On June 2, 2024 CatalYm reported positive new follow-up results from its ongoing "GDFATHER" Phase 1/2a trial (GDF-15 Antibody-mediaTed Human Effector Cell Relocation Phase 1/2a) (NCT04725474) in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2024 in Chicago (Press release, Catalym, JUN 2, 2024, View Source;to-Last-Line-Metastatic-NSCLC-Urothelial-and-Hepatocellular-Cancer-Patients-Treated-with-VisugromabNivolumab-Combination [SID1234643958]). Featuring matured data from the non-small cell lung cancer (NSCLC) and urothelial cancer (UC) cohorts, as well as novel, early data for the hepatocellular carcinoma (HCC) cohort and an additional biomarker cohort, the presentation highlighted that treatment with a combination of CatalYm’s lead candidate, visugromab, combined with the anti-PD-1 antibody nivolumab achieves compelling deep and durable anti-tumoral activity in anti-PD-1/PD-L1 relapsed/refractory patients as defined by strict criteria. The combination of visugromab and nivolumab further demonstrates an excellent safety and tolerability profile. Visugromab is a monoclonal antibody designed to neutralize the tumor-produced Growth Differentiation Factor-15 (GDF-15), a central mediator of immune resistance to cancer therapies.

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The oral presentation by International Coordinating Investigator Prof. Ignacio Melero, MD, PhD, Co-Director of Immunology and Immunotherapy (CIMA) at the Universidad de Navarra, Pamplona/Spain, provides further evidence for the potential of visugromab to improve the clinical response depth and duration for patients with advanced, metastatic tumors.

"These recent data continue to impress us with the significant ability to generate deep partial and complete responses with enormous durability in heavily pretreated patients that have failed their approved therapies including prior anti-PD-(L)1 treatment as defined by strict criteria," said Prof. Dr. Eugen Leo, Chief Medical Officer at CatalYm. "Remarkably, more than half of all responders experienced a response level/depth as per RECIST 1.1 (up to lasting CR) that had not been achieved on their prior/initial anti-PD-(L)1 treatment. This demonstrates that GDF-15 blockade by visugromab can induce a remission depth and durability, and long-term immunologic tumor control that other cancer immunotherapies could not induce. Visugromab may have the potential to bring us a major step closer to finally providing deep long-term tumor control and potentially cure for metastatic solid tumor patients with non-squamous NSCLC, UC, and HCC."

Summary of Key Clinical Results:

The matured results from the Phase 2a indication-specific cohorts for NSCLC, UC, and all HCC so far treated show the following Objective Response Rates (ORR):
non-squamous NSCLC: ORR of 19.0% (4/21), with 2 partial responses (PR) and 2 complete responses (CR)
UC: ORR of 19.2% (5/26), with 4 PR and 1 CR
HCC: ORR of 20.0% (4/20), with 3 PR and 1 CR in the primary early readout
The DoR results indicate that visugromab may have a significant impact on deepening and prolonging responses to checkpoint inhibitor (CPI) therapy:
non-squamous NSCLC and UC: mean DoR surpassed 15 and 14 months, respectively, with 7/9 responses ongoing
HCC: data still maturing with 12 patients ongoing on study treatment at data cut-off in the newly initiated cohort
Overall, in a total of 90 patients with the above indications treated in various cohorts (including a biomarker-oriented cohort with varying tumor types), an ORR of 16.7% across all three main tumor types is currently observed, with data partly maturing further.
In totality, 8/15 RECIST 1.1 responders (53.3%) experienced a response level/depth (PR, CR) that had not been achieved with their initial CPI therapy:
Complete responses (CRs): Among the 4 patients who achieved CR, 3 had no prior CR on any treatment regimen, including previous CPI treatments.
Partial responses (PRs): 5/11 patients who achieved PR had no RECIST 1.1 response at all on prior CPI treatments.
The combination of visugromab with nivolumab showed excellent overall tolerability, with a safety profile very similar to nivolumab treatment alone:
most Treatment-Emergent Adverse Events (TEAEs) were mild to moderate
only 8.1% of patients experienced severe TEAEs (Grade ≥ 3)
Patient sample analyses strongly support the involvement of GDF-15 in the creation of an immunosuppressed tumor microenvironment and highlight the therapeutic potential of GDF-15 neutralization in these indications:
Elevated serum levels of GDF-15 were shown to correlate inversely with intratumoral T cell numbers and their proliferation in samples of patients with non-squamous NSCLC, UC, and HCC.
Blockade of GDF-15 by visugromab, in combination with nivolumab treatment, resulted in the rise of serum interferon-γ levels, a critical cytokine for the stimulation of an immune response, in NSCLC and UC patients.
Blockade of GDF-15 by visugromab, in combination with nivolumab treatment, resulted in the rise of serum interferon-γ inducible chemokines CXCL9 and CXCL10 which remained significantly elevated over the monitoring period of six weeks.
Additional preclinical studies indicated that GDF-15 was significantly elevated by standard cancer treatments, specifically e.g. platinum-based chemotherapies, checkpoint inhibitor treatment, and respective combinations. This is another layer of support for the significant role of GDF-15 in the development of immune resistance to these treatment regimens and reason to develop visugromab in the first- and second- line settings where these agents are in standard use.
"We have designed a broad Phase 2b development plan to thoroughly investigate where visugromab can have its biggest impact for patients. These new results further confirm that neutralizing GDF-15 may be a critical strategy in overcoming cancer therapy resistance by breaking immunosuppressive barriers that currently limit therapeutic outcomes," said Phil L’Huillier, Managing Director and Chief Executing Officer at CatalYm. "Validated by the strong clinical and preclinical data on visugromab’s mechanism of action and GDF-15’s relevance in therapeutic resistance to date, we will now investigate the clinical benefit of visugromab in first- and second-line treatment and there in combination with standard-of-care that has been shown to increase GDF-15 levels further on top of the tumoral production of GDF-15. It is our goal to significantly improve patient responses and establish a new benchmark in cancer care."

