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L. Paz-Ares Rodriguez

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MO12 - Prognostic and Predictive Biomarkers III (ID 96)

Event: WCLC 2013
Type: Mini Oral Abstract Session
Track: Medical Oncology
Presentations: 1

Moderators:B. Han, M. Edelman
Coordinates: 10/29/2013, 10:30 - 12:00, Parkside Ballroom B, Level 1

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MO12.07 - The prevalence of MET expression by immunohistochemistry (IHC) in the MetLung (OAM4971g) trial: a randomized, placebo-controlled, phase III study with erlotinib + onartuzumab (MetMAb) vs erlotinib + placebo in patients with previously treated non-small cell lung cancer (NSCLC) (ID 2709)

10:30 - 12:00 | Author(s): L. Paz-Ares Rodriguez

Abstract
Presentation
Slides

Background
MET signaling is correlated with a poor prognosis in multiple tumor types, including NSCLC. A randomized, controlled, phase II clinical trial demonstrated a PFS and OS benefit of inhibiting MET signaling with erlotinib + onartuzumab, a humanized monovalent antibody to the MET receptor, in patients whose NSCLC over-expressed MET by IHC (in press). A phase III trial (OAM4971g) is ongoing to confirm the benefit of onartuzumab when combined with erlotinib in patients with previously treated NSCLC whose tumors over-express MET by IHC (2+/3+ only). Here, we present the prevalence rates of MET expression and EGFR mutation status for patients whose tumor tissues were screened and for those enrolled in the phase III study.

Methods
Archival or fresh biopsy tumor specimens were submitted to a central laboratory for both MET IHC and EGFR mutation assessment. MET IHC status was determined using the CONFIRM SP44 anti-MET monoclonal antibody (Ventana Medical Systems, Inc., Tucson, AZ). Patients were selected based on expression of MET by IHC, as defined by moderate or strong staining in at least 50% of tumor cells (clinical score 2+/3+). The cobas[®]EGFR mutation test was used to stratify enrollment.

Results
Between November 2011 and June 2013, 1605 tumor tissue samples were submitted for MET IHC and EGFR activating mutation analysis, from 188 clinical study centers. The majority of screened and enrolled patients were over 60 years of age, Caucasian, male, and had non-squamous NSCLC histology (see table). MET IHC results are available for 1474 (92%) of all submitted samples: IHC 0 (n=118, 8%), IHC 1+ (n=619, 42%), IHC 2+ (n=575, 39%), IHC 3+ (n=162, 11%). The incidence of MET IHC 2+/3+ in screened patient subgroups is as follows: non-squamous 52.5%; squamous 29.2%; non-Asian 45.9%; Asian 48%; EGFR wild type 50.3%; EGFR mutant 57.5%. Table: Patient characteristics for screened and enrolled patients in the OAM4971g study

	Screened (n=1605)	Enrolled (n=443)
Age (years)
n	1482	442
Median	63.0	62.5
Range	24–89	24–84
Race
n	1482	443
White	1187 (80.1%)	316 (71.3%)
Asian	185 (12.5%)	72 (16.3%)
Black or African American	44 (3.0%)	11 (2.5%)
Sex
n	1483	443
Male	937 (63.2%)	244 (55.1%)
Histology
n	1451	440
Non-squamous	1096 (75.5%)	374 (85.0%)
MET IHC score
n	1474	443
3+	162 (11.0%)	97 (21.9%)
2+	575 (39.0%)	346 (78.1%)
1+	619 (42.0%)	0 (0.0%)
0	118 (8.0%)	0 (0.0%)
EGFR activating mutation
n	1422	443
Yes	114 (8.0%)	46 (10.4%)
No	1308 (92.0%)	397 (89.6%)

Conclusion
In this large population, the prevalence of MET IHC 2+/3+ was 50% in screened samples, consistent with prior IHC results for MET prevalence. The prevalence of MET IHC 2+/3+ was higher in non-squamous vs squamous tissue samples, but equally distributed across ethnicity and EGFR mutation status. The ongoing OAM4971g study will prospectively confirm whether blocking MET signaling in patients with MET IHC 2+/3+ over-expressing NSCLC provides clinically meaningful benefit in all enrolled patients and in important clinical subpopulations.

