A Randomized, Open-label Phase III Study in Patients With Previously Treated Unresectable or Metastatic NRAS Mutant Cutaneous Melanoma Comparing the Combination of Naporafenib + Trametinib to Physician's Choice of Therapy (Dacarbazine, Temozolomide or Trametinib Monotherapy) With a Dose Optimization lead-in [SEACRAFT-2]

Stage 1: To select the optimal dose of naporafenib + trametinib to be studied in Stage 2.
Stage 2: To compare progression free survival (PFS) and overall survival (OS) for patients with NRAS-mutant (NRASm) melanoma who are randomized to receive the combination of naporafenib + trametinib to that of patients who are randomized to physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy).

Start Date29 Apr 2024

Sponsor / Collaborator

Erasca, Inc.

NCT05907304 / RecruitingPhase 1

An Open-label Study to Assess the Safety and Efficacy of Naporafenib (ERAS-254) Administered With Trametinib in Previously Treated Patients With Locally Advanced Unresectable or Metastatic Solid Tumor Malignancies With RAS Q61X Mutations

To evaluate the efficacy of naporafenib administered with trametinib in patients with rat sarcoma viral oncogene (RAS) Q61X solid tumors
* To evaluate the safety and tolerability of naporafenib administered with trametinib in patients with RAS Q61X solid tumors
* To characterize the pharmacokinetic (PK) profile of naporafenib and trametinib when administered to patients with RAS Q61X solid tumors

Start Date17 Aug 2023

Sponsor / Collaborator

Erasca, Inc.

NCT04417621 / Active, not recruitingPhase 2

A Randomized, Open-label, Multi-arm, Two-part, Phase II Study to Assess Efficacy and Safety of Multiple LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic BRAFV600 or NRAS Mutant Melanoma

The primary purpose of this study is to evaluate the efficacy of LXH254 combinations in previously treated unresectable or metastatic melanoma

Start Date30 Oct 2020

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with Naporafenib

100 Translational Medicine associated with Naporafenib

100 Patents (Medical) associated with Naporafenib

Literatures (Medical) associated with Naporafenib

01 Nov 2024·LUNG CANCER

A phase Ib study of the combination of naporafenib with rineterkib or trametinib in patients with advanced and metastatic KRAS- or BRAF-mutant non-small cell lung cancer

Article

Author: Felip, Enriqueta ; Wolf, Jürgen ; Solomon, Benjamin ; Heist, Rebecca S. ; Sanmamed, Miguel F. ; Wermke, Martin ; Sebastian, Martin ; Couillebault, Xuân-Mai ; Moschetta, Michele ; Santoro, Armando ; Garrido, Pilar ; Yang, Jie ; Min Kim, Tae ; Heist, Rebecca S ; Bootle, Douglas ; Poggio, Teresa ; Dooms, Christophe ; Planchard, David ; Gaur, Anil ; Mueller, Christina ; Sanmamed, Miguel F ; Sun, Jong-Mu ; Reguart, Noemi

BACKGROUND:

Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib.

METHODS:

This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics.

RESULTS:

Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAF^non-V600-mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with KRAS-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in DUSP6 mRNA levels from baseline were 45.5% and 76.1% with naporafenib plus rineterkib or trametinib, respectively.

CONCLUSIONS:

Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect.

CLINICALTRIALS:

gov identifier: NCT02974725.

07 Oct 2024·MOLECULAR PHARMACEUTICS

Preclinical Evaluation of a Radiolabeled Pan-RAF Inhibitor for RAF-Specific PET/CT Imaging

Article

Author: Lu, Jingbin ; Ge, Xiaoguang ; Wang, Leqiang ; Zhang, Wenhui ; Wu, Xiaonan ; Gao, Shi ; Liu, Junzhi