The Phase 2a GDFATHER-2 program was initiated in March 2022. The ongoing study consists of two segments with up to seven cohorts and is expected to enroll over 200 patients in various cohorts. An evaluation of potential response-predictive biomarker(s) is ongoing. Based on a previous positive readout presented at the ESMO (Free ESMO Whitepaper) IO Congress in 12/2023, CatalYm is in preparations to launch randomized, controlled studies in several major cancer indications in combination with checkpoint inhibitors and standard-of-care in first- and second-line treatment in the first half of 2025.

Presentation Details

Title: Effects of neutralization of tumor-derived immunosuppressant GDF-15 on anti-PD-1 activity in anti-PD-(L)1 relapsed/refractory non-squamous NSCLC, urothelial, and hepatocellular cancer

Presenter: Dr. Ignacio Melero Bermejo, MD | Clinica Universidad de Navarra

Abstract Number: 2513

Date and time: Sunday, June 2, 2024, from 11:30 AM – 1:00 PM CDT

About the GDFATHER-2 Trials

The GDFATHER-2 trial (GDF-15 Antibody-mediaTed Human Effector cell Relocation Phase 2) (NCT04725474) is the Phase 2a part of the ongoing Phase 1/2a trial with several cohorts investigating the effect of visugromab (CTL-002) in combination with a PD-1 checkpoint inhibitor in patients in various advanced-stage/last-line and by strict criteria anti-PD1/PD-L1 relapsed/refractory solid tumor types. The study can enroll up to 200 patients and has extensive biomarker-evaluations integrated to assess for potential responder patient population identification or similar.

About Visugromab (CTL-002)

Visugromab is a monoclonal antibody that neutralizes the tumor-derived Growth Differentiation Factor-15 (GDF-15), a locally acting immunosuppressant fostering immunotherapy resistance. Neutralizing GDF-15 with visugromab reverses key cancer resistance mechanisms to reinstate an efficient anti-tumor response by reenabling immune cell activation and tumor infiltration. Visugromab has demonstrated a good safety profile and potent and durable anti-tumor efficacy in combination with anti-PD-1 treatment in advanced cancer patients The antibody is currently being investigated in ongoing Phase 2a studies in multiple solid tumor indications.

On June 2, 2024 Genmab A/S (Nasdaq: GMAB) reported new efficacy and safety data from two ongoing Phase 1/2 clinical trials evaluating epcoritamab, a T-cell engaging bispecific antibody administered subcutaneously, in adult patients with certain types of follicular lymphoma (FL) (Press release, Genmab, JUN 2, 2024, View Source [SID1234643957]). A preliminary analysis of data from the EPCORE NHL-2 study (NCT04663347), evaluating epcoritamab in combination with rituximab-lenalidomide (R2), demonstrated an overall response rate (ORR) of 95% and complete response rate (CRR) of 85% in patients with previously untreated FL. The safety and efficacy for this use have not been established. The data were shared during a rapid oral presentation (Abstract #7014) at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, being held in Chicago, IL and virtually, May 31-June 4, 2024.

