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

On June 12, 2023 Galapagos NV (Euronext & NASDAQ: GLPG) reported that it will feature the CAR-T point-of-care manufacturing platform and will present previously disclosed initial Phase 1/2 data with CD19 CAR-T candidate, GLPG5201, at the European Hematology Association (EHA) (Free EHA Whitepaper) 2023 congress, taking place from 8 June to 11 June 2023 in Frankfurt, Germany (Press release, Galapagos, JUN 5, 2023, View Source [SID1234632656]).

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"Patients who develop rrCLL and become resistant to new agents have a very poor prognosis and a significant high unmet medical need for novel therapeutic options such as CAR-T cell therapy. The previously disclosed initial efficacy, safety and feasibility data from the ongoing EUPLAGIA-1 study with our CD19 CAR-T candidate, GLPG5201, manufactured at point-of-care, are encouraging, and we are on track to provide Phase 1 topline results around mid this year," said Jeevan Shetty, Head of Clinical Development Oncology at Galapagos. "Our innovative approach in CAR-T cell therapy development and manufacturing underscores our commitment to accelerating transformational innovation to address the unmet needs of patients with advanced cancers, and we very much look forward to meeting and connecting with you at our booth."

Details of the abstract P1399:

Title Authors Presentation date/time
Initial Clinical Results of Euplagia-1, a Phase I/II Trial of Point-of-Care
Manufactured GLPG5201 in R/R CLL/SLL with or without Richter’s transformation Nuria Martinez-Cibrian, Sergi Betriu, Valentin Ortiz-Maldonado, Daniel Estban, Leticia Alserawan, Mercedes Montoro, Anna DD van Muyden, Maike Spoon, Margot J. Pont, Christian Jacques, Julio Delgado Abstract
Poster presentation on
9 June 2023, 18:00 – 19:00 CET
At the safety and efficacy analysis cut-off date of 9 January 2023, 7 patients diagnosed with rrCLL (including 4 patients with RT) were enrolled in the EUPLAGIA-1 study (n=4 at dose level 1 (DL1); n=3 at dose level 2 (DL2)). All patients received GLPG5201 as a fresh infusion with a median vein-to-vein time of 7 days. The dose levels that are evaluated in the Phase 1 part of the study are 35×106 (DL1), 100×106 (DL2) and 300×106 (dose level 3 (DL3)) CAR+ viable T cells.

The initial results from these 7 patients that were eligible for efficacy analysis (cut-off date: 9 January 2023) indicated that a 7-day vein-to-vein time is feasible and demonstrated strong and consistent in vivo CAR-T expansion levels. Moreover, the initial efficacy results are encouraging with an objective response rate (ORR) of 100% observed. 6 out of 7 patients (86%) reached a complete response (CR) and all Richter’s patients achieved a CR. A duration of response of up to 7.9 months has been reported and follow-up is ongoing. Only 1 patient (DL1) progressed (progressive disease, (PD) after partial response (PR)) and had a CD19-negative relapse with confirmed RT.

In the safety analysis of these 7 patients, adverse events were consistent with the known toxicities of CD19 CAR-T treatment. None of the patients experienced a CRS higher than grade 2 at both dose levels and no ICANS was reported. No dose limiting toxicities (DLTs) were reported and the majority of grade ≥3 adverse events were hematological. Only one serious adverse event was reported at DL2 with a patient experiencing a CRS grade 2, but the event was resolved after 7 days. Patient recruitment of the study is ongoing.

About point-of-care manufacturing
CellPoint (a Galapagos company) has developed, in a strategic collaboration with Lonza, a novel point-of-care supply model, which is designed to enable clinicians to administer fresh CAR-T cells within 7 days of leukapheresis, without complex logistics or cryopreservation, thereby aiming to address important limitations of current CAR-T treatments. The proprietary platform consists of CellPoint’s end-to-end xCellit workflow management and monitoring software, and Lonza’s Cocoon Platform, a functionally closed, automated manufacturing platform for cell therapies. This novel point-of-care model is compliant with the EMA and FDA guidance for clinical trials.

About the EUPLAGIA-1 study (EudraCT 2021-003815-25)
EUPLAGIA-1 is an ongoing Phase 1/2 open-label, multi-center study evaluating the feasibility, safety, and efficacy of point-of-care manufactured GLPG5201 in patients with rrCLL and small cell lymphocytic lymphoma (rrSLL), with or without RT. GLPG5201 is a second generation anti-CD19/4-1BB CAR-T product candidate, administered as intravenous infusion of a fresh product candidate in a single fixed dose. Patients with CD19+ rrCLL or rrSLL with ≥2 lines of prior therapy are eligible to participate, and patients with RT are eligible regardless of prior therapy. The primary objective of the Phase 1 part of the study is to evaluate safety and determine the recommended dose for the Phase 2 part of the study. The primary objective of the Phase 2 part of the study is to assess the ORR and the secondary objectives include the analysis of the complete response rate (CRR), duration of response, progression free survival, overall survival, safety pharmacokinetic profile, and feasibility of point-of-care manufacturing.

