On September 9, 2024 Relay Therapeutics, Inc. (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, reported positive interim data for RLY-2608, the first known investigational allosteric, pan-mutant and isoform-selective inhibitor of PI3Kα (Press release, Relay Therapeutics, SEP 9, 2024, View Source [SID1234646442]). The data showed that despite heavy pre-treatment, patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer who received RLY-2608 600mg BID + fulvestrant demonstrated clinically meaningful progression free survival (PFS).

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"These interim data suggest that by selectively targeting mutant PI3Kα, RLY-2608 has the potential to offer a level of benefit to patients that has not previously been possible with existing non-selective medicines, while also having significantly less toxicity," said Don Bergstrom, M.D., Ph.D., President of R&D at Relay Therapeutics. "We are very encouraged to see that RLY-2608 + fulvestrant led to clinically meaningful progression free survival in heavily pre-treated patients with PI3Kα-mutated, HR+, HER2- metastatic breast cancer. We will move quickly to share these data with regulators and align on the design of a pivotal study, which we anticipate starting in 2025."

ReDiscover – RLY-2608 First-in-Human Study

RLY-2608 is currently being evaluated in ReDiscover, an ongoing first-in-human study, which was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of RLY-2608 alone, in combination with fulvestrant, and in combination with fulvestrant and ribociclib or atirmociclib (Pfizer’s selective CDK4 inhibitor). As of the August 12, 2024 interim data cut-off, the RLY-2608 + fulvestrant arm of the study had enrolled 118 patients with PI3Kα-mutated, HR+, HER2- locally advanced or metastatic breast cancer across all doses in both the dose escalation and dose expansion portions of the study, including 64 patients at the company’s recommended Phase 2 dose (RP2D) of 600mg BID (17 in dose escalation and 47 in dose expansion). Among these 64 patients, 31 had a kinase mutation and 33 had a non-kinase mutation. Twelve patients also had a PTEN or AKT co-mutation and were therefore excluded from the efficacy analysis, consistent with the currently proposed pivotal population. An abstract has been submitted for presentation at the San Antonio Breast Cancer Symposium, taking place December 10-13, 2024.

Patients were Heavily Pre-Treated

All patients across doses had received a significant level of prior therapy in the advanced setting, including at least one prior endocrine therapy and at least one prior CDK4/6 inhibitor. Among the 64 patients who received the RP2D:

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45% of patients (n=29) had received two or more prior lines of therapy
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52% of patients (n=33) had received a prior selective estrogen-receptor degrader (SERD), such as fulvestrant or a novel SERD
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25% of patients (n=16) had received chemotherapy or an ADC
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59% percent of patients (n=38) had visceral metastases
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34% of patients (n=22) had a BMI of at least 30 and/or HbA1c of at least 5.7%

Promising Efficacy Data in Proposed Pivotal Population

Among the 52 patients who received the RP2D and did not have a PTEN or AKT co-mutation:

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Median PFS was 9.2 months across all mutations and 10.3 months among patients with kinase mutations
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Clinical benefit rate (CBR) was 57% across all patients (20 of 35 CBR-evaluable patients; CBR defined as the proportion of patients with complete response, partial response or stable disease for at least 24 weeks)
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Among the 30 patients with measurable disease, one third achieved a partial response (PR) (33% objective response rate, ORR; n=10; 8 confirmed, 1 confirmed post data cut-off date, 1 unconfirmed in an ongoing patient)
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Nearly three quarters of patients experienced tumor reductions (73%; n=22)
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Among the 15 patients with measurable disease who had a kinase mutation, more than half achieved a PR (53% ORR; n=8; 7 confirmed, 1 confirmed post data cut-off date)
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Median follow-up was 7.5 months

Maintained Meaningfully Differentiated Tolerability Profile

RLY-2608 + fulvestrant was generally well tolerated in the 118 patients treated across all doses as of the data cut-off date. The overall tolerability profile consisted of mostly low-grade treatment-related adverse events (TRAEs) that were manageable and reversible. Safety outcomes were generally as expected across dose levels based on exposure and consistent with mutant-selective PI3Kα inhibition. Among the 64 patients who received the RP2D:

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The low rate of TRAE-related dose modifications allowed for 95% median dose intensity
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Only two patients discontinued treatment due to TRAEs (Grade 1 pruritis; Grade 1 nausea, loss of appetite)
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The majority of hyperglycemia was Grade 1; only one patient experienced Grade 3 hyperglycemia; no Grade 4-5 hyperglycemia
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Only 25% of patients experienced a Grade 3 TRAE; no Grade 4-5 TRAEs

Continued Progression of Front-Line Breast Cancer Regimens

Two front-line triplet regimens are being progressed – one with the existing CDK4/6 standard-of-care ribociclib and one with Pfizer’s investigative selective-CDK4 inhibitor atirmociclib.

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RLY-2608 + ribociclib + fulvestrant dose escalation portion of the ReDiscover study is currently testing biologically active doses of RLY-2608
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On track to identify a dose of RLY-2608 that is combinable with full-dose ribociclib
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Initial safety data expected in the fourth quarter of 2024
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Expect to initiate dose expansion cohort(s) in first half of 2025
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RLY-2608 + atirmociclib + fulvestrant triplet on track for initiation by the end of 2024

Anticipated RLY-2608 Next Steps

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Doublet – Breast Cancer:
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Initiate 2L pivotal study of RLY-2608 + fulvestrant in 2025, pending regulatory discussions
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Triplets – Breast Cancer:
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Report initial safety data for RLY-2608 + ribociclib + fulvestrant in the fourth quarter of 2024
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Initiate RLY-2608 + ribociclib + fulvestrant triplet dose expansion cohort(s) in the first half of 2025
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Initiate RLY-2608 + atirmociclib (CDK4) + fulvestrant triplet by the end of 2024
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Monotherapy – Solid Tumors:
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Initiate RLY-2608 monotherapy solid tumor dose expansion cohort(s) by the end of 2024
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Monotherapy – Vascular Malformations:
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Initiate vascular malformations study in the first quarter of 2025

Lirafugratinib Update

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Updated FGFR2 fusion tumor agnostic data, which have generally stayed consistent with the October 2023 disclosure, will be presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), taking place October 23-25, 2024
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The company met with the FDA regarding the lirafugratinib regulatory path. The FDA suggested that the company first file a new drug application (NDA) in cholangiocarcinoma, followed by a tumor agnostic supplemental NDA for FGFR2 fusions with data from more patients and more follow up
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The company plans to seek a global commercialization partner for lirafugratinib in order to maintain focus on the remainder of the portfolio

Portfolio Prioritization is a Continued Focus

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The company continues to advance high-value next-generation programs:
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Fabry disease: clinical start anticipated in the second half of 2025
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NRAS: clinical start anticipated in the second half of 2025
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Ongoing streamlining of the research organization

Wholly-Owned Portfolio Provides Strategic Flexibility for Cash Runway

As of the end of the second quarter of 2024, cash, cash equivalents and investments were approximately $688 million, which the company expects to be sufficient to fund its current operating plan into the second half of 2026, assuming all current programs remain wholly owned and are fully prosecuted.

Conference Call Information

Relay Therapeutics will host a conference call and live webcast today, Monday, September 9, 2024, at 8:00 a.m. ET. Registration and dial-in for the conference call may be accessed on Relay Therapeutics’ website under Events in the News & Events section through the following link: View Source An archived replay of the webcast will be available following the event.

About RLY-2608

RLY-2608 is the lead program in Relay Therapeutics’ efforts to discover and develop mutant selective inhibitors of PI3Kα, the most frequently mutated kinase in all cancers, with oncogenic mutations detected in about 14% of patients with solid tumors. RLY-2608 has the potential, if approved, to address more than 300,000 patients per year in the United States, one of the largest patient populations for a precision oncology medicine.