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Separately, new data from the cycle 1 optimization part (C1 OPT) of the EPCORE NHL-1 study (NCT03625037), evaluating epcoritamab in patients with relapsed/refractory (R/R) FL, showed that following additional mitigation strategies, cytokine release syndrome (CRS) (any grade) was reported in 49 percent of patients vs. 66 percent of patients (any grade) in the pivotal cohort. Additionally, there were no Grade 3 or higher CRS events and no reported immune effector cell-associated neurotoxicity syndrome (ICANS). CRS and ICANS are adverse reactions, which can be serious and/or life threatening. Patients need to be monitored and carefully managed per current practice guidelines. These results (Abstract #7015) were selected to be a part of Best of ASCO (Free ASCO Whitepaper) (July 19-20 in Boston, MA), which features the most impactful research from the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting.

FL is the second most common form of non-Hodgkin’s lymphoma (NHL), accounting for 20-30 percent of all NHL cases.i About 15,000 people develop FL each year in the U.S.ii FL is considered incurable with current standard of care therapies and patients often relapse.iii,iv With each subsequent line of therapy, patients receiving currently available treatments may experience shorter durability of remission.v

"Follicular lymphoma is considered incurable and patients at all stages of disease need innovative treatment options. Our data at this year’s ASCO (Free ASCO Whitepaper) suggest that epcoritamab can potentially provide promising overall and complete responses for patients with follicular lymphoma, whether previously untreated or post-relapse. Importantly, we’ve also focused on reducing incidence of CRS and ICANS through optimizing dosing safety of epcoritamab for patients with relapsed/refractory disease," said Judith Klimovsky, Executive Vice President & Chief Development Officer, Genmab. "These data reflect our efforts, alongside our partner AbbVie, to continue the development of epcoritamab as a potential core therapy across B-cell malignancies."

EPCORE NHL-2 Results in First-Line FL (Abstract #7014)

The EPCORE NHL-2 study analysis included results from two arms of the study. Arm 6 evaluated epcoritamab in combination with R2 in patients with previously untreated FL (n=41). With a median follow-up of 21.1 months, additional findings from this arm showed durable responses, with an estimated 89 percent of patients remaining progression free and 93 percent of patients who had achieved a CR remaining in CR at 18 months.

"The results from this preliminary analysis of epcoritamab in combination with rituximab-lenalidomide as a first-line, chemotherapy-free treatment for patients with FL are encouraging and support the continued evaluation of epcoritamab in this patient population," said Joshua Brody, MD, Director, Lymphoma Immunotherapy Program Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine.

The most common treatment-emergent adverse events (TEAEs) in these first-line patients were COVID-19 (63 percent), CRS (56 percent) and neutropenia (56 percent). All CRS events were low grade (41 percent Grade 1 and 15 percent Grade 2) and resolved. Most CRS events occurred after patients received their first full dose of epcoritamab, and none led to treatment discontinuation. Two fatal TEAEs occurred due to COVID-19 pneumonia and septic shock.

The EPCORE NHL-2 study results also included the first data disclosure from arm 7, which evaluated epcoritamab administered every 8 weeks for patients with first- or second-line FL in CR or partial response (PR) following standard-of-care treatment (n=20). Median follow-up was 19.7 months. An estimated 90 percent of patients remained alive at 21 months. Notably, 100 percent of patients who entered the arm with a PR converted to a CR (n=8).

In arm 7, the most common TEAEs were COVID-19 (70 percent) and CRS (55 percent). Only one CRS event (Grade 1) occurred during Q8W maintenance dosing. All other CRS events were during cycle 1 (C1) step-up dosing, as expected for these patients who had not previously received epcoritamab. One fatal TEAE occurred related to respiratory failure caused by post-acute COVID syndrome.