Abnormalities in the RAS-RAF signaling pathway occur in many solid tumors, leading to aberrant tumor proliferation, invasion, and metastasis. Due to the elusive pharmacology of RAS, RAF inhibitors have become the main targeted therapeutic drugs. Naporafenib (LXH-254) is a high-affinity pan-RAF inhibitor with FDA Fast Track Qualification. We sought to develop an ¹⁸F-labeled molecular probe from LXH-254 for PET imaging of tumors overexpressing RAF to noninvasively screen patients for susceptibility to targeted RAF therapy. To reduce the lipid solubility, LXH-254 was designed with triethylene glycol di(p-toluenesulfonate) (TsO-PEG₃-OTs) to obtain the precursor (LXH-254-OTs) and a nucleophilic substitution reaction with ¹⁸F to obtain the tracer ([¹⁸F]F-LXH-254). [¹⁸F]F-LXH-254 exhibited good molar activity (7.16 ± 0.81 GBq/μmol), radiochemical purity (>95%), and stability. Micro-PET imaging revealed distinct radioactivity accumulation of [¹⁸F]F-LXH-254 in tumors in the imaging groups, whereas in the blocked group, the tumor radioactivity level was consistent with the background tissue, illustrating the affinity and specificity of [¹⁸F]F-LXH-254 in targeting RAF. Overall, [¹⁸F]F-LXH-254 is a promising radiotracer for screening and diagnosing patients with RAF-related disease and monitoring their treatment. This is the first attempt at using an ¹⁸F-labeled RAF-specific radiotracer.

01 Jan 2024·European journal of cancer (Oxford, England : 1990)

First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations

Article

Author: Dummer, Reinhard ; Janku, Filip ; Iyer, Gopakumar ; McCarthy, Fiona ; Maur, Michela ; Kim, Tae Min ; Chen, Chi ; Kiladjian, Jean-Jacques ; Basu, Sumit ; Cooke, Vesselina ; Moschetta, Michele ; Marmé, Frederik ; de Jonge, Maja ; Baffert, Fabienne ; Ascierto, Paolo Antonio ; Buigues, Amparo ; van der Wekken, Anthonie J ; Elez, Elena ; Kim, Jaeyeon ; Spreafico, Anna ; Yamamoto, Noboru ; Giorgetti, Elisa

BACKGROUND:

We investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations.

METHODS:

This first-in-human phase 1 study had two dose-escalation arms: single-agent naporafenib (starting at 100 mg once-daily [QD]) and naporafenib (starting at the recommended dose/regimen)/spartalizumab (400 mg every 4 weeks). The naporafenib/spartalizumab dose-expansion part enrolled patients with KRAS-mutated non-small cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to establish the maximum tolerated doses (MTD)/recommended doses for expansion (RDE) and evaluate tolerability and safety.

RESULTS:

A total of 142 patients were included in the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12) and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/RDE of naporafenib was 600 mg twice-daily (BID). In naporafenib escalation, five patients experienced 7 dose-limiting toxicities: decreased platelet count (1200 mg QD); neuralgia, maculopapular rash, pruritus (600 mg BID); increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs occurred in the naporafenib/spartalizumab arm: the RDE was established at 400 mg BID. The most common treatment-related adverse events were rash and dermatitis acneiform (each 24.1%; naporafenib), nausea and pruritus (each 33.3%; naporafenib/spartalizumab; escalation) and rash (39.5%; naporafenib/spartalizumab; expansion). Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib escalation, and 1 complete response and 3 PRs in the naporafenib/spartalizumab NRAS-mutated melanoma and KRAS-mutated NSCLC arms, respectively.

CONCLUSIONS:

Naporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation.

