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N. Thatcher
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ORAL 32 - EGFR WT and MT Targeting (ID 144)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:K.J. O'Byrne, D.R. Gandara
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL32.03 - Efficacy and Safety of Necitumumab Continuation Therapy in Phase 3 SQUIRE Study (ID 1391)
17:07 - 17:18 | Author(s): N. Thatcher
- Abstract
- Presentation
Background:
The SQUIRE study demonstrated that the addition of necitumumab (N) to gemcitabine-cisplatin (GC) improved survival in patients with stage IV sq-NSCLC. This retrospective analysis compares efficacy and safety outcomes for patients who received single-agent N as continuation therapy after completion of chemotherapy treatment (CT) in GC+N arm to the continuation therapy-eligible population of the GC arm.
Methods:
Patients were randomized 1:1 to GC (G=1250 mg/m² iv, days 1 and 8; C=75 mg/m² iv, day 1) plus N (800 mg iv, days 1 and 8), or GC alone every 21 days up to 6 cycles. Patients in GC+N with no progression continued on N alone until progressive disease. In this analysis, we consider patients in GC+N arm who were alive and progression-free before the start of N single-agent therapy (GC+N arm continuation therapy patients) and patients in GC arm who were alive, progression-free after completion of CT and did not discontinue treatment due to adverse event (AE) (GC arm non-progressor patients). This analysis included patients in both arms who received ≥4 cycles of CT. Overall survival (OS) and progression-free survival (PFS) were measured from the date of randomization, with parameters estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs between subgroups were estimated from stratified Cox proportional hazards models. OS and PFS for post-induction period were measured from the completion of CT + 21 days. Selected treatment-emergent AEs (TEAEs) for patients in each arm are presented in the table.
Results:
261 patients were progression-free, received ≥4 cycles of CT, and received ≥1 dose of N alone in GC+N arm. 215 pts in GC arm completed ≥4 cycles of CT, were progression-free, and did not discontinue due to AE. Patient baseline characteristics and exposure to CT were well balanced between GC+N and GC arms. Median OS from randomization in GC+N vs GC was 15.9 vs 15.0 months; HR 0.85 (95% CI, 0.69, 1.05). Median OS for post-induction period in GC+N vs GC was 11.5 vs 10.9 months; HR 0.84 (95% CI, 0.68; 1.04). Median PFS from randomization in GC+N vs GC was 7.4 vs 6.9 months; HR 0.86 (95% CI, 0.70, 1.06). Median PFS from post-induction period in GC+N vs GC was 3.2 vs 2.3 months; HR 0.85 (95% CI, 0.70, 1.04). Selected TEAEs (Overall):GC+N Continuation PatientsN = 261, % GC Non-ProgressorsN = 215, % Category Any Grade Grade ≥3 Any Grade Grade ≥3 Neutropenia 55.9 34.1 57.7 33.0 Anemia 46.7 10.0 49.3 8.8 Thrombocytopenia 26.1 9.6 29.3 12.6 Hypomagnesemia 42.1 14.9 18.6 0.9 Conjunctivitis 11.9 0.8 3.3 0 Rash 87.4 8.8 10.2 0.5 Arterial thromboembolic event 5.7 3.1 0.5 0 Venous thromboembolic event 9.2 3.8 4.2 0.9
Conclusion:
There was a consistent treatment effect in favor of GC+N continuation patients as compared to GC non-progressors with no unexpected increases in AEs.
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ORAL32.05 - EGFR IHC and FISH Correlative Analyses (SQUIRE Trial): Necitumumab + Gemcitabine-Cisplatin vs Gemcitabine-Cisplatin in 1st-Line Squamous NSCLC (ID 2651)
17:28 - 17:39 | Author(s): N. Thatcher
- Abstract
- Presentation
Background:
SQUIRE, a randomized phase III study, demonstrated that the addition of necitumumab (N) (a second-generation, recombinant, human immunoglobulin G1 EGFR antibody) to gemcitabine-cisplatin (GC) improved overall survival (OS) in patients with stage IV squamous non-small cell lung cancer (NSCLC). Analyses of the relationship between efficacy and epidermal growth factor receptor (EGFR) protein expression using the immunohistochemistry (IHC) H-score=200 cut-point were previously reported (Thatcher et al. Lancet Onc, 2015; doi: 10.1016/S1470-2045(15)00021-2). Here we report additional exploratory analyses of the relationship with EGFR protein, as well as analyses of EGFR gene copy number.
