Deep modality-agnostic pipeline to shut down the RAS/MAPK pathway

We have assembled the deepest RAS/MAPK pathway-focused pipeline in the industry, comprising 11 modality-agnostic programs aligned with our three therapeutic strategies of: (1) targeting key upstream and downstream signaling nodes in the RAS/MAPK pathway; (2) targeting RAS directly; and (3) targeting escape routes that emerge in response to treatment. The target breadth and molecular diversity represented in our pipeline enable us to pursue a systematic, data-driven clinical development effort to identify single agent and combination approaches with the goal of prolonging survival in a wide range of patient populations with high unmet needs.

Our programs target the RAS/MAPK pathway at every turn

Phase 1
Phase 2
Phase 3
Erase Cancer Strategy
Worldwide Rights
Naporafenib (ERAS-254) (BRAF/CRAF)
Pan-RAS Q61X tissue agnostic
We plan to initiate SEACRAFT-1, a Phase 1b clinical trial for naporafenib in combination with various agents in RAS Q61X tissue agnostic solid tumors, in H2 2023.
NRASm melanoma
We plan to initiate SEACRAFT-2, a potential Phase 3 pivotal clinical trial for naporafenib in combination with various agents in NRASm melanoma, in H1 2024.
NF1 LOF, pan-RAS G13R, KRAS G12C, BRAF Class 2/3 solid tumors
We plan to initiate SEACRAFT-3 for naporafenib in combination with various agents.
ERAS-007* (ERK1/2)
Tissue agnostic RAS/MAPK altered solid tumors
We initiated HERKULES-1, a tumor-agnostic Phase 1b/2 clinical trial for ERAS-007 as a single agent and in combination with ERAS-601 (MAPKlamp) in advanced solid tumors.
We initiated HERKULES-2, a Phase 1b/2 clinical trial of our ERK-inhibitor, ERAS-007/MAPKlamp in combination with various agents in patients with non-small cell lung cancer.
BRAFm & RAS/MAPK altered GI Tumors
We initiated HERKULES-3, a Phase 1b/2 clinical trial for ERAS-007/MAPKlamp in combination with various agents in patients with colorectal cancer.
KRAS G12C-driven NSCLC and GI Tumors
SU2C1 Trial
ERAS-601* (SHP2)
RAS/MAPK altered tumors
We initiated FLAGSHP-1, a Phase 1 clinical trial of our oral SHP2 inhibitor, ERAS-601, in patients with advanced solid tumors.
EGFR altered GBM
We initiated THUNDERBBOLT-1, a Phase 1 clinical trial for ERAS-801 in patients with recurrent GBM.
ERAS-3490 (KRAS G12C)
KRASm G12C solid tumors
We plan to initiate AURORAS-1, a Phase 1 clinical trial for ERAS-3490, our KRAS G12C inhibitor with high CNS penetration.
RASm solid tumors
KRASm G12D solid tumors
RASm solid tumors
RAS/MAPK altered solid tumors
RAS/MAPK altered cancers
MYC & RAS/MAPK altered solid tumors
ERAS-12 (EGFR D2/D3)
EGFR & RAS/MAPK altered solid tumors
Affini-T (KRAS G12V/D)
KRASm solid tumors
Small molecule
Large molecule
Protein degrader
TCR T cell therapy
Target RAS directly
Target escape routes
* Together, ERAS-007 and ERAS-601 comprise our first innovative MAPKlamp
1 SU2C = Stand Up To Cancer

Therapeutic Programs

Our lead product candidates are naporafenib (ERAS-254, our oral pan-RAF inhibitor), ERAS-007 (our oral ERK1/2 inhibitor), and ERAS-601 (our oral SHP2 inhibitor). These programs are examples of our innovative MAPKlamp strategy to target key upstream and downstream MAPK nodes. We are also advancing multiple other programs targeting key oncogenic drivers in the RAS/MAPK pathway.


