Intratumoral therapies and in-situ vaccination for melanoma

How to cite this article: Thoms K-M. Advanced melanoma-A curable disease? Implications of systemic treatment on patients' daily life.

9505 Background: Immune checkpoint inhibitors (ICI) are front-line standard-of-care treatment (tx) for advanced (unresectable or metastatic) melanoma. Despite recent advances in front-line tx, a majority of patients (pts) do not achieve long-term benefit. Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, potentially induces durable responses in pts with advanced melanoma previously treated with ICI. This study evaluates lifileucel combined with anti-PD-1 therapy in front-line advanced melanoma. Methods: IOV-COM-202 (NCT03645928) Cohort 1A assesses the efficacy and safety of lifileucel and pembrolizumab (pembro) in pts with ICI-naive unresectable or metastatic melanoma. Pts may have received BRAF/MEK inhibitor tx if BRAF mutation-positive. Eligible pts must have ≥1 resectable lesion (≥1.5 cm diameter) for 22-day cryopreserved lifileucel manufacturing, and ≥1 measurable lesion for response assessment per RECIST v1.1. The tx regimen consists of pembro, nonmyeloablative lymphodepletion (cyclophosphamide and fludarabine), a single lifileucel infusion (1 × 109 – 150 × 109 cells), ≤6 doses of IL-2 (600,000 IU/kg IV), and continued pembro until disease progression, or unacceptable toxicity for ≤24 months. The endpoints are investigator-assessed objective response rate (ORR) and incidence of grade ≥3 treatment-emergent adverse events (TEAE). Results: As of 22-Dec-2023, 22 pts with a median (range) age of 48.5 (18–68) years received lifileucel and pembro. At baseline, the median (range) target lesion sum of diameters was 54.5 (14–355) mm; 7 (31.8%) pts had liver lesions. Metastatic staging at study entry was as follows: 4 (18.2%) had M1a, 2 (9.1%) had M1b, 10 (45.5%) had M1c, and 2 (9.1%) had M1d. Eight (36.4%) pts had V600 BRAF mutations; 3 (13.6%) pts had prior BRAF/MEK inhibitor tx. Confirmed ORR was 63.6% (14/22), including 22.7% (5/22) CR and 40.9% (9/22) PR; 6 pts (27.3%) had SD. Median time to initial response was 2.5 months. All response evaluable pts demonstrated regression of target lesions. At a median follow-up of 17.2 months, median duration of response was not reached. Responses deepened over time; 10/14 (71.4%) pts had ongoing response and 8/14 (36.4%) pts had response ≥12 months. TEAEs were consistent with the underlying disease and known safety profiles of pembro, nonmyeloablative lymphodepletion, and IL-2. Most common grade ≥3 TEAEs were thrombocytopenia (68.2%), neutropenia (50.0%), and anemia (45.5%). Conclusions: These results demonstrate encouraging efficacy and durability for the combination of lifileucel and pembro and support its further evaluation in pts with untreated advanced melanoma in the phase 3 study TILVANCE-301 (NCT05727904). Clinical trial information: NCT03645928 .

Intratumoral therapies represent a unique avenue for drug development in melanoma as patients often have accessible lesions that are particularly amenable to these approaches. In addition, a majority of intratumoral therapies have focused on stimulating antitumor immune responses, making them a particularly attractive option for use in melanoma. In this review, we describe applications for talimogene laherparepvec, a US Food and Drug Administration-approved intratumoral therapy in melanoma, as well as several classes of intratumoral therapies in development including novel oncolytic viruses, mRNA-based intratumoral injections, and cytokines and other signaling molecules.

BackgroundDespite improved outcomes in advanced (unresectable or metastatic) melanoma, many patients progress after ICI,1-3 and have low response rates to subsequent therapy.4-7 Lifileucel, a one-time autologous TIL cell therapy, demonstrated...