The dose levels that are evaluated in the Phase 1 part of the study are 35×106 (DL1), 100×106 (DL2) and 300×106 (DL3) CAR+ viable T cells. The study uses a Bayesian Optimal Interval (BOIN) design (n=15 patients) for Phase 1. Following screening and enrolment, patients will receive ibrutinib daily until leukapheresis of mononuclear cells. During GLPG5201 manufacturing, patients receive cyclophosphamide (300 mg/m2/day)/fludarabine (30 mg/m2/day) for 3 days. After a resting period of at least 2 days, GLPG5201 is administered via intravenous infusion. All patients remain hospitalized for at least 7 days and the end-of-study visit is at Week 14 post CAR-T infusion. Phase 1 patient recruitment is ongoing to establish a recommended dose for Phase 2.

About chronic lymphocytic leukemia and small cell lymphocytic lymphoma
Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin. CLL and small cell lymphocytic lymphoma (SLL) are essentially the same type of B-cell non-Hodgkin lymphoma (NHL), with the only difference the location where the primary cancer occurs. CLL affects B-cells in the blood and bone marrow and SLL cancer cells are located in lymph nodes and/or the spleen3. RT is an uncommon clinicopathological condition observed in patients with CLL. It is characterized by the sudden transformation of the CLL into a significantly more aggressive form of large cell lymphoma and occurs in approximately 2-10% of all CLL patients. CLL/SLL usually follows an indolent course and is an incurable disease. Patients who develop relapsed and refractory disease and become resistant to new agents have a dismal prognosis and a high unmet medical need for new therapeutic options such as CAR-T cells. With estimated incidence of 4.7 new cases per 100,000 individuals, CLL/SLL are the most prevalent lymphoid malignancies and are the most common adult leukemias in the US and in Europe.

On June 5, 2023 Elicio Therapeutics reported positive interim clinical data from its ongoing Phase I AMPLIFY-201 study evaluating its cancer immunotherapy, ELI-002, in patients with high relapse risk pancreatic and colorectal cancer (Press release, Elicio Therapeutics, JUN 5, 2023, View Source [SID1234632557]).

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The multicentre study evaluated ELI-002 as a monotherapy in patients with mutant KRAS-driven tumours who are at high risk for relapse due to minimal residual disease detection after standard surgery and chemotherapy.

Five cohorts of patients received a 1.4 mg fixed dose of the two mutant KRAS peptide antigens including Amph-mKRAS G12D and Amph-mKRAS G12R and 0.1mg, 0.5mg, 2.5mg, 5mg or 10.0mg doses of AMP TLR-9 agonistic DNA adjuvant, Amph-CpG-7909.

ELI-002 2P was found to be well-tolerated with no dose-limiting toxicity or cytokine release syndrome observed across five cohorts.

Responses were observed at all dose levels, with an increased proportion of patients having tumour biomarker reduction including a subset with clearance.

Notable mKRAS-specific T cell responses were induced in 87% of patients with an average of a 56-fold increase directly ex vivo.

The recommended Phase II dose (RP2D) is Amph-CpG-7909 10mg.

Elicio executive vice-president, research and development head and chief medical officer Christopher Haqq said: "ELI-002 is designed with our proprietary AMP technology, which allows for smart delivery to the lymph nodes, the ‘brain centre’ of the immune system.

"The immune responses observed were robust and durable in addition to being able to carry out multiple anti-tumour functions.

"These data validate the clinical activity of ELI-002 with two peptides and support our bridge to the seven-peptide formulation of ELI-002, designed to stimulate an immune response against the seven most common KRAS mutations present in 25% of solid cancer patients."

On June 5, 2023 Elicio, a developer of immunotherapies for the treatment of cancer, reported positive interim clinical data from the ongoing Phase 1 study of its lead asset, ELI-002, an investigational therapeutic cancer immunotherapy (Press release, Elicio Therapeutics, JUN 5, 2023, View Source [SID1234632555]).

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Elicio engineers proteins that appear frequently in cancerous cells but less frequently in healthy cells, and presents these to the immune system, together with an adjuvant (immune response booster) that brings the antigen directly to the lymph nodes, part of the body’s immune system.

