79P - CREBBP alterations found in extreme responders to PD-1 inhibition in patients (pts) with refractory solid tumors treated in a phase 1 trials unit

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Immunotherapy
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Therapy
Presenter Valentina Boni
Citation Annals of Oncology (2016) 27 (6): 15-42. 10.1093/annonc/mdw363
Authors V. Boni1, J. Garcia-Donas1, E. Garralda1, C. Muñoz Sanchez-Miguel1, A. Calles1, J.F. Rodriguez-Moreno2, E. Calvo1
  • 1Oncology, START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, 28050 - Madrid/ES
  • 2Gyn, Gu And Skin Cancer Unit, CIOCC-Fundacion Hospital de Madrid, Madrid/ES

Abstract

Background

Clinical data have revealed the remarkable potential for T-cell-modulating agents to induce potent and durable responses in a subset of cancer pts. Biomarker-driven selection would minimize unnecessary exposure of pts to life-threatening immune-related toxicities and reduce the financial costs of these expensive agents. Genomic profiling of tumor samples of pts who achieved extreme responders (> 1year) may help identifying predictive biomarkers.

Methods

We analyzed formalin fixed paraffin embedded (FFPE) tissue from pts with refractory solid tumors extreme responders (> 1 year) to PD1 inhibition. A platinum refractory, bladder pt (#1), having PR lasting 18-months (m), still on treatment; one TNBC (#2, in 3th line) with PR lasting 24-m, one bladder pt (#3, in 4th line), achieving PR lasting 14-m were analyzed. Genomic profiling using Foundation Medicine T5a test was performed in a CLIA-certified lab (Foundation Medicine, Inc.).

Results

CREBBP alterations were found in extreme responders. Pt #1 presented a frame shift mutation R1443fs*10 involving the domain for histone acetylation; pt #2 had a frame shift mutation E649*5 in the KIX, KID binding domain; pt #3 harbored a mutation in the splice site 1941 + 1G > A for the transcriptional adaptor zinc finger 2. Additional mutations are described in the Table below.

1# 2# 3#
CDKN2A/B loss S12*
CREBBP R1443fs*10 E649fs*5 splice site 1941 + 1G > A
EGFR amplification (amp)
NCOR1 Q1993*
TP53 S241C K320fs*25 S215R
CCND1 amp
ERBB2 G292R
FGF19 amp
MLL2 P1038fs*18
NOTCH3 S1871*
CCND3 amp
CCNE1 amp
LRP1B truncation
MAP3K13 deletion
PIK3CA E542K

Conclusions

Present genomic analyses revealed CREBBP alterations in extreme responders to PD1 inhibition independently by the tumor type. CREBBP is ubiquitously expressed and it is known to play many different roles in immune response. Functionally, the described mutations could impair histone acetylation and transcriptional regulation of CREBBP targets. This association deserves validation in a wider anti-PD1 treated cohort of pts but it suggests that CREBBP mutations could have a potential role as predictive biomarker for immunological treatments.

Clinical trial identification

Legal entity responsible for the study

START MAdrid-CIOCC

Funding

START Madrid-CIOCC

Disclosure

All authors have declared no conflicts of interest.