Purpose: TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors. Patients and Methods: TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, N = 6) or certolizumab (400/200 mg, N = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1. Results: Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts. Conclusions: Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations.

Methods and Patients This randomized, placebo-controlled, phase 3 trial investigated the efficacy of lenalidomide (LEN) maintenance after transplantation for multiple myeloma. Patients, under 65 years of age, with non-progressive disease after a first-line autologous stem-cell transplant (ASCT) were randomized to receive maintenance with placebo or LEN (10 to 15 mg/d) until disease progression or unacceptable toxic effects. From July 2006 to August 2008, 614 patients were randomized. In January 2011, the DSMB recommended to stop LEN due to the increased incidence of second primary malignancies (SPMs). The median duration of maintenance treatment with LEN was 2 years (IQ range= 1-3). We previously reported this trial with a median follow-up of 45 months (Attal et al, N Engl J Med 2012). Results As of May 2013, median follow-up was 70 months from diagnosis and 60 months from randomization. LEN maintenance improved the 5-year progression-free survival (PFS) post randomization: 42%, versus 18% with placebo (p<0.0001), respectively. Overall, 403 patients had disease progression and 364 have started a second line therapy. The median 2nd PFS for the treated patients (time from progression in first-line to the second progression or last follow-up or death) was 10 months within the LEN arm versus 18 months within the placebo arm (p<0.0001), respectively. The median 2nd PFS in the LEN and placebo groups were 9 and 8 months (NS) for patients treated with a bortezomib-based regimen, 8 months and 18 months (p<0.01) for patients treated with an IMiD-based regimen, 14 months and 28 months (p=0.03) for patients treated with a regimen without new agents or with a second line ASCT, respectively. The 5-year post randomization overall survival (OS) was similar in the 2 groups: 68% in the LEN group versus 67% in the placebo group (HR=1). In the multivariate analysis, the OS was significantly related to age (p=0.001), International Staging System (p=0.03), and poor cytogenetics (t(4;14) or chromosome 17 deletion; p=0.008). The median survival after the first progression was 29 months in the LEN group versus 48 months in the placebo group (p< 0.0001). An increased incidence of SPMs was observed in the LEN group: 44 SPMs (hematologic: 20, non-hematologic: 24) in 35 patients were reported in the LEN group versus 28 SPMs (hematologic: 6, non-hematologic: 22) in 20 patients in the placebo group. The incidence of SPMs (excluding non melanoma skin cancers) was 2.3 per 100 patient-years in the LEN group versus 1.3 in the placebo group (p=0.03). Conclusion This new analysis confirms that lenalidomide is an effective treatment to prolong PFS after transplantation for multiple myeloma patients. However, this impressive benefit is not currently associated with an improved overall survival, due to a shorter survival after the first progression. Disclosures: Attal: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Off Label Use: FRONTLINE THERAPY WITH CARFILZOMIB IN MULTIPLE MYELOMA. Facon:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Hulin:JANSSEN: Honoraria; CELGENE: Honoraria. Moreau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Roussel:JANSSEN: Honoraria; CELGENE: Honoraria. Avet-Loiseau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau.

These results emphasise that ADRs leading to hospitalisation are frequent, with one-third of them likely to be preventable. Moreover, the risk of ADRs mainly involved a small number of drugs. Our experience suggests that there is a need for further studies to validate the French standardised scale of preventability assessment.

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