Traditionally, the development of PI3Kα inhibitors has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus wild-type (WT) PI3Kα and off-isoform activity. Toxicity related to inhibition of WT PI3Kα and other PI3K isoforms results in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation. The Dynamo platform enabled the discovery of RLY-2608, the first known allosteric, pan-mutant, and isoform-selective PI3Kα inhibitor, designed to overcome these limitations. Relay Therapeutics solved the full-length cryo-EM structure of PI3Kα, performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to support the design of RLY-2608. RLY-2608 is currently being evaluated in a first-in-human trial designed to treat patients with advanced solid tumors with a PIK3CA (PI3Kα) mutation. For more information on RLY-2608, please visit here.

On September 9, 2024 Cellworks Group Inc., a leader in Personalized Therapy Decision Support and Precision Drug Development, reported findings from a study using the Cellworks Platform to predict the benefits of adding chemotherapy to osimertinib treatment in patients with EGFR mutated non-small cell lung cancer (NSCLC) (Press release, Cellworks, SEP 9, 2024, View Source [SID1234646458]). Leveraging data from a real-world retrospective cohort, the biosimulation study confirmed that adding chemotherapy to osimertinib led to a higher predicted overall response rate (ORR). The study revealed that while all patients responded to the addition of chemotherapy, the magnitude of benefit varied among individuals and was intricately determined by underlying genomic abnormalities, enabling the identification of patients who would benefit from combination therapies, and others who would achieve similar outcomes without the addition of chemotherapy.

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Results from the study were showcased in a poster presentation (P1.06A.03) titled ‘Use of Biosimulation to Predict Concomitant Chemotherapy Benefit in NSCLC Patients with EGFR Mutations Being Treated with Osimertinib’ as part of the IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer in San Diego, California on September 8, 2024.

"Osimertinib has become a standard treatment option in patients with NSCLC harboring EGFR mutations," said Dr. Charu Aggarwal, MD, MPH, Professor of Medicine, University of Pennsylvania, Associate Director, PC3I and Director, Program in Precision Oncology Innovation, Penn Center for Cancer Care Innovation; and Principal Investigator for the study. "However, while targeted therapies are generally effective for these patients, response rates can vary significantly, and the potential advantage of incorporating chemotherapy in some patients remains unclear. This study demonstrates how utilizing Cellworks biosimulation can provide valuable insights by more accurately predicting the benefit of chemotherapy, as it allows for a deeper understanding of an individual patient’s therapy response based on biosimulation of their full mutation profile."

"This study opens new potential avenues for optimizing treatment strategies in NSCLC patients with EGFR mutations," said Dr. Michael Castro, Cellworks Chief Medical Officer. "By identifying additional biomarkers that influence chemotherapy response in NSCLC patients, we gain a deeper understanding of how each patient’s unique disease profile impacts therapy effectiveness. EGFR blockade can reverse chemotherapy resistance for some patients by downregulating apoptotic blockade and DNA repair caused by EGFR. Through the use of Cellworks personalized therapy biosimulation, we can pave the way for individualized decision making to determine which patients should be offered combination therapy upfront, thereby improving survival outcomes."

Study Design

Cellworks computational biosimulation was performed in this study to evaluate the additive value of chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations. A real-world retrospective cohort of 116 frontline NSCLC patients treated with osimertinib were obtained from the nationwide (US based) de-identified Flatiron Health-Foundation Medicine NSCLC clinico-genomic database (FH-FMI-CGDB). Biosimulated efficacy scores were generated for both osimertinib alone and in combination with carboplatin and pemetrexed. The study then analyzed chemotherapy-driven improvements in predicted clinical response, using the upper 95% confidence interval of the osimertinib ES as a threshold.

Study Results

The efficacy scores for osimertinib were significantly associated with clinical outcomes, confirming the predictive power of Cellworks computational biosimulation. Importantly, the biosimulated addition of chemotherapy to osimertinib led to a higher efficacy score for some patients, allowing for a more refined selection of patients, moving beyond the generalized conclusion that chemotherapy is beneficial in combination, which may apply to some, but not all, patients. The benefit of chemotherapy is unevenly distributed in the population, and biosimulation aids in the selection of which patients are most likely to get a benefit from combination compared to sequential treatment.