News (Medical) associated with Naporafenib

12 Nov 2024

·www.globenewswire.com

Erasca Reports Third Quarter 2024 Business Updates and Financial Results

Positive preliminary Phase 1b data in SEACRAFT-1 NRASm melanoma cohort bolsters conviction in ongoing SEACRAFT-2 registrational trial; Stage 1 randomized data expected in 2025 Strong execution across potentially best-in-class RAS targeting franchise; planned IND submissions on track Robust balance sheet with cash, cash equivalents, and marketable securities of $463 million as of September 30, 2024, is expected to fund operations into H1 2027 SAN DIEGO, Nov. 12, 2024 (GLOBE NEWSWIRE) -- 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, today provided business updates and reported financial results for the fiscal quarter ended September 30, 2024. “We made significant progress across our pipeline programs and are pleased with the pace of our execution. Positive preliminary data from SEACRAFT-1, which we reported at the 36th EORTC-NCI-AACR (ENA) Symposium last month, has refined our clinical development focus of naporafenib plus trametinib on patients with NRAS-mutant (NRASm) melanoma, and importantly, heightens our conviction in the ongoing SEACRAFT-2 registrational trial targeting a similar patient population,” said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. “SEACRAFT-2 has the potential for approval based on the high unmet need of these patients as well as the alignment with US and European regulators on the NRASm melanoma indication. We expect randomized dose optimization data from Stage 1 of this Phase 3 trial in 2025.” Dr. Lim added, “Our RAS targeting franchise, which includes a potential best-in-class pan-RAS molecular glue ERAS-0015 and a potential first-in-class pan-KRAS inhibitor ERAS-4001, holds significant promise to help a broad range of patients with RAS-mutant (RASm) solid tumors. Following the in-licensing of these molecules in May, we have rapidly and effectively confirmed in-house the potential best-in-class profiles of both agents and executed across multiple activities to support their planned investigational new drug (IND) application submissions, which remain on track for the first quarter of 2025 for ERAS-4001 and the first half of 2025 for ERAS-0015. We continue to be well capitalized with an anticipated cash runway into the first half of 2027 and are poised for strong execution across our pipeline.” Research and Development (R&D) Highlights Presented Promising SEACRAFT-1 Phase 1 Data: In October 2024, Erasca presented Phase 1b SEACRAFT-1 data for naporafenib plus trametinib (MEKINIST®) in patients with locally advanced unresectable or metastatic solid tumor malignancies with RAS Q61X mutations at the 36th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics and as part of a company R&D update. Data support rationale for pursuing an NRASm melanoma indication and reinforces the potential of the ongoing Phase 3 SEACRAFT-2 registrational trial.Announced Progress Across RAS Targeting Franchise: In October 2024, Erasca presented a program update for pan-RAS molecular glue ERAS-0015 and pan-KRAS inhibitor ERAS-4001 as part of a company R&D update, highlighting the rapid progress across both programs including in-house confirmation of potential best-in-class profiles for both agents and advancement of activities to support planned IND application submissions. Key Upcoming Milestones SEACRAFT-2: Randomized pivotal Phase 3 trial for naporafenib plus trametinib in patients with NRASm melanoma Phase 3 Stage 1 randomized dose optimization data expected to be reported in 2025 AURORAS-1: Phase 1 trial for ERAS-0015 (pan-RAS molecular glue) in patients with RASm solid tumors IND filing expected in H1 2025Initial Phase 1 monotherapy data in relevant tumor types expected to be reported in 2026 BOREALIS-1: Phase 1 trial for ERAS-4001 (pan-KRAS inhibitor) in patients with KRASm solid tumors IND filing expected in Q1 2025Initial Phase 1 monotherapy data in relevant tumor types expected to be reported in 2026 Third Quarter 2024 Financial Results Cash Position: Cash, cash equivalents, and marketable securities were $463.3 million as of September 30, 2024, compared to $322.0 million as of December 31, 2023. Erasca expects its current cash, cash equivalents, and marketable securities balance of $463.3 million to fund operations into the first half of 2027. Research and Development (R&D) Expenses: R&D expenses were $27.6 million for the quarter ended September 30, 2024, compared to $25.2 million for the quarter ended September 30, 2023. The increase was primarily driven by increases in expenses incurred in connection with clinical trials, preclinical studies, and discovery activities, partially offset by decreases in personnel costs, including stock-based compensation expense, and outsourced services and consulting fees. General and Administrative (G&A) Expenses: G&A expenses were $9.6 million for the quarter ended September 30, 2024, compared to $9.4 million for the quarter ended September 30, 2023. Net Loss: Net loss was $31.2 million, or $(0.11) per basic and diluted share, for the quarter ended September 30, 2024, compared to $30.4 million, or $(0.20) per basic and diluted share, for the quarter ended September 30, 2023. About ErascaAt Erasca, our name is our mission: To erase cancer. We are a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers. Our company was co-founded by leading pioneers in precision oncology and RAS targeting to create novel therapies and combination regimens designed to