LBA3 - Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: Results from a multicenter, randomized phase III trial

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 ≥5x10⁹ 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

NCT02278887.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

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