On September 13, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily for malignancies, reported that it has released the clinical data of olverembatinib (HQP1351), the company’s novel drug candidate, in patients with succinate dehydrogenase- (SDH-) deficient gastrointestinal stromal tumor (GIST), in a Mini Oral at the 2024 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, Ascentage Pharma, SEP 13, 2024, View Source;ascentage-pharma-releases-latest-data-showing-sustained-clinical-efficacy-of-olverembatinib-in-sdh-deficient-gist-during-a-mini-oral-presentation-302248193.html [SID1234646579]).

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These data of olverembatinib, presented in the Mini Oral at ESMO (Free ESMO Whitepaper) 2024, showed sustained clinical benefit in patients with SDH-deficient GIST. As of March 12, 2024, six of the 26 patients with SDH-deficient GIST enrolled in the study achieved partial responses (PRs). The objective response rate (ORR) was 23.1%, and the median progression-free survival (PFS) was 22 months. Furthermore, studies on mechanism of action (MOA) revealed that olverembatinib exerts its antitumor activity by modulating multiple signaling pathways involved in angiogenesis, apoptosis, proliferation, and survival.

Olverembatinib, a novel orally-administered tyrosine kinase inhibitor (TKI) developed by Ascentage Pharma, is the first approved third-generation BCR-ABL inhibitor in China. To date, olverembatinib has been approved for two indications in China, including adult patients with TKI-resistant chronic-phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation; and adult patients with CML-CP resistant to and/or intolerant of first-and second-generation TKIs. Olverembatinib is jointly commercialized in China by Ascentage Pharma and Innovent Biologics. This is a study of an investigational drug not yet approved by the US Food and Drug Administration (FDA).

In addition to hematologic indications, olverembatinib is also being clinically evaluated for the treatment of GIST. To date, olverembatinib has already been granted a Breakthrough Therapy Designation by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) for the treatment of patients with SDH-deficient GIST who had received first-line treatment. Recently, olverembatinib was cleared by the China CDE to enter a registrational Phase III study in patients with SDH-deficient GIST.

Prof. Haibo Qiu, of Sun Yat-Sen University Cancer Center, and the presenter of the report, commented, "SDH-deficient GIST is an extremely rare type of cancer. According to Chinese and International clinical guidelines, there are currently no standard treatment options for unresectable SDH-deficient GIST. In this Phase I study, we have observed encouraging clinical benefit data and further explored the MOA of olverembatinib. Supported by existing data, we will soon initiate a registrational Phase III study in efforts to bring a new treatment option to more patients with SDH-deficient GIST."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "Clinical data presented in the Mini Oral reaffirmed olverembatinib’s clinical benefit and favorable tolerability in patients with SDH-deficient GIST, thus indicated another potential breakthrough for an indication with a huge unmet medical need. We will actively advance this clinical development program which hopefully will soon offer patients a safe and effective new treatment option."

As one of the world’s leading and most influential oncology congresses, the ESMO (Free ESMO Whitepaper) Congress showcases the latest results in some of the most cutting-edge cancer research from around the world.

Highlights of the data on olverembatinib presented at this year’s ESMO (Free ESMO Whitepaper) Congress are as follows:

Updated efficacy results of olverembatinib (HQP1351) in patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST) and potential mechanisms of action (MOA)

Format: Mini oral
Presentation#: 1722MO
Category: Sarcoma
Date & Time: Friday September 13, 2024, 16:30 – 16:35 CEST
Speaker: Haibo Qiu, MD, PhD, Sun Yat-sen University Cancer Center
Highlights:

