Response ◽

Tumor Resection ◽

Tumor Infiltrating Lymphocytes ◽

Open Label ◽

Safety And Efficacy ◽

Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

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673 Precision microbiome mapping identifies a microbiome signature predictive of Immune checkpoint inhibitor response across multiple research study cohorts

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0673 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A711-A711

Author(s):

Matthew Robinson ◽

Kevin Vervier ◽

Simon Harris ◽

David Adams ◽

Doreen Milne ◽

...

Keyword(s):

Gut Microbiome ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Advanced Melanoma ◽

List Type ◽

Metagenomic Sequencing ◽

Genome Database ◽

Sequencing Platform ◽

Melanoma Patients

BackgroundThe gut microbiome of cancer patients appears to be associated with response to Immune Checkpoint Inhibitor (ICIs) treatment.1–4 However, the bacteria linked to response differ between published studies.MethodsLongitudinal stool samples were collected from 69 patients with advanced melanoma receiving approved ICIs in the Cambridge (UK) MELRESIST study. Pretreatment samples were analysed by Microbiotica, using shotgun metagenomic sequencing. Microbiotica’s sequencing platform comprises the world’s leading Reference Genome Database and advanced Microbiome Bioinformatics to give the most comprehensive and precise mapping of the gut microbiome. This has enabled us to identify gut bacteria associated with ICI response missed using public reference genomes. Published microbiome studies in advanced melanoma,1–3renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC)4 were reanalysed with the same platform.ResultsAnalysis of the MELRESIST samples showed an overall change in the microbiome composition between advanced melanoma patients and a panel of healthy donor samples, but not between patients who subsequently responded or did not respond to ICIs. However, we did identify a discrete microbiome signature which correlated with response. This signature predicted response with an accuracy of 93% in the MELRESIST cohort, but was less predictive in the published melanoma cohorts.1–3 Therefore, we developed a bioinformatic analytical model, incorporating an interactive random forest model and the MELRESIST dataset, to identify a microbiome signature which was consistent across all published melanoma studies. This model was validated three times by accurately predicting the outcome of an independent cohort. A final microbiome signature was defined using the validated model on MELRESIST and the three published melanoma cohorts. This was very accurate at predicting response in all four studies combined (91%), or individually (82–100%). This signature was also predictive of response in a NSCLC study and to a lesser extent in RCC. The core of this signature is nine bacteria significantly increased in abundance in responders.ConclusionsAnalysis of the MELRESIST study samples, precision microbiome profiling by the Microbiotica Platform and a validated bioinformatic analysis, have enabled us to identify a unique microbiome signature predictive of response to ICI therapy in four independent melanoma studies. This removes the challenge to the field of different bacteria apparently being associated with response in different studies, and could represent a new microbiome biomarker with clinical application. Nine core bacteria may be driving response and hold potential for co-therapy with ICIs.Ethics ApprovalThe study was approved by Newcastle & North Tyneside 2 Research Ethics Committee, approval number 11/NE/0312.ReferencesMatson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359(6371):104–108.Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359(6371):97–103.Frankel AE, Coughlin LA, Kim J, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 2017;19(10):848–855.Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359(6371):91–97.

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