New-onset uveitis during CTLA-4 blockade therapy with ipilimumab in metastatic melanoma patient

Introduction: Novel early-line therapies for advanced (unresectable or metastatic) melanoma are needed to improve the rate of deep and durable responses and increase the proportion of patients with long-term benefit. TILVANCE-301 will evaluate the efficacy and safety of lifileucel autologous TIL cell therapy plus pembrolizumab in patients with untreated advanced melanoma. Methods: TILVANCE-301 (NCT05727904) is a phase 3, multicenter, randomized, open-label, parallel group study that will randomize ~670 patients (1:1; Day 0) to Arm A: lifileucel plus pembrolizumab (Day 3: tumor tissue resection for TIL manufacturing; Day 5: pembrolizumab 200 mg; Day 26: pembrolizumab 400 mg; Day 28-29: cyclophosphamide 60 mg/kg; Day 28-32: fludarabine 25 mg/m2; Day 33: lifileucel; Day 34-37: ≤6 doses of high-dose IL-2; Week 10: pembrolizumab 400 mg Q6W) or Arm B: pembrolizumab alone (same pembrolizumab dosing as Arm A). Patients in Arm B with confirmed progressive disease verified by blinded independent review committee (BIRC) have the option to receive lifileucel monotherapy as immediate next treatment and may continue pembrolizumab until start of nonmyeloablative lymphodepletion. Eligible adults have histologically confirmed advanced melanoma, Eastern Cooperative Oncology Group performance status of 0-1, estimated life expectancy >6 months, ≥1 resectable lesion to generate lifileucel, and ≥1 remaining measurable lesion. Prior neoadjuvant or adjuvant treatment including immune checkpoint inhibitors may be allowed. Prior therapy for metastatic disease, symptomatic untreated brain metastases, organ allograft or prior cell therapy, uveal/ocular melanoma, and chronic systemic steroid therapy are not permitted. The dual primary efficacy endpoints are BIRC-assessed (RECIST v1.1) objective response rate (ORR) and progression-free survival (PFS). Key secondary efficacy endpoint is overall survival. Additional secondary efficacy endpoints include BIRC-assessed complete response (CR) rate, duration of response (DOR), and event-free survival (EFS); investigator-assessed ORR, PFS, CR rate, DOR, EFS, and PFS2; and safety as characterized by severity and seriousness of treatment-emergent adverse events and relationship to study drug. Exploratory endpoints include in vivo T-cell persistence (unique CDR3 sequences in peripheral blood mononuclear cell [PBMC] over time) and correlative biomarkers (eg, lifileucel phenotypic and functional characteristics; lifileucel, tumor, and PBMC gene expression profiles; tumor mutational landscape). The study will enroll globally, with initial sites in Europe, North America, and Australia. Trial registration: NCT05727904 Citation Format: Sajeve Thomas, Young Ki Hong, Yazan Samhouri, James Larkin, David J. Olson, Gino K. In, Victoria Atkinson, Philip Lammers, Andrew J. Furness, Juan Martin-Liberal, Patrick Terheyden, Andrew S. Poklepovic, Ryan H. Nguyen, Idit Peretz, Marcus Butler, Adnan Khattak, Lavinia Spain, E.M. Gaughan, Melissa Wilson, John W. Dubay, Anja Williams, Stephanie Goff, Gary C. Doolittle, Jason Chesney, Friedrich Graf Finckenstein, Jeffrey Chou, Xiao Wu, Giri Sulur, Wen Shi, John Haanen. TILVANCE-301, a phase 3 study of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab vs pembrolizumab alone in treatment-naive unresectable or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT286.

Melanoma has long been considered as an extremely therapy-resistant tumour. Recent developments in the area of immunotherapy as well as targeted therapy showed rapid development and excellent results. The anti-CTLA-4 antibody ipilimumab, which was approved in the USA and Europe in 2011, was the first substance in melanoma therapy to demonstrate an overall survival benefit. Another approval is expected in Europe for the specific BRAF-inhibitor vemurafenib, which has shown a significant impact on progression-free survival and overall survival in patients with the BRAF(V600E) mutation. In this review the relevant agents in the substance classes of immunomodulatory drugs and small molecules are presented and discussed, and future prospects for combination therapies and developments in melanoma treatment are outlined.

