Abstract 489P
Background
In the management of metastatic colorectal cancer (mCRC) patients, the anti-EGFR antibody cetuximab has demonstrated a clinical benefit only in KRAS wild-type (wt) tumors. Although KRAS mutational status is an important biomarker to stratify patients for anti-EGFR therapy, still not all the patients harboring KRASwt benefit from this treatment. In addition, after an initial response, secondary resistance emerges due to genetic alterations in the PI3K and MEK pathways. Therefore PI3K inhibitors might be an effective therapeutic option in selected patients that have progressed to cetuximab. MEN1611 is a PI3K inhibitor in clinical development showing high activity against p110 α, β and ɣ isoforms and minimal inhibition of δ isoform.
Methods
In this work we investigate MEN1611 efficacy in combination with cetuximab in different patient derived xenograft (PDX) models obtained from mCRC patients characterized by N-KRASwt, BRAFwt and mutated PIK3CA. Mice were treated twice weekly with 20 mg/kg cetuximab (ip), daily with 6.5 mg/kg MEN1611 (os) or with their combination. No tolerability issues were observed with the described combination treatment.
Results
Two, among the established PDX models, were proven to be cetuximab resistant (in progressive disease -PD- according to mRECIST criteria). They harbored respectively H1047R (a driver mutation with allele frequency -AF- 17% in CRC patient population) or V344G PIK3CA mutation (AF 5%). In both models MEN1611 was ineffective (PD according to mRECIST), but, impressively, the combination was able to overcome cetuximab resistance inducing tumor- growth delay or disease stabilization, respectively, thus substantiating the potential utility of PI3K inhibition in mCRC.
Conclusions
In conclusion, in the selected genetic setting, the combination of MEN1611 with cetuximab displayed higher activity compared to single agents showing a synergistic effect in cetuximab-resistant PDX models. These data support the ongoing C-Precise phase Ib/II study investigating anti-tumor activity and safety of MEN1611 in combination with cetuximab in PIK3CAmut/N-K-RASwt/BRAFwt mCRC patients (NCT04495621).
Clinical trial identification
NCT04495621.
Editorial acknowledgement
Legal entity responsible for the study
Menarini Ricerche.
Funding
Menarini Ricerche.
Disclosure
All authors have declared no conflicts of interest.