ДУ "Інститут урології
імені академіка О.Ф.Возіанова"

PRESS RELEASE

EMBARGOED until 8 October 2016, 08:15 hours (CEST)

Ipilimumab as adjuvant therapy improves overall survival in high risk stage III melanoma

LUGANO-COPENHAGEN, 8 October, 2016 – Ipilimumab as adjuvant therapy significantly improves overall survival in patients with high risk stage III melanoma, according to the EORTC 18071 phase III trial results presented for the first time today at the ESMO 2016 Congress in Copenhagen.¹

“Ipilimumab is an immune checkpoint inhibitor that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4),” said lead author Professor Alexander Eggermont, director general, Institut Gustave Roussy, Villejuif, France. “It was approved in 2011 for first-line treatment of advanced melanoma in the US and Europe. The next question was its utility in the adjuvant setting.”

The EORTC 18071 phase III trial evaluated ipilimumab as adjuvant therapy for patients with high risk stage III melanoma. During 2008 to 2011, 951 patients were randomised to ipilimumab or placebo. Interferon was not used as the comparator because in Europe it is not routinely used nor accepted as a standard of care.

As reported in 2015, the study met its primary endpoint after a median follow up of 2.3 years, with ipilimumab significantly improving recurrence-free survival.² The drug was subsequently approved by the US Food and Drug Administration as adjuvant therapy for stage III melanoma.

Now, at 5.3 years median follow up, the impact on overall survival is reported and represents a 28% reduction of the relative risk of death (hazard ratio 0.72, p=0.001). There was consistency across all endpoints with hazard ratios of 0.76 for recurrence-free survival and distant metastases-free survival (p<0.001 and p=0.002). In absolute terms, the overall survival rate at five years was 11% higher in the ipilimumab arm (65%) than in the placebo arm (54%).  

Ipilimumab is known to create immune-related adverse events. At 5.3 years, there were no additional toxicities or deaths since the initial report at 2.3 years. The most important grade 3-4 adverse events were gastrointestinal (16%), hepatic (11%) and endocrine (8%). These were managed by established algorithms and usually resolved within 4-8 weeks. Endocrine adverse events took much longer to resolve or required permanent hormonal replacement therapies.

Eggermont said: “Ipilimumab adjuvant therapy brings a significant improvement of overall survival and has a favourable risk-benefit ratio. It clearly represents a serious option for patients with stage III melanoma.”

Commenting on the results, Dr Olivier Michielin, head of Personalised Analytical Oncology, CHUV, Lausanne, Switzerland, said: “This was the first attempt to use checkpoint blockade in the adjuvant setting of melanoma. The effect was a 28% reduction in the risk of death, which is statistically and clinically significant, and an 11% absolute gain in overall survival at five years.”

“This was also an important scientific discovery,” added Michielin. “Ipilimumab works by stimulating the immune system against tumour antigens. In the adjuvant setting there is microscopic residual disease and, until now, it was not clear if there was a sufficient amount of antigens to trigger a response.”

He continued: “The risks and benefits of this option should now be discussed with our patients. The toxicity is not negligible and patients need to be aware of the adverse event profile. The 10 mg/kg regimen used in the trial is associated with potentially severe toxicities and should be reserved for experienced centres.”

Michielin concluded: “This trial represents an important milestone in the treatment of melanoma. These results open the door for other studies based on checkpoint blockade to try and improve cure rates in the adjuvant setting of melanoma as well as other disease types. We are currently waiting for the results of several trials including EORTC 1325 which is investigating pembrolizumab, a PD-1 checkpoint blocking antibody, compared to placebo in the adjuvant setting.”

-END-

Notes to Editors

References

¹ Abstract LBA2_PR – ‘Ipilimumab (IPI) vs placebo (PBO) after complete resection of stage III melanoma: final overall survival results the EORTC 18071 randomized, double-blind, phase 3 trial’ will be presented by Professor Alexander Eggermont during Presidential Symposium 1 on Saturday 8 October, 16:30 to 18:00 hours (CEST).

² Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A.Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522–530. doi: 10.1016/S1470-2045(15)70122-1.