EPCORE NHL-1 Data in Later-line FL (Abstract #7015)

In this C1 optimization cohort in patients with R/R FL, patients received epcoritamab in 3 step-up doses (0.16, 0.8, and 3 mg), along with dexamethasone prophylaxis and hydration recommendations followed by full 48-mg doses until disease progression or unacceptable toxicity. There was no mandatory hospitalization. With a median follow-up of 5.7 months, CRS rate was 49% (Grade 1 40%, Grade 2 9%), primarily occurring during cycle 1, and all events resolved. CRS was adequately identified in the outpatient setting and appropriately treated. There were no ICANS events.

These findings show that mitigation measures implemented early in the epcoritamab treatment cycle may lead to substantial improvements in the incidence and severity of CRS and ICANS. Further, among the 81 response-evaluable patients in the cohort, ORR was 91 percent and CR rate was 68 percent, suggesting that the additional CRS mitigation did not impact efficacy.

On February 26, 2024, the U.S. Food and Drug Administration (FDA) granted Priority Review for the supplemental Biologics License Application (sBLA) for epcoritamab-bysp for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after two or more lines of systemic therapy. Use of epcoritamab in FL is not approved in the U.S. or in the EU or in any other territory. The safety and efficacy of epcoritamab for use in FL have not been established.

About the EPCORE NHL-2 Trial

EPCORE NHL-2 is a phase 1b/2, open-label, multinational, interventional trial to evaluate the safety, and preliminary efficacy of epcoritamab in combination with standard of care agents in patients with B-cell non-Hodgkin’s lymphoma, including FL, and across multiple lines of therapy. The trial consists of two parts – Part 1 (dose escalation) and Part 2 (dose expansion) – and 10 different treatment arms. The primary objective of Part 1 is safety, and it includes arm 1-5 and arm 10. Part 2 includes all 10 arms (arm 1-10) with the objective of preliminary efficacy. However, the primary objective of arm 7 is safety. More information on this trial be found at View Source (NCT: 04663347).

About the EPCORE NHL-1 Trial

EPCORE NHL-1 is an open-label, multi-center safety and preliminary efficacy trial of epcoritamab that consists of three parts: a dose escalation part; an expansion part; and an optimization part. The trial was designed to evaluate subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma (B-NHL), including FL. In the expansion part, additional patients were enrolled to further explore the safety and efficacy of epcoritamab in three cohorts of patients with different types of relapsed/refractory B-NHLs who have limited therapeutic options and generated pivotal data for patients with FL and diffuse large B-cell lymphoma (DLBCL). The optimization part evaluated additional cytokine release syndrome (CRS) mitigation strategies during cycle 1. The primary endpoint of the expansion part was ORR as assessed by an IRC. Secondary efficacy endpoints included duration of response, complete response rate, duration of complete response, progression-free survival, and time to response as determined by the Lugano criteria. Overall survival, time to next therapy, and rate of minimal residual disease negativity were also evaluated as secondary efficacy endpoints. The primary endpoint of the optimization part was the rate of ≥ Grade 2 CRS events and all grade CRS events from first dose of epcoritamab through 7 days following administration of the second full dose of epcoritamab.

About Follicular Lymphoma (FL)

FL is typically an indolent (or slow-growing) form of non-Hodgkin’s lymphoma (NHL) that arises from B-lymphocytes.vi FL is the second most common form of NHL overall, accounting for 20-30 percent of all NHL cases, and represents 10-20 percent of all lymphomas in the western world.i,vii Although FL is an indolent lymphoma, it is considered incurable with conventional therapy and patients who achieve remission also often experience relapse.iii,iv,viii Additionally, with each relapse the remission and time to next treatment is shorterix, adding increased cost to the health system and negatively impacting the patient’s quality of life.x

About Epcoritamab

Epcoritamab is an IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology and administered subcutaneously. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B cells and induces T-cell-mediated killing of CD20+ cells.xi

Epcoritamab (approved under the brand name EPKINLY in the U.S. and Japan, and TEPKINLY in the EU) has received regulatory approval in certain lymphoma indications in several territories. Use of epcoritamab in FL is not approved in the U.S. or in the EU or in any other territory. Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization.

Genmab and AbbVie continue to evaluate the use of epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes four ongoing phase 3, open-label, randomized trials including a trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL compared to investigators choice chemotherapy (NCT: 04628494), a trial evaluating epcoritamab in combination with R-CHOP in adult participants with newly diagnosed DLBCL (NCT: 05578976), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) in patients with R/R FL (NCT: 05409066), and a trial evaluating epcoritamab in combination with R2 compared to chemoimmunotherapy in patients with previously untreated FL (NCT: 06191744). The safety and efficacy of epcoritamab has not been established for these investigational uses. Please visit clinicaltrials.gov for more information.

