Erasca Announces Update on ERAS-007, an ERK Inhibitor, from HERKU...

ERAS-007, an innovative oral inhibitor targeting ERK, and palbociclib, an oral inhibitor of CDK4/6 known for its ability to suppress tumor cell proliferation, have displayed encouraging results in various laboratory and animal studies. The combination of ERAS-007 and palbociclib has demonstrated significant efficacy in a range of colorectal cancer (CRC) and pancreatic cancer models, both in vitro and in vivo. These findings provide strong evidence for the potential therapeutic benefits of combining ERAS-007 and palbociclib in patients with RAS-mutant CRC and pancreatic ductal adenocarcinoma (PDAC), thus offering a promising treatment strategy.

Study insights reveal that the adverse effects encountered by patients who underwent the combined treatment of ERAS-007 and palbociclib were temporary and controllable. Additionally, there were no significant interactions observed between the two drugs in terms of their pharmacokinetics. The safety profile of ERAS-007 combined with palbociclib in patients with either KRAS-mutant or KRAS wild-type colorectal cancer (CRC) or KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) was deemed acceptable, as the adverse events were reversible and manageable. However, despite these positive safety findings, the study revealed a lack of clinical effectiveness, leading to the decision not to pursue further development of the ERAS-007 and palbociclib combination in this specific patient population. The safety review committee has approved the highest dosage assessed so far, which involves administering ERAS-007 at a dose of 100 mg BID-QW, in combination with the approved monotherapy dosage of palbociclib at 125 mg QD, one week off schedule.

Table 1: TREAs Reported in ≥20% of all Patients
ERAS-007 Dose + palbociclib Dose	75 mg BID-QW + palbociclib 75 mg QD N=7	75 mg BID-QW + palbociclib 100 mg QD N=2	100 mg BID-QW + palbociclib 100 mg QD N=7	75 mg BID-QW + palbociclib 125 mg QD N=14	100 mg BID-QW + palbociclib 125 mg QD N=15	125 mg BID-QW + palbociclib 125 mg QD N=1	All
Diarrhea	28.6%	100%	57.1%	42.9%	40.0%	0%	43.5%
Nausea	28.6%	100%	42.9%	14.3%	60.0%	0%	39.0%
Vision Blurred	42.9%	0%	28.6%	28.6%	26.7%	0%	28.3%
Vomiting	14.3%	100%	28.6%	28.6%	20.0%	100%	28.3%
Fatigue	0%	100%	14.3%	14.3%	33.3%	100%	23.9%
Dermatitis acneiform	0%	50%	14.3%	21.4%	33.3%	0%	21.7%

KOL insights

“We are pleased that the early ERAS-007 clinical data continue to reinforce its potential to become a backbone for combination therapy. Moreover, through our signal-seeking trials, we have tested three biological hypotheses: preventing in-pathway resistance, reversing in-pathway resistance, and targeting adjacent pathways. We believe the encouraging efficacy data for ERAS-007 in combination with encorafenib and cetuximab in EC-naïve patients with BRAF CRC (preventing in-pathway resistance) provide compelling evidence to continue with further enrollment in this patient population” –Expert Opinion.

Conclusion

The combination of ERAS-007 and palbociclib in patients with KRAS/NRAS-mutant colorectal cancer (CRC) or KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) demonstrates anticipated initial safety, as adverse events were reversible and manageable. The safety review committee has approved the highest evaluated dosage thus far, which consists of administering ERAS-007 at 100 mg BID-QW, along with the approved monotherapy dose of palbociclib at 125 mg QD. These findings provide conclusive evidence regarding the preliminary safety profile of the ERAS-007 and palbociclib combination therapy in this patient population