Background: SDH-deficient GIST is a rare disease with limited treatment options. The oncogenic mechanism of SDH deficiency has not been elucidated. Olverembatinib, already approved in China for the treatment of adult patients with TKI-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP), with or without the T315I mutation, has shown promising clinical efficacy in SDH-deficient GIST. This report provides the most updated Phase I efficacy data and translational data of olverembatinib in SDH-deficient GIST.
Methods: This study (HQP1351-SJ0003; NCT03594422) was designed to evaluate the safety and efficacy of olverembatinib in patients (≥12 years of age) with GIST or other solid tumors. Olverembatinib was administered orally every other day (QOD). The study evaluated the clinical efficacy of olverembatinib and analyzed the drug’s MOA using multiple in vitro and in vivo assays including a SDHB knock-down rat pheochromocytoma PC12 (#5F7)-derived mouse xenograft model.
Enrolled Patients: As of March 12, 2024, a total of 26 patients with SDH-deficient GIST (confirmed by IHC) were treated with olverembatinib, including 25 (96.2%) who had received 1 to 4 TKIs and 13 (50.0%) who had received ≥3 TKIs.
Efficacy and Safety Results: Olverembatinib was well tolerated at doses of 30 to 50 mg. In all, 6 (23.1%) patients achieved partial responses (PRs) and the median PFS was 22.0 months (range: 12.9-38.6).
Preclinical Results: Olverembatinib had superior antiproliferative activity (vs. other approved TKIs) in SDHB-deficient cell lines (IC50, 0.129-5.132 μM). In PC12#5F7 (SDHB knock-down) cells, olverembatinib decreased HIF 2α, VEGFA, and FGFR1 protein levels and inhibited phosphorylation of FGFR1, IGF 1R, SRC, AKT, and ERK1/2. In PC12#5F7-derived xenograft models, olverembatinib demonstrated dose dependent antitumor activity at 10 and 20 mg/kg (QOD).
Conclusions: Olverembatinib showed sustained clinical efficacy in SDH-deficient GIST, indicating potential benefit of this treatment as well as providing a benchmark for future studies in this rare subtype of GIST. MOA studies revealed that olverembatinib exerts antitumor activity by modulating multiple signaling pathways involved in angiogenesis, apoptosis, proliferation, and survival.

On September 13, 2024 MediLink Therapeutics (MediLink) reported clinical data for YL201, a novel B7H3-targeting antibody drug conjugate (ADC) developed based on MediLink’s Tumor Microenvironment Activable LINker-payload (TMALIN) platform, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, Suzhou Medilink Therapeutics, SEP 13, 2024, View Source [SID1234646573]). This is the first disclosure of clinical data for YL201 featured in an oral presentation.

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Presented results are from phase I studies (NCT05434234 & NCT06057922) conducted in China and the US to explore the safety and efficacy of YL201 in patients with advanced solid tumors. As shown in the abstract, by August 9 2024, a total of 312 patients were enrolled in the dose escalation and expansion studies with various tumor types, including small cell lung cancer (SCLC, n=79), nasopharyngeal carcinoma (NPC, n=75), and non-small cell lung cancer without actionable genomic alterations (NSCLC without AGAs, n=68). All enrolled patients have been treated with prior standard therapy, and 60% had at least 2 prior treatment lines.

During dose escalation stage, dose limiting toxicities were observed at 2.8 mg/kg (n=1) and 3.0 mg/kg (n=2). For dose expansion, 2.0 mg/kg and 2.4 mg/kg were selected as recommended expansion doses. As of 09 Aug 2024, 276 patients had at least one post-baseline tumor assessment per RECIST V1.1., The overall response rate (ORR) was 44.6%, the disease control rate (DCR) was 83.7%. The median follow-up duration was 5.4 months, and 46% of the patients are still on treatment.

Antitumor activity was observed in multiple solid tumor types. In extensive-stage SCLC patients, among 72 patients who had evaluable tumor assessment, all patients had prior treatment with platinum-based chemotherapy, and 95% had prior treatment with anti-PD-(L)1. The ORR was 68.1% (at dose levels >= 2.0 mg/kg: 70.0%) and the median progress-free survival (mPFS) was 6.2 months (at dose levels >= 2.0 mg/kg: 6.2 months). Also worth mentioning was that in patients with brain metastasis, the ORR was 52.2% and mPFS was 5.3 months, comparable to those of overall population.

In 70 NPC patients with evaluable tumor assessment, the ORR was 48.6% (at dose levels >= 2.0 mg/kg: 48.6%), and mPFS was 7.2 months (at dose levels >= 2.0 mg/kg: 7.2 months). In heavily-treated NPC patients receiving at least 2 prior lines of treatment, the efficacy was also comparable, with ORR of 51.0% and mPFS of 7.0 months.

In NSCLC without AGA, all patients had prior treatment with anti-PD-(L)1 and platinum-based chemotherapy. In the histological subtypes of adenocarcinoma and LELC, ORR were 29.2% and 60.9%, respectively, and mPFS were unmatured and 8.1 months, respectively.