EPKINLY (epcoritamab-bysp) U.S. IMPORTANT SAFETY INFORMATION

Important Warnings—EPKINLY can cause serious side effects, including:

Cytokine release syndrome (CRS), which is common during treatment with EPKINLY and can be serious or life-threatening. To help reduce your risk of CRS, you may receive other medicines before receiving EPKINLY and you will also be given smaller doses of EPKINLY for the first 2 doses (called "step-up" dosing). Your first full dose of EPKINLY will be given on day 15 of your first cycle of treatment and you should be hospitalized for 24 hours after due to risk of CRS and neurologic problems. If your dose of EPKINLY is delayed for any reason, you may need to repeat the step-up dosing schedule.
Neurologic problems that can be life-threatening and lead to death. Neurologic problems may happen days or weeks after you receive EPKINLY.
Tell your healthcare provider or get medical help right away if you develop a fever of 100.4°F (38°C) or higher; dizziness or lightheadedness; trouble breathing; chills; fast heartbeat; feeling anxious; headache; confusion; shaking (tremors); problems with balance and movement, such as trouble walking; trouble speaking or writing; confusion and disorientation; drowsiness, tiredness or lack of energy; muscle weakness; seizures; or memory loss. These may be symptoms of CRS or neurologic problems. Do not drive or use heavy machinery or do other dangerous activities if you have any symptoms that impair consciousness until your symptoms go away.

EPKINLY can cause other serious side effects, including:

Infections that may lead to death. Tell your healthcare provider right away if you develop any symptoms of infection during treatment, including fever of 100.4°F (38°C) or higher, cough, chest pain, tiredness, shortness of breath, painful rash, sore throat, pain during urination, or feeling weak or generally unwell.
Low blood cell counts are common during treatment with EPKINLY and can be serious or severe. Your healthcare provider will check your blood cell counts during treatment. EPKINLY may cause low blood cell counts, including low white blood cells (neutropenia), which can increase your risk for infection; low red blood cells (anemia), which can cause tiredness and shortness of breath; and low platelets (thrombocytopenia), which can cause bruising or bleeding problems.
Your healthcare provider will monitor you for symptoms of CRS, neurologic problems, infections, and low blood cell counts during treatment with EPKINLY. Your healthcare provider may temporarily stop or completely stop treatment with EPKINLY if you develop certain side effects.

Before you receive EPKINLY, tell your healthcare provider about all your medical conditions, including if you have an infection, are pregnant or plan to become pregnant, or are breastfeeding or plan to breastfeed. If you receive EPKINLY while pregnant, it may harm your unborn baby. If you are a female who can become pregnant, your healthcare provider should do a pregnancy test before you start treatment with EPKINLY and you should use effective birth control (contraception) during treatment and for 4 months after your last dose of EPKINLY. Tell your healthcare provider if you become pregnant or think that you may be pregnant during treatment with EPKINLY. Do not breastfeed during treatment with EPKINLY and for 4 months after your last dose of EPKINLY.

The most common side effects of EPKINLY include CRS, tiredness, muscle and bone pain, injection site reactions, fever, stomach-area (abdominal) pain, nausea, and diarrhea. These are not all the possible side effects of EPKINLY. Call your doctor for medical advice about side effects.

You are encouraged to report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch or to Genmab US, Inc. at 1-855-4GENMAB (1-855-443-6622).

Please see Medication Guide, including Important Warnings.

On June 1, 2024 TiumBio Co., Ltd. (Kosdaq: 321550), a clinical-stage biopharmaceutical company focused on discovering and developing innovative therapeutics for patients with rare and incurable diseases, reported interim results from the Phase 1b clinical trial of TU2218 in combination with pembrolizumab at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, TiumBio, JUN 2, 2024, View Source [SID1234643955]).

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TU2218 is a novel oral dual inhibitor targeting transforming growth factor beta receptor 1 (TGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2). TGF-ß and VEGF pathways in tumor microenvironment interfere with the anti-tumor activity of immune checkpoint inhibitors, so TU2218 is expected to maximize the efficacy of immuno-therapies by inhibiting them.

