Related Experiment Video
Updated: Jun 5, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors
Pasi A Jänne1, David S Boss, D Ross Camidge
1Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA. pjanne@partners.org
Purpose:
PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies.
Experimental Design:
PF299804 was administered once daily continuously (schedule A) and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken predose and after 14 days of treatment to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non-small cell lung cancer (NSCLC) patients.
Results:
121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/d. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non-small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804.
Conclusions:
The MTD of PF299804 is 45 mg/d. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients.
Insights
PF299804, a tyrosine kinase inhibitor targeting HER1, HER2, and HER4, showed a maximum tolerated dose of 45 mg/d in advanced solid tumors. Encouraging antitumor activity was seen in some non-small cell lung cancer patients previously treated with other therapies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- PF299804 is an orally available, irreversible inhibitor targeting human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4.
- Investigating novel targeted therapies is crucial for managing advanced solid malignancies.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in a first-in-human study.
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities of PF299804.
- To explore the antitumor activity of PF299804 in patients with advanced solid tumors, particularly non-small cell lung cancer (NSCLC).
Main Methods:
- A dose escalation study using continuous (schedule A) and intermittent (schedule B) administration of PF299804.
- Pharmacokinetic/pharmacodynamic analysis based on skin biopsies taken before and after 14 days of treatment.
- Tumor response assessment every 2 cycles, with efficacy correlated to tumor genotypes in NSCLC patients.
Main Results:
- The MTD was determined to be 45 mg/d, with dose-limiting toxicities including stomatitis and skin toxicities.
- Most adverse events were mild, primarily skin toxicities, fatigue, and gastrointestinal issues.
- Pharmacokinetic data showed dose-dependent drug exposure and target inhibition. Four NSCLC patients previously treated with gefitinib or erlotinib achieved partial responses.
Conclusions:
- The MTD for PF299804 is 45 mg/d, with both administration schedules demonstrating good tolerability.
- PF299804 exhibited encouraging signs of antitumor activity in NSCLC patients who had prior treatment with gefitinib or erlotinib.
- Further investigation into PF299804 as a targeted therapy for specific cancer types is warranted.