In terms of safety, the grade 3 and higher treatment-related TEAEs (TRAEs) occurred in 51% of the patients, and serious TRAEs occurred in 28%. The most common TRAE were leukopenia (G≥3 29%), anemia (G≥3 22%) and neutropenia (G≥3 30%), while decreased appetite (G≥3 1%) and nausea (G≥3 1%) were the most common non-hematological TRAEs. Only 3 (1%) were reported as treatment related interstitial lung disease.

"We are excited to share the results of YL201 at the ESMO (Free ESMO Whitepaper) Congress," said Dr. Steve Chin, Chief Medical Officer of MediLink. "Clinical data accumulated from a sample size of over 300 patients has solidly demonstrated the antitumor activity of YL201 in multiple solid tumor types, especially in SCLC, NPC, and NSCLC without AGA. Significant improvement was shown in these population compared to historical data of existing standard treatment regimens. Also, YL201 is well tolerated with the most common TRAEs being hematological toxicities, which are deemed to be manageable. We were actively preparing Phase 3 studies of YL201 in SCLC, NPC, etc."

About YL201

YL201 is an innovative antibody-drug conjugate that specifically targets B7-H3. B7-H3 is overexpressed on differentiated malignant cells and cancer-initiating cells of various tumor types, but has a restricted expression in normal tissue, indicating its potential as ADC drug. YL201 has been developed by utilizing MediLink’s Tumor Microenvironment Activable LINker-payload (TMALIN) conjugated with a highly specific B7-H3 antibody. Currently, YL201 is being investigated in four Phase I or II studies, including one multi-national Phase I clinical study.

On September 13, 2024 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the publication of a manuscript in Cancer Discovery, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which describes the design and characterization of NVL-655 and details Nuvalent’s approach to rationally targeting ALK (Press release, Nuvalent, SEP 13, 2024, View Source [SID1234646572]). NVL-655 is currently being studied in the ongoing ALKOVE-1 Phase 1/2 clinical trial for patients with advanced ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors.

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The manuscript, entitled "NVL-655 is a selective and brain-penetrant inhibitor of diverse ALK mutant oncoproteins, including lorlatinib-resistant compound mutations," is published online and can be accessed here: View Source

"Currently available ALK tyrosine kinase inhibitors (TKIs) are important treatment options for patients with ALK-driven lung cancer. However, limitations including treatment-emergent drug resistance, off-target neurological adverse events, and inadequate control of brain metastases, support the need for continued development in this disease," said senior author Alexander Drilon, MD, Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, and investigator in the ALKOVE-1 trial. "As detailed in this publication, preclinical characterization and preliminary clinical data provide a compelling rationale for the ongoing clinical investigation of NVL-655 and evaluation of its potential to address the limitations of available ALK TKIs for patients with ALK-positive NSCLC."

The manuscript details the design principles underlying the activity of NVL-655 against ALK single and compound resistance mutations, including the most commonly occurring resistance mutation, ALK G1202R. Additionally, it outlines a molecular rationale for the selectivity of NVL-655 for ALK over the structurally related tropomyosin receptor kinase (TRK) family, whose inhibition has been associated with neurological adverse events that can be dose limiting. Preclinical characterization of the activity and selectivity of NVL-655 is presented, including in vivo xenograft studies, preclinical assessments of brain penetrance and intracranial activity, and a comparison of eight ALK TKIs across multiple biochemical and cellular assays.

The manuscript further documents three case studies from the ALKOVE-1 trial of patients with ALK fusion-positive lung cancers who had received a range of ALK TKIs, including lorlatinib, and presented with brain metastases or with tumors that harbored ALK G1202R. NVL-655 elicited tumor responses in these patients without accompanying CNS effects attributed to off-target TRK inhibition. These findings support the potential for NVL-655 as a future treatment for these patient populations that may also enhance tolerability through improved selectivity for ALK.

"With this publication in Cancer Discovery, we are pleased to have now also elucidated our focused approach for ALK-positive NSCLC. Along with our parallel lead program for ROS1-positive NSCLC, these selective inhibitors form the foundation for our pipeline of precisely targeted therapies which aim to deliver potential best-in-class activity against recalcitrant targets through solving for multiple, and at times competing, challenges in structure-based drug design," said Joshua Horan, Ph.D., Vice President, Chemistry at Nuvalent. "We are grateful to our collaborators for their contributions to this manuscript and to the continued advancement of NVL-655."

