Breakthrough Clinical Results
Pierre Fabre Laboratories announced the acquisition of worldwide rights for PFL-721 and PFL-241, mutant-specific EGFR inhibitors, from Antares Therapeutics. These drugs are being developed to treat non-small cell lung cancer (NSCLC). PFL-721 targets EGFR exon 20 and HER2 exon 20 mutations, while PFL-241, a brain-penetrant inhibitor, addresses C797S resistance mutations. This acquisition strengthens Pierre Fabre's R&D portfolio, adding to its existing oncology assets. Both drugs are currently in first-in-human clinical trials, with PFL-721 soon to transition to dose optimization.
Key Highlights
- Acquisition of worldwide rights for PFL-721 and PFL-241 from Antares Therapeutics.
- PFL-721 and PFL-241 are mutant-specific EGFR inhibitors targeting NSCLC.
- Both drugs are in first-in-human clinical trials.
- Acquisition strengthens Pierre Fabre's oncology R&D portfolio.
Incidence and Prevalence
Non-small cell lung cancer (NSCLC) Epidemiology
NSCLC is a significant global health concern. Here's a summary of the latest incidence and prevalence estimates based on the provided PubMed articles:
Incidence:
- GLOBOCAN 2022: Estimated approximately 2.48 million new cases globally in 2022, making it the most frequently diagnosed cancer. Lung cancer incidence rates exhibited disparities based on sex and world region, with rates generally increasing with higher Human Development Index (HDI). If these rates remain stable, projections for 2050 estimate a rise to 4.62 million new cases.
- US (2010-2017): Incidence per 100,000 decreased from 46.4 to 40.9 overall. Specifically, incidence decreased in those under 65 (15.5 to 13.5) and those 65 and older (259.9 to 230.0). While stage II, IIIA, and IIIB incidence remained stable, stage IV incidence slightly decreased (21.7 to 19.6), and stage I incidence increased (10.8 to 13.2).
- Global Trends (1978-2012): Nineteen countries showed significantly declining trends in men, while 26 countries showed significantly increasing trends in women.
Prevalence:
- US (2010-2016): Prevalence per 100,000 increased from 175.3 to 198.3. This increase was observed in younger patients (77.5 to 87.9), but a decrease was seen in older patients (825.1 to 812.4).
- Global Estimates: Limited specific prevalence data was available in the provided abstracts. However, several sources highlighted the substantial global burden of NSCLC, with varying trends influenced by factors like smoking, air quality, and access to healthcare.
Key Factors Influencing Incidence and Prevalence:
- Tobacco smoking: Remains the most significant risk factor for lung cancer, accounting for up to 90% of cases.
- Air pollution: A growing concern, especially in developing nations.
- Radon exposure: The second leading cause of lung cancer in developed countries.
- Occupational hazards: Asbestos exposure and other occupational carcinogens.
- Improved detection: Increased incidence of stage I NSCLC may be attributed to better evaluation of incidental nodules.
- Aging population: Contributes to the overall increase in cancer cases.
- Access to healthcare: Impacts both diagnosis and treatment rates, influencing prevalence and survival.
It's important to note that these are estimates, and actual figures may vary. Furthermore, the available data highlights the significant disparities in NSCLC burden across different regions and populations, emphasizing the need for targeted interventions and further research.
Mechanism of Action
Several experimental drugs are being investigated for non-small cell lung cancer (NSCLC), and while not yet approved, they employ diverse mechanisms of action (MOAs) to combat the disease. Three prominent MOAs among these investigational therapies include:
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Bispecific Antibodies: These engineered antibodies can simultaneously bind to two different targets, enhancing their anti-tumor activity. For example, amivantamab targets both EGFR and MET, two receptors frequently implicated in NSCLC development and resistance. The simultaneous targeting can overcome resistance mechanisms that arise from alterations in either receptor alone. Amivantamab's MOAs include ligand blocking, receptor degradation, and immune cell-directing activity (antibody-dependent cellular cytotoxicity and trogocytosis). Importantly, amivantamab's efficacy doesn't require all three MOAs to occur concurrently, broadening its potential applicability.
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Next-Generation Tyrosine Kinase Inhibitors (TKIs): While earlier TKIs effectively target specific EGFR mutations, resistance often develops. Next-generation TKIs are designed to overcome these resistance mechanisms. Osimertinib, a third-generation TKI, targets the T790M resistance mutation, which commonly arises in patients treated with first- and second-generation TKIs. Lazertinib, another third-generation TKI, is being investigated in combination with amivantamab, showing promising activity in treatment-naive and osimertinib-relapsed NSCLC. These newer TKIs aim to improve efficacy and delay or prevent resistance emergence.
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Targeting the PI3K/Akt/mTOR Pathway: This intracellular signaling pathway plays a crucial role in cell growth, proliferation, and survival, and its dysregulation is implicated in NSCLC. Several inhibitors targeting components of this pathway, including PI3K, Akt, and mTOR, are under investigation. While early clinical trials have shown disappointing results, ongoing research focuses on patient enrichment strategies using predictive biomarkers and combination approaches to improve efficacy. A deeper understanding of the molecular biology and epigenetic alterations within this pathway is crucial for identifying appropriate biomarkers and guiding combination therapies.
It's important to note that these are just three examples of the many MOAs being explored in investigational NSCLC therapies. Other approaches include antibody-drug conjugates, immune checkpoint inhibitors, and therapies targeting other driver mutations or signaling pathways. The ongoing research and clinical trials are crucial for identifying the most effective strategies to combat NSCLC and improve patient outcomes.
Completion Rate of Trials
Completion Rates and Abandonment in NSCLC Trials
Regarding completion rates for NSCLC trials started in the past 10 years, a study analyzing 10,252 phase III clinical trials registered on ClinicalTrials.gov (up to May 26, 2023) found an overall median drop-out rate of 11%. This suggests a median completion rate of 89%. It's important to note that this data encompasses all phase III trials, not just those specific to NSCLC. Furthermore, the study did not find any change in started or completed sample sizes over the past 20 years.
Another study examined PRO completion rates in randomized open-label and double-blind cancer trials submitted to the FDA from 2007-2017. While this study doesn't isolate NSCLC trials started in the last 10 years, it offers relevant insights into completion rates. The median completion rate for investigational arms was 89.7%, and 88.2% for control arms. Importantly, this study highlighted that when large differences in completion rates between arms existed, they often favored the experimental arm in open-label trials. This suggests potential bias related to patients' awareness of treatment allocation.
Unfortunately, the provided texts do not directly identify the most common cause of trial abandonment in NSCLC trials. However, a study exploring strategies to improve PROM completion rates in cancer trials offers some potential contributing factors. These include patient burden, low health literacy, and conflicting recommendations. While these factors relate to PRO completion, they could also contribute to overall trial abandonment. Additionally, disease progression, adverse events, and patient choice are common reasons for discontinuing treatment, which would contribute to lower completion rates.
In summary, while the exact completion rates for NSCLC trials in the past 10 years are not explicitly stated, data suggests a rate around 89%. The most common cause of trial abandonment is not directly addressed in the provided texts, but factors like patient burden, low health literacy, disease progression, and adverse events likely play a role.