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F. Morin
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OA06 - Prognostic & Predictive Biomarkers (ID 452)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:F. Shepherd, Y. Yatabe
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 1
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OA06.05 - Proteomic Analysis of ERCC1 Predicts Benefit of Platinum Therapy in NSCLC: A Reevaluation of Samples from the TASTE Trial (ID 5361)
14:20 - 15:50 | Author(s): F. Morin
- Abstract
- Presentation
Background:
It is hypothesized that low or absent expression of the excision repair cross-complementation group 1 (ERCC1) protein predicts improved survival in NSCLC patients treated with platinum-based therapy. However, the International Adjuvant Lung Cancer Trial Collaborative Group concluded that current ERCC1 assessment methods are inadequate for clinical decision-making. Due to the unreliability of ERCC1 immunohistochemistry (IHC), the IFCT-0801 TASTE (Tailored Postsurgical Therapy in Early-Stage NSCLC) trial of adjuvant therapy for NSCLC was discontinued. We reevaluated a subset of samples from the TASTE trial using mass spectrometry-based proteomics to quantitate ERCC1 protein. We correlated ERCC1 proteomic status with survival after chemotherapy with cisplatin/pemetrexed and compared it to ERCC1 IHC ranking.
Methods:
Formalin-fixed, paraffin-embedded NSCLC tumor tissues were laser microdissected, solubilized, digested, and proteomically analyzed. A multiplexed, selected reaction monitoring mass spectrometric assay was used to quantitate levels of multiple proteins including ERCC1. The Kaplan-Meier method and univariate Cox analysis assessed overall survival (OS) and relapse-free survival (RFS). A chi-squared test compared binary proteomic levels of ERCC1 (detectable vs. undetectable) with the IHC status assessed using an anti-ERCC1 antibody (8F1) during the TASTE trial.
Results:
Of 146 evaluable patients, 33 (22.6%) had undetectable ERCC1 by quantitative proteomics. Proteomics found no detectable ERCC1 protein in 8/36 (22.2%) IHC-positive patients nor in 8/22 (19.3%) IHC-indeterminate patients. ERCC1 was detected in 71/88 (80.7%) IHC-negative patients (range: 36-137 amol/µg total tumor protein). Undetectable ERCC1 by proteomics was prognostic of OS (hazard ratio [HR]: 5.45; p=0.031). In survival analyses of cisplatin-treated patients (n=122), only one of the 15 deaths occurred among the patients with undetectable ERCC1 protein. These patients had better OS than cisplatin-treated patients with detectable ERCC1, although the difference statistically nonsignificant (HR: 3.98; p=0.102). RFS was similar between patients with and without detectable ERCC1. GARFT protein (predictive of response to pemetrexed) was quantified in 100% of patients (range: 492-4006 amol/µg). The 10 cisplatin/pemetrexed-treated patients with GARFT levels >900 amol/µg had nonsignificantly worse OS than their counterparts with lower GARFT levels (p=0.08).
Conclusion:
Although underpowered to detect statistically significant survival differences, this study clearly demonstrates that quantitative proteomics can increase accuracy in identifying NSCLC patients who will respond to platinum-based therapy because they do not express ERCC1. Approximately 28% of such patients were misclassified by ERCC1 IHC in the TASTE trial. Clinicians should be aware that multiplexed quantitative proteomics can quantitate ERCC1 simultaneously with multiple clinically relevant proteins in lung tumors and small biopsies.
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OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:L.M. Montuenga, J. Heymach
- Coordinates: 12/06/2016, 11:00 - 12:30, Stolz 2
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OA11.01 - Prolonged OS of Patients Exposed to Weekly Paclitaxel and Bevacizumab: Impact of the Cross-Over in the IFCT-1103 ULTIMATE Study (ID 4988)
11:00 - 12:30 | Author(s): F. Morin
- Abstract
- Presentation
Background:
Overall survival (OS) is considered as the gold standard for evaluating efficacy of antineoplastic treatments, including chemotherapy and targeted therapies. In randomized trials, allowing patients to cross-over to the other arm usually prevents demonstration of a survival benefit. However, it may provide important information with clinical relevance.
Methods:
The phase III IFCT-1503 ULTIMATE study compared weekly paclitaxel and bevacizumab (wPB) vs. docetaxel (DOC) as second- or third-line therapy in non-squamous NSCLC. At progression, patients were allowed to cross over to the other arm. Date of progression was collected for patients who crossed over to the other arm and for those who did not cross over but received a post-discontinuation treatment within 60 days following progression. Post-discontinuation progression-free survival (PFS2) and OS2 were calculated from day 1 of post-discontinuation treatment.