Enrollment is ongoing in the global Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, designed with registrational intent. Updated data from the Phase 1 portion of the trial will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 in Barcelona, Spain during a Proffered paper session on Saturday September 14, 2024 from 9:30 – 9:40 a.m. CEST.

About NVL-655

NVL-655 is a novel brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with single or compound treatment-emergent ALK mutations such as G1202R. In addition, NVL-655 is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy. NVL-655 has received breakthrough therapy designation for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with two or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC. NVL-655 is currently being evaluated in the Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, a first-in-human study of NVL-655 in patients with advanced ALK-positive NSCLC and other solid tumors (NCT05384626).

On September 13, 2024 GlaxoSmithKline reported that the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) in China has granted Breakthrough Therapy Designation (BTD) for Blenrep (belantamab mafodotin) combined with bortezomib plus dexamethasone (BorDex) for the treatment of relapsed or refractory multiple myeloma (Press release, GlaxoSmithKline, SEP 13, 2024, View Source [SID1234646569]). NMPA BTD is intended to expedite the development of therapies for serious and life-threatening diseases for which there are no existing treatments or where initial evidence has shown an improvement in patient outcomes over available treatment options.2

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Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK, said: "Breakthrough Therapy Designation in China underscores the potential for Blenrep to redefine outcomes for patients with multiple myeloma at or after their first relapse. We look forward to continuing to work with the health authority in China and others worldwide to bring Blenrep-based combinations to patients as expeditiously as possible."

BTD was granted based on the interim results of the phase III head-to-head DREAMM-7 trial, which met its primary endpoint, showing statistically significant and clinically meaningful improvements in progression-free survival (PFS) for belantamab mafodotin combined with BorDex compared to daratumumab plus BorDex in relapsed or refractory multiple myeloma.

A positive overall survival (OS) trend was observed but was not statistically significant at the time of interim analysis. Follow-up for OS continues. Results also showed clinically meaningful improvements across all other secondary efficacy endpoints, including deeper and more durable responses compared to the standard of care combination. The safety and tolerability profile of the belantamab mafodotin combination in the DREAMM-7 trial was broadly consistent with the known profiles of the individual agents.

Multiple myeloma is a growing health concern in China with approximately 30,000 new cases each year.3 The incidence in China has doubled and mortality has increased 1.5-fold in the past three decades.4 This underscores the need for novel, efficacious treatment options for patients in China, particularly those with progressing disease that has become resistant to the current standard of care.

About multiple myeloma
Multiple myeloma is the third most common blood cancer globally and is generally considered treatable but not curable.5,6 There are approximately more than 180,000 new cases of multiple myeloma diagnosed globally each year.7 Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments.8

About DREAMM-7
The DREAMM-7 phase III clinical trial is a multicentre, open-label, randomised trial evaluating the efficacy and safety of belantamab mafodotin in combination with BorDex compared to a combination of daratumumab and BorDex in patients with relapsed/refractory multiple myeloma who previously were treated with at least one prior line of multiple myeloma therapy, with documented disease progression during or after their most recent therapy.

A total of 494 participants were randomised at a 1:1 ratio to receive either belantamab mafodotin in combination with BorDex or a combination of daratumumab and BorDex. Belantamab mafodotin was scheduled to be dosed at 2.5mg/kg intravenously every three weeks.

The primary endpoint is PFS as per an independent review committee. The key secondary endpoints include OS, duration of response (DOR), and minimal residual disease (MRD) negativity rate as assessed by next-generation sequencing. Other secondary endpoints include overall response rate (ORR), safety, and patient reported and quality of life outcomes.

Results from DREAMM-7 were first presented9 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Plenary Series in February 2024, shared in an encore presentation at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting, and published in the New England Journal of Medicine.

About Blenrep
Blenrep is an antibody-drug conjugate comprising a humanised B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. The drug linker technology is licensed from Seagen Inc.; the monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa Inc., a member of the Kyowa Kirin Group.

Blenrep is approved as monotherapy in Hong Kong, Israel and Singapore. Refer to the local Summary of Product Characteristics for a full list of adverse events and complete important safety information.