TiumBio’s ongoing Phase 1b clinical trial (NCT05784688) in the United States evaluates safety, pharmacokinetics, and preliminary efficacy of TU2218 in combination with Keytruda (pembrolizumab) in patients with advanced solid tumors. The study consists of three dosage groups (105 mg, 150 mg, and 195 mg/day), and the presentation at the ASCO (Free ASCO Whitepaper) Annual Meeting included results from 12 patients across the three cohorts. Data from the full Phase 1b trial, which includes 18 patients, will be available in the second half of 2024.

In the poster released at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting, five patients treated at the recommended phase 2 dose (RP2D) of 195mg/day TU2218 in combination with pembrolizumab demonstrated an ORR of 40% at PR (n=2) and 60% at SD (n=3) with a DCR of 100%. And across all dosage groups, patients (n=12) receiving the combination therapy showed PR at 16.7% (n=2), SD at 50.0% (n=6) and PD at 25.0% (n=3). In this study, TU2218 was well-tolerated as a combination therapy with pembrolizumab, showing no signs of DLTs, which is consistent with a previous monotherapy trial.

"We are encouraged by the preliminary efficacy results with a favorable safety profile in patients with advanced tumors and are looking forward to top-line data from the study, which is expected in the second half of this year," said Hun-Taek Kim, Ph.D., MBA, CEO at TiumBio. "We plan to initiate a Phase 2a clinical trial in head and neck cancer, biliary tract cancer, and colorectal cancer to develop an innovative novel drug for patients with limited treatment options," he added.

On June 2, 2024 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported the phase II trial data of KROCUS Study, fulzerasib (GFH925, KRAS G12C inhibitor) in combination with cetuximab for first-line non-small cell lung cancer (NSCLC) treatment，at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting (Press release, GenFleet Therapeutics, JUN 2, 2024, View Source;safety-result-from-phase-ii-trial-for-first-line-nsclc-treatment-in-krocus-study-fulzerasib-kras-g12c-inhibitor-in-combination-with-cetuximab-in-a-late-breaking-abstract-at-the-oral-p-302161182.html [SID1234643952]).

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The preliminary result of the trial was accepted as a late-breaking abstract and selected for oral presentation at the clinical science symposium of lung cancer treatment, highlighting the combination therapy’s promising efficacy and its excellent safety/tolerability profile. Notably, this marks the first time that a KRAS G12C inhibitor is combined with an EGFR inhibitor as a first-line NSCLC treatment with its data presented at a global academic event.

The KROCUS Study, led by renowned lung cancer expert Dr. Rafael Rosell, is a European multi-center phase Ib/II study initiated in March 2023. As of April 19 this year, a total of 40 subjects were enrolled and 33 of them received at least one available post-treatment tumor assessment: the objective response rate (ORR) reached 81.8% and the disease control rate (DCR) reached 100%. The post-treatment evaluation revealed that most patients (27/33) exhibited tumor response: one patient achieved complete response; the other two achieved partial response with a shrinkage in their tumor size by 100%.

Additionally, the combination therapy demonstrated a favorable safety/tolerability profile, with both treatment-related adverse events (TRAEs) and TRAEs above grade 3 occurring at a lower rate than those in the fulzerasib monotherapy study in second line and above NSCLC. The data was presented by Dr. Vanesa Gregorc from Italy’s Candiolo Cancer Institute, Italy.

The new drug application for fulzerasib monotherapy in treating advanced KRAS G12C-mutant NSCLC has been accepted and granted priority review designation by China’s National Medical Products Administration (NMPA). Based on the data presented at 2023 ESMO (Free ESMO Whitepaper) Asia, the registrational phase II study of GFH925 monotherapy for NSCLC showed an ORR of 46.6% and a DCR of 90.5%; the median progression-free survival (mPFS) was 8.3 months. In addition, fulzerasib monotherapy received two breakthrough designations for advanced G12C-mutant NSCLC and metastatic colorectal cancer (CRC) patients.

"I am delighted that the preliminary data of this phase II trial was selected for oral presentation at ASCO (Free ASCO Whitepaper), an acknowledgement of this innovative combination therapy’s potential in treating NSCLC patient in a of first-line setting. Currently, there are multiple global trials exploring the combination of KRAS G12C and EGFR inhibitors for later-line CRC. However, GenFleet is propelling the validation of this synergistic mechanism further into first-line treatment for NSCLC, the cancer type with the largest G12C-mutant patient population. We eagerly anticipate the trial’s continued progress, aiming to offer more frontline options for patients worldwide. "said Dr. Rafael Rosell, the principal investigator of KROCUS study.

