On September 7, 2022 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 1/1b monotherapy data for ERK1/2 inhibitor ERAS-007 and SHP2 inhibitor ERAS-601 in BRAF-driven and RAS/MAPK-altered solid tumors (Press release, Erasca, SEP 7, 2022, View Source [SID1234639375]).
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A retrospective pooled analysis of all trials evaluating ERAS-007 or ERAS-601 in advanced solid tumors was performed that included Erasca’s ongoing HERKULES-1 and FLAGSHP-1 trials and Asana BioSciences’ previously completed ASN007-101 trial. The analysis was designed to identify responsive subsets that were particularly sensitive to ERAS-007 or ERAS-601 for prioritized combination development within indications of high unmet medical need where no approved targeted therapies are available. Patients with solid tumors with RAS/MAPK alterations were segmented into two groups based on differing levels of responsiveness to monotherapy inhibition and differences in RAS/MAPK pathway reactivation: (1) patients with colorectal cancer (CRC) and (2) patients with non-CRC.
"Worldwide, an estimated 5.5 million lives are at stake annually due to RAS/MAPK pathway alterations, with over 70% of unmet needs lacking approved targeted therapies. We believe the promising single agent responses and favorable safety and tolerability profiles for ERAS-007 and ERAS-601 in patient subsets are highly encouraging and further support our prioritized combination development strategy," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "These early data suggest combining ERAS-007 with the cell cycle inhibitor palbociclib may synergistically achieve tumor cell killing and overcome compensatory responses to RAS/MAPK inhibition in RAS mutant CRC, which represents half of all patients with CRC, and KRAS mutant pancreatic cancer, which accounts for over 90% of patients with pancreatic cancer. Moreover, these preliminary efficacy signals heighten our conviction regarding the therapeutic potential of our first MAPKlamp, combining ERAS-007 with ERAS-601 in specific patient populations with RAS/MAPK alterations such as certain BRAF-driven malignancies. We anticipate initiating a dose escalation trial for ERAS-007 in combination with ERAS-601 in the first half of 2023."
Key findings from the retrospective pooled interim analysis of ERAS-007 and ERAS-601 include*:
23% (6/26) of patients with RAS/MAPK-altered non-CRC solid tumors responded (2 confirmed and 4 unconfirmed PRs) to single agent ERAS-007 or ERAS-601
44% (4/9) with a subset of BRAF-driven non-CRC solid tumors responded (1 confirmed and 3 unconfirmed PRs) to single agent ERAS-007 or ERAS-601
ERAS-007 and ERAS-601 had favorable safety and tolerability monotherapy profiles with largely non-overlapping treatment-related adverse events that are expected to be monitorable and manageable at the likely recommended combination doses
Wei Lin, M.D., Erasca’s chief medical officer, added, "What we have learned from other targeted therapies is that combinations are the best approach to provide durable treatment responses in patients with RAS/MAPK alterations. These early data demonstrating monotherapy activity with ERAS-007 or ERAS-601 and favorable safety profiles are highly encouraging and support the potential of ERAS-007 and ERAS-601 to be foundational combination agents for the treatment of solid tumors with RAS/MAPK alterations. We look forward to further exploring the therapeutic potential of combinations involving ERAS-007 and ERAS-601, including with each other as part of Erasca’s first MAPKlamp combination, across different patient types."
* Data cutoff dates of 11/6/20, 7/11/22, and 5/16/22 for ASN007-101, FLAGSHP-1, and HERKULES-1 trials, respectively.
About ERAS-007
ERAS-007 is a potential best-in-class oral, selective ERK1/2 inhibitor being investigated alone or in combination with different inhibitors targeting upstream nodes of the RAS/MAPK pathway as part of Erasca’s MAPKlamp strategy. The extracellular signal-regulated kinases (ERK), ERK1 and ERK2, belong to a family of serine-threonine kinases that regulate cellular signaling and comprise the terminal node of the RAS/MAPK pathway. ERAS-007 is being investigated across a series of HERKULES clinical trials that span multiple tumor types and includes both monotherapy and combinations with approved and investigational agents, such as receptor tyrosine kinase (RTK), RAS, RAF, and/or cell cycle inhibitors. HERKULES-1 is a Phase 1b/2 clinical trial for ERAS-007 as a single agent and will include a combination with the SHP2 inhibitor ERAS-601 (together, Erasca’s first MAPKlamp) in advanced solid tumors. HERKULES-2 is a Phase 1b/2 master protocol for ERAS-007 in combination with various agents in patients with non-small cell lung cancer (NSCLC). HERKULES-3 is a Phase 1b/2 master protocol for ERAS-007 in combination with various agents in patients with gastrointestinal cancers.
About ERAS-601
ERAS-601 is a potential best-in-class oral, selective SHP2 inhibitor being investigated alone or in combination. SHP2 acts as a convergent node for RTK signaling, relaying growth and survival signals from RTKs to intracellular signaling pathways. ERAS-601 combined with the ERK1/2 inhibitor ERAS-007 makes up Erasca’s first innovative MAPKlamp strategy. ERAS-601 is being investigated across a series of clinical trials that span multiple tumor types and include both monotherapy and combinations with approved and investigational agents. FLAGSHP-1 is a Phase 1/1b clinical trial evaluating ERAS-601 as a monotherapy in advanced solid tumors and in combination in triple wildtype (KRAS/NRAS/BRAF wildtype) CRC and human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). HERKULES-1 is a Phase 1b/2 clinical trial that will include evaluation of ERAS-601 in combination with ERAS-007 in advanced solid tumors. HERKULES-2 is a Phase 1b/2 master protocol that includes evaluation of ERAS-601 in combination with various agents in patients with NSCLC.