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O21 - SCLC II (ID 119)

Event: WCLC 2013
Type: Oral Abstract Session
Track: Medical Oncology
Presentations: 1

Moderators:M. Ahn, P. Lara
Coordinates: 10/29/2013, 16:15 - 17:45, Parkside Ballroom B, Level 1

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O21.05 - A multicenter, double-blind, placebo-controlled, randomized phase 2 study of ganitumab or rilotumumab with platinum-based chemotherapy as first-line treatment for extensive-stage small-cell lung cancer (SCLC) (ID 725)

16:15 - 17:45 | Author(s): L. Paz-Ares Rodriguez

Abstract
Presentation
Slides

Background
The type 1 insulin-like growth factor receptor (IGF1R) and MET, the receptor for hepatocyte growth factor (HGF)/scatter factor, appear to play key roles in SCLC. Ganitumab and rilotumumab are investigational, fully human monoclonal antibodies targeting IGF1R and HGF, respectively. A phase 1b/2 study evaluated ganitumab or rilotumumab combined with etoposide plus carboplatin (CE) or cisplatin (PE) in extensive-stage SCLC. The phase 1b results were previously reported (Lorigan et al. Ann Oncol 2010;21[supplement 8]: abstract 444P). Here, the phase 2 results are reported.

Methods
Key eligibility criteria: ≥18 years, confirmed SCLC, ECOG performance status ≤1, no prior chemotherapy. Patients were randomized 1:1:1 to receive blinded investigational product (IP) either ganitumab (18 mg/kg IV, day 1) or rilotumumab (15 mg/kg IV, day 1) or placebo, with etoposide (100 mg/m[2] IV, days 1-3) plus, at investigator’s discretion, either carboplatin (AUC=5 mg/mL*minute IV, day 1) or cisplatin (75 mg/m[2] IV, day 1) every three weeks for 4-6 cycles followed by IP monotherapy. Patients were stratified by gender and chemotherapy (CE; PE). Primary endpoint: overall survival (OS). Key secondary endpoints included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), pharmacokinetics.

Results
185 patients (ganitumab/rilotumumab/placebo: 62/62/61) were enrolled between 2 February 2010 and 12 January 2011. Male: 77%/76%/77%. Median age: 60/61/61 years. More patients received carboplatin (41/40/40) than cisplatin (21/22/21). Most common reason for discontinuation of IP was disease progression (69%/61%/74%). Among 179 patients (59/61/59) who received IP, the most frequent any grade AEs (occurring in ≥30% of patients in any arm) were neutropenia (69%/59%/71%), anemia (39%/34%/36%), nausea (41%/30%/22%), alopecia (41%/23%/27%), thrombocytopenia (22%/30%/12%), and vomiting (19%/10%/31%). Grade ≥3 AEs and serious AEs were reported in 69%/72%/80% and 39%/38%/36% of patients, respectively. There were three IP-related grade 5 AEs: cardiac arrest (rilotumumab, n=1), febrile neutropenia (rilotumumab, n=1), gastric ulcer hemorrhage (placebo, n=1). No neutralizing antibodies were observed for either ganitumab or rilotumumab. Efficacy is shown in the table. Ganitumab and rilotumumab combined with chemotherapy showed comparable exposures as those under monotherapy and did not affect the pharmacokinetics of chemotherapy.

	Ganitumab (n=62)	Rilotumumab (n=62)	Placebo (n=61)
OS
Median (95% CI) months	10.7 (8.1–14.1)	12.2 (8.8–14.6)	10.8 (9.4–11.9)
Adjusted HR[a] (95% CI)	1.01 (0.67–1.52)	0.91 (0.60–1.39)
PFS
Median (95% CI) months	5.5 (4.4–5.7)	5.4 (4.4–5.7)	5.4 (4.6–5.8)
Adjusted HR[a] (95% CI)	1.03 (0.70–1.52)	1.03 (0.69–1.52)
Objective Response
Complete response, n (%)	0 (0)	2 (3)	1 (2)
Partial response, n (%)	39 (63)	40 (65)	35 (57)
Stable disease, n (%)	13 (21)	12 (19)	16 (26)

[a]Adjusted for baseline lactate dehydrogenase levels and stratification factors. CI=confidence interval; HR=hazard ratio.

Conclusion
In this study of chemonaïve patients with extensive-stage SCLC, the combination of ganitumab or rilotumumab with CE or PE was tolerable; no unexpected toxicities were observed. There were no meaningful improvements in OS, PFS, or ORR with either combination. Survival analyses in biomarker and pharmacokinetic subgroups are ongoing.