Cell Therapy Improves Progression-Free Survival in Advanced Melanoma, First Phase 3 Study Shows [ESMO Congress 2022 Press Release]

J.B.A.G. Haanen¹, M. Rohaan¹, T.H. Borch², J.H. van den Berg³, Ö. Met², M. Geukes Foppen¹, J. Stoltenborg Granhøj², B. Nuijen⁴, C. Nijenhuis³, J.H. Beijnen⁴, I. Jedema⁵, M. van Zon³, I. Mansfield Noringriis², R. Kessels⁶, S. Wilgenhof¹, H.V. van Thienen¹, F. Lalezari⁷, A.C.J. van Akkooi⁸, M. Donia², I.-M. Svane^2
1Department Of Medical Oncology, Netherlands Cancer Institute, Amsterdam/Netherlands, ²Department Of Oncology, National Center for Cancer Immune Therapy, Herlev/Denmark, ³Biotherapeutics Unit, Netherlands Cancer Institute, Amsterdam/Netherlands, ⁴Department Of Pharmacy And Pharmacology, Netherlands Cancer Institute, Amsterdam/Netherlands, ⁵Department Of Molecular Oncology And Immunology, Netherlands Cancer Institute, Amsterdam/Netherlands, ⁶Department Of Biometrics, Netherlands Cancer Institute, Amsterdam/Netherlands, ⁷Department Of Radiology, Netherlands Cancer Institute, Amsterdam/Netherlands, ⁸Department Of Surgical Oncology, Netherlands Cancer Institute, Amsterdam/Netherlands

Background: Immune checkpoint inhibitors and targeted therapies have greatly improved the outcome of patients (pts) with advanced melanoma. However, as approximately half will not derive durable benefit, a large unmet need for additional treatment options remains. Adoptive cell therapy with TIL is a treatment modality with promising response rates (RR) of 36-70% in pts with advanced melanoma, observed in multiple phase 1/2 trials. To date, no data from phase 3 trials is available to determine the role of TIL in the current treatment landscape.

Methods: In this multicenter, open-label phase 3 trial, pts with unresectable stage IIIC-IV melanoma (7^th edition), ≥18 ≤ 75 years, were randomized 1:1 to TIL or ipilimumab (3mg/kg q3wks, max 4 doses). Pts were stratified for BRAF^V600 mutation status, treatment line and center. Pts randomized to TIL underwent resection of a melanoma lesion (2-3cm) for the ex vivo outgrowth and expansion of tumor resident T cells. Infusion of ≥5×10⁹ TIL was preceded by non-myeloablative, lymphodepleting chemotherapy with cyclophosphamide + fludarabine and followed by high-dose interleukin-2. The primary endpoint was progression-free survival (PFS) per RECIST 1.1. Secondary endpoints were (overall and complete) RR, overall survival (OS) and safety.

Results: In total, 168 pts, the majority (86%) refractory to anti-PD-1 treatment, were randomized to TIL (n=84) or ipilimumab (n=84). With a median follow-up of 33.0 months, median PFS was 7.2 months for TIL (95% CI, 4.2 – 13.1), compared to 3.1 months (95% CI, 3.0 – 4.3) for ipilimumab (HR: 0.50 [95% CI, 0.35 – 0.72]; P<0.001). Overall RR was 49% (95% CI, 38% – 60%) for TIL and 21% (95% CI, 13% – 32%) for ipilimumab, with 20% (95% CI, 12% – 30%) and 7% (95% CI, 3% – 15%) complete responses, respectively. Median OS for TIL was 25.8 months (95% CI, 18.2 – not reached) and 18.9 months (95% CI, 13.8 – 32.6) for ipilimumab (HR: 0.83 [95% CI, 0.54 – 1.27]; P=0.39). Grade ≥3 treatment-related adverse events occurred in all TIL and 57% of ipilimumab pts.