On September 13, 2024 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science, reported initial clinical data from the ongoing clinical trial of CFT1946, an orally bioavailable small molecule degrader of BRAF V600 mutations in solid tumors (Press release, C4 Therapeutics, SEP 13, 2024, View Source [SID1234646568]). These data, the first clinical results for a BRAF V600X degrader, were shared as a proffered paper in an oral presentation by Maria Vieito, M.D., MSc, medical oncologist at Vall d’Hebron University Hospital, Barcelona, Spain, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024, being held September 13 – 17 in Barcelona, Spain.

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"We are thrilled to share initial CFT1946 monotherapy data and highlight how this molecule, the first and only clinical-stage degrader of BRAF V600 mutants, may disrupt the current treatment landscape as it quickly progresses through clinical development," said Andrew Hirsch, president and chief executive officer of C4 Therapeutics. "In addition to addressing the needs of patients with BRAF V600 mutant solid tumors, we believe these clinical data further reinforce the potential of our TORPEDO platform to design innovative small molecule degraders that excite the medical community and have the potential to improve patients’ lives."

"The data presented at the ESMO (Free ESMO Whitepaper) Congress 2024 are impressive given the early stage of development of CFT1946 and the novel modality," said Dr. Vieito. "I am especially encouraged by the safety and tolerability of CFT1946, which may allow for additional monotherapy exploration as well as combination approaches to better understand how this oral degrader medicine may support the needs of patients refractory to BRAF inhibitor therapies."

"We are pleased with the safety profile CFT1946 has demonstrated over a range of doses, as well as its pharmacokinetics, pharmacodynamics and initial anti-tumor activity. Taken together, these data support our hypothesis that degradation may offer a new therapeutic option over inhibition for BRAF V600 mutant solid tumors," said Len Reyno, M.D., chief medical officer of C4 Therapeutics. "We are deeply appreciative of the contributions from patients, caregivers and the oncology community that have enabled us to deliver this preliminary monotherapy data and we look forward to continuing these important relationships as we progress CFT1946 toward additional milestones in 2025 and beyond."

At the ESMO (Free ESMO Whitepaper) Congress 2024, C4T reported initial monotherapy data from the ongoing dose escalation Phase 1 clinical trial evaluating twice daily oral dosing of CFT1946, a degrader of BRAF V600 mutants, in patients with BRAF V600X solid tumors who have received at least one prior standard of care therapy for unresectable locally advanced or metastatic disease. Prior therapy must include a BRAF inhibitor, unless access is limited by regional regulatory approvals or reimbursement. As of the data cutoff date of July 19, 2024, a total of 36 patients received CFT1946 monotherapy across five dose escalation cohorts (20 mg BID, 80 mg BID, 160 mg BID, 320 mg BID and 640 mg BID). Patients received a median of three prior therapies; 35 patients (97 percent) had received prior BRAF inhibitor therapy. Thirty-three patients (92 percent) had a BRAF V600E mutation, two patients (six percent) had a BRAF V600K mutation and one patient (two percent) had a BRAF V600R mutation. Fourteen patients (39 percent) had melanoma, 14 patients (39 percent) had colorectal cancer, two patients (six percent) had non-small cell lung cancer and six patients (17 percent) had other cancers. All patients had unresectable, locally advanced or metastatic disease, and 32 patients (89 percent) entered the study with Stage IV cancer.

Safety and Tolerability: CFT1946 has a well-tolerated safety profile that supports further clinical development as monotherapy and in combination with MEK and EGFR inhibitors.

There were no dose-limiting toxicities and no treatment-related serious adverse events.
Adverse events occurring in more than 10 percent of patients were all Grade 1 or Grade 2.
No patients discontinued therapy or experienced treatment interruptions due to treatment-related adverse events.
No patients receiving CFT1946 monotherapy experienced a Grade 3 or higher treatment-related cutaneous adverse event. These cutaneous adverse events, which are related to BRAF wild-type inhibition, are commonly seen with BRAF inhibitors.
Pharmacokinetics (PK) and Pharmacodynamics (PD): Initial data demonstrating dose-dependent bioavailability and degradation of BRAF V600E protein support CFT1946 proof of mechanism.

