On June 5, 2023 Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, reported promising preliminary Phase 1b data for ERK inhibitor ERAS-007 in patients with metastatic BRAF V600E-mutated (BRAFm) colorectal cancer (CRC) and provided a portfolio update (Press release, Erasca, JUN 5, 2023, View Source [SID1234639354]). Erasca will host a virtual investor event to discuss these updates today at 4:30 PM ET. To register for the event, please click here.
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"We are pleased that the early ERAS-007 clinical data continue to reinforce its potential to become a backbone for combination therapy," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "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 BRAFm CRC (preventing in-pathway resistance) provide compelling evidence to continue with further enrollment in this patient population."
Dr. Lim continued, "Due to a lack of clinical activity, we will not continue exploring ERAS-007 combined with palbociclib in patients with RAS-mutated gastrointestinal malignancies (targeting adjacent pathways) or ERAS-007 combined with osimertinib in patients with post-osimertinib EGFR-mutated non-small cell lung cancer (reversing in-pathway resistance). We have also decided to deprioritize certain discovery programs: ERAS-9 (SOS1), ERAS-11 (MYC), and ERAS-2/3 (RAS switch-II groove targeting), but are pursuing other promising research approaches to target RAS mutations beyond G12C. Further refining our efforts and prioritizing resources will allow us to focus on clinical and research programs with potential therapeutic differentiation and will increase our capacity to realize the many exciting opportunities ahead of us to help patients. We continue to be well positioned to execute on important catalysts over the next 18 months and beyond for our four clinical programs, our pan-RAF inhibitor naporafenib, ERK inhibitor ERAS-007, SHP2 inhibitor ERAS-601, and CNS-penetrant EGFR inhibitor ERAS-801."
ERAS-007 Development Update
Meaningful activity in patients with EC-naïve BRAFm CRC supports initial focus on and dose expansion of this patient population*:
50% (3/6) response rate, including two confirmed partial responses (cPR) and one unconfirmed partial response (uPR), and 67% (4/6) disease control rate (DCR; defined as complete response + partial response + stable disease) in EC-naïve response evaluable patients at the highest dose of ERAS-007 tested (100 mg BID-QW), with duration of exposure for both cPRs >40 weeks as of the data cutoff date; across all dose levels in EC-naïve response evaluable patients, 38% (3/8) response rate, including two cPRs and one uPR, and 63% (5/8) DCR. Per site communication, the patient with the uPR was still in response at the subsequent scan (May 26, 2023), which was conducted 25 days after the first post-baseline scan
ERAS-007 + EC was generally well tolerated with mostly low-grade treatment-related adverse events (TRAEs) at all combination doses tested. No Grade 4 or 5 TRAEs were observed
One dose-limiting toxicity (DLT) was reported for ERAS-007 100 mg BID-QW + EC (Grade 3 macular edema)
Pharmacokinetic (PK) exposures of ERAS-007, encorafenib, and cetuximab were comparable to the respective monotherapy PK data, suggesting no apparent PK drug-drug interactions (DDI) between the study drugs
* Safety data cutoff date was March 23, 2023. Efficacy data cutoff date was May 21, 2023
Across the HERKULES studies, early clinical data reinforce ERAS-007’s potential to be a backbone for combination therapy:
Target PK profile achieved with adequate exposures and well-defined PK in monotherapy and combinations
No apparent PK DDI liabilities were observed for ERAS-007 when dosed in combination with multiple approved therapies
ERAS-007 has been safely combined with other agents at biologically relevant doses and schedules
ERAS-007 monotherapy responses observed in multiple tumor types support further evaluation of intermittent scheduling in combination
Encouraging signs of efficacy for select ERAS-007 combinations
Portfolio Update
A data-driven prioritization focuses Erasca’s resources on opportunities with the highest probability of success for patients.
Development Programs
HERKULES-3: ERAS-007 + EC in EC-naïve patients with BRAFm CRC (preventing in-pathway resistance): Conducting dose expansion based on encouraging early efficacy data in EC-naïve patients
HERKULES-3: ERAS-007 + EC in EC-treated patients with BRAFm CRC (reversing in-pathway resistance): Gating evaluation on efficacy data in EC-naïve CRC population (i.e., EC-treated population may be explored if efficacy data continue to be promising in the EC-naïve population), as it is more challenging to show treatment benefit in EC-treated population than in EC-naïve population
HERKULES-2: ERAS-007 + osimertinib in patients with post-osimertinib EGFR-mutant NSCLC (reversing in-pathway resistance): Deprioritized as clinical efficacy data do not support continued evaluation
HERKULES-3: ERAS-007 + palbociclib in patients with KRAS- or NRAS-mutant CRC and KRAS-mutant PDAC (targeting adjacent pathways): Deprioritized as clinical efficacy data do not support continued evaluation
HERKULES-1: ERAS-007 + ERAS-601 in patients with advanced solid tumors: Deprioritized as dose escalation safety data do not support continued evaluation of regimen tested
AURORAS-1: ERAS-3490 in patients with KRAS G12C-mutated solid tumors: Deprioritized due to increasingly competitive landscape for small- and mid-cap biopharma companies despite the program’s potential differentiation
Research Programs
ERAS-9 SOS1: Deprioritized to focus on SHP2 as the key upstream RAS/MAPK pathway node due to promise of ERAS-601 SHP2 inhibitor
ERAS-11 MYC: Deprioritized as preclinical characterization does not support continued work
ERAS-2/3 RAS Switch-II Groove targeting: Deprioritized and pursuing other promising research approaches to target RAS mutations beyond G12C
Key Upcoming Milestones
Erasca re-affirmed its prior guidance for the following, with respect to anticipated key milestones and clinical trial readouts:
Naporafenib (pan-RAF inhibitor)
SEACRAFT-1: Phase 1b trial for naporafenib plus trametinib in patients with RAS Q61X solid tumors
First patient dosing expected in second half of 2023
Initial Phase 1b combination signal-seeking efficacy data in relevant tumor types expected between the second and fourth quarters of 2024
SEACRAFT-2: Randomized pivotal Phase 3 trial for naporafenib plus trametinib in patients with NRASm melanoma
First patient dosing expected in first half of 2024
ERAS-007 (ERK1/2 inhibitor)
HERKULES-3: Phase 1b trial for ERAS-007 plus EC in EC-naïve BRAFm CRC patients
Phase 1b combination expansion data in patients with BRAFm CRC expected between the second half of 2023 and the first half of 2024
ERAS-601 (SHP2 inhibitor)
FLAGSHP-1: Phase 1b trial in patients with advanced solid tumors
Phase 1b combination expansion data in relevant patient populations, including patients with human papillomavirus (HPV)-negative advanced head and neck squamous cell carcinoma (HNSCC) expected in first half of 2024
ERAS-801 (CNS-penetrant EGFR inhibitor)
THUNDERBBOLT-1: Phase 1 trial in patients with recurrent glioblastoma (GBM)
Initial Phase 1 monotherapy dose escalation data in patients with recurrent GBM expected in second half of 2023