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A.C. Lueers
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MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:Y. Yatabe, R. Perez-Soler
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI05.03 - P53 Disruptive Mutation Is a Negative Predictive Factor in EGFR M+ NSCLC Treated with TKI (ID 903)
16:45 - 18:15 | Author(s): A.C. Lueers
- Abstract
- Presentation
Background:
p53 mutations are common in lung cancer, and have also been described in EGFR mutated patients. The impact of p53 mutations in EGFR M+ patients is controversial, especially if classified as “disruptive” and “non-disruptive” according to their functional effect on the p53 protein as proposed by Poeta and colleagues. The aim of the study was therefore to systematically analyze EGFR and p53 mutations within a cohort of patients with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and to investigate a potential impact of p53 mutations on treatment outcome.
Methods:
267 patients from a single center diagnosed with lung cancer stage IV were studied for the presence of EGFR as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing. P53 mutations were detected by Sanger Sequencing. Clinical characteristics including smoking status were available for all patients.
Results:
267 consecutive patients at the lung cancer center of the Pius-Hospital Oldenburg were studied. The overall EGFR mutation rate was 19% (51/267) in all patients, 80% (41/51) showing common mutations of exon 19 or 21. P53 disruptive mutation showed in 16% (8/51) and p53 nondisruptive mutation occurred in 11% (22/51) whereas p53 WT was found in 47% (24/51). In 8/51 (16%) patients p53 analysis was not successful. OS was 37 months in p53 disruptive mutation and p53 WT patients compared to 19 months in p53 nondisruptive mutation (p<0,05). PFS on 1st line TKI therapy was 18 months in p53 nondisruptive mutation and p53 WT patients and 6 months in p53 disruptive mutation (p<0,024). Similar results could be shown in the EGFR common mutation subgroup but not in the uncommon mutation subgroup.
Conclusion:
Significant differences in PFS and OS in EGFR M+ patients were observed depending on p53 mutation status. P53 mutational status is only predictive when disruptive and non-disruptive P53 mutations are differentiated. P53 should be tested prospectively in EGFR M+ patients as management of patients on 1st line TKI may be different.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-050 - Influence of Maintenance Therapy on Incidence of 2nd Line Therapy and OS in NSCLC IV (ID 823)
09:30 - 17:00 | Author(s): A.C. Lueers
- Abstract
Background:
One of the strongest rationale for maintenance therapy in NSCLC is the fact that exposure to 2nd line therapy is only 40-60% in clinical trials in specialized treatment centers. Even with follow-up intervals of 6 weeks, the 2nd line treatment rate does not seem to increase. We analyzed the exposure of 2nd line therapy as well as OS and PFS in patients with stage IV NSCLC in the subgroups no 2nd line, 2nd line after maintenance and 2nd line without maintenance therapy.
Methods:
All primary lung cancer cases stage IV in the lung cancer center were analyzed based on the documentation files between 2009 and 2013. Patients were followed-up between 1st and 2nd line therapy every 6-8 weeks according to S3 guidelines. Patients with EGFR+, ALK+ or ROS1+ were excluded from the analysis.
Results:
221 patients were diagnosed with NSCLC IV (UICC7), or had systemic relapse of localized disease and were treated with 1st line therapy for metastatic disease. Of these, 160 (72%) received 1st line combination therapy with Carboplatin, 50 (23%) with Cisplatin and 11 (5%) with platin-free single agent therapy. 45 (19%) of all patients received maintenance therapy, most of them with bevacizumab. Of 221 patients, 203 (92%) progressed after 1st line therapy or 1st line and maintenance therapy. 106/163 (65%) of non-maintenance therapy patients received 2nd line therapy, 57 patients (36%) did not. Of 40 patients receiving maintenance therapy and requiring 2nd line therapy, 31 (78%) received 2nd line therapy. Reasons for not obtaining 2nd line therapy were captured and were manifold. Survival analyses showed significant differences regarding overall survival (median survival 21 (maintenance and 2nd line) vs. 13 (1st and 2nd line) months) but no relevant differences regarding progression free survival on 2nd line (median 2 months).
Conclusion:
In a certified lung cancer center and stringent follow-up every 6 to 8 weeks, 1/3 of patients do not receive 2nd line therapy because of various reasons. The application of maintenance therapy raises the chances of receiving 2nd line therapy and increases overall survival whereas progression free survival is not affected.
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P2.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 210)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.02-034 - Induction Therapy with Intercalated TKI and Chemotherapy in NSCLC with Activating EGFR Mutation in Stages II-IIIB: NeoIntercal (ID 2255)
09:30 - 17:00 | Author(s): A.C. Lueers
- Abstract
Background:
EGFR TKI treatment is standard of care in patients with metastasized NSCLC carrying an activating EGFR mutation. 1[st] and 2[nd] generation agents lead to response rates of up to 70% in metastatic EGFRM+ NSCLC. Recently, new light has been shed on intercalated regimens of chemotherapy and TKI have shown improved PFS as well as OS in the metastatic setting in an unselected Asian population (Wu et al. 2013 The Lancet Oncology 14 (8): 777-86). Response is a predictor of PFS and OS in limited and locally advanced NSCLC. Chemotherapy induction alone leads to pCR rates of no more than 15%. No data have been generated for induction therapy including EGFR TKI in EGFRM+ NSCLC. Four cases treated in one center have demonstrated the feasibility and tolerability of an intercalated induction therapy concept (Lüers et al. 2013 Abstract WCLC).