Naporafenib is a potential first-in-class pan-RAF kinase inhibitor (with high potency and selectivity against BRAF and CRAF), and has been studied in over 500 patients to date. We are planning to evaluate the molecule in indications where it has already shown promising clinical proof of concept – namely, NRASm melanoma and pan-RAS Q61X tissue agnostic solid tumors, as well as explore various combinations with other programs in our pipeline to target other RAS/MAPK pathway-driven tumors.


ERAS-007 is the most potent ERK inhibitor in development and has the longest target residence time among ERK inhibitors that we are aware of. ERAS-007 has been evaluated as a single agent in a Phase 1 trial in patients with advanced solid tumors. Multiple objective responses were observed in patients with various tumor types, all of which harbor alterations (BRAF, HRAS, and NRAS) in the RAS/MAPK pathway, including melanoma, salivary gland cancer, NSCLC, and thyroid cancer. The adverse event profle was reversible, manageable, and consistent with ERK inhibition. These findings support the development of ERAS-007 as a monotherapy or in combination in diverse, biomarker-selected tumor types. We are pursuing a broad clinical development plan for ERAS-007 across multiple tumor types that includes both monotherapy and combinations with approved and investigational agents, such as RTK, SHP2, RAS, and/or RAF inhibitors. The first series of trials will be proof-of-concept studies in solid tumors, NSCLC, and CRC. While providing proof-of-concept data, these trials may be expanded to enable potential accelerated approvals in their respective indications.


The second prong of our first MAPKlamp, ERAS-601, is a potent, selective oral inhibitor of SHP2, a convergent node for upstream RTK signaling and a critical “on/off switch” that activates GTP-bound RAS signaling. SHP2 also drives tumor cell proliferation and development of resistance. Our SHP2 inhibitor is designed to block oncogenic signal transduction and delay the onset of resistance—thereby potentially serving as a backbone of combination therapy.

ERAS-801: our CNS-penetrant EGFR inhibitor

EGFR-mediated signaling plays a key role in the growth of many tumor types. Targeting of wildtype EGFR (wtEGFR) and mutant variants of EGFR (EGFRm) by small molecules and antibodies has resulted in improved patient outcomes in NSCLC, CRC, and HNSCC. However, the ability of these agents to effectively target wtEGFR and EGFRm in the CNS remains an unmet medical need. The lack of clinical activity is likely multifactorial, but we believe there are two primary reasons why approved EGFR inhibitors are not effective: (1) the molecules do not penetrate the CNS well, and (2) the molecules are weak inhibitors of the EGFRvIII mutant protein as homodimers or heterodimers that include wildtype EGFR. ERAS-801 is designed to be a potent, selective, reversible, and orally available small molecule with both: (1) highly enhanced CNS penetration (3.7:1 brain:plasma ratio in mice) and (2) the ability to target both EGFR alterations such as EGFRvIII, the most common mutant form of EGFR found in GBM, and wtEGFR, which heterodimerizes with EGFRvIII.


RAS proteins are the most frequently mutated oncoproteins, with KRAS being the most abundantly expressed RAS isoform. Despite decades of research focused on KRAS as a target of interest in oncology, it was generally deemed to be undruggable until 2013, when Dr. Shokat and his colleagues at UCSF identified a new binding pocket, S-IIP, via crystallography studies. Importantly, they also described the discovery of small molecules that irreversibly bound to this pocket on KRAS G12C – a finding that turned an undruggable target into a druggable one.

This historic discovery spurred multiple companies to develop KRAS G12C inhibitors, including one that was recently approved and some that are currently in clinical trials. While single agent activity to date has been most promising in NSCLC, opportunities remain for improvement in CNS penetration to be able to address the propensity of NSCLC to metastasize to the brain in approximately 25% to 50% of patients on standard of care therapies. Hence, we believe a CNS-penetrant KRAS G12C inhibitor, either as a monotherapy or in combination therapies, would represent an important advance in maintaining systemic disease control, prolonging response, and preventing CNS progression. We have designed and optimized ERAS-3490 and other KRAS G12C inhibitors that have shown comparable or superior anti-tumor activity to reference compounds and robust ability to cross the blood-brain barrier (BBB) in order to address this key limitation.