In the past, immunotherapies for cancer have yielded fairly weak responses, but Elicio hopes that its immunotherapy will be more effective, thanks to the mechanism whereby the antigen is presented directly to the lymph nodes, and because its product tackles several proteins at once.

The company’s first product, ELI-002 2P, targets mutant KRAS-driven cancers. It says that the seven KRAS driver mutations targeted by the ELI-002 7P formulation are present in 25% of all solid tumors (that is, not blood cancers). The trial is designed to assess the safety, immunogenicity and antitumor activity of ELI-002 2P as a monotherapy in patients with mutant KRAS-driven tumors who are at high risk for relapse due to detection of MRD ( minimal residual disease) following standard surgery and chemotherapy.

On June 5, 2023 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast cancers harboring ESR1 mutations, reported a poster presentation detailing the results of its ELAINE-2 clinical study with longer patient follow-up (Press release, Sermonix Pharmaceuticals, JUN 5, 2023, View Source [SID1234632524]). The poster was initially presented yesterday at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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ELAINE-2 (NCT04432454), an open-label, Phase 2 Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) study of Sermonix’s lead investigational drug, lasofoxifene, in combination with Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib, evaluated 29 women with ER+/HER2- locally advanced or metastatic breast cancer and an ESR1 mutation. The primary endpoint was safety/tolerability, with secondary endpoints including progression-free survival (PFS) and overall response rate (ORR). Earlier ELAINE-2 results were shared at ASCO (Free ASCO Whitepaper) 2022.

With patient follow-up through Jan. 31, 2023, the combination of lasofoxifene and abemaciclib continued to be well-tolerated, with clinically meaningful efficacy in women with ER+/HER2- metastatic breast cancer and an ESR1 mutation. The PFS, a median of 13 months, and ORR of 56% were promising.

"No new safety signals were noted when looking at lasofoxifene and abemaciclib with longer patient follow-up," said Paul Plourde, M.D., vice president of oncology clinical development at Sermonix. "The combination demonstrated meaningful antitumor activity, and observed decreases in ESR1 ctDNA suggest potent target engagement. We look forward to ELAINE-3 and the continued investigation of this potentially practice-changing option for treating ESR1 mutations in women with metastatic breast cancer."

Noteworthy safety results:

Lasofoxifene/abemaciclib was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting.
Three patients (10.3%) had venous thromboembolic events, all occurring after patients had achieved clinical benefit.
One patient discontinued treatment due to grade 2 diarrhea, and no deaths on treatment occurred.
Abemaciclib underwent dose reduction once in 6 (20.7%) patients; there were no dose reductions for lasofoxifene.
There was no clinical evidence of any drug-drug interactions, and no pK impact of lasofoxifene on abemaciclib or abemaciclib on lasofoxifene exposure identified (data not shown).
Noteworthy efficacy results:

Median PFS was 56.0 wks (~13 mos), CBR was 65.5%, and ORR was 55.6%; median overall survival was not estimable at the time.
PFS rate (95% CI) was 76.1%, 56.1%, and 38.8% at 6, 12, and 18 mos respectively; 8 (27.6%) patients achieved PFS over 96 weeks.
Of the four patients who had prior abemaciclib exposure, two achieved clinical benefit, and one with RECIST progression at week 16 remained on study with stable disease until week 40.
In 26 patients with evaluable baseline and week 4 ctDNA, ESR1 mutant allele fractions (MAF) decreased at week 4 in 21 (80.8%) patients, including 14 (53.8%) whose ESR1 MAF were undetectable.
Antitumor activity of lasofoxifene/abemaciclib was not compromised by co-occurring alterations that confer endocrine resistance.
Sermonix in March initiated ELAINE-3, a registrational Phase 3 study of 400 patients assessing the efficacy of lasofoxifene and abemaciclib. Enrollment will begin soon.

The company also convened meetings of its ELAINE-3 Steering Committee and ELAINE-3 Translational Committee at ASCO (Free ASCO Whitepaper) 2023.

To learn more about Sermonix Pharmaceuticals and lasofoxifene, visit View Source To learn more about the ELAINE studies, visit View Source

About Lasofoxifene
Lasofoxifene is an investigational novel endocrine therapy in clinical development which has demonstrated robust target engagement as an ESR1 antagonist in the breast, particularly in the presence of ESR1 mutations. Lasofoxifene has demonstrated anti-tumor activity as monotherapy and in combination with a CDK4/6 inhibitor in Phase 2 studies and has unique tissue selectivity distinguishing it from other current and investigational endocrine therapies, with beneficial effects seen on vagina and bone in previous clinical studies. Lasofoxifene, which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ:LGND), has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a novel targeted and tissue selective oral endocrine therapy could, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.