Session Item

A synergy between radiotherapy (RT) and anti-CTLA-4 antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to: i) determine the maximum tolerated dose (MTD) and safety profile of RT combined with ipilimumab (ipi) in patients (pts) with metastatic melanoma, and ii) assess the impact of ipi + RT systemic immune antitumor response (SIAR) and tumor growth rate (TGR) variation (ΔTGR) of irradiated (TGR_irr) and non-irradiated (TGR_non-irr) lesions.

A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of RT at week 4 combined with 10 mg/kg ipi every 3 weeks for 4 doses. The adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for AEs, version 4.0. Blood samples were collected at baseline, W4 (before 2nd ipi injection) and W6 (after ipi + RT) to phenotype T cells. TGR, defined as an increase in tumor volume during 1 month, was computed for TGR_irr, and TGR_non-irr in 2 periods: (i) Reference-TGR (REF-TGR) on baseline, and (ii) Experimental-TGR (EXP-TGR) between baseline and 1st evaluation. The ΔTGR between REF-TGR and EXP-TGR was used to assess the treatment effect. A negative value reflected a slowdown of disease progression.

19 pts received ipi between August 2011 and July 2015. Nine pts received the 4 doses of ipi. All pts received the combined RT. Grade 3 AEs occurred in 8 pts, the most common being colitis and hepatitis. No drug-related death occurred. DLT occurred in 2/6 pts in the cohort receiving 15 Gy. The MTD was 9 Gy dose. Two pts had complete response, 3 had partial response and 7 had stable disease, giving an objective response rate of 37%. Ipi alone could increase effector T cells (TEM), Treg and ICOS+ CD4+ T cells at W4. At W6, only TEM and ICOS+ CD4+ T cells significantly increased suggesting that combination could increase activated memory CD4+ T cells rather than Treg cells. CD8+ T cells did not increase at W4 while central memory T cells (TCM) and terminally differentiated (TEMRA) increased between W4 and W6, suggesting that RT + ipi could boost these CD8⁺ T populations. Increased CD8 from baseline to W4 was significantly correlated to progession-free survival (PFS) (p=0.0163). Interestingly, a higher effect of ipi+ RT seemed to be associated with a deeper ΔTGR_non-irr than ΔTGR_irr, although insignificant. The EXP-TGR_non-irr was significantly associated with progressive disease.

When combined with ipi at 10 mg/kg, the MTD of RT was 9 Gy. This combination of ipi + RT appeared to be associated with antitumor activity. Ipi + RT could increase CD4+ and CD8+ ICOS+ T cells. Increased CD8+ was significantly associated to PFS. Thus, immune biomarkers may be useful for early response evaluation. ΔTGR_non-irr lesions could be more important than for irradiated lesion in responding pts and may be related to abscopal effect.