ERAS-2/3: our other RAS-GTP programs

Our ERAS-2/3 program is focused on the development of small molecule inhibitors that target a novel region on RAS called the switch II groove (S-IIG). Unlike the S-IIP, the S-IIG is accessible in both the GDP-bound and GTP-bound states of RAS, making it a robust binding region across multiple RAS mutants. Dr. Shokat identified a new binding site called S-IIG. The original S-IIP that was the binding site for KRAS G12C inhibitors is present in the RAS-GDP state only. When RAS cycles to the RAS-GTP state, the S-IIP becomes obscured by switch II. Unlike the S-IIP, the S-IIG is not obscured by switch II, which enables small molecules to access the S-IIG independently of the phosphorylation state of the bound guanosine. Therefore, S-IIG is present in both the RAS-GTP and RAS-GDP states. Disruption of these switch regions can inhibit RAS signaling since GTP-bound RAS binds to effector proteins at these switch regions. We entered into an exclusive worldwide license agreement with UCSF for Dr. Shokat’s work related to RAS-GTP which guides our ERAS-2/3 programs.


Our ERAS-4 program endeavors to develop small molecules that potently and selectivity bind KRAS G12D. When bound to KRAS G12D, these inhibitors will prevent RAS-mediated signaling by locking KRAS G12D in the inactive GDP-bound state and/or obstructing KRAS G12D’s ability to bind downstream effector proteins, such as BRAF and CRAF. We are accelerating advancement of this program by leveraging our in-house chemistry, biology, and structural biology expertise gained from working on our RAS-GDP and other RAS-GTP programs. We have generated molecules with low nanomolar IC50 potency against KRAS G12D and high selectivity vs. KRAS wildtype (WT). We are optimizing the properties of these molecules utilizing SBDD and structure-activity relationships while continuing to focus on generating other highly potent and selective compounds against KRAS G12D, with the intention to nominate and advance a DevCan into IND-enabling activities.

ERAS-5: our ULK program

The ULK1 and ULK2 kinases are key regulators of the metabolic process known as autophagy. Under physiological conditions, cells utilize autophagy to recycle cellular components, breaking down older components that may be malfunctioning due to age and stress into subunits that are combined to form new components. This process can act as a survival mechanism during stress, such as nutrient starvation, by enabling cells to break down non-critical cellular components to support critical functions. Autophagy can be upregulated in tumor cells where RAS/MAPK pathway signaling is inhibited, acting as an escape route mechanism by preventing tumor cell death. Our ERAS-5 program is focused on developing potent, selective inhibitors of ULK1/2 so that we can further boost tumor cell death in combination with our RAS/MAPK pathway inhibitors.

ERAS-9: our SOS1 program

SOS1 is a protein that binds to RAS and enables it to transition from the inactive RAS-GDP state to the active RAS-GTP state. RAS proteins bind GDP tightly, and a cofactor, such as a SOS1, is required to facilitate RAS’s release of GDP followed by its binding to GTP. Without this cofactor, RAS will accumulate in the inactive state as active state RAS hydrolyzes bound GTP. We are developing small molecule inhibitors in our ERAS-9 program that obstruct SOS1-RAS binding and thereby prevent RAS from cycling to the active RAS-GTP state. SOS1-RAS inhibition can prevent RAS activation mediated by upstream signaling (e.g., via EGFR activation) and can be combined with downstream RAS/MAPK pathway inhibitors to potentially address RAS and RAF mutations that result in constitutive RAS/MAPK pathway signaling. Our ERAS-9 program is focused on developing potent, selective inhibitors of SOS1 for potential combination with our RAS/MAPK pathway inhibitors.

