LP-184 Demonstrates Favorable Efficacy and Safety in Advanced Solid Tumors

The clinical landscape for patients with advanced solid tumors, particularly those who are heavily pretreated, remains challenging, demanding novel agents with improved selectivity and mechanism-based efficacy. The development of LP-184, a synthetic small molecule leveraging synthetic lethality, represents a significant step toward addressing this unmet need.^1,2

Data from extensive preclinical validation and the recently completed first-in-human phase 1a trial (NCT05933265) shows LP-184’s efficacy signals and promising safety profile.

The study, which enrolled a heavily pretreated, heterogeneous patient population (most having failed 3 or more prior lines of therapy), provided encouraging signs of clinical activity.

At the recommended phase 2 dose (RP2D), the disease control rate was 44%, with 22% of patients maintaining disease control beyond 6 months. The majority of evaluable patients dosed above the therapeutic threshold achieved stable disease (SD).

The pharmacokinetics analysis confirmed that therapeutic drug concentrations were achieved from dose level 7 onwards. Furthermore, analysis confirmed high prostaglandin reductase 1 (PTGR1) expression in 87.5% of patient tumor samples, validating the prevalence of the target biomarker in the advanced cancer population.

The most compelling efficacy data were observed in a subset of patients with tumors harboring specific DNA damage repair (DDR) alterations (ATM, CHEK2, BRCA1). These patients achieved durable SD, with 1 patient with squamous non–small cell lung cancer (NSCLC) and a BRCA1 alteration remaining on treatment for approximately 2 years (34 cycles). Reductions in target lesion size (up to 26%) were also noted in these long-term responders.

Safety Profile of LP-184

The primary objective of the phase 1a trial was to establish the safety and tolerability of LP-184, which was successfully achieved.

The drug demonstrated a favorable safety and tolerability profile, especially for an agent designed to induce DNA damage. Most adverse events were grade 1 or 2 and were manageable, with expected nausea and vomiting controlled with a single dose of antiemetics.

The trial established the maximum tolerated dose at dose level 11 and the RP2D at dose level 10.

Two patients experienced acute, reversible transaminitis at dose level 12, defining the dose limiting toxicity (DLT) level. Importantly, this reversible hepatotoxicity was the only DLT observed.

Furthermore, no visual or ocular toxicities were observed, differentiating its safety profile from other DNA-damaging agents.

LP-184’s Mechanism of Action

LP-184 is a prodrug designed for tumor-selective activation via a dual-biomarker strategy, offering a potentially wide therapeutic window.

LP-184 is activated by the enzyme PTGR1, which is frequently overexpressed in various tumor cells but expressed at low levels in normal tissues. This overexpression acts as the first filter, converting the inert prodrug into a potent DNA-alkylating agent that specifically targets the 3'-position of adenine, inducing lethal double-stranded DNA breaks. An RT-qPCR assay has been developed to enable patient stratification based on PTGR1 expression.

The second requirement for maximum efficacy is a deficiency in the tumor’s DDR pathways. Once the activated LP-184 inflicts DNA damage, tumor cells lacking functional DDR pathways—such as homologous recombination or nucleotide excision repair (NER)—are unable to repair the breaks, inexorably leading to apoptosis.

LP-184 has received 6 FDA designations recognizing its potential to address serious unmet medical needs: fast track designation (FTD) for triple-negative breast cancer (TNBC), FTD for glioblastoma multiforme, orphan drug designation (ODD) for malignant gliomas, ODD for pancreatic cancer, and orphan and pediatric rare disease drug designation for atypical teratoid rhabdoid tumors.³

Next Steps in Research

LP-184’s confirmed ability to cross the blood-brain barrier opens a critical therapeutic avenue, especially for indications like triple-negative breast cancer (TNBC) where brain metastases are common.¹

The future is focused on biomarker-driven phase 1b/2 trials utilizing a Simon 2-stage design to efficiently assess efficacy in specific populations:

• Monotherapy: Metastatic, hormone receptor (HR)-deficient TNBC.
• Combination Strategies: Leveraging powerful preclinical synergy, trials will explore LP-184 with PARP inhibitors (in TNBC, including PARP-resistant disease) and with dual I-O therapy in challenging populations like KRAS/STK11-mutated NSCLC.
• Investigator-Sponsored Trial: A biomarker-driven study in bladder cancer, targeting PTGR1-positive and NER-deficient tumors, capitalizing on the high prevalence of ERCC mutations in this cancer type.

In a webinar from Lantern Pharma, Igor Astsaturov, MD, Fox Chase Cancer Center, remarked on the "remarkable" achievement of completing the phase 1a trial for a compound previously abandoned by the industry. He emphasized that the durable SD observed in heavily pretreated patients "is clearly speaking to the fact that this is a mechanism-based therapeutic."

He noted the clear rationale for PTGR1 testing and clinical niche for LP-184 in HR-deficient cancers like breast and pancreas, also highlighting opportunity in bladder cancer due to the high prevalence of ERCC mutations. He was particularly encouraged by the lack of significant liver toxicity, viewing it as strong evidence of the drug's tumor-selective dual-requirement mechanism.

REFERENCES

1.Inside the data – LP-184 phase 1a results and future trials with Dr. Igor Astsaturov. Webinar. Lantern Pharma. November 21, 2025. Accessed December 3, 2025. https://tinyurl.com/28f6bec9

2.Study of LP-184 in patients with advanced solid tumors. ClinicalTrials.gov. Updated March 6, 2025. Accessed December 3, 2025. https://clinicaltrials.gov/study/NCT05933265

3.Lantern Pharma reports additional positive LP-184 phase 1a results showing durable disease control in heavily pre-treated advanced cancer patients as company advances precision oncology program into multiple biomarker-guided phase 1b/2 trials. News release. Lantern Pharma. Published and accessed December 3, 2025. https://tinyurl.com/3e9adzmn