Methods:
SQUIRE included mandatory tissue collection from archived tumor. EGFR protein expression was assessed by IHC in a central lab, using the Dako EGFR PharmDx kit. Analyses of the relationships between efficacy outcomes with EGFR across the range of protein levels were performed, using methodologies including subpopulation treatment effect pattern plot (STEPP) with a sliding window target size of 200 patients. An exploratory assessment of EGFR gene copy number gain was performed in tissue sections using fluorescence in situ hybridization (FISH) (J Clin Pathol; 2009;62(11):970-7). Efficacy outcomes were estimated using the Kaplan-Meier method and hazard ratios estimated using an un-stratified Cox model. .
Results:
A total of 982 patients (89.8% of the ITT) had evaluable IHC assay results. The large majority of these patients (95.2%) had tumor samples expressing EGFR protein; only 4.8% had tumors without detectable EGFR protein (H-score=0). The STEPP analyses showed no consistent trend or obvious cut-point for the relationship between either OS or PFS with EGFR protein across the range of IHC values when comparing treatment arms. Archived tumor tissue with evaluable results for exploratory EGFR FISH analysis was available for 51.0% of patients (557 of 1093 ITT patients). Of these patients, 208 patients (37.3%) had increased EGFR gene copy number (FISH positive). A trend for greater necitumumab benefit was observed in EGFR FISH positive patients. Treatment HR (95% CI) for FISH positive and negative patients were 0.70 (0.52, 0.96) and 1.02 (0.80, 1.29) for OS, and 0.71 (0.52, 0.97) and 1.04 (0.82, 1.33) for PFS. However, the interaction of EGFR gene copy number gain with treatment was not statistically significant for either OS or PFS (p=0.066 and 0.057, respectively).
Conclusion:
The analysis of EGFR protein expression did not identify consistent trends related to efficacy outcomes across the range of IHC values. EGFR gene copy number gain showed a trend for a more favorable HR, but did not appear to be strongly predictive. However, both markers showed some evidence of potential trends that will be investigated further in future trials.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-062 - Rash as a Marker for the Efficacy of Necitumumab in the SQUIRE Study (ID 97)
09:30 - 09:30 | Author(s): N. Thatcher
- Abstract
Background:
SQUIRE, a randomized, phase III study (n=1,093), demonstrated that the addition of the EGFR monoclonal antibody necitumumab (N) to gemcitabine-cisplatin (GC) improved overall survival in patients with stage IV squamous NSCLC. Rash is an established class side-effect associated with EGFR-targeting agents. Previous studies have suggested a positive association between rash and clinical outcomes with EGFR-targeted therapy.
Methods:
Pre-emptive treatment for rash was not allowed per protocol until completion of the first cycle of study therapy. For the purpose of this analysis, patients randomized to the N+GC arm were categorized and grouped according to whether or not they experienced rash during the first two cycles of study therapy. Patients who died or were lost to follow-up before completing two cycles of study therapy were not included in this analysis. Overall survival (OS) and progression-free survival (PFS) were measured from the date of randomization, with parameters estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs between subgroups were estimated from stratified Cox proportional hazards models, with comparisons between arms using a stratified log-rank test.
Results:
505 patients were evaluable in the N+GC arm at the end of cycle 2 of which 69% experienced rash during cycle 1 and/or cycle 2. Patients experiencing rash in the N+GC arm had improved OS (HR=0.738, p=0.0001) and PFS (HR=0.808, p=0.0066) compared with patients in the GC arm. Patients experiencing rash in the N+GC arm had improved OS (HR=0.656, p=0.0001) compared with patients in the N+GC arm who did not experience rash. The difference in PFS between patients in the N+GC arm experiencing rash versus those not experiencing rash was not statistically significant. Median PFS and OS for patients experiencing rash in the N+GC arm was 6.2 mo and 13.6 mo respectively, as compared to 5.6 and 10.2 mo for patients in the N+GC arm without rash and 5.6 and 10.6 mo for patients in the GC arm.