ERAS-10: our protein degrader program

We are exploring protein degradation as an alternative mechanism to complement our approach of enzymatically inhibiting oncogenic proteins. Degraders can offer advantages over enzymatic inhibitors, such as the ability of a single degrader molecule to tag many copies of the target oncoprotein for degradation and the ability of a degrader to more effectively inhibit the function of non-enzymatic proteins. We think this approach will allow us to target a broader range of proteins within the RAS/MAPK pathway and may help us more effectively target a subset of oncogenic proteins than via enzymatic inhibition alone.

ERAS-11: our MYC program

MYC is a transcription factor that is mutated in 40% of cancers. These mutations promote cancer by hyperactivating MYC and/or its protein dimerization partners. Inhibiting MYC by disrupting its ability to dimerize with other proteins or bind DNA has been pursued for over 20 years but has not yet been successful. We are exploring novel approaches to targeting MYC utilizing our internal discovery expertise complemented with partnerships to overcome the challenges that have prevented the successful development of MYC protein inhibitors.

ERAS-12: our EGFR D2/D3 bispecific antibody program

Inhibition of wildtype EGFR signaling mediated by overexpression of EGFR has shown promise in treating various tumors, including HNSCC and CRC. In tumors where overexpression of EGFR is thought to be the primary driver of EGFR signaling, an antibody-based approach is the most effective way to target the receptor, and approved antibodies have demonstrated good tolerability as well as activity by inhibiting EGFR activation and mediating antibody-dependent cellular cytotoxicity (ADCC), a process by which the antibody alerts the immune system to attack the bound tumor cell. However, all approved anti-EGFR antibodies target domain III (D3) only, which is the inactive conformation of wildtype EGFR, and no approved antibodies target domain II (D2), which is the active, ligand binding, conformation of wildtype EGFR. Antibodies targeting D2 are expected to be more effective when epidermal growth factor (EGF) or other members of the EGF family are overexpressed. We are developing a bispecific antibody that is active against both the inactive and active conformations of wildtype EGFR.

Clinical Trials

Erasca is in the process of initiating a number of clinical trials to evaluate the safety and efficacy of our therapeutic candidates—as monotherapy and in combination regimens—across a range of tumor types.

As an oncology healthcare professional, should you have a patient who may be interested in participating in such a clinical trial, consult the list below of our clinical trials currently open for enrollment—for eligibility criteria and further details. Your interest and participation is critical to the success of these trials and is instrumental in the development of desperately needed new medicines with the potential to benefit many people with cancer.

Product/Target Naporafenib (ERAS-254) / RAF

Clinical Trial

SEACRAFT-1 (ERAS-254-01) SEACRAFT-2 (ERAS-254-02) SEACRAFT-3 (ERAS-254-03)


In any nautical journey, seacraft are needed to traverse the vast blue ocean not just in their capacity as seagoing ships, but also for their important second meaning: skill in navigation. Erasca is navigating the “blue ocean” of unmet medical needs using next generation sequencing and other techniques to identify RAS/MAPK pathway-altered tumors that can be treated with naporafenib, a potent, selective, orally bioavailable pan-RAF inhibitor, in combination with other targeted therapies. The SEACRAFT series of trials, beginning with SEACRAFT-1, SEACRAFT-2, and SEACRAFT-3, will test whether naporafenib can improve outcomes in NRASm melanoma, pan-RAS Q61X solid tumors, & other RAS/MAPK-driven tumors, respectively.

Product/Target ERAS-007/ERK

Clinical Trial

HERKULES-1 (ERAS-007-01): A Study to Evaluate ERAS-007 in Patients with Advanced or Metastatic Solid Tumors ClinicalTrials.gov Study Identifier NCT04866134   HERKULES-2 (ERAS-007–02): A Study to Evaluate ERAS-007 in Combination with Other Anti-Cancer Therapies in Patients with Advanced Non-Small-Cell Lung Cancer ClinicalTrials.gov Study Identifier NCT04959981 HERKULES-3 (ERAS-007-03): A Study of ERAS-007 in Patients With Advanced Gastrointestinal Malignancies ClinicalTrials.gov Study Identifier NCT05039177


Hercules is one of the most iconic figures in classical mythology and one of the greatest adventurers of all time. He is best recognized for his extraordinary feats of strength and durability, attributes that would be desirable for cancer treatments, as well. ERAS-007 is an investigational therapy that has exhibited similar characteristics when administered in specific clinical trial participants diagnosed with certain cancers that are caused by abnormal RAS/MAPK pathway signaling. The HERKULES series of trials, beginning with HERKULES-1, HERKULES-2, and HERKULES-3, will continue to test the safety and effectiveness of ERAS-007 in trial participants with various solid tumors.

Product/Target ERAS-601/SHP2

Clinical Trial

FLAGSHP-1 (ERAS-601-01): A Study to Evaluate ERAS-601 in Patients with Advanced or Metastatic Solid Tumors ClinicalTrials.gov Study Identifier NCT04670679


On any journey involving a fleet, the flagship is the most important ship. ERAS-601 is an investigational therapy that has shown potent anti-cancer activity in animals by blocking SHP2. If ERAS-601 successfully blocks SHP2 and RAS/MAPK activity in patients, it has the potential to become a flagship therapy for patients with various solid tumors. The FLAGSHP-1 trial will test whether ERAS-601 can achieve this.

Product/Target ERAS-801/EGFR

Clinical Trial

THUNDERBBOLT-1: A Study to Evaluate ERAS-801 in Patients With Recurrent Glioblastoma ClinicalTrials.gov Study Identifier NCT05222802


Zeus, the great thunderbolt-wielding god of the sky in ancient Greek mythology, was once felled by an unstoppable growth in his head. Relief came only when Athena, the goddess of wisdom, was released from the confines of his skull. In THUNDERBBOLT-1, we hope to similarly unburden our patients through investigating ERAS-801 in glioblastoma (GBM), a devastating cancer of the brain. ERAS-801 is a highly brain-penetrant targeted inhibitor of EGFR, a protein programmed by the erbb1 gene. Much like the precision of Zeus’ thunderbolt, ERAS-801 is specifically designed to target GBM driven by alterations to erbb1 / EGFR. And, in the spirit of Athena, we hope that this investigation will shed more light on this disease, from predictive biomarkers to possible cures. THUNDERBBOLT-1 is currently underway studying safety and activity in patients with recurrent GBM.

Expanded Access Policy

Erasca is a clinical-stage precision oncology company driven by our mission to erase cancer. Evaluation of our investigational therapies in clinical trials is necessary to collect all the information required for regulatory review and to eventually make life-saving therapies commercially available to the relevant patient populations. As such, our development resources are focused on obtaining the efficacy and safety information required for regulatory approval for our investigational therapies as expeditiously and safely as possible. Participation in a clinical trial is the best way for a patient to gain access to investigational therapies. Additional Information about all our ongoing clinical trials can be found at clinicaltrials.gov.

When enrollment into a clinical trial is  not possible and all other available treatment options have been exhausted, access to an investigational therapy in the United States may be provided prior to regulatory approval or commercial approval under a provision referred to as “Expanded Access” (sometimes also referred to as “compassionate use”).

Expanded Access is a potential pathway for a patient with a serious or immediately life-threatening disease or condition to gain access to an investigational therapy for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. FDA guidelines indicate that Expanded Access may be appropriate when all of the following apply:

  1. The patient has a serious or immediately life-threatening disease or condition;
  2. There is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition;
  3. Patient enrollment in a clinical trial is not possible;
  4. Potential patient benefit justifies the potential risks of treatment; and
  5. Providing the investigational therapy will not interfere with clinical trials that could support the therapy’s development or marketing approval for the treatment indication.

Although an Expanded Access program may be available in the future, at this time we do not provide access to our investigational therapies outside of our clinical trials prior to regulatory approval. 

In accordance with the 21st Century Cures Act, Erasca may revise this Expanded Access Policy at any time.

If you have any questions about our Expanded Access Policy, please contact Erasca through the following email address: clinicaltrials@erasca.com.