On September 9, 2024 CytomX Therapeutics, Inc. (Nasdaq: CTMX), a leader in the field of masked, conditionally activated biologic therapeutics, reported that the first patient has been dosed with CX-801 monotherapy in a Phase 1 study (NCT06462794) in patients with solid tumors (Press release, CytomX Therapeutics, SEP 9, 2024, View Source [SID1234646428]). CX-801 is a dually-masked interferon alpha-2b PROBODY cytokine with potential broad applicability in both traditionally immune-oncology sensitive as well as insensitive (cold) tumors.

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The CX-801 Phase 1 dose escalation study is designed to evaluate safety and signs of clinical activity for CX-801 as monotherapy and in combination with Merck’s (known as MSD outside of the US and Canada) anti-PD-1 therapy KEYTRUDA (pembrolizumab). In dose escalation, the Phase 1 study will enroll patients with select solid tumors including advanced melanoma, renal cell carcinoma, and head and neck squamous cell carcinoma to inform a potential decision to move into Phase 1b indication-specific dose expansion cohorts.

"Interferon-alpha-2b is a powerful immune-modulating cytokine that has demonstrated clinical activity in multiple cancer types such as metastatic melanoma, renal cancer and bladder cancer but its clinical benefit has been limited by significant toxicities when administered systemically. CX-801 utilizes CytomX’s industry leading conditional activation platform to maintain potency and expand interferon’s therapeutic index to potentially become a foundational component of immuno-oncology combination regimens," said Wayne Chu, M.D., chief medical officer of CytomX Therapeutics.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

On September 9, 2024 Replimune Group, Inc. (NASDAQ: REPL), a clinical stage biotechnology company pioneering the development of novel oncolytic immunotherapies, reported it has completed a successful pre-Biologics License Application (pre-BLA) meeting with the U.S. Food and Drug Administration (FDA) that supports the Company’s plans to submit a BLA for RP1 (vusolimogene oderparepvec) for the treatment of anti-PD1 failed melanoma via the accelerated approval pathway in 2H 2024 (Press release, Replimune, SEP 9, 2024, View Source [SID1234646443]).

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"This successful pre-BLA meeting confirmed that the accelerated approval path is available for RP1 in anti-PD1 failed melanoma," said Sushil Patel, Ph.D., Chief Executive Officer at Replimune. "With the confirmatory IGNYTE-3 trial underway, we remain on track to submit the BLA in 2H 2024 and continue our preparations to bring RP1 to patients with advanced melanoma."

Topline results from the primary analysis of the IGNYTE clinical trial of RP1 plus nivolumab shared earlier this year showed an overall response rate of 33%. Independently reviewed data from the IGNYTE clinical trial, including key secondary endpoints and subgroup analyses will be presented as a late-breaking abstract during an oral session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress 2024 in Barcelona on Sunday, September 15, 2024, at 3:45pm CEST.

About RP1
RP1 (vusolimogene oderparepvec) is Replimune’s lead product candidate and is based on a proprietary strain of herpes simplex virus engineered and genetically armed with a fusogenic protein (GALV-GP R-) and GM-CSF, intended to maximize tumor killing potency, the immunogenicity of tumor cell death, and the activation of a systemic anti-tumor immune response.

On September 9, 2024 Bayer reported encouraging results from the expansion part of the ongoing Phase I/II SOHO-01 study evaluating the safety and preliminary efficacy of BAY 2927088 in advanced HER2-mutant non-small cell lung cancer (NSCLC). Data were presented during the Presidential Symposium at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer, taking place in San Diego, United States, from September 7-10, 2024 (Press release, Bayer, SEP 9, 2024, View Source [SID1234646459]).

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"The encouraging results from the expansion phase of the SOHO-01 trial demonstrate the potential of this targeted therapy to advance outcomes for patients with HER2-mutant NSCLC, a type of lung cancer with limited treatment options and poor prognosis," said Christian Rommel, Ph.D., Head of Research and Development at Bayer’s Pharmaceuticals Division. "The development of BAY 2927088 underscores our ongoing commitment in lung cancer and our continued drive to develop precise and personalized healthcare solutions in disease areas with the highest unmet needs."