*In comparison to the N+GC group with rashPatients alive and under follow-up after Cycle 2 N+GC with rash N=350 N+GC no rash N=155 GC N=508 Overall Survival, mo (CI) 13.6 mo (11.6, 15.2) 10.2 (8.7, 11.6) 10.6 (9.5, 11.9) HR* (95% CI) 0.656 (0.529, 0.813) 0.738 (0.631, 0.864) Stratified log-rank p value* 0.0001 0.0001 PFS, mo (CI) 6.2 mo (5.7, 6.9) 5.6 (5.0, 5.7) 5.6 (5.3, 5.6) HR* (95% CI) 0.867 (0.693, 1.084) 0.808 (0.692, 0.942) Stratified log-rank p value* 0.2127 0.0066
Conclusion:
Rash occurring during the first two cycles of treatment with necitumumab (N+GC) is associated with improved OS in patients with advanced squamous NSCLC.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-072 - Final Efficacy and Safety Results of ECOG Performance Status (PS) Subgroup Analyses From the SQUIRE Phase III Study (ID 1660)
09:30 - 09:30 | Author(s): N. Thatcher
- Abstract
Background:
As previously reported, the SQUIRE study demonstrated that the addition of necitumumab (N) to gemcitabine-cisplatin (GC) chemotherapy significantly improved survival in patients with stage IV squamous NSCLC. Overall survival (OS), progression-free survival (PFS), and safety results are presented for Eastern Cooperative Oncology Group (ECOG) PS 0–1/2 subgroups.
Methods:
Patients with stage IV squamous NSCLC were randomized 1:1 to N (800 mg iv, days 1 and 8) plus GC (G=1250 mg/m² iv, days 1 and 8; C=75 mg/m² iv, day 1) or GC alone every 21 days for up to six cycles in this multicenter, open-label study. N+GC patients without progression continued on N alone until progressive disease or intolerable toxicity. The study was powered for OS and PFS (previously reported). Preplanned subgroup analyses were performed for ECOG PS 0–1 and 2.
Results:
Subgroups PS 0–1/2 (n=996 [91%]/n=96 [9%]) were well balanced regarding baseline characteristics (males, 83% vs 86%; median age, 62 vs 65 yrs; smoking/ex-light smoker/nonsmoker, 91/4/5% vs 89/6/5%). GC median relative dose intensity was similar between PS 0–1/2 subgroups; N (overall) was higher for the PS 0–1 than for PS 2 subgroup (94.8% and 90.0%). Post-study therapy use was generally higher in the PS 0–1 than in the PS 2 subgroup, but was balanced between both arms. The OS hazard ratio (HR) for N+GC vs. GC was 0.85 (95% CI: 0.74, 0.98; p=0.026) for PS 0–1 and 0.78 (95% CI: 0.51, 1.21; p=0.275) for PS 2. The PFS HR (N+GC vs. GC) was 0.86 (95% CI: 0.75, 0.99; p=0.035) for PS 0–1 and 0.79 (95% CI: 0.50, 1.24; p=0.292) for PS 2. Select Grade ≥3 treatment-emergent adverse events (TEAEs) are shown in the table. The percentage of patients with adverse events leading to discontinuation of any study drug was lower in the PS 0–1 subgroup (N+GC=30%; GC=23%) than the PS 2 subgroup (N+GC=42%; GC=41%). The percentage of patients hospitalized was higher in the PS 0–1 subgroup (N+GC=43%; GC=34%) than the PS2 subgroup (N+GC=25%; GC=30%). Table. Select TEAEs
[*][Adverse events of possible relevance to treatment, according to either composite categories or preferred terms (febrile neutropenia only)]Grade ≥3 Event* PS 0-1 N+GC (%) N=490 PS 0-1 GC (%) N=495 PS 2 N+GC (%) N=48 PS 2 GC (%) N=46 Neutropenia 25.5 28.1 12.5 21.7 Febrile neutropenia 0.6 1.4 2.1 0 Anemia 11.2 10.3 4.2 17.4 Thrombocytopenia 10.4 10.5 8.3 13.0 Fatigue 7.1 7.1 8.3 6.5 Hypomagnesemia 9.8 1.0 4.2 2.2 Rash 7.8 0.4 0 0 Arterial thromboembolic events 3.7 1.8 6.3 4.3 Venous thromboembolic events 5.5 2.6 0 2.2
Conclusion:
OS and PFS treatment results for N+GC were consistent and considered favorable across subgroups including ECOG PS 2 patients. Administration of N+GC was well tolerated in PS 2 patients, with no evidence of an increased safety risk in this subgroup.
