KEY TAKEAWAYS
- The PARADIGM trial showed that first-line mFOLFOX6 plus panitumumab (PAN) resulted in longer median overall survival (OS) compared to bevacizumab (BEV) in patients with RAS wild type (WT) and left-sided metastatic colorectal cancer (mCRC).
- The study evaluated the usefulness of negative hyperselection by gene alterations in ctDNA related to primary resistance to anti-EGFR therapy.
- Baseline plasma ctDNA was assessed using a custom panel for preplanned gene alterations for hyperselection.
- Among the evaluated patients, 28% had at least one gene alteration, including KRAS/NRAS, BRAFV600E, PTEN, EGFR, HER2, MET, and fusions.
- Negative hyperselection using ctDNA may identify appropriate patients for first-line PAN over BEV, regardless of primary sidedness, and these results warrant further validation in additional cohorts.
Patients (pts) with RAS wild type (WT) and left-sided metastatic colorectal cancer (mCRC) in the PARADIGM trial had a longer median overall survival (OS) with first-line mFOLFOX6 plus panitumumab (PAN) compared to bevacizumab (BEV) (37.9 vs 34.3 months, respectively; hazard ratio [HR], 0.82; P=0.031) compared to (HR 1.09; Yoshino T, et al. ASCO 2022 LBA1). They assessed the value of ctDNA gene alteration-based negative hyperselection for initial resistance to anti-EGFR therapy.
Patients enrolled in the biomarker research (NCT02394834) had their plasma ctDNA levels
(>10 ng/mL and >10 nM DNA) measured at baseline with a specialised panel (PlasmaSELECT-R 91, PGDx). HER2 and MET amplifications, as well as ALK, RET, or NTRK1 fusions, were among the predetermined gene modifications used for hyperselection.
They were able to analyse ctDNA from pretreatment samples for 733 (91%) of the 802 pts in the whole study set. Of these patients, 204 (28%) had at least 1 gene mutation, the most common being KRAS/NRAS (8%) followed by BRAFV600E (11%), PTEN (5%), EGFR (3%), HER2 (5%), MET (1%), and fusions (1%). PAN vs BEV was associated with a longer OS in 529 (72%) hyperselected pts without any gene changes; the OS HRs ranged from 0.76 to 0.82, and the median OS gains ranged from 6.6 to 8.0 months, regardless of main sidedness (Table).
Patients with any of these gene changes had a similar or worse OS with PAN vs BEV regardless of the dominant side (Table). Patients who might benefit more from first PAN than BEV could be selected using negative hyperselection using ctDNA rather than tumour sidedness. This study’s findings need to be confirmed in larger cohorts.
Source: https://meetings.asco.org/abstracts-presentations/215764
Clinical trial: https://clinicaltrials.gov/ct2/show/NCT02394795/
Shitara, K., Muro, K., Watanabe, J., Yamazaki, K., Ohori, H., Shiozawa, M., Yasui, H., Oki, E., Sato, T., Naito, T., Komatsu, Y., Kato, T., Soeda, J., Yamamoto, K., Yamashita, R., Akagi, K., Ochiai, A., Uetake, H., Tsuchihara, K. and Yoshino, T. (2023). Negative hyperselection of patients with RAS wild-type metastatic colorectal cancer for panitumumab: A biomarker study of the phase III PARADIGM trial. Journal of Clinical Oncology, 41(4_suppl), pp.11–11. doi:https://doi.org/10.1200/jco.2023.41.4_suppl.11.