Results:
The study met its primary endpoint, PFS, which was significantly improved in the wPB arm (medians 5.4 vs. 3.9 mo, hazard ratio (HR) 0.62, p=0.006). No overall survival was observed (medians 9.9 vs. 11.4 mo, HR 1.18, p=0.4). Out of patients treated with DOC (n=55), those who crossed over to wPB (n=21, 38.2%) had a median PFS2 of 4.9 mo [3.1-6.2] and a median OS2 of 12.5 mo (7.0-NR), whereas those who did not cross over but received a post-discontinuation treatment (n=13, 23.7%) had a median PFS2 of 1.7 mo [1.1-2.2] and a median OS2 of 4.1 mo [2.1-5.9]. Out of patients treated with wPB (n=111), median PFS2 was 1.9 mo [1.2-2.2] for those who crossed over to DOC (n=9, 8.3%) and median PFS2 and OS2 were 1.9 mo [1.7-2.6] and 5.0 m [3.4-9.0] for those who did not cross over but received a post-discontinuation treatment (n=57, 52.3%).
Conclusion:
Allowing patients to cross over to the other arm demonstrated benefit of wPB following progression on docetaxel and explains the absence of OS benefit.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-037 - Prognostic Impact of 1st-Line Treatment and Molecular Testing in Advanced NSCLC in France - Results of the IFCT-PREDICT.amm Study (ID 5628)
14:30 - 15:45 | Author(s): F. Morin
- Abstract
Background:
In 2013, recommendations for 1st line treatment in advanced NSCLC included a platinum based chemotherapy (pCT) with or without bevacizumab (BEV-pCT), an EGFR-TKI, or a non-platinum based CT (non-pCT) depending on clinical, pathological and molecular characteristics. Molecular testing for KRAS, EGFR and ALK, is routinely performed in France for advanced non-squamous NSCLC. However, the prognostic impact of the molecular status knowledge before beginning 1st line treatment is unknown.
Methods:
After a cross-validation study, KRAS, EGFR and ALK molecular status were assessed in 843 consecutive patients (pts) with previously untreated advanced NSCLC (all histologic subtypes) and categorized as: EGFR/ALK+, KRAS+, wild-type (WT), undetermined (UD) and not done (ND). Treatments from the 1st to 3rd line were separated into 4 groups: p-CT, BEVA-pCT, EGFR/ALK TKI and non-pCT. Demographic, clinical and pathological characteristics were collected and pts were followed-up until death. Overall survival (OS) and progression-free survival (PFS) for each line were determined. Prognostic factors including treatment categories (p-CT as reference) and biomarkers status (WT as reference) were studied by Cox model.
Results:
Treatments were analyzed in 767 (91.0%) of the 843 pts enrolled between 01/2013 and 02/2014. Pts were 93.1% Caucasians, 66.2% males. Median age was 62.4 yr (28-92). 13.4% were never smokers. PS ≥2 were 21.4% and 90.3% were stage IV. 76.5% had adenocarcinoma, 14.5% squamous cell carcinoma and 9% others with WT=40.4%, KRAS+=23.1%, EGFR/ALK+=10.2%, UD=5.1%, ND=21.2%. 1st line treatments were: p-CT=75.9%, BEVA-pCT=14.2%, EGFR/ALK TKI=7.8% and non-pCT=2.1%. With a 30.3 months (mo) median of follow-up, median OS and PFS were 10.7 mo and 5.3 mo, respectively. Factors independently associated with shorter OS were PS≥2 (HR=2.08, p<.0001), KRAS+, UD and ND mutation status (HR=1.40, p=.002; 1.53, p=.02; 1.29, p=.02), and non-pCT as 1st line treatment (HR=1.92, p=.01), while EGFR/ALK+ (HR=.38, p<.0001) and BEVA-pCT (HR=.54, p<.001) were associated with better survival. There was no interaction effect between biomarkers status and OS treatment groups. However, BEVA-pCT in 1st line therapy in KRAS+ and WT NSCLC (p<.0001 and <.0003, respectively) was associated with longer survival compared to p-CT, while giving a TKI or p-CT in 1st line therapy in EGFR/ALK+ NSCLC did not affect OS.
Conclusion:
Results from the IFCT-PREDICT.amm study suggest that prognosis of advanced NSCLC might be optimized in 1st line setting by the knowledge of EGFR/ALK molecular status and the opportunity to give a BEVA-pCT regimen, especially in patients with KRAS+ and WT tumor.