"The design of the KROCUS Study is based on deep research into synergistic mechanisms, animal models validation, as well as clinical data generated from the fulzerasib monotherapy in the second-line setting. We are excited to see that the preliminary data from our first-line combination study exceeding our expectation. Furthermore, this chemo- and immuno-free combination could potentially mitigate overlapped toxicities and delay drug resistance, leaving space to allow later-line immunotherapy to extend the patients’ overall survival." stated by Yu Wang, M.D.,Ph.D., Chief Medical Officer of GenFleet.

KROCUS: a Phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC
Presenter: Dr. Vanesa Gregorc
Abstract No. : LBA8511

A total of 40 treatment naïve advanced KRAS G12C positive NSCLC patients were treated with GFH925 in combination with cetuximab (fulzerasib 600mg BID + cetuximab 500 mg/m2 Q2W) as of April 19, 2024. Most patients (95%) were diagnosed with stage IV disease and 13 (32.5%) patients with brain metastases.

Efficacy: As of cutoff date, of the 33 patients who received at least one post-treatment tumor assessment, investigator-assessed ORR was 81.8% (95% CI: 64.5, 93.0) and DCR was 100% (95% CI: 89.4, 100); ORR among patients with brain metastasis was 70%. The median duration of response (DoR) was not reached yet and 88% of patients were still on treatment with a median follow-up of 5.1 months.

Safety: As of cutoff date, the combination therapy was well tolerated. Treatment-related adverse events (TRAEs) occurred in 87.5% of subjects and the majority of the TRAEs were grade 1-2. About 17.5% of subjects reported grade 3 TRAEs. There were no grade 4-5 TRAEs. No new safety signals were identified compared with fulzerasib or cetuximab as single agent.

About KROCUS Study and fulzerasib (GFH925)
The multi-center study of fulzerasib in combination with cetuximab started in scores of clinical research centers worldwide from March 2023 and sets its objectives to evaluate the safety/tolerance, efficacy and the pharmacokinetic characteristics of the combination in advanced NSCLC patients harboring KRAS G12C mutation.

Fulzerasib the first China-developed KRAS G12C inhibitor that has its NDA submission accepted and granted with Priority Review Designation by NMPA. Fulzerasib also received Breakthrough Therapy Designations this year for treating advanced KRAS G12C-mutant NSCLC patients that have received at least one systemic therapy and CRC patients who have received at least two systemic therapies.

RAS protein family can be divided into KRAS, HRAS and NRAS categories. KRAS mutations are detected in nearly 90% of pancreatic cancer, 30-40% of colon cancer, and 15-20% lung cancer patients. The occurrence of KRAS G12C mutation subset is more frequently observed than those with ALK, ROS1, RET and TRK 1/2/3 mutations combined. GFH925 is a novel, orally active, potent KRAS G12C inhibitor designed to effectively target the GTP/GDP exchange, an essential step in pathway activation, by modifying the cysteine residue of KRAS G12C protein covalently and irreversibly. Preclinical cysteine selectivity studies demonstrated high selectivity of fulzerasib towards G12C. Subsequently, fulzerasib effectively inhibits the downstream signal pathway to induce tumor cells’apoptosis and cell cycle arrest.

On June 2, 2024 Dizal (SSE:688192), a biopharmaceutical company committed to developing novel medicines for the treatment of cancer and immunological diseases, reported the latest data from the inaugural global pivotal study WU-KONG1 Part B (WU-KONG1B) of sunvozertinib in relapsed or refractory non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins) at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Dizal Pharma, JUN 2, 2024, View Source [SID1234643947]). The study demonstrated statistically significant outcomes on the primary endpoint for sunvozertinib and highlighted its significant clinical value to patients around the globe.

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As a rationally designed, oral, potent EGFR inhibitor targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity, sunvozertinib was previously granted Breakthrough Therapy designations by both the US FDA and the China Center for Drug Evaluation (CDE) in treating NSCLC with EGFR exon20ins. Sunvozertinib has obtained conditional approval in China through a phase II pivotal study (WU-KONG6), making it the world’s first and only oral drug for the treatment of NSCLC patients with EGFR exon20ins.

