1943 - GRAY-B: An open label multicenter phase-2 GEM study on ipilimumab and radiation in patients with melanoma and brain metastases

Background

Estimated median overall survival (OS) in patients (pts) with brain metastases (BM) ranges between 1.8-10.5 months (mo). Ipilimumab (IPI) has shown activity against mel-BM. Radiation (RT) might be synergistic to anti-CTLA-4 blockade through an ‘abscopal’ effect.

Methods

Open label single stage multicenter phase 2 study, assuming a historical 20% 1-year survival rate (1y SR) with RT. Target sample size: 56 evaluable pts. Target 1y SR: 35% (α= 0.05, ß= 0.2). Objectives: Primary: 1y SR; Secondary: progression free survival (PFS); OS; objective response rate (mWHO); safety and feasibility. Treatment: IPI 3 mg/Kg iv q 3 weeks (4 cycles); whole brain RT (WBRT) 30 Gy in 10 fractions (or equivalent), started between C1 and C2. Main eligibility: First episode of BM in mel pts; Karnofsky PS > 70%; Barthel Index > 10; RTOG-RPA class 2; measurable disease; LDH  16 mg/d (or equivalent).

Results

This is a preliminary analysis after recruiting 43/56 pts (Apr 2014 - Mar 2016). Demographical characteristics are shown in the table.

Age (median (range))	65 (37-83)
Gender (male; female)	25; 18
Karnofsky PS(100-90; 70-80)	33; 8
Barthel Index (>15; 10-15)	35; 2
BRAF mutation	33% (11/33)
Previous lines (0; 1; >1)	22; 14; 7
Previous BRAF/MEK inh	9.3% (4/43)
Brain mets (single; multiple; NA)	8; 29; 6
Liver mets	10/43
Corticosteroids at baseline/C1	32.4%

Treatment exposure: IPI: 19 pts completed 4 cycles; RT: 3 pts had early termination. Efficacy: Estimated 1y SR: 31.4% (95%CI 14.0;48.8%), median OS 5.2 mo (95%CI 3.1;6.3); median PFS: 3.21 mo (95%CI 1.7;4.7). Safety: Serious AEs were reported for 23 pts (53.5%), 4 were treatment-related, G3 hepatic toxicity (IPI), G3 cephalalgia and vomiting (RT), G2 scalp erythema (RT) and G3 left hemiparesis. Treatment-related G3 toxicities were seen in 6 pts (14%): asthenia, skin rash, cephalalgia, emesis, hypothyroidism, liver toxicity, hemiparesia. A total of 22 pts died; none of the deaths were study-related.

Conclusions

Concomitant IPI + WBRT is feasible. There were no unexpected safety issues. Despite the frequent need for costicosteroids at baseline, interim 1y SR is 31.4%. The trial is ongoing. Updated results will be presented.

Clinical trial identification

EudraCT 2013-001132-22

Legal entity responsible for the study

GEM (Grupo Español de Melanoma / Melanoma Spanish Group)

Funding

BMS

Disclosure

J.A. Lopez Martin: BMS: research grant, Advisory Board MSD: research grant, advisory board Roche: research grant Novartis: research grant. I. Marquez Rodas: Advisory role: BMS honoraria and travel accomodation: BMS. S. Martin-Algarra: BMS: Advisory Board, paid lectures. All other authors have declared no conflicts of interest.