"HER2-mutant NSCLC is a challenging disease that can predominantly affect individuals who are young and never smoked a cigarette. Given the current lack of therapeutic options, there is an immediate need for effective, manageable treatments," said SOHO-01 lead trialist, Xiuning Le, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston, TX. "BAY 2927088 showed promising preliminary efficacy in both response rate and duration, and a manageable safety profile, which emphasizes the importance of ongoing innovation to elevate the standard of care."

The objective of the expansion phase of the study was to determine the safety, tolerability, and pharmacokinetics of BAY 2927088 in patients with HER2-mutant NSCLC. These data support the ongoing investigation of BAY 2927088 in patients with advanced NSCLC harboring HER2 mutations. Just recently Bayer announced that the first patient has been enrolled in the global Phase III SOHO-02 trial, an open-label, randomized, multicenter clinical trial, assessing the efficacy and safety of investigational agent BAY 2927088 as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC), whose tumors have activating HER2 mutations.

Detailed Results from SOHO-01
SOHO-01 is an ongoing, open-label, multicenter Phase I/II study. Results from patients with advanced NSCLC harboring a HER2-activating mutation with disease progression after ≥1 systemic therapies for advanced disease, and who are naïve to HER2-targeted therapy were presented. In the trial, patients received oral BAY 2927088 20 mg twice daily. Forty-three out of forty-four patients enrolled were evaluable for efficacy, with a confirmed objective response rate (ORR) of 72.1% (n=31; 95% CI 56.3, 84.7) including 1 complete response (2.3%). Median duration of response (DOR) and progression-free survival (PFS) were 8.7 months (95% CI 4.5, not estimable) and 7.5 months (95% CI 4.4, 12.2), respectively. In patients with HER2 YVMA insertions, the most frequent mutation, ORR was 90.0%, DoR was 9.7 months, and PFS was 9.9 months.

The safety profile of BAY 2927088 was found to be manageable, and consistent with previous reports. Treatment-related adverse events (TRAEs) were reported in 95.5% of patients, with grade 3 TRAEs reported in 40.9%. Diarrhea was the most common TRAE (86.4%, 25.0% grade 3), followed by rash (43.2% grade 1 or 2) and paronychia (25.0% grade 1 or 2). Three patients (6.8%) discontinued due to TRAEs.

About BAY 2927088
BAY 2927088 is an investigational agent and has not been approved by any health authority for use in any country, for any indication. It is currently being evaluated as a potential new targeted treatment option for patients with NSCLC harboring HER2 activating mutations. BAY 2927088 is an oral, reversible tyrosine kinase inhibitor (TKI) that potently inhibits mutant human epidermal growth factor receptors 2 (HER2), including HER2 exon 20 insertions and HER2 point mutations, as well as epidermal growth factor receptors (EGFR), with high selectivity for mutant vs wild-type EGFR. Investigational agent BAY 2927088 is derived from Bayer’s strategic research alliance with the Broad Institute of MIT and Harvard in Cambridge, MA, USA.

About Breakthrough Therapy Designation
This Breakthrough Therapy designation for BAY 2927088 is supported by preliminary clinical evidence from the Phase I/II, open-label, multicenter first-in-human study (NCT05099172) evaluating the safety, pharmacokinetics and preliminary efficacy of BAY 2927088 in adult patients with advanced NSCLC harboring HER2 or EGFR. The Breakthrough Therapy designation is a process designed to expedite the development and review of novel medicines that are intended for the prevention or treatment of serious, life-threatening diseases or conditions that severely impact the quality of life for which there is no existing treatment, or where sufficient evidence indicates advantages of the novel drug over available treatment options.

About Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is the leading cause of cancer-related deaths worldwide. NSCLC is the most common type of lung cancer, accounting for more than 85% of cases. Activating HER2 mutations are found in 2% to 4% of advanced NSCLC. 80% of people diagnosed with NSCLC have already progressed to advanced stages, which makes it more difficult to treat. Patients with HER2-mutant NSCLC currently face limited treatment options, highlighting an urgent need for more effective therapies.