comprehensively shut down the RAS/MAPK pathway for the treatment of patients with cancer. We have assembled one of the deepest RAS/MAPK pathway-focused pipelines in the industry. We believe our team’s capabilities and experience, further guided by our scientific advisory board which includes the world’s leading experts in the RAS/MAPK pathway, uniquely position us to achieve our bold mission of erasing cancer. Cautionary Note Regarding Forward-Looking Statements Erasca cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: our expectations regarding the potential therapeutic benefits of our product candidates, including naporafenib, ERAS-0015, and ERAS-4001; the planned advancement of our development pipeline, including the anticipated timing of data readouts for the SEACRAFT-2, AURORAS-1, and BOREALIS-1 trials; our alignment with regulatory authorities on the regulatory pathway for naporafenib; the anticipated timing of the IND filings for the AURORAS-1 and BOREALIS-1 trials; our ability to successfully prioritize our pipeline portfolio to focus on existing programs that we believe have the highest probability of success; and the sufficiency of our cash, cash equivalents, and marketable securities to fund operations into the first half of 2027. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: our approach to the discovery and development of product candidates based on our singular focus on shutting down the RAS/MAPK pathway, a novel and unproven approach; results from preclinical studies or early clinical trials not necessarily being predictive of future results; preliminary results of clinical trials are not necessarily indicative of final results and one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data and more patient data become available; our planned SEACRAFT trials may not support the registration of naporafenib; our assumptions about ERAS-0015’s or ERAS-4001’s development potential are based in large part on the preclinical data generated by the licensors and we may observe materially and adversely different results as we conduct our planned studies and trials; we only have one product candidate in clinical development and all of our other development efforts are in the preclinical or development stage; our assumptions around which programs may have a higher probability of success may not be accurate, and we may expend our limited resources to pursue a particular product candidate and/or indication and fail to capitalize on product candidates or indications with greater development or commercial potential; potential delays in the commencement, enrollment, data readout, and completion of clinical trials and preclinical studies; our dependence on third parties in connection with manufacturing, research, and preclinical and clinical testing; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval, and/or commercialization, or may result in recalls or product liability claims; unfavorable results from preclinical studies or clinical trials; the inability to realize any benefits from our current licenses, acquisitions, and collaborations, and any future licenses, acquisitions, or collaborations, and our ability to fulfill our obligations under such arrangements; regulatory developments in the United States and foreign countries; later developments with the FDA or EU health authorities may be inconsistent with the feedback received to date regarding our development plans and trial designs; our ability to obtain and maintain intellectual property protection for our product candidates and maintain our rights under intellectual property licenses; we may use our capital resources sooner than we expect; and other risks described in our prior filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in our annual report on Form 10-K for the year ended December 31, 2023, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Erasca, Inc.Selected Condensed Consolidated Balance Sheet Data(In thousands)(Unaudited) September 30, December 31, 2024 2023 Balance Sheet Data: Cash, cash equivalents, and marketable securities $463,303 $321,992 Working capital 300,149 294,520 Total assets 528,896 395,297 Accumulated deficit (735,431) (606,013)Total stockholders’ equity 450,042 316,686 Erasca, Inc.Condensed Consolidated Statements of Operations and Comprehensive Loss(In thousands, except share and per share amounts)(Unaudited) Three months ended September 30, Nine months ended September 30, 2024 2023 2024 2023 Operating expenses: Research and development $27,631 $25,213 $89,237 $79,016 In-process research and development — — 22,500 — General and administrative 9,611 9,445 32,138 28,637 Total operating expenses 37,242 34,658 143,875 107,653 Loss from operations (37,242) (34,658) (143,875) (107,653)Other income (expense) Interest income 5,869 4,346 14,810 12,474 Other income (expense), net 173 (49) (353) (162)Total other income (expense), net 6,042 4,297 14,457 12,312 Net loss $(31,200) $(30,361) $(129,418) $(95,341)Net loss per share, basic and diluted $(0.11) $(0.20) $(0.60) $(0.64)Weighted-average shares of common stock used in computing net loss per share, basic and diluted 282,384,964 150,450,201 217,355,959 150,000,613 Other comprehensive income (loss): Unrealized gain on marketable securities, net 2,021 218 1,748 466 Comprehensive loss $(29,179) $(30,143) $(127,670) $(94,875) MEKINIST® is a registered trademark owned by or licensed to Novartis AG, its subsidiaries, or affiliates. Contact:Joyce AllaireLifeSci Advisors, LLCjallaire@lifesciadvisors.com Source: Erasca, Inc.

