Benjamin A. Weinberg, MD
The tide may finally be shifting as drugs targeting specific KRAS mutations have made their way into the clinic, and there is particular excitement around the oral WEE1 inhibitor, adavosertib (AZD1775). WEE1 is a cell cycle regulatory protein and WEE1 inhibition may have increased activity in tumors with DNA repair deficiency. In a phase 2 maintenance study, Seligmann and colleagues randomized 69 patients with RAS- and TP53-mutated mCRC with sta ble disease or better after 16 weeks of induction chemotherapy 2:1 to receive adavosertib vs active monitoring. Median progression-free survival (mPFS) was significant improved with adavosertib (3.61 vs 1.68 months), and patients with left-sided primary tumors appears to derive more benefit. While this finding needs to be further explored in larger clinical trials, it is exciting that there may finally be a new treatment option for patients with this specific molecular subtype of mCRC.
Another maintenance mCRC trial of interest is the PANAMA trial, a phase 2 study in which 248 patients with RAS wild-type mCRC were randomized 1:1 to 5-fluorouracil/leucovorin with or without panitumumab, an anti-epidermal growth factor receptor antibody, following induction chemotherapy with 6 cycles FOLFOX/panitumumab. Modest and co-workers report that mPFS was significantly improved with continuing panitumumab in the maintenance setting (8.8 vs. 5.7 months), and there was a trend towards an overall survival benefit as well. This study further supports continuing anti-EGFR therapy with maintenance chemotherapy for patients with RAS wild-type mCRC.
Finally, in stage III CRC, there is a big movement towards using circulating tumor DNA (ctDNA) as a method to monitor disease recurrence by detecting minimal residual disease based on tumor DNA being shed into the bloodstream . Henriksen et al . evaluated 168 patients with stage III CRC who underwent surgical resection and plasma ctDNA testing using 16 patient-specific DNA variants (tumor tissue-informed testing). The rates of recurrence were much higher in patients with detectable ctDNA post-operatively and/or after the completion of adjuvant chemotherapy, whereas those patients with persistently undetectable ctDNA did not recur. ctDNA is a powerful new technology that we are still learning how to best harness in the clinic, and this study demonstrates its prognostic value and potential ability to detect recurrence prior to standard imaging surveillance. Moreover, the rate of ctDNA rise was also prognostic of survival. ctDNA testing is likely to become standard of care in the management of stage II/III colorectal cancer in the very near future, and we hope that eventually it may be able to predict who needs to receive adjuvant chemotherapy and who does not.