458 First phase 2 results of autologous tumor-infiltrating lymphocyte (TIL; LN-145) monotherapy in patients with advanced, immune checkpoint inhibitor-treated, non-small cell lung cancer (NSCLC)

Abstract

BackgroundA majority of patients with advanced NSCLC develop disease progression with first-line immune-checkpoint inhibitors (ICI) ± chemotherapy. In the setting of ICI resistance, effective strategies to provide deep and durable responses are urgently needed. Lifileucel (LN-144) and LN-145 are centrally manufactured (cryopreserved drug-product, 22-day manufacturing process) autologous TIL products that have demonstrated activity in advanced melanoma, cervical cancer, and head and neck carcinoma.1–4 Here, we report the first safety and efficacy data for LN-145 as monotherapy in patients with advanced NSCLC.MethodsIOV-COM-202 (NCT03645928) is a phase 2 multicenter, multicohort, open-label study evaluating autologous TIL cell therapy in patients with solid tumors. We report data from Cohort 3B, investigating LN-145 monotherapy in patients with advanced or metastatic NSCLC. Eligibility required 1–3 prior lines of systemic therapy, including either ICI or oncogene-directed therapy. Treatment included nonmyeloablative lymphodepletion, TIL infusion, and ≤6 interleukin-2 doses. Primary endpoints were safety (incidence of Grade ≥3 treatment-emergent adverse events [TEAEs]) and objective response rate (ORR, investigator-assessed using RECIST v1.1). Exploratory biomarker analyses, including T-cell receptor (TCR) repertoire, were performed.ResultsAs of 24June2021, 28 patients received LN-145 (full-analysis set [FAS]; table 1) and 24 were efficacy-evaluable; all had received prior ICI. TIL were most commonly harvested from lung metastases (57.1%). Safety was consistent with the underlying disease and known TEAE profiles of nonmyeloablative lymphodepletion and interleukin-2. Grade ≥3 TEAEs in ≥30% of patients were thrombocytopenia and anemia. The ORR in the FAS and efficacy-evaluable set was 21.4% (6/28) and 25.0% (6/24; figure 1), respectively. Median duration of response was not reached and 83% (5/6) of responses were ongoing at last follow-up (median study follow-up, 8.2 months). One patient had a complete metabolic response, ongoing at 20.7 months; 2 responses occurred in patients who were PD-L1–negative. All responders received ≥2 prior lines of systemic therapy. Twenty-six patients had TIL available from the final drug-product for TCR repertoire analysis; mean (min-max) number of unique TCR clones was 13,142 (3093–35,734) and Shannon Entropy index was 7.34 (3.7–12). Updated data will be presented.Abstract 458 Figure 1Best percentage change from baseline in target lesion sum of diameters for efficacy-evaluable setAbstract 458 Table 1Baseline patient demographic and clinical characteristics; efficacy parametersConclusionsLN-145 was successfully manufactured and one-time treatment produced an expected safety profile and durable responses in heavily pretreated patients with NSCLC, regardless of PD-L1 expression. The activity of LN-145 monotherapy is encouraging and warrants further investigation of LN-145 as a single-agent and in combination in patients with NSCLC in ongoing studies IOV-LUN-202 (NCT04614103) and IOV-COM-202 Cohorts 3A and 3C (3B closed to enrollment).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 RegistrationNCT03645928ReferencesSarnaik AA, et al. J Clin Oncol 2021; doi: 10.1200/JCO.21.00612.. Thomas SS, et al. J Clin Oncol 2021;39: (suppl; abstract 9537).Jazaeri A, et al. J Clin Oncol 2019;37: (suppl; abstract 2538).Jimeno A, et al. J Immunother Cancer 2020;8: (suppl; abstract A378).Ethics ApprovalThe study was approved by Advarra Institutional Review Board, approval number Pro00035064 and all study participants provided written consent via signature of the IRB-approved Informed Consent form.

Surgical Considerations for Tumor Tissue Procurement to Obtain Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

“… 6 Recently, in a multicenter phase II study of patients with advanced NSCLC, more than 50% of lesions resected were from the lung, and patients could be administered therapeutic TIL doses with minimal morbidity. 16 The feasibility of TIL production from NSCLC tumors was also demonstrated in a phase I study, in which adequate tumor tissue was collected from excisional biopsy of metastases in pleural nodules or supraclavicular lymph nodes, with most patients discharged within a day following the biopsy procedure. 15 …”

“…Further, the in vivo fate of individual TIL clones is not dependent on their frequency in the infusion product, as minor clones within the infusion product can expand preferentially after infusion, hypothetically reflecting antigen-driven clonal proliferation 51 . The TCR repertoire of TILs (LN-145) generated from NSCLC tumors of patients with advanced NSCLC demonstrated a highly polyclonal product with unique TCR clones, as indicated by the Shannon Entropy Index and Simpson Clonality Index 16 . The number of unique TCR clones obtained from NSCLC tumors, as well as measures of diversity and clonality, was similar to those previously published for lifileucel for melanoma 51 and LN-145 for cervical cancer 52 .…”

“…As TIL cell therapy approaches commercialization, standardized protocols are required. Recent multicenter studies in advanced melanoma, HNSCC, cervical cancer, and NSCLC represent a major advance in this respect 6,12,16 . These studies benefit from a centralized Good Manufacturing Practice process, which allows for timely delivery of therapy and facilitates the production of reproducible high-quality TIL cell therapy products for broader patient accessibility.…”

“… 45 , 46 The operating surgeon is best qualified to prosect and select the most viable tumor tissue for optimal TIL production. Although no formal minimal size criteria have been established for resection of viable solid tumor tissue, some studies and trials in progress recommend a postprosection aggregate tumor tissue diameter of 1 cm or greater 47 or 1.5 cm or greater but less than 4 cm, 6 , 16 , 48 whereas others recommend a metastatic tumor tissue of 1 cm 3 or greater (>2 cm 3 for lymph nodes). 7 If the volume of tissue from 1 lesion is not adequate, an additional lesion can be resected to make up the size specifications, with 1.5 cm or greater in aggregate diameter after trimming to meet the minimum TIL manufacturing requirements.…”

“…Adoptive cell therapy using investigational TIL cell therapy has demonstrated encouraging efficacy and safety in clinical trials for several patient populations with high unmet medical need, including advanced melanoma, 6 , 8 – 13 non–small cell lung cancer (NSCLC), 14 – 16 cervical cancer, 12 , 17 and head and neck squamous cell carcinoma (HNSCC). 12 , 18 Most of these studies included heavily pretreated patients who had failed all prior therapies and had limited treatment options.…”