WU-KONG1B, a multinational pivotal study, is the equivalent study with a similar design of WU-KONG6 to investigate sunvozertinib in relapsed or refractory NSCLC patients with EGFR exon20ins from 10 countries and regions in Asia, Europe, North America, and South America. The primary endpoint and key secondary endpoint were independent review committee (IRC) assessed objective response rate (ORR) and duration of response (DoR) respectively.

As of March 22, 2024, a total of 111 patients were enrolled to receive sunvozertinib treatment at 300mg as the optimal recommended phase 2 dose (RP2D). 107 patients who met the full analysis set (FAS) definition were included in efficacy analysis, of which Asian, White, and Black or African American enrollees were 57.9%, 40.2% and 1.9%, respectively. The key findings of the primary analysis were as follows:

Per IRC assessment, sunvozertinib achieved a best ORR of 53.3%.
The median DoR has not been reached, and the 9-month DoR rate was 57%, indicating durable efficacy of sunvozertinib.
Anti-tumor efficacy was observed regardless of amivantamab treatment. The best ORRs in patients with or without prior amivantamab treatment were 50% and 53.8%, respectively.
Sunvozertinib was well tolerated with a favorable safety profile consistent with previous reports.
"The WU-KONG1B study is significant in that it enrolled more than 40% of non-Asian patients. On a global scale, sunvozertinib demonstrated potent and durable anti-tumor efficacy with a best ORR of 53.3% and a 9-month DoR of 57% in relapsed or refractory NSCLC patients with EGFR exon20ins. The revelation of 3 patients (2.8%) achieving a confirmed complete response (CR) indicated deep tumor shrinkage with sunvozertinib treatment." said Prof. James Chih-Hsin Yang, MD, PhD at National Taiwan University Hospital and National Taiwan University Cancer Center, the leading principal investigator of WU-KONG1B. "Safety findings were similar to what has been previously reported in other sunvozertinib clinical studies. The majority of treatment-related adverse events (TEAEs) were reversible and clinically manageable. We look forward to more data readouts to validate the clinical benefit of sunvozertinib in EGFR Exon20ins NSCLC."

"It’s encouraging to see that the global pivotal study demonstrated statistically significant and clinically meaningful benefits of sunvozertinib as a single agent in NSCLC patients with EGFR exon20ins. Compared to what is available, sunvozertinib offers significant advantages as a single, oral drug: convenient, safe, and superior efficacies." said Xiaolin Zhang, PhD, CEO of Dizal.

He added, "In parallel, we are advancing the development of sunvozertinib in the first-line setting of NSCLC with EGFR exon20ins through a global phase III study (WU-KONG28). The accumulated clinical data for sunvozertinib has attracted lots of attention and facilitated our studies. We want to thank our patients and investigators for their hard work. We are committed to accelerate ongoing clinical studies and make the drug available to patients globally as soon as possible."

WU-KONG28, a phase III, multinational, randomized study, is ongoing to assess sunvozertinib versus platinum-based doublet chemotherapy in the first-line setting with patients from 14 countries and regions in Asia, Europe, North America, and South America.

About sunvozertinib (DZD9008)

Sunvozertinib is an irreversible EGFR inhibitor discovered by Dizal scientists targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity. In August 2023, sunvozertinib received approval from NMPA to treat advanced NSCLC with EGFR exon20ins after platinum-based chemotherapies. The approval is based on the results of WU-KONG6 study, the pivotal study of sunvozertinib in platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins. The primary endpoint of the study was the confirmed overall response rate (cORR) as assessed by the Independent Review Committee (IRC) reached 60.8%. Anti-tumor efficacy was observed across a broad range of EGFR exon20ins subtypes, and in patients with pretreated and stable brain metastasis. In addition, sunvozertinib also demonstrated encouraging anti-tumor activity in NSCLC patients with EGFR sensitizing, T790M, and uncommon mutations (such as G719X, L861Q, etc.), as well as HER2 exon20ins.

Sunvozertinib showed a well-tolerated and manageable safety profile in the clinic. The most common drug-related TEAEs (treatment-emergent adverse event) were Grade 1/2 in nature and clinically manageable.

Two global pivotal studies are ongoing in ≥ 2nd line (WU-KONG1 Part B) and 1st line setting (WU-KONG28), respectively, in NSCLC patients with EGFR exon20ins.

Pre-clinical and clinical results of sunvozertinib were published in peer-reviewed journals Cancer Discovery (IF:39.397) and The Lancet Respiratory Medicine (IF: 76.2).