A phase 1B study of anti-DLL4 (Delta-Like Ligand 4) antibody demcizumab (DEM) with pemetrexed (PEM) and carboplatin (CARBO) in patients with 1st-line non-squamous NSCLC (ELCC 2015) - Apr 9, 2015 - Abstract #114P; P1b, N=39; NCT01189968; Sponsor: OncoMed Pharmaceuticals; "One of 33 (3%) evaluable patients had a RECIST complete response, 15 (45%) a partial response and 13 (39%) stable disease for a clinical benefit rate of 88%. Eight patients at 5 and 7.5 mg/kg of DEM (6 off study for reasons other than progression) were progression free for >300 days; 6 ongoing on Days 408 + , 448 + , 456+ (no current therapy), 546 + , 677+ (no current therapy) & 680 + , and 2 with progression after 314 & 850 days."
P1 data • Non Small Cell Lung Cancer • Oncology
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2015 European Lung Cancer Conference, Apr 15 - 18, 2015, Geneva, Switzerland
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Aim: DEM is a humanized IgG2 antibody targeting DLL4, a ligand of the Notch pathway. In patient-derived tumor xenograft models, DEM inhibits tumor growth, decreases cancer stem cell frequency and has anti-angiogenic effects through dysfunctional sprouting of new vessels.
Methods: In Cohorts 1 - 4, patients (pts) received DEM (2.5 or 5 mg/kg), PEM 500 mg/m2 & CARBO (AUC = 6) every 3 weeks (q3w) for 6 cycles followed by DEM maintenance. In Cohorts 5 & 6, pts received truncated DEM (5 or 7.5 mg/kg q3w x4 cycles), PEM 500 mg/m2 & CARBO (AUC = 6) q3w x4 cycles followed by PEM maintenance. Objectives were to determine maximum tolerated dose, safety, efficacy, immunogenicity, pharmacokinetics & biomarkers of Notch signaling.
Results: Thirty-nine pts were enrolled. In Cohorts 1 - 4, six received 2.5 mg/kg and twenty 5 mg/kg of DEM. In Cohorts 5 >20%) were nausea (51%), fatigue (46%), hypertension (46%), vomiting (31%), edema (26%), increased B-type natriuretic peptide (BNP; 26%), neutropenia (26%) and anemia (21%). BNP increases are an early indicator of cardiac effects of DEM. Mildly elevated BNP values therefore triggered cardioprotective therapy with an ACE inhibitor or carvedilol. In Cohorts 1 - 4, 2 pts at 5 mg/kg developed reversible pulmonary hypertension with heart failure (on Days 167 6 ongoing on Days 408 + , 448 + , 456+ (no current therapy), 546 + , 677+ (no current therapy) & 680 + , and 2 with progression after 314 & 850 days.
Conclusions: This combination therapy was generally well tolerated with a safety profile consistent with common chemotherapy AEs and target-mediated AEs, i.e. hypertension and BNP increases. Early signs of clinical activity were encouraging, in particular clinical benefit rate and pts with progression-free survival >300 days.
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