Phase 1Financial StatementAACRPhase 3

24 Oct 2024

·www.globenewswire.com

Erasca Announces Strong Momentum for Naporafenib and RAS Targeting Franchise

Positive preliminary Phase 1b SEACRAFT-1 data for naporafenib plus trametinib reinforce therapeutic potential in NRASm melanoma and further support ongoing Phase 3 SEACRAFT-2 trial SEACRAFT-2 has potential for approval based on alignment with US and European regulatory agencies on path for tissue-specific indication in melanoma; Stage 1 randomized data expected in 2025 Rapid progress across RAS targeting franchise; planned IND submissions remain on track Erasca to host investor event today at 8:30 AM Eastern Time SAN DIEGO, Oct. 24, 2024 (GLOBE NEWSWIRE) -- 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, today announced clinical progress for naporafenib and preclinical execution across the company’s RAS targeting franchise. “The SEACRAFT-1 trial in patients with RAS Q61X solid tumors has successfully accomplished several key objectives: delivering clinical data supporting the potential for durable efficacy in patients with NRAS-mutant (NRASm) melanoma, who currently have limited treatment options following frontline immunotherapy; identifying the most promising antitumor signal for the combination, which has been observed in melanoma patients, supporting a tissue-specific approach; and reducing the frequency and severity of dermatologic toxicities through mandatory primary prophylaxis,” said Shannon R. Morris, M.D., Ph.D., Erasca’s chief medical officer. “In totality, these data strengthen our conviction in the ongoing SEACRAFT-2 Phase 3 trial, for which we gained US and European alignment on the regulatory path in patients with NRASm melanoma. We look forward to randomized dose optimization data from Stage 1 of this trial, which is expected in 2025.” Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder, added, “We were excited to bolster our pipeline with the in-licensing of our RAS-targeting franchise in May, including the pan-RAS molecular glue ERAS-0015 and the pan-KRAS inhibitor ERAS-4001. These two assets with competitive profiles, potential for significant patient benefit, and broad application across solid tumors, have become key priorities for the company. In addition to reproducing data in-house supporting the best-in-class potential of both compounds, we continue to execute effectively and efficiently across several functional disciplines, including generating additional in vivo data and progressing the in-life portion of the Good Laboratory Practice (GLP) toxicology studies as anticipated, as well as advancing our drug substance and drug product development and manufacturing activities for both molecules according to plan. Investigational new drug (IND) application submissions remain on track for the first quarter of 2025 for ERAS-4001 and the first half of 2025 for ERAS-0015.” Naporafenib Program Update Naporafenib is a potential first-in-class and best-in-class pan-RAF inhibitor. Naporafenib plus trametinib (MEKINIST®) is being evaluated in the Phase 1b SEACRAFT-1 trial in patients with RAS Q61X mutations and the Phase 3 SEACRAFT-2 trial in patients with NRASm melanoma. In a post-hoc pooled analysis of Phase 1b and Phase 2 data from trials in patients with NRASm melanoma conducted by Novartis, naporafenib in combination with trametinib demonstrated favorable median overall survival (mOS) and median progression free survival (mPFS). The U.S. Food and Drug Administration has granted Fast Track Designation to naporafenib plus trametinib for the treatment of NRASm melanoma. NRASm melanoma has a high unmet medical need 25-30% of melanomas are NRASm, which has a worse prognosis vs. other molecular alterationsCurrent treatment options following frontline immunotherapy are poor: chemotherapy (approved standard of care) demonstrated 7% ORR and 1.5 months mPFS; binimetinib demonstrated 15% ORR and 2.8 months mPFS Promising initial Phase 1b efficacy results in the SEACRAFT-1 melanoma cohort further bolsters rationale for pursuing NRASm melanoma indication*: 40% (4/10) response rate observed in the melanoma cohort, including three confirmed partial responses (cPR) and one unconfirmed partial response (uPR); the melanoma cohort in SEACRAFT-1 is representative of the patient population currently being enrolled in the pivotal SEACRAFT-2 trial70% (7/10) of patients were on treatment as of the data cutoff, including all four responders Generally well-tolerated with mostly low-grade adverse events in the majority of patients* Results suggest that mandatory primary rash prophylaxis helped reduce frequency and severity of dermatological toxicities, reduced drug discontinuation rate due to adverse events, and improved the tolerability profile as measured by an increased relative dose intensity as compared to the prior clinical trials of naporafenib plus trametinib conducted by Novartis, which did not include the use of mandatory primary rash prophylaxis Data reinforce potential of ongoing Phase 3 SEACRAFT-2 trial in patients with NRASm melanoma Potential for approval in both US and Europe based on high unmet need and regulatory alignmentRandomized dose optimization data from Stage 1 of the SEACRAFT-2 Phase 3 trial expected in 2025 * Safety data cutoff date was September 3, 2024. Efficacy data cutoff date was September 5, 2024 RAS Targeting Franchise Update (ERAS-0015 and ERAS-4001) ERAS-0015 is a preclinical pan-RAS molecular glue with best-in-class potential for patients with RASm solid tumors that showed up to 10-fold greater potency and favorable