Abstract 382P
Background
Solid biopsy (SB) is commonly used to assess RAS mutations (mt) in mCRC pt. But cfDNA analysis is a less invasive method and may show tumour’s genetic heterogeneity. We present outcomes of serial monitoring RAS mt status by cfDNA at different 1L treatment time points in RASwt pts in SB, overall response rate (ORR), and progression free survival (PFS).
Methods
Prospective, observational, multi-centre study in RASwt mCRC pt assessed by SB and treated according to clinical practice. The cfDNA RAS mt status was evaluated before starting 1L, at 20 (±2) weeks (w), and at disease progression (DP) by Idylla™ test (MAF cut-offs: 0.4% [KRAS]; 1.5% [NRAS]). Moreover, next-generation sequencing (NGS) AVENIO® was used to analyze other genes additional to RAS at DP.
Results
In pt under P+CT, % of RASmt pt varied across time, with the highest % at DP and only 2 pt with emergent mt at 20w (Table). Six/40 pt with sample available at baseline and DP converted to RASmt. The NGS revealed genomic variants associated with anti-EGFR resistance in 6/8 pts at DP. There were no statistically significant differences in ORR by baseline cfDNA: 81.3% (71.8 - 88.7) RASwt pt (n= 91) vs 71.4% (29.0 - 96.3) RASmt pt (n= 7) (p= 0.618). There were also no differences in ORR between pt always wt (n= 84) and pt with mt cfDNA at any time point (n= 14): 82.1% (72.3 - 89.7) vs 71.4% (41.9 - 91.6) (p= 0.463). There were also no differences in PFS between these 2 pt groups: 12.9 months (m) (10.3 - 14.6) vs 10.3 m (5.3 - 19.2) (p= 0.626). Table: 382P
| Patients treated with panitumumab (n= 103) | |||
| Baseline (n=103) | 20 ± 2 weeks (n=74) | Disease progression (n=45) | |
| RASmt, n (%) | 7 (6.8%)* | 2 (2.7%) | 7 (15.6%) |
| KRASmt, n (%) | 5 (4.9%) | 2 (2.7%) | 5 (11.1%) |
| NRASmt, n (%) | 2 (1.9%) | 0 (0%) | 2 (4.5%) |
Proportions of mutated patients based on the number of samples analysed at each time point. ∗ Discordant patients between solid biopsy and circulating free DNA.
Conclusions
The highest proportion of RASmt pt was at DP, when a significant percentage of pt presented emerging mutations, explaining in part the appearance of resistance to 1L treatment. NGS analysis suggested that resistance is promoted by a complex mutational process. In our study, RASmt by itself did not predict the ORR or PFS for P+CT, although they tended to be higher in RASwt pt.
Clinical trial identification
NCT02792478, April 2015.
Editorial acknowledgement
The authors wish to thank Irene Mansilla-Núñez from TFS HealthScience for the medical writing support.
Legal entity responsible for the study
Amgen S.A.
Funding
Amgen S.A.
Disclosure
M. Valladares: Financial Interests, Other: Roche, Merck, Amgen, Sanofi, Servier, Bayer, Celgene. M.J. Safont Aguileria: Financial Interests, Advisory Role, and funding to attend congresses and training.: Roche, Merck, Amgen, Sanofi; Financial Interests, Advisory Role: Servier, Bayer, MSD, BMS, Pierre Fabre. E. González-Flores: Financial Interests, Advisory Board, and lectures: Amgen. P. García Alfonso: Financial Interests, Advisory Role, and speaker: Amgen, Merck, Bristol, Sanofi, Servier, Bayer, MSD, Lilly, Pierre Fabre, Roche. E. Aranda Aguilar: Financial Interests, Advisory Role: Amgen, Merck, Bristol Myers Squibb, Sanofi, Bayer, Roche. M. Llanos-Munoz: Financial Interests, Invited Speaker, and advisory board.: Amgen, Roche; Financial Interests, Invited Speaker: AAA, Servier, Sanofi, Ipsen, Pierre Fabre; Financial Interests, Advisory Board: Incyte. J. Aparicio: Financial Interests, Advisory Role: Amgen, Merck, Sanofi, Servier, Bayer, Pierre Fabre. M. Salgado Fernandez: Financial Interests, Advisory Role, and speaker: Amgen. R. Vidal Tocino: Financial Interests, Advisory Role, and educational and scientific activities and travel support: Amgen, Sanofi, Roche, BMS; Financial Interests, Advisory Role: Merck, Servier, Bayer; Financial Interests, Other: educational and scientific activities and travel support: Pierre Fabre, Lilly. B. Massuti Sureda: Financial Interests, Speaker’s Bureau, Travel, Accommodations, Expenses and Advisory role: Roche; Financial Interests, Advisory Role, and Travel, Accommodations, Expenses: Merck Sharp & Dohme, Boehringer Ingelheim, Janssen; Financial Interests, Advisory Role: Bristol-Myers Squibb; Financial Interests, Speaker’s Bureau: AstraZeneca, Pfizer, Merck Serono, Amgen. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Bayer, HMP, Ipsen, Merck, Midatech, MSD, Novartis, Pierre Fabre, Roche, Servier; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Other, Other, Honoraria received by spouse for advisory board or invited speaker roles: AbbVie, AstraZeneca, Bayer, Boehringer, Bms, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, Pharma Mar, Roche, Sanofi, Servier, Takeda. A. Lloansi Vila: Financial Interests, Full or part-time Employment, and stakeholder: Amgen. All other authors have declared no conflicts of interest.