- First randomised study to show cell therapy improves outcomes in patients with solid cancers
- Patients randomised to tumour-infiltrating lymphocytes (TIL) therapy had 50% reduction in disease progression or death compared to standard-of-care treatment
- Findings raise hopes for improved treatment and potential cure for patients with a wide range of metastatic solid tumours
PARIS, France - A novel treatment strategy with personalised cell therapy significantly improves progression-free survival compared to standard immunotherapy in patients with advanced melanoma, according to ground-breaking results reported at the ESMO Congress 2022 from the phase 3 M14TIL trial (1).
“This study shows for the first time in a randomised, controlled trial that cell therapy can be efficacious and beneficial for patients with solid cancers,” said lead author John Haanen, Netherlands Cancer Institute, Amsterdam, Netherlands. “For patients with melanoma, we see a 50% reduction in the chance of progression of the disease or dying from the disease, which is absolutely practice changing. This is the first time that a TIL-based approach has been compared directly to standard-of-care treatment, in this case ipilimumab. So we are now able to position TIL treatment much better in the management landscape for patients with metastatic melanoma.”
“TIL therapy is an extraordinary therapy,” commented George Coukos, Lausanne University Hospital and the Ludwig Institute for Cancer Research, Lausanne, Switzerland, who was not involved in the study. “TIL is a new paradigm for treating cancers and, as these results clearly demonstrate, it’s efficacious and feasible at large scale. The findings raise hopes for the management and potential cure of metastatic solid tumours.”
The treatment essentially involves taking a small sample from a patient’s resected tumour, growing immune T cells from the tumour in the laboratory and then infusing the personalised TIL therapy back into the patient following chemotherapy. TILs recognise tumour cells as abnormal, penetrate them and then work to kill them.
The phase 3 M14TIL trial randomised 168 patients with unresectable stage IIIC-IV melanoma to immunotherapy with the anti-CTLA-4 antibody ipilimumab or to TIL treatment; most patients had failed prior anti-PD-1 treatment. Results reported for the first time at the ESMO Congress 2022 showed that patients treated with TIL therapy had significantly longer median progression-free survival of 7.2 months compared to 3.1 months in those receiving ipilimumab; the overall response rate to TILs was 49% versus 21% for ipilimumab; median overall survival was 25.8 months versus 18.9 months. Patients are still being followed up for overall survival.
Treatment options for patients with metastatic melanoma have changed considerably over the last 10 years with the development of checkpoint inhibitors, including the PD-1 inhibitors nivolumab and pembrolizumab and the CTLA-4 inhibitor ipilimumab. These drugs release a natural brake on the immune system so that the body’s own immune cells can recognise and attack tumour cells. “They have a very good safety profile and quite high efficacy and are now often given as first-line therapy. But if patients fail first-line treatments then the options become very scarce, particularly for patients failing anti-PD-1 drugs so there is a real unmet need,” explained Haanen. He added: “In our study, 89% of patients had failed anti-PD-1 treatment.” The remaining patients joined the trial before anti-PD-1 therapies were licensed.
Exploring the possible mechanism by which TIL therapy is effective in patients who have failed anti-PD-1 treatment, Haanen suggested: “We think that the mechanism of resistance to anti-PD-1 treatment is mostly delivered by the tumour microenvironment. So when we take these cells out of their natural environment, reactivate them in the laboratory, grow them up to very large numbers and give them back to the patients we can overcome some of the escape mechanisms. And that’s what we are seeing – otherwise TILs wouldn’t work in this setting.”
Even though grade 3 or higher adverse events occurred in all patients treated with TIL therapy and 57% of those randomised to ipilimumab, Haanen specified: “The side-effects are well manageable and most resolve by the time patients leave the hospital after their TIL therapy”. He also added that most side-effects are related to the other therapies, including chemotherapy and interleukin-2, that patients receive as part of the TIL regimen. About the impact of TIL therapy, Haanen concluded: “TIL has the potential to benefit patients with a wide range of solid tumours and trials are currently underway in many cancer types, including lung, cervical and head and neck cancers.”
Haanen explained that the trial was run by academics in the Netherlands and Denmark, with no industry involvement. The researchers are now working to obtain EMA approval for their TIL therapy to try to ensure that it remains affordable, free from commercial pressures.
“The results from this phase 3 study could potentially lead to regulatory approval that would be practice changing,” said Coukos. “It would enable countries that would consider this path to establish centres that can deliver TIL therapy for patients and establish this a potential second-line treatment in advanced melanoma.”
Disclaimer
This press release contains information provided by the author of the highlighted abstract and reflects the content of this abstract. It does not necessarily reflect the views or opinions of ESMO who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct.
References
- LBA3 ‘Treatment with tumor infiltrating lymphocytes (TIL) versus ipilimumab (IPI) for advanced melanoma: results from a multicenter, randomized phase 3 trial’ will be presented by John Haanen during Presidential Symposium 1 on Saturday, 10 September, 16:30 to 18:00 CEST in Paris Auditorium. Annals of Oncology, Volume 33 Supplement 7, September 2022
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. Svane2
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 (7th edition), ≥18 ≤ 75 years, were randomized 1:1 to TIL or ipilimumab (3mg/kg q3wks, max 4 doses). Pts were stratified for BRAFV600 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: 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.