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T. Bauer
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ORAL 10 - SCLC (ID 98)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:C. Faivre-Finn, P. Lara Jr.
- Coordinates: 9/07/2015, 10:45 - 12:15, 605+607
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ORAL10.01 - A DLL3-Targeted ADC, Rovalpituzumab Tesirine, Demonstrates Substantial Activity in a Phase I Study in Relapsed and Refractory SCLC (ID 1598)
10:45 - 12:15 | Author(s): T. Bauer
- Abstract
Background:
Rovalpituzumab tesirine (i.e. SC16LD6.5) is a Delta-like protein 3 (DLL3) targeted antibody-drug conjugate (ADC) comprised of a humanized monoclonal antibody, dipeptide linker, and pyrrolobenzodiazepine (PBD) dimer toxin with a drug-to-antibody ratio of 2. DLL3 is highly expressed in human neuroendocrine tumors and their tumor-initiating cells, including approximately two-thirds of small cell lung cancer (SCLC). DLL3 is not expressed at detectable levels in normal tissues. Rovalpituzumab tesirine induced tumor regression and prolonged time to progression significantly outperforming cisplatin/etoposide in DLL3-expressing SCLC patient-derived xenograft tumor models. Based on this promising activity, a first-in-human phase I trial in patients (pts) with recurrent SCLC was initiated and preliminary results are reported below.
Methods:
SCLC pts with progressive disease after 1 or 2 previous lines of therapy received escalating doses of rovalpituzumab tesirine as a single agent once every 3 weeks (Q3W) in 1-3 pt cohorts until dose limiting toxicities (DLTs) were observed. The doses were 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg Q3W. Midway through accrual, pharmacokinetic data revealed a longer than expected ADC half-life of ~11 days, prompting evaluation of a Q6W schedule. A DLL3 antibody was developed and utilized to assess antigen expression in archived tumor specimens. Biomarker positive (BM+) tumors were defined by IHC membrane-associated H-Scores ≥ 120.
Results:
52 pts were treated: 34 Q3W and 18 Q6W; 24F/28M; median age, 61 years (44-82). Acute and chronic DLTs of thrombocytopenia and capillary leak syndrome (CLS) were observed at 0.8 and 0.4 mg/kg Q3W, respectively. Maximum tolerated doses (MTD) of 0.2 mg/kg Q3Wx3 cycles and 0.3 mg/kg Q6Wx2 cycles were further evaluated in expansion cohorts. The most common treatment emergent adverse events of any grade among all pts were fatigue (40%), rash (39%), nausea (29%), dyspnea (23%), decreased appetite (21%) and vomiting (21%). Grade 3+ CLS and thrombocytopenia were seen in 7 (14%) and 3 (6%) pts, respectively, with no reported Grade 5 toxicity. Of 38 archived tumor specimens received from enrolled pts, 23 (61%) were DLL3 BM+. Among the 16 confirmed DLL3 BM+ pts treated at the MTDs, 7 pts (44%) had partial response (PR) and 8 pts (50%) achieved stable disease (SD) for a combined clinical benefit rate (CBR) of 94%. In all evaluable pts treated at the MTD without regard for DLL3 biomarker status (n=32), the ORR was 22% (n=7 PR) and SD 53% (n=17), for a CBR of 75%. Notably, all pts with PRs that were treated at the MTD, and those having the most durable clinical benefit (up to 569 days OS), were BM+. Similar response rates were observed among pts sensitive and refractory to first-line therapy, and in the third-line setting where no standard-of-care currently exists.
Conclusion:
Rovalpituzumab tesirine, a first-in-class DLL3-targeted ADC, has manageable toxicity and demonstrated significant anti-tumor activity (44% ORR and 95% CBR) as a single agent in second- and third-line pts with recurrent DLL3 BM+ SCLC. A pivotal study is being planned.
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.07 - Clinical Activity and Safety of the ALK/ROS1 TK Inhibitor PF-06463922 in Advanced NSCLC (ID 295)
16:45 - 18:15 | Author(s): T. Bauer
- Abstract
- Presentation
Background:
Overcoming acquired resistance in ALK+ and ROS1+ non-small-cell lung cancer (NSCLC) patients (pts) is key to optimizing therapy. PF-06463922 is a selective, brain-penetrant tyrosine kinase inhibitor (TKI) with demonstrated clinical activity against de novo fusions as well as resistance mutations, including ALK G1202R, that arise during treatment with other TKIs.
Methods:
In this ongoing phase I study, eligible pts had ALK+ or ROS1+ NSCLC, with or without brain metastases, and were treatment naïve or had disease progression after at least 1 prior TKIs. Pts with central nervous system (CNS) metastases, including untreated asymptomatic metastases, were eligible. Tumor tissue (archival sample or de novo biopsy) was required for enrollment. A modified continual reassessment method was used to estimate the maximum tolerated dose (MTD) and select a recommended phase II dose (RP2D). Once- (QD) or twice-daily (BID) dosing in 21-day cycles was explored. Secondary objectives included efficacy, safety, tolerability, pharmacokinetics (PK), effect on cognitive function, patient-reported outcomes, potential to induce/inhibit CYP3A4, biomarkers of drug response and resistance, and intracranial antitumor activity.
Results:
25 ALK+ pts (20 with CNS metastases, 23 previously treated with at least 1 ALK TKIs) and 5 ROS1+ pts (3 with CNS metastases, 3 previously treated with crizotinib) have been enrolled across 7 QD dose levels and 2 BID dose levels. Of 21 patients evaluable for intracranial response, 16 had stable disease or confirmed complete/partial response. The most common treatment-related adverse events (AEs) were hypercholesterolemia, peripheral neuropathy, and peripheral edema, occurring in 47%, 27% and 23% of pts, respectively. Peripheral neuropathy was reversible following treatment delay or dose reduction. The most common grade 3 and higher treatment-related AE was hypercholesterolemia, occurring in 10% of pts, which was well managed with statins. One DLT was reported for a pt at 200 mg QD, who received less than 16 of the 21 planned doses of study drug due to grade 2 CNS effects. To date, 20 pts remain on treatment. Preliminary PK analyses suggest that exposure increased linearly from 10 to 75 mg QD, with a terminal half-life of 20-28 hrs. At doses beyond 75 mg QD, the increase in exposure appeared to be non-proportional. PF-06463922 is considered a moderate inducer of CYP3A4.
Conclusion:
PF-06463922 is a potent ALK/ROS1 TKI that has demonstrated clinical activity in ALK+ and ROS1+ NSCLC pts, most of whom had CNS metastases and had received at least 1 prior TKI. The RP2D has not yet been established.
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