Genomic loss of heterozygosity (LOH) and survival in patients (pts) treated with epirubicin, oxaliplatin, capecitabine (EOC) ± panitumumab (P) in the REAL3 trial

Background

Background: Homologous recombination deficiency can result from deleterious BRCA1/2 mutations or other mechanisms and leads to a common phenotype of genomic LOH. LOH is correlated with platinum response and sensitivity to rucaparib (PARP inhibitor) in ovarian cancer (McNeish ASCO 2015). We hypothesized that genomic LOH would be associated with survival in pts treated with EOC ± P in the REAL3 study.

Methods

Methods: REAL3 was a randomised, open-label phase 3 trial in pts with treatment naïve, metastatic or locally advanced oesophagogastric cancer (OGC) assessing addition of P to EOC; no survival benefit was associated with EOC-P therapy. Pre-treatment tumour biopsies were selected for high tumour content (>30%). The percentage of interrogable genome with LOH (%LOH) was quantified by assessment of single-nucleotide polymorphisms spanning the whole genome using a next-generation sequencing based assay (Frampton et al., Nat. Biotechnol. 2013). Optimisation of survival benefit as measured by Hazard Ratio (HR), its significance, sensitivity and specificity was used to derive an LOH cut-off separating pts into LOH high and low cohorts which were associated with survival.

Results

Results: Eighty six (of a total 553 pts treated) tumours were sequenced (n = 42 EOC, n = 44 EOC-P). LOH was inferred for 54 (63%). Median %LOH for the entire cohort was 12.1%; this was highest for oesophagogastric junction (OGJ) tumours (15.4%), median %LOH for stomach and oesophageal tumours were 11.4% and 11.6% respectively. Pts with LOH ≥21% (n = 9/54, 17%) appeared to have a progression free (HR 0.48 (95% CI 0.21-1.09), p = 0.08) and overall survival (HR 0.43 (95% CI 0.19-0.97), p = 0.04) benefit. The proportion of pts with oesophageal, OGJ and stomach cancers with LOH ≥21% were 16%, 23% and 8% respectively.

Conclusions

Conclusions: Genomic LOH was inferred for the majority of sequenced samples. OGJ tumours had the highest median LOH. An LOH high cutoff of ≥21% (17% of the population) was associated with an overall survival benefit for pts treated with platinum chemotherapy. LOH high platinum sensitive pts may benefit from PARP inhibitor therapy; we will investigate this hypothesis using rucaparib in the PLATFORM trial.

Clinical trial identification

Not applicable

Legal entity responsible for the study

The Royal Marsden Hospital NHS Foundation Trust

Funding

Clovis Oncology

Disclosure

I. Chau: Advisory board: Sanofi Oncology, Eli-Lilly, Bristol Meyers Squibb, MSD, Merck Serono, Gilead Science. Research Funding: Janssen-Cilag, Sanofi Oncology, Roche, Merck-Serono, Novartis Honoraria: Taiho, Pfizer, Amgen, Eli-Lilly, Bayer. D. Cunningham: Research funding: Amgen, AstraZeneca, Bayer, Celgene, Medimmune, Merck Serono, Sanofi, Clovis. All other authors have declared no conflicts of interest.