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F. Griesinger
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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)
16:55 - 17:00 | Author(s): F. Griesinger
- 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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ORAL 20 - Chemoradiotherapy (ID 124)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:G. Blumenschein, J.Y. Chang
- Coordinates: 9/08/2015, 10:45 - 12:15, 201+203
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ORAL20.02 - Safety Results of the Consolidation Phase of a Phase III (PROCLAIM): Pemetrexed, Cisplatin or Etoposide, Cisplatin plus Thoracic Radiation Therapy followed by Consolidation Cytotoxic Chemotherapy in Locally Advanced Nonsquamous Non-Small Cell Lung Cancer (ID 645)
10:56 - 11:07 | Author(s): F. Griesinger
- Abstract
- Presentation
Background:
Standard treatment for inoperable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy. However, many patients die from recurrent disease, indicating that new treatment strategies are needed.
Methods:
PROCLAIM is a phase III trial comparing overall survival in patients with unresectable stage III nonsquamous NSCLC receiving pemetrexed+cisplatin (PemCis) and concurrent radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation (Arm A) versus etoposide+cisplatin (EtoCis) and concurrent radiotherapy for 2 cycles followed by consolidation with a platinum-based doublet of choice for up to 2 cycles (Arm B). Possible consolidation therapies in Arm B were EtoCis, vinorelbine+cisplatin (VinCis), and paclitaxel+carboplatin (PacCarb). Overall efficacy and safety results for the intent-to-treat population will be presented in a separate disclosure. Safety was a secondary objective. Interim safety results for the concurrent phase were previously presented. Here we present safety results for the consolidation phase. Treatment-emergent adverse events (TEAEs) were assessed according to the Common Terminology Criteria for Adverse Events (v3.0, CTCAE). TEAE incidences were compared using Fisher’s exact test (two-sided α=0.05).
Results:
Of 598 randomized patients, 555 were treated in the concurrent phase (Arm A: N=283; Arm B: N=272), most of whom (Arm A: n=229 [80.9%]; Arm B: n=202 [74.3%]) continued on to the consolidation phase (Arm B patients: EtoCis [33.5%], PacCarb [26.8%], VinCis [14.0%]). Baseline characteristics, including age, gender, performance status, smoking status, stage, and origin, were well-balanced across arms. Percentages of patients in Arm A completing ≥2, ≥3, and 4 consolidation cycles were 95.2%, 84.3%, and 73.4%, respectively. Percentages of patients in Arm B completing 2 consolidation cycles (maximum) were EtoCis (89.0%), PacCarb (93.2%), and VinCis (86.8%). Mean dose intensities for pemetrexed, etoposide, vinorelbine, cisplatin, paclitaxel, and carboplatin were 95.4%, 94.0%, 84.2%, 91.2%, 88.7%, and 92.7%, respectively. More patients in Arm B, compared to Arm A, experienced dose reductions, dose omissions, and cycle delays. Patients in Arm B reported more grade 3/4/5 drug-related TEAEs than Arm A (51.0% versus 31.0%, p<0.001; Table). Rates of drug-related serious AEs were similar between groups (Arm A: 14.4%; Arm B: 13.4%).Drug-related Grade 3/4/5 TEAEs Occurring in ≥2% of Patients (or of Clinical Relevance) in the Consolidation Phase
CTCAE Arm A (N=229) n (%) Arm B (N=202) n (%) Neutrophils 27 (11.8) 76 (37.6)* Leukocytes 19 (8.3) 29 (14.4) Hemoglobin 6 (2.6) 9 (4.5) Platelets 5 (2.2) 10 (5.0) Febrile neutropenia 7 (3.1) 7 (3.5) Lymphopenia 8 (3.5) 5 (2.5) Pneumonitis/pulmonary infiltrates 5 (2.2) 2 (1.0) Fatigue 2 (0.9) 4 (2.0) Pneumonia 5 (2.2) 0 Esophagitis 0 3 (1.5) *p<0.001, Fisher’s exact test. Note: Of the TEAEs listed here, only one case (0.4%, Arm A, pneumonia) was grade 5.
Conclusion:
During the PROCLAIM consolidation phase, most patients were able to complete the planned number of cycles in either arm, with the highest dose intensity corresponding to pemetrexed. Pemetrexed consolidation had a significantly lower incidence of drug-related grade 3/4/5 TEAEs than the platinum doublets in Arm B. A more detailed analysis of Arm B (by treatment regimen) is underway.
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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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P1.01-086 - TIGER-3: A Phase 3 Open-Label, Randomized Study of Rociletinib vs Chemotherapy in NSCLC (ID 949)
09:30 - 09:30 | Author(s): F. Griesinger
- Abstract
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) that has demonstrated efficacy against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X, a Phase I/II dose-ranging trial, has provided evidence that rociletinib is associated with durable response and is well tolerated in patients with NSCLC and positive T790M status following progression on a TKI.[1 ]Efficacy has also been noted for patients with T790M negative status in TIGER-X.[2] TIGER-3 is designed to investigate single agent rociletinib vs chemotherapy in patients who have failed EGFR therapy and platinum-based doublet chemotherapy, which is a setting of acquired resistance