Methods:
Therefore, NeoIntercal a single arm phase II study has been initiated in 9 centers in Germany. In a first step, patients with stage II to IIIB staged according to local standards will be screened for EGFR mutations by a ring certified pathologist. EGFRM+ patients will receive gefitinib 250 mg / die p.o. on d-12 to -1 (d1 = first day of first cycle of chemotherapy) followed by 3 cycles of taxane and platinum containing chemotherapy with intercalated gefitinib on d4-d20 of each cycle. After 2 cycles, restaging CT is performed and patients are scheduled to undergo surgery during the 4[th] or 5[th] week of the last cycle of CTx-gefitinib. Pathologic response rate is the primary endpoint. If more than 30% of patients achieve pCR (regression grades IIB and III according to Junker) in the mediastinal lymph nodes, it is planned to additionally enroll 28 patients in the 2[nd] part of the study. Secondary endpoints include OS, PFS, relapse rate and pattern, toxicity and feasibility. A liquid biopsy project is included in the study to correlate EGFR mutation status from tumor biopsy results with ctDNA plasma analysis. Furthermore, therapy effects will be monitored by liquid biopsy.
Results:
Study preparation and recruitment of clinical trial centers is nearly completed and the enrollment of the first patient is planned for 3Q2015. An interim analysis will be performed approximately 12 months after enrollment initiation with data from 21 patients. Should the interim analysis be positive and an additional 28 patients are included, the study is scheduled to end in approximately 2019 after a follow up period of 24 months.
Conclusion:
According to our knowledge, NeoIntercal is the first study in the neoadjuvant setting with curative intent applying an intercalating combination of chemotherapy and targeted therapy. The NeoIntercal study group believes that this study will potentially contribute to the improvement of EGFRM+ NSCLC therapy.
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P3.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 214)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.03-018 - Intercalated TKI and Chemotherapy Induction in EGFR mt+ NSCLC Stage IIIA and IIIB: 3 Cases with Complete Remission in Mediastinal Lymph Nodes (ID 3223)
09:30 - 17:00 | Author(s): A.C. Lueers
- Abstract
Background:
EGFR TKI treatment is standard of care in patients with metastasized NSCLC carrying an activating EGFR mutation. However, induction concepts in locally advanced NSCLC with EGFR mutation including TKI have not been studied extensively. Recently new focus has been shed on intercalated regimens of chemotherapy and TKI, showing improved PFS as well as OS. This concept was used as induction regimen in 3 patients with activating EGFR mutation in stages IIIA and IIIB.
Methods:
Patients were diagnosed and worked up according to standard imaging, histology and immunohistology methods. EGFR, KRAS, BRAF, ALK and P53 mutation analysis were performed with standard procedures as described by Halbfass et al. 2013. Remission induction was measured by RECIST 1.1, regression grading by Junker criteria.
Results:
2 female never smokers (pt #1 and 3), 62 and 59 y.o. and 1 male light smoker (pt#2) (5 packyear), 58 y.o . were diagnosed with with TTF1+ adenocarcinoma of the lung, 2 with exon 21 L858R (#2,3) and 1 with Exon 19 deletion (#1). All patients carried a p53 mutation, exon 6 (#2,3), exon 8 (#1). Tumor stage was T (extension to mediastinal pleura) N2 (2R, 4R) M0, IIIA4 (#1), T2aN3(4L,7,2R)M0 IIIB (#2) and T2N3M0. Induction therapy was started with erlotinib 150 mg/die p.o. days -12 to -1 (#1,2) and gefitinib (#3) in order to prove responsiveness of the tumor to EGFR-TKI. On day 0 partial response or no progression was achieved in all 3 patients. Therapy was continued with 3 cycles of docetaxel 75 mg/m2 d1 and cisplatin 50 mg/m2 d1 and 2 qd22 in combination with erlotinib d4-19 (#1), 1 cycle of docetaxel and cisplatin followed by 2 cycles of paclitaxel and carboplatin (#2) and switch from erlotinib to gefitinib with cycle 2 (#2) because of diarrhea) and 3 cycles of docetaxel and cisplatin with gefinitib 250 mg d4-19 (#3). PR was was achieved after 2 cycles in all patients. All three patients were resected and regression grade IIB was remarked in mediastinal lymph nodes (#1-3), regression IIA was remarked in the primary tumor in 2 patients (#2,3), regression grade III in 1 patient (#1). All three patients received adjuvant radiotherapy. Patients #1 and 3 are in CR, patient 2 developed one isolated CNS metastasis which has been stereotactically irradiated. No additional therapy, including TKI was administered postoperatively.
Conclusion:
Intercalated TKI treatment is a promising treatment choice in patients with EGFR mt+ locally advanced NSCLC. A phase II trial (NeoIntercal) trial is currently under way in 9 German centers in stages II and III using gefitinib in combination with induction taxane based chemotherapy, supported by ASTRA Zeneca.