Advanced and metastatic melanoma has historically been one of the most difficult cancers to treat, with few treatment options. For over 20 years, dacarbazine chemotherapy was the only treatment approved by the US Food and Drug Administration for melanoma. In recent years, breakthroughs have been made in the areas of monoclonal antibody immunotherapies and genetically targeted therapies, leading to FDA approval of several new drugs for metastatic melanoma that have demonstrated improved patient response and survival. In an effort to understand the changing landscape of therapies for advanced and metastatic melanoma, we have reviewed 38 publicly available randomized clinical trials from http://ClinicalTrials.gov in metastatic and unresectable melanoma since the year 2000, to assess developments in the design and conduct of clinical trials over time and to compare the clinical efficacy of old and new therapies. We first present a brief history of FDA approvals of therapies for melanoma, followed by an exploration of trends in the patient population and demographics, eligibility criteria, and statistical methods of clinical trials over time. Next, we compare the efficacy results of old and new study treatments, examining the endpoints of progression-free survival, overall survival, and response rate. Overall, we find that the clinical trial population largely reflected the general population of patients with melanoma in demographic factors, with the exception of patient age. Our findings suggest that the developments of immunotherapies and targeted therapies have improved patient trial results on the discussed endpoints.

TPS9607 Background: Most patients (pts) with advanced (unresectable or metastatic) melanoma receiving front-line immune checkpoint inhibitor (ICI) therapy progress within a year (Robert Lancet Oncol 2019; Larkin NEJM 2019; Tawbi NEJM 2022). Early-line therapies are needed to improve the rate of deep and durable responses and increase the proportion of pts with long-term benefit. Lifileucel demonstrated an ORR of 31.4% and median DOR not reached (median 36.5 mo follow-up) in pts with post-ICI advanced melanoma (Sarnaik SITC 2022). Earlier-line treatment with lifileucel plus pembrolizumab (pembro) in pts with ICI-naïve advanced melanoma demonstrated an ORR of 67%, including a CR rate of 25% (Iovance Press Release, April 5, 2022; O’Malley JITC 2021). TILVANCE-301 will evaluate the efficacy and safety of lifileucel plus pembro compared with pembro alone in pts with untreated advanced melanoma. Methods: TILVANCE-301 (NCT05727904) is a phase 3, multicenter, randomized, open-label, parallel group, treatment study that will randomize ~670 pts (1:1) to either Arm A: lifileucel plus pembro (study intervention includes tumor tissue resection, pembro, nonmyeloablative lymphodepletion [NMA-LD], lifileucel infusion, an abbreviated course of high-dose IL-2, and thereafter, continued pembro) or Arm B: pembro alone. Pts in Arm B who receive pembro and experience confirmed progressive disease verified by blinded independent review committee (BIRC) have the option to receive lifileucel as the immediate next line of treatment. Eligible adults have histologically confirmed advanced melanoma (Stage IIIC, IIID, or IV); ECOG PS of 0 or 1; estimated life expectancy > 6 mo; ≥1 resectable lesion ~1.5 cm in diameter postresection to generate lifileucel and ≥1 measurable lesion (RECIST v1.1); and adequate hematologic parameters and organ function. Neoadjuvant or adjuvant treatment including ICI meeting protocol-specified criteria may be allowed. Exclusion criteria include prior therapy for metastatic disease; symptomatic untreated brain metastases; organ allograft or prior cell transfer therapy; uveal/ocular melanoma; chronic systemic steroid therapy; active systemic infections; cardiovascular, respiratory, or immune system illnesses; primary/acquired immunodeficiency; or other primary malignancy in the last 3 y. The dual primary efficacy endpoints are BIRC-assessed (RECIST v1.1) ORR and PFS. Key secondary efficacy endpoint is OS. Additional secondary efficacy endpoints include BIRC-assessed CR rate, DOR, and EFS; investigator-assessed ORR, PFS, CR rate, DOR, EFS, and PFS2; and safety as characterized by severity and seriousness of TEAEs, and relationship to study drug. The study will enroll globally. Clinical trial information: NCT05727904 .

Systemic therapy of advanced metastatic malignant melanoma has been considerably changed by the approval of new drugs in recent years. The targeted therapy with the B-RAF inhibitors vemurafenib and dabrafenib achieves rapid tumor reduction but is often followed by the development of resistance in the further course of therapy. By immunotherapy with ipilimumab, on the other hand, a plateau effect becomes apparent in the survival curves. The aim of this article is to discuss the treatment options for patients with advanced melanoma with special reference to new treatment options and substances for which approval is soon to be expected. Treatment recommendations, taking into account the S3 guidelines on diagnosis, treatment and follow-up of melanoma and recent publications (Pubmed and manual search) are presented. In patients with B-RAF mutations, targeted therapy with the B-RAF inhibitor vemurafenib achieves response rates of 50-60 %, comparable with the B-RAF inhibitor dabrafenib, yet resistance often occurs after approximately 7 months. By immunotherapy with ipilimumab long-term survival can be achieved in approximately 20 % of patients. The treatment options for patients with metastatic melanoma have considerably improved in recent years. Several highly effective substances have recently become available and the approval of more potent substances is expected this year.

Melanoma ManagementVol. 4, No. 2 CommentaryWhat is new in melanoma after European Cancer Congress 2017?Piotr RutkowskiPiotr Rutkowski*Author for correspondence: E-mail Address: piotr.rutkowski@coi.pl Department of Soft Tissue/Bone Sarcoma & Melanoma, Maria Sklodowska-Curie Institute – Oncology Center, Roentgena 5, 02–781 Warsaw, PolandSearch for more papers by this authorPublished Online:15 May 2017https://doi.org/10.2217/mmt-2017-0004AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: adjuvantanti-CTLA-4anti-PD-1BRAF inhibitorimmunotherapyMEK inhibitormelanomametastasesneoadjuvantReferences1 Autier P, Koechlin A, Boniol M. Prediction of numbers of melanoma deaths by 2050. Presented at: 2017 European Cancer Conference. Amsterdam, The Netherlands, 27–30 January 2017.Crossref, Google Scholar2 Rutkowski P. Introduction to the special issue of European Journal of Surgical Oncology: new roads in melanoma management. Eur. J. Surg. Oncol. 43(3), 513–516 (2017).Crossref, Medline, CAS, Google Scholar3 Garbe C, Peris K, Hauschild A et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – update 2016. Eur. J. Cancer 63, 201–217 (2016).Crossref, Medline, Google Scholar4 NCCN Guidelines. Melanoma. Version 1. www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdfGoogle Scholar5 Ugurel S, Roehmel J, Ascierto PA et al. Survival of patients with advanced metastatic melanoma: the impact of novel therapies. Eur. J. Cancer 53, 125–134 (2016).Crossref, Medline, Google Scholar6 Haanen J, Blank C, Van Thienen H et al. Downsizing of locally advanced stage III (bulky) BRAF V600E/K melanoma with combination targeted therapy to achieve R0 resection. Presented at: 2017 European Cancer Conference. Amsterdam, The Netherlands, 27–30 January 2017.Crossref, Google Scholar7 Long G. Neoadjuvant therapy in bulky stage III melanoma: are we there yet? Presented at: 2017 European Cancer Conference. Amsterdam, The Netherlands, 27–30 January 2017.Google Scholar8 Amaria R. Treatment with neoadjuvant and adjuvant BRAF and MEK inhibitors is associated with improved relapse-free survival over standard-of-care therapy in patients with high risk resectable BRAF-mutant melanoma. Presented at: 2017 European Cancer Conference. Amsterdam, The Netherlands, 27–30 January 2017.Google Scholar9 Blank CU, Van Akkooi A, Rozeman EA et al. (Neo-)adjuvant ipilimumab + nivolumab (Ipi + Nivo) in palpable stage 3 melanoma. Initial data from the OpACIN trial. Ann. Oncol. 27(6), 1–36 (2016).Medline, Google Scholar10 Eggermont AM, Chiarion-Sileni V, Grob JJ et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. 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Amsterdam, The Netherlands, 27–30 January 2017.Crossref, Google Scholar14 Long GV, Blank C, Ribas A et al. Impact of baseline serum lactate dehydrogenase concentration on the efficacy of pembrolizumab and ipilimumab in patients with advanced melanoma: data from KEYNOTE-006. Presented at: 2017 European Cancer Conference. Amsterdam, The Netherlands, 27–30 January 2017.Crossref, Google Scholar15 Butler M, Hamid O, Ribas A et al. Efficacy of pembrolizumab in patients with advanced mucosal melanoma enrolled in the KEYNOTE-001, 002, and 006 studies. Presented at: 2017 European Cancer Conference. Amsterdam, The Netherlands, 27–30 January 2017.Crossref, Google Scholar16 D'Angelo SP, Larkin J, Sosman JA et al. Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis. J. Clin. Oncol. 35(2), 226–235 (2016).Crossref, Medline, Google Scholar17 Long GV, Robert C, Arance A et al. Antitumor activity of ipilimumab after pembrolizumab in patients with advanced melanoma in KEYNOTE-006. Presented at: 2017 European Cancer Conference. Amsterdam, The Netherlands, 27–30 January 2017.Crossref, Google ScholarFiguresReferencesRelatedDetails Vol. 4, No. 2 Follow us on social media for the latest updates Metrics Downloaded 26 times History Published online 15 May 2017 Published in print May 2017 Information© Future Medicine LtdKeywordsadjuvantanti-CTLA-4anti-PD-1BRAF inhibitorimmunotherapyMEK inhibitormelanomametastasesneoadjuvantFinancial & competing interests disclosureP Rutkowski served as a member of Advisory Board for Novartis, GSK, MSD, Roche, BMS, Amgen and Bayer. He had received honoraria for lectures from Novartis, Pfizer, BMS, MSD, Roche. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

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.

Background BRAF V600 mutations are frequently found in metastatic melanoma. This mutation constitutively activates the MAPK pathway, which leads to melanoma progression. Patients with BRAF V600-mutant metastatic melanoma typically receive BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi), such as enco + bini, or immune checkpoint inhibitors (CPIs; eg, pembro). However, these have limitations. BRAFi and MEKi may increase BRAF V600-mutant tumor sensitivity to CPIs. Previous studies reported improved progression-free survival (PFS) in patients with advanced BRAF V600-mutant melanoma receiving BRAFi + MEKi + CPI compared with targeted therapy alone. This phase 3 trial will evaluate the efficacy and safety of enco + bini + pembro vs placebo + pembro for unresectable locally advanced or metastatic BRAF V600-mutant melanoma. A safety lead-in (SLI) was built in to determine the recommended phase 3 dose (RP3D) prior to starting phase 3. Trial design STARBOARD (NCT04657991) is a randomized, double-blind, placebo-controlled, phase 3 study evaluating approximately 600 patients with BRAF V600 advanced melanoma. Patients will be stratified by prior systemic adjuvant treatment (CPI, BRAFi/MEKi, or none) and by disease stage (per AJCC 8th edition; IIIB, IIIC, IIID, IV M1a[0], and IV M1b[0] vs IV M1a[1], IV M1b[1], IV M1c[0], IV M1c[1], IV M1d[0], and IV M1d[1]). Patients must have measurable disease (per RECIST 1.1); ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients must not have received prior systemic therapy for unresectable or metastatic melanoma; adjuvant treatment with BRAFi/MEKi, anti-PD-1, or anti-CTLA-4 is permitted. Patients cannot have symptomatic brain metastases. Study treatments and end points are shown in Table 1. RP3D was established in May 2022; phase 3 enrollment began in June 2022. Table 1. Study treatments and end points Phase 3 Treatment (21-day cycle) RP3D from SLI: enco + bini + pembro Control: placebo + pembro Primary PFS (RP3D vs control; by BICR) Secondary Key: OS (RP3D vs control) Other: PFS by investigator assessment, objective response rate, duration of response, disease control rate, and time to response, all by BICR and investigator assessment, PFS2, quality of life, safety, pharmacokinetics BICR, blinded independent central review; OS, overall survival. Citation Format: Dirk Schadendorf, Reinhard Dummer, Caroline Robert, Antoni Ribas, Ryan J. Sullivan, Timothy Panella, Meredith McKean, Edgardo S. Santos, Jill Clancy, Anna Polli, Alessandra di Pietro, Paolo A. Ascierto. Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT069.

Developments in Intralesional Therapy for Metastatic Melanoma.

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.