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Abstract for LBA2_PR

Ipilimumab (IPI) vs placebo (PBO) after complete resection of stage III melanoma: final overall survival results from the EORTC 18071 randomized, double-blind, phase 3 trial

A.M.M. Eggermont¹, V. Chiarion-Sileni², J-J. Grob³, R. Dummer⁴, J.D. Wolchok⁵, H. Schmidt⁶, O. Hamid⁷, C. Robert⁸, P.A. Ascierto⁹, J.M. Richards¹⁰, C. Lebbé¹¹, V. Ferraresi¹², M. Smylie¹³, J.S. Weber¹⁴, C. Taitt¹⁵, V. de Pril¹⁶, G. de Schaetzen¹⁷, S. Suciu¹⁷, A. Testori^18
1Oncological Surgery, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France, ²Department of Dermatology, IOV-IRCCS, Melanoma Oncology Unit, Padua, Italy, ³Department of Dermatology & Skin Cancer, Aix-Marseille University, Hôpital de La Timone APHM, Marseille, France, ⁴Department of Dermatology, University of Zürich Hospital, Zurich, Switzerland, ⁵Melanoma and Immunotherapeutics Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, ⁶Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark, ⁷Clinical Research, The Angeles Clinic and Research Institute, Los Angeles, CA, USA,⁸Dermatology Unit, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France, ⁹Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy, ¹⁰Division of Hematology/Oncology, Oncology Specialists S.C., Park Ridge, IL, USA, ¹¹Department of Dermatology, APHP, Dermatology and CIC departments Hôpital Saint Louis, University Paris 7 INSERM U976, Paris, France, ¹²Department of Medical Oncology, Istituti Fisioterapici Ospitalieri, Rome, Italy, ¹³Department of Oncology, Cross Cancer Institute, Edmonton, AB, Canada, ¹⁴Department of Medicine, H Lee Moffitt Cancer Center (currently at Perlmutter Cancer Center at NYU-Langone Medical Center), Tampa, FL, USA, ¹⁵Worldwide Medical, Bristol-Myers Squibb, Princeton, NJ, USA, ¹⁶Worldwide Medical, Bristol-Myers Squibb, Braine-l’Alleud, Belgium, ¹⁷Melanoma and Children Leukemia Groups, EORTC Headquarters, Brussels, Belgium, ¹⁸Divisione Melanoma e Sarcomi Muscolo-Cutanei, European Institute of Oncology, Milan, Italy

Background: IPI has been an approved treatment for stage III melanoma in the US since 2015, based on a significant improvement in recurrence-free survival (RFS; hazard ratio [HR] 0.75; P=0.0013) (Eggermont et al, Lancet Oncol, 2015). Here, we report the impact of IPI on overall survival (OS) and distant metastasis-free survival (DMFS).

Methods: In this trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis alone). 951 pts (20%/44%/36% who had stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement) were randomized, stratified by stage and region, 1:1 to IPI 10 mg/kg (n=475) or PBO (n=476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was RFS (updated here). Secondary endpoints included DMFS, OS, and safety.

Results: At 5.3 yrs median follow-up, IPI demonstrated a statistically and clinically significant improvement in OS vs. PBO (HR=0.72, i.e. 28% risk reduction of death). Similar impact for RFS and DMFS were observed.

CI: Confidence interval, *95%, **95.8% or ***95.1%; NR: not reached; †stratified by stage Among pts who started IPI (n=471) or PBO (n=474), 54.1% (IPI) and 26.2% (PBO) experienced grade 3/4 AEs, consistent with previous reports. The most common grade 3/4 immune-related adverse events (AEs) in the IPI-treated pts were gastrointestinal (16.1%), hepatic (10.8%), and endocrine (7.9%). 251 (53.3%) pts discontinued IPI due to AEs; 5 (1.1%) died due to drug-related AEs.

Conclusions: IPI as adjuvant therapy provided a clinically and statistically significant improvement in OS with a favorable benefit-risk ratio in high-risk stage III melanoma patients. These data reinforce IPI as an important treatment option for these pts.

Clinical trial identification: NCT00636168

Legal entity responsible for the study: Bristol-Myers Squibb

Funding: Bristol-Myers Squibb

Keywords: adjuvant therapy, ipilimumab, survival, stage III melanoma