CFT1946 exhibits dose-dependent bioavailability in the five dose levels explored to date.
In all available post-treatment biopsies collected to date, degradation of BRAF V600E protein is observed.
Anti-Tumor Activity: CFT1946 demonstrates evidence of monotherapy anti-tumor activity, supportive of early proof of degrader concept.

At data cutoff, 27 patients were evaluable for anti-tumor activity, which is measured by RECIST 1.1 criteria.
16 patients demonstrated reduction of target metastatic lesions.
Two patients achieved a confirmed Partial Response.
Reduction of target lesion tumors was observed across histologies. Of the 27 patients evaluable for anti-tumor activity:
Eleven patients had melanoma, eight of whom had evidence of tumor reduction. One patient with Stage IV BRAF V600K melanoma enrolled in the 320 mg BID cohort achieved a 67 percent decrease in target lesions as measured by RECIST 1.1 criteria. This patient remains on CFT1946 treatment and in response.
Nine patients had colorectal cancer, three of whom had evidence of tumor reduction.
Seven patients have other tumor histologies, three of whom had evidence of tumor reduction. One patient with Stage IV BRAF V600E pancreatic cancer, who has liver metastases, enrolled in the 640 mg BID cohort achieved a 55 percent decrease in target lesion as measured by RECIST 1.1 criteria. This patient remains on CFT1946 treatment and in response.
As of data cutoff, 11 of the patients who were evaluable for anti-tumor activity remain on therapy.
Next Steps and Future Milestones for CFT1946
The CFT1946 Phase 1 trial is ongoing and multiple indication-specific cohorts are advancing. Next steps and related milestones for CFT1946 include:

Complete Phase 1 monotherapy dose escalation – This portion of the trial is enrolling patients with BRAF V600X mutations across solid tumor indications. Patients are currently enrolling in the 640 mg BID PD backfill cohort as this dose level was recently declared safe. The full monotherapy dose escalation data are expected in 2025.
Complete expansion cohort exploring CFT1946 monotherapy in melanoma – This Phase 1 exploratory expansion cohort is evaluating the potential of CFT1946 monotherapy for melanoma patients refractory to BRAF inhibitor therapies. Enrollment for the 320 mg BID dose level is complete, and enrollment is ongoing for the 640 mg BID dose level. Data from these dose levels are expected in 2025.
Complete dose escalation cohort exploring CFT1946 in combination with cetuximab in colorectal cancer – This Phase 1b dose escalation cohort is enrolling patients at the 160 mg BID dose level to explore safety and tolerability, PK, PD and anti-tumor activity of CFT1946 in combination with cetuximab. These data are expected in 2025.
Initiate dose escalation cohort exploring CFT1946 in combination with trametinib in melanoma – This Phase 1b dose escalation cohort will explore safety and tolerability, PK, PD and anti-tumor activity of CFT1946 in combination with trametinib. C4T expects to initiate this cohort by year-end 2024.
C4T Webcast for Analysts and Investors
C4T will host an investor webcast today, September 13, 2024, at 12:00 pm ET. To join the webcast, please visit this link or the "Events & Presentations" page of the Investors section on the company’s website at www.c4therapeutics.com. A replay of the webcast will be archived and available following the event.

About BRAF V600 Mutant Solid Tumors
BRAF mutations are found in approximately five percent of all cancers, including melanoma, colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and other malignancies. Of these BRAF mutation cancer diagnoses, up to 90 percent contain an activating BRAF V600 mutation. BRAF V600 mutations are observed in up to 50 percent of patients with melanoma, nearly 10 percent of patients with CRC and approximately five percent of patients with NSCLC. Resistance to FDA-approved BRAF inhibitors results in median progression-free survival rates of less than 15 months across all indications.

About CFT1946
CFT1946 is an investigational, orally bioavailable small molecule degrader of BRAF V600 mutations in solid tumors currently being evaluated in a Phase 1/2 global clinical trial in patients refractory to BRAF inhibitors. CFT1946 is designed to be potent and selective against the BRAF V600 mutant form. Initial clinical data from the Phase 1 trial demonstrate that CFT1946 has a well-tolerated safety profile, demonstrates dose-dependent bioavailability and degradation of BRAF V600E protein, and demonstrates evidence of monotherapy anti-tumor activity. CFT1946 is the only degrader of BRAF V600 mutant solid tumors in clinical trials. More information about this trial may be accessed at www.clinicaltrials.gov (identifier: NCT05668585).