Desm Desmoi oid tu tumor or tri trial usi sing a ga gamma secretase inhibitor PF PF-03084014 03084014 Victor M. Villalobos, M.D., Ph.D. Assistant Professor Director, Sarcoma Medical Oncology Division of Medical Oncology
Disclosures • Advisory capacity: • Lilly, Novartis, Janssen
Gamma secretase inhibition in desmoid • Gamma secretase is an integral membrane protein that cleaves multiple different transmembrane protein complexes including: • NOTCH • E-CADHERIN • Amyloid Precursor Protein • others • PF-03084014 is a noncompetitive, reversible, targeted agent that selectively inhibits gamma secretase • Activation of WNT pathway through B-Cat or APC mutations appears to be primary driver in desmoid tumors • Hypothesis that cooperativity exists between WNT pathway activation and active NOTCH signaling. • Inhibition of NOTCH may reverse activation of B- catenin due to mutations in Bcat or APC. Hughes, D. P. M. et al. , Clinical Cancer Research 21, 7–9 (2015).
A Phase I, Dose-Finding Study in Patients with Advanced Solid Malignancies of the Oral g-Secretase Inhibitor PF-03084014 • 64 patients (solid tumors) enrolled in 3+3 dose escalation design. • MTD: 220 mg BID orally (n=16) • RP2D was 150 BID orally (n=23) • A total of 9 desmoid patients were enrolled (7 at UC Denver) Messersmith, W. A. et al. Clinical Cancer Research 21, 60–67 (2015).
PF-03084014 in Desmoid tumors 0.7 Known germline APC mutation • 7 desmoids accrued at Spontaneous desmoid 0.6 � 80 mg BID UCD (9 total) 0.5 � 100 mg BID 0.4 � 130 mg BID • Overall RECIST response ● 150 mg BID 0.3 ◼ 220 mg BID rate of 71.4% 0.2 0.1 • Median TTP – Not met 0 - 12 24 36 48 60 72 84 • Median DOR – 49.8+ mo . -0.1 -0.2 (47.9-67+ mo.) -0.3 • Mean time to response - -0.4 8.7 mo . -0.5 -0.6 • Effective even at low -0.7 Arrows: Patients stopped therapy, maintained disease doses (80 mg BID) -0.8 stability despite no further intervention Patient was biopsied at end of study and pathology showed -0.9 paucicellular tissue with prominent collagenous fibrosis -1
Treatment effects 0.7 � 80 mg BID 0.6 � 100 mg BID • Even in absence of � 130 mg BID 0.5 ● 150 mg BID 0.4 RECIST response, ◼ 220 mg BID 0.3 there were 0.2 considerable 0.1 0 treatment effects 12 24 36 48 60 72 84 - -0.1 -0.2 • Arrow – came off -0.3 study at 42 -0.4 months due to -0.5 -0.6 patient preference -0.7 -0.8 -0.9 -1
Pretreatment 4 months 2 months 14 months 6 months 10 months 48 months 36 months 54 months Off Therapy
Pathologic response to therapy 2012 Biopsy prior to treatment 2015 End of treatment biopsy Desmoid fibromatosis Paucicellular fibroconnective tissue with prominent collagenous fibrosis
Time to treatment failure of therapies (chronologic) 42 9.5 7 54 6 PF-03084014 (GSI) 15 5 Off Rx Free of Progression Tamoxifen/Sulindac Surgery Methotrexate/Vinblastine 47 15 4 Vinorelbine Imatinib Indomethacin 13 53 Liposomal Doxorubicin 3 78 2 78 1 0 1 2 3 4 5 6 7 8 9 10 11 12 Treatment duration (years)
Time to treatment failure of therapies (chronologic) 42 9.5 7 54 6 PF-03084014 (GSI) 15 5 Off Rx Free of Progression Tamoxifen/Sulindac Surgery Methotrexate/Vinblastine 47 15 4 Vinorelbine Imatinib Indomethacin 13 53 Liposomal Doxorubicin 3 78 2 78 1 0 1 2 3 4 5 6 7 8 9 10 11 12 Treatment duration (years)
Week 63 4/28/11 Taken off study baseline RECIST 11.7 cm RECIST 17cm for patient % Change -31% % Change ---- protocol WHO 34.6 cm2 WHO 171.7 cm2 violation % Change -80% % Change ----- 5/12/16 10/8/14 Week 262 Week 142 RECIST 12cm RECIST 12.3 cm % Change -30% % Change +5% WHO 24.7 cm2 WHO 27.1 cm2 % Change -85% % Change + 10%
Conclusions – PF-03084014 gamma secretase inhibitor • Exciting potential for use in desmoid patients • 72% RECIST response rate • Active at even low doses (as low as 80mg BID) • Tolerable side effect profile (primarily diarrhea, hypophosphatemia) • Clinical benefit in 100% of patients (only patient with progression had mild regression lasting 12 months) • Even if no response by size criteria, evidence of tumor activity on pathology • Working on further clinical development
Acknowledgements • Phase I team • Wells Messersmith MD • Antonio Jimeno MD, PhD • Lia Gore MD • Sarcoma Team • Anthony Elias MD • Brianna Hoffner NP • Pfizer
T1 post T1 post T1 post Pretreatment 6 weeks after starting 4 years after starting T2 pre T2 pre T2 pre Pretreatment 6 weeks after starting 4 years after starting
Recommend
More recommend