absorption, distribution, metabolism, and excretion (ADME) properties and pharmacokinetics (PK) performance in preclinical studies when compared to another pan-RAS molecular glue currently in clinical development. ERAS-4001 is a preclinical pan-KRAS inhibitor that has shown first-in-class and best-in-class potential with high potency, strong antitumor activity, favorable ADME and PK properties in preclinical studies, including oral bioavailability, and ability to spare H/NRAS while limiting resistance through KRAS wild type activation. Nonclinical data continue to support potential best-in-class profiles, including data generated in-houseIn-life portion of Good Laboratory Practice (GLP) toxicology studies tracking as anticipated: ERAS-0015 completed, ERAS-4001 near completionOn track to achieve previously articulated guidance of IND filing in H1 2025 for ERAS-0015 and Q1 2025 for ERAS-4001 About ErascaAt Erasca, our name is our mission: To erase cancer. We are a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers. Our company was co-founded by leading pioneers in precision oncology and RAS targeting to create novel therapies and combination regimens designed to comprehensively shut down the RAS/MAPK pathway for the treatment of cancer. We have assembled one of the deepest RAS/MAPK pathway-focused pipelines in the industry. We believe our team’s capabilities and experience, further guided by our scientific advisory board which includes the world’s leading experts in the RAS/MAPK pathway, uniquely position us to achieve our bold mission of erasing cancer.Cautionary Note Regarding Forward-Looking Statements Erasca cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: our expectations regarding the potential therapeutic benefits of our product candidates, including naporafenib, ERAS-0015, and ERAS-4001; the planned advancement of our development pipeline, including the anticipated timing of the data readout for Stage 1 of the SEACRAFT-2 trial, our alignment with regulatory authorities on the regulatory pathway for naporafenib, and the anticipated timing of the IND filings for ERAS-0015 and ERAS-4001. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: our approach to the discovery and development of product candidates based on our singular focus on shutting down the RAS/MAPK pathway, a novel and unproven approach; preliminary results of clinical trials are not necessarily indicative of final results and one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data and more patient data become available; the analysis of pooled Phase 1 and Phase 2 naporafenib plus trametinib data covers two clinical trials with different designs and inclusion criteria, which cannot be directly compared, and therefore may not be a reliable indicator of survival data; due to differences between trial designs and subject characteristics, comparing data across different trials may not be a reliable indicator of data; our assumptions about ERAS-0015’s and ERAS-4001’s development potential are based in part on the preclinical data generated by the licensors and we may observe materially and adversely different results as we conduct our planned studies and trials; results from preclinical studies or early clinical trials not necessarily being predictive of future results; we only have one product candidate in clinical development and all of our other development efforts are in the preclinical or development stage; our SEACRAFT trials may not support the registration of naporafenib; our assumptions around which programs may have a higher probability of success may not be accurate, and we may expend our limited resources to pursue a particular product candidate and/or indication and fail to capitalize on product candidates or indications with greater development or commercial potential; potential delays in the commencement, enrollment, data readout, and completion of clinical trials and preclinical studies; our dependence on third parties in connection with manufacturing, research, and preclinical and clinical testing; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval, and/or commercialization, or may result in recalls or product liability claims; unfavorable results from preclinical studies or clinical trials; the inability to realize any benefits from our current licenses, acquisitions, and collaborations, and any future licenses, acquisitions, or collaborations, and our ability to fulfill our obligations under such arrangements; regulatory developments in the United States and foreign countries; later developments with the FDA or EU health authorities may be inconsistent with the feedback received to date regarding our development plans and trial designs; Fast Track Designation may not lead to a faster development or regulatory review or approval process, and does not increase the likelihood that our product candidates will receive marketing approval; our ability to obtain and maintain intellectual property protection for our product candidates and maintain our rights under intellectual property licenses; our ability to fund our operating plans with our current cash, cash equivalents, and marketable securities; and other risks described in our prior filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in our annual report on Form 10-K for the year ended December 31, 2023, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. MEKINIST® is a registered trademark owned by or licensed to Novartis AG, its subsidiaries, or affiliates. Contact:Joyce AllaireLifeSci Advisors, LLCjallaire@lifesciadvisors.com Source: Erasca, Inc.

