113P - p16 immunohistochemical (IHC) expression (exp) predicts benefit from irinotecan in metastatic colorectal cancer (mCRC): A translational analysis of the TRIBE and TRIBE2 studies

Background

CDKN2A encodes the inhibitor of the cyclin-dependent kinase p16 and is frequently methylated in CRC, thus reducing p16 exp levels. In CRC preclinical models, CDKN2A demethylation induces topoisomerase I upregulation increasing the sensitivity to irinotecan. In mCRC patients (pts), the role of p16 exp has been poorly investigated.

Methods

Tumor samples of pts from phase III TRIBE2 study comparing upfront FOLFOXIRI/bevacizumab (bev) versus (vs) FOLFOX/bev were assessed for p16 IHC exp. A validation analysis in pts treated with FOLFIRI/bev in the TRIBE study was conducted.

Results

231 tumors of the TRIBE2 study were assessed for p16 exp. Overall, 152 (66%) and 79 (34%) were classified as p16⁺ (IHC 2+ and 3+) and p16^- (IHC 0 and 1+), respectively. In the p16⁺ group, 69 (45%) and 83 (55%) pts received FOLFOXIRI/bev and FOLFOX/bev, respectively, while in the p16^- cohort, FOLFOXIRI/bev was administered in 37 (47%) and FOLFOX/bev in 42 (53%) cases. Pts with p16^- tumors had more frequently an ECOG PS of 1-2 (16% vs 6% p=0.0098) and a BRAF mut tumor (26% vs 7% p=0.0002). No PFS difference was observed between p16⁺ and p16^- pts, while a trend for a longer OS was shown for p16⁺ pts (25.5 vs 21.3 months [m] HR 0.74 95% CI 0.53-1.02 p=0.068), though not confirmed at the multivariate analysis (p=0.61). In the p16⁺ cohort, pts treated with FOLFOXIRI/bev reported longer PFS (12.8 vs 9.4 m HR 0.55 95% CI 0.39-0.78 p=0.0008) and OS (30.0 vs 21.4 m HR 0.66 95% CI 0.46-0.95 p=0.026) than those receiving FOLFOX/bev. Conversely, no difference was observed among p16^- pts in terms of both PFS (9.0 vs 9.4 m, HR 0.91 95% CI 0.57-1.46 p=0.69) and OS (21.3 vs 19.5 m, HR 0.95 95% CI 0.58-1.57 p=0.85), thus suggesting a differential treatment effect according to p16 exp (p_interaction PFS =0.12; p_interaction OS =0.19). Among pts treated with FOLFIRI/bev in the TRIBE study (n=58), pts with p16⁺ tumors reported longer PFS and OS than those with p16^- (HR PFS: 0.47 95% CI 0.22-0.99 p=0.041; HR OS 0.43 95% CI 0.21-0.91 p=0.024).

Conclusions

In mCRC, p16⁺ exp seems associated with higher benefit from irinotecan. Prospective confirmation in independent randomized series is warranted.

Legal entity responsible for the study

The authors.

Funding

Italian Ministry of University and Research under PNRR - M4C2- I1.3 Project PE_00000019 "HEAL ITALIA” to Chiara Cremolini CUP: I53C22001440006; GONO Foundation; ARCO Foundation.

Disclosure

D. Rossini: Financial Interests, Personal, Other, Honoraria: Takeda Pharmaceuticals. F. Pietrantonio: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, MSD, Bayer, Astellas, Takeda, GSK, Johnson&Johnson, Rottapharm; Financial Interests, Personal, Invited Speaker: Amgen, Merck Serono, BMS, Lilly, Servier, Bayer, Pierre Fabre, AstraZeneca, Astellas, Daiichi Sankyo, Takeda; Financial Interests, Personal, Expert Testimony: Ipsen; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Incyte, Agenus; Financial Interests, Institutional, Invited Speaker: Lilly, Amgen. C. Cremolini: Financial Interests, Personal, Advisory Board: Roche, MSD, Pierre Fabre, Nordic Pharma, Takeda; Financial Interests, Personal, Invited Speaker: Bayer, Servier, Merck Serono; Financial Interests, Personal, Expert Testimony: Amgen; Financial Interests, Institutional, Invited Speaker: Roche, Bayer, Servier, Merck, Seagen, Hutchinson. All other authors have declared no conflicts of interest.