Conclusions: TIL therapy significantly improved PFS compared to ipilimumab in pts with advanced melanoma, the vast majority being anti-PD-1 refractory, making it a possible new treatment option in this pt population.

Clinical trial identification: Trial registration number: NCT02278887.
Legal entity responsible for the study: Netherlands Cancer Institute

Funding: Foundation or academic group WITHOUT funding from a pharma, biotech, or other commercial company
 – the Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, Copenhagen University Hospital, Herlev, the Danish Cancer Society and Capital Region of Denmark Research Foundation

Disclosure: J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squipp; Financial Interests, Institutional, Advisory Board: Achilles Therapeutics; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech; Financial Interests, Institutional, Advisory Board: Immunocore; Financial Interests, Institutional, Advisory Board: Gadeta; Financial Interests, Institutional, Advisory Board: Ipsen; Financial Interests, Institutional, Advisory Board: Merck Sharpe & Dohme; Financial Interests, Institutional, Advisory Board: Merck Serono; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Advisory Board: Molecular Partners; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Advisory Board: Sanofi; Financial Interests, Institutional, Advisory Board: Third Rock Venture; Financial Interests, Institutional, Advisory Board, SAB member: Instil Bio; Financial Interests, Institutional, Advisory Board: Iovance Biotherapeutics; Financial Interests, Institutional, Advisory Board, SAB member: PokeAcel; Financial Interests, Institutional, Advisory Board, SAB member: T-Knife; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: BioNTech US; Financial Interests, Institutional, Research Grant: Merck Sharpe & Dohme; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Asher Bio; Non-Financial Interests, , Member: ASCO; Non-Financial Interests, , Member: AACR; Non-Financial Interests, , Member: SITC; Other, , Other, Editor-in-Chief IOTECH: ESMO; Other, , Other, Editorial Board ESMO Open: ESMO; Other, , Other, Editorial Board: Kidney Cancer. J.H. van den Berg: Financial Interests, Institutional, Other, Research collaboration: NEON therapeutics; Financial Interests, Institutional, Other, Research collaboration: Bristol Meyers Squibb; Financial Interests, Institutional, Other, Research collaboration: Medimmune. J.H. Beijnen: Financial Interests, Personal, Stocks/Shares, part time employee and (in)direct stock holder : Modra Pharmaceuticals. S. Wilgenhof: Financial Interests, Institutional, Advisory Board: Eisai; Financial Interests, Institutional, Advisory Board: Bristol Meyers Squibb.  A.C.J. van Akkooi: Financial Interests, Institutional, Advisory Board: Amgen; Financial Interests, Institutional, Advisory Board: Bristol Myers-Squibb; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: MSD – Merck; Financial Interests, Institutional, Advisory Board: Merck-Pfizer; Financial Interests, Institutional, Advisory Board: Pierre Fabre; Financial Interests, Institutional, Advisory Board: Sanofi; Financial Interests, Institutional, Advisory Board: Sirius Medical; Financial Interests, Institutional, Advisory Board: 4SC; Financial Interests, Institutional, Advisory Board: Provectus; Financial Interests, Institutional, Research Grant, NIVEC study: Amgen; Financial Interests, Institutional, Research Grant: Merck-Pfizer.  I. Svane: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Stocks/Shares, Cofounder and Founder warrents: IO Biotech; Financial Interests, Institutional, Research Grant: Adaptimmune; Financial Interests, Institutional, Research Grant: Enara Bio; Financial Interests, Institutional, Research Grant: Lytix Biopharma; Financial Interests, Institutional, Research Grant: TILT Biotherapeutics; Financial Interests, Institutional, Funding: Evaxion; Non-Financial Interests, , Principal Investigator: BMS; Non-Financial Interests, , Principal Investigator: Roche; Non-Financial Interests, , Principal Investigator: TILT Biotherapeutics; Non-Financial Interests, , Principal Investigator: Lytix Biopharma; Non-Financial Interests, , Principal Investigator: Novartis.  All other authors have declared no conflicts of interest.