Phase 1Clinical ResultPhase 3Fast TrackPhase 2

25 Sep 2024

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Erasca to Present Preliminary SEACRAFT-1 Phase 1 Data for Naporafenib Plus Trametinib in RAS Q61X Mutant Solid Tumors as Oral Presentation at 36th EORTC-NCI-AACR Symposium

Naporafenib is a potential first-in-class and best-in-class pan-RAF inhibitor Erasca is also evaluating naporafenib plus trametinib in the ongoing SEACRAFT-2 pivotal Phase 3 trial in NRAS-mutant melanoma where favorable survival was previously demonstrated in pooled analyses Erasca to host virtual R&D update for investors on Thursday, October 24, 2024, at 8:30 AM ET SAN DIEGO, Sept. 25, 2024 (GLOBE NEWSWIRE) -- 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, today announced an oral presentation of preliminary SEACRAFT-1 Phase 1 data for naporafenib plus trametinib (MEKINIST®) in patients with locally advanced unresectable or metastatic solid tumor malignancies with RAS Q61X mutations at the 36th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics taking place October 23-25 in Barcelona, Spain. Naporafenib is a potential first-in-class and best-in-class pan-RAF inhibitor. Erasca plans to host a virtual investor event to provide a research and development (R&D) update on naporafenib and the RAS targeting franchise on Thursday, October 24, 2024, at 8:30 AM ET in conjunction with the 36th ENA Symposium. A live question and answer session will follow the formal presentation. To register for the event, please click here. Oral Presentation Details Preliminary results from SEACRAFT-1: An open-label study of naporafenib with trametinib in patients with locally advanced unresectable or metastatic solid tumor malignancies with RAS Q61X mutations Presenter: Dr. Elisa Fontana, Sarah Cannon Research Institute, London, UK Date and Time: Thursday, October 24, 2024, at 10:18 AM CEST Session: Proffered Papers: Advancing patient care through novel clinical trials; Plenary 3; Catalog 2 About ErascaAt Erasca, our name is our mission: To erase cancer. We are a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers. Our company was co-founded by leading pioneers in precision oncology and RAS targeting to create novel therapies and combination regimens designed to comprehensively shut down the RAS/MAPK pathway for the treatment of cancer. We have assembled one of the deepest RAS/MAPK pathway-focused pipeline in the industry. We believe our team’s capabilities and experience, further guided by our scientific advisory board which includes the world’s leading experts in the RAS/MAPK pathway, uniquely position us to achieve our bold mission of erasing cancer. Cautionary Note Regarding Forward-Looking Statements Erasca cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: our expectations regarding the potential therapeutic benefits of our product candidates, including naporafenib; the planned advancement of our development pipeline; and our ability to successfully prioritize our pipeline portfolio to focus on existing programs that we believe have the highest probability of success. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: our approach to the discovery and development of product candidates based on our singular focus on shutting down the RAS/MAPK pathway, a novel and unproven approach; we only have one product candidate in clinical development and all of our other development efforts are in the preclinical or development stage; the analysis of pooled Phase 1 and Phase 2 naporafenib plus trametinib data covers two clinical trials with different designs and inclusion criteria, which cannot be directly compared, and therefore may not be a reliable indicator of survival data; due to differences between trial designs and subject characteristics, comparing data across different trials may not be a reliable indicator of data; preliminary results of clinical trials are not necessarily indicative of final results and one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data and more patient data become available; our SEACRAFT trials may not support the registration of naporafenib; our assumptions around which programs may have a higher probability of success may not be accurate, and we may expend our limited resources to pursue a particular product candidate and/or indication and fail to capitalize on product candidates or indications with greater development or commercial potential; potential delays in the commencement, enrollment, data readout, and completion of clinical trials and preclinical studies; our dependence on third parties in connection with manufacturing, research, and preclinical and clinical testing; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval, and/or commercialization, or may result in recalls or product liability claims; unfavorable results from preclinical studies or clinical trials; the inability to realize any benefits from our current licenses, acquisitions, and collaborations, and any future licenses, acquisitions, or collaborations, and our ability to fulfill our obligations under such arrangements; regulatory developments in the United States and foreign countries; later developments with the FDA or EU health authorities may be inconsistent with the feedback received to date regarding our development plans and trial designs; our ability to obtain and maintain intellectual property protection for our product candidates and maintain our rights under intellectual property licenses; our ability to fund our operating plans with our current cash, cash equivalents, and marketable securities; and other risks described in our prior filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in our annual report on Form 10-K for the year ended December 31, 2023, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. MEKINIST® is a registered trademark owned by or licensed to Novartis AG, its subsidiaries, or affiliates. Contact:Joyce AllaireLifeSci Advisors, LLCjallaire@lifesciadvisors.com Source: Erasca, Inc.

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Indication	Highest Phase	Country/Location	Organization	Date
NRAS Mutant Melanoma	Phase 3	US	Erasca, Inc.	29 Apr 2024
NRAS Mutant Melanoma	Phase 3	AU	Erasca, Inc.	29 Apr 2024
NRAS Mutant Melanoma	Phase 3	CA	Erasca, Inc.	29 Apr 2024
NRAS Mutant Melanoma	Phase 3	CZ	Erasca, Inc.	29 Apr 2024
NRAS Mutant Melanoma	Phase 3	FR	Erasca, Inc.	29 Apr 2024
NRAS Mutant Melanoma	Phase 3	IT	Erasca, Inc.	29 Apr 2024
NRAS Mutant Melanoma	Phase 3	NL	Erasca, Inc.	29 Apr 2024
NRAS Mutant Melanoma	Phase 3	ES	Erasca, Inc.	29 Apr 2024
NRAS Mutant Melanoma	Phase 3	GB	Erasca, Inc.	29 Apr 2024
Metastatic melanoma	Phase 2	US	Novartis Pharmaceuticals Corp.	30 Oct 2020

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02974725 (Pubmed \| Lung Cancer) Manual	Phase 1	NRAS Mutant Melanoma \| KRAS mutant Non-small Cell Lung Cancer \| BRAF Mutation Non-small Cell Lung Cancer KRAS Mutation \| BRAF Mutation \| NRAS Mutation	216	Naporafenib + Rineterkib	olmpovscyf(jkiaaypkjj) = dawmnnqlxu survwshykk (iikksjnjmx ) View more	Negative	01 Nov 2024
				Naporafenib + Trametinib	olmpovscyf(jkiaaypkjj) = dihfnspjcr survwshykk (iikksjnjmx ) View more
NCT02974725 (Pubmed \| J Clin Oncol)	Phase 1	NRAS Mutant Melanoma \| BRAF Mutation Non-small Cell Lung Cancer	242	Naporafenib 200 mg twice a day plus Trametinib 1 mg once daily	chnfxlavfs(baokjaiowo) = apmsrpedni gxjosqbmos (zelrqmykym, 1.97 - NE) View more	Positive	22 Mar 2023
				Naporafenib 400 mg twice a day plus Trametinib 0.5 mg once daily	chnfxlavfs(baokjaiowo) = boxowlmlqj gxjosqbmos (zelrqmykym, 2.04 - NE) View more
NCT04417621 (ESMO2022) Manual	Phase 2	Unresectable Melanoma BRAF V600 Mutation \| NRAS Mutation	133	BRAF V600-mutant	xosaxmirqc(xeugpgoqvj) = szcfsdgxhm fyepnicljh (jhqcxupvkh, 5 - 25) View more	Positive	10 Sep 2022
				LXH254+LTT462 (BRAF V600-mutant)	xosaxmirqc(xeugpgoqvj) = umlfwpgtbp fyepnicljh (jhqcxupvkh, 1 - 23) View more
NCT02974725 (AACR2022) Manual	Phase 1	NRAS Mutant Melanoma Second line NRAS \| KRAS \| BRAF	-	LXH-254 +Trametinib (dose-escalation (ESC) part ：KRAS- or BRAF-mutant NSCLC ：NRAS-mutant melanoma ，median of 3 (range: 1-6) prior treatments，88.9% pts including IO)	drpycjuihh(qqazpmpjey) = cvmzwsxqet lihmmmenzf (yzvvwmwdtl ) View more	Positive	15 Jun 2022
				LXH-254 + Trametinib (dose-expansion (EXP) part ：NRAS-mutant melanoma ，median of 2 (range: 1-7) prior treatments，96.7% pts including IO)	jfzbcgwhmu(gfkznvzply) = bjuqmionwe ppnasdlfel (lqdmymgjqo ) View more
NCT02974725 (ESMO2020)	Phase 1	Non-Small Cell Lung Cancer	49	LXH254 + LTT462	hqwwrmffsy(cuudjsdbci) = 4% hbcjwanqmc (porqcnjrsk ) View more	-	17 Sep 2020
NCT02607813 (ASCO2018) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	75	LXH-254	irgqfqlwvv(yvvxwhdssf) = xyapbnjtkw qsiaonvfla (oovjgdqlzw ) View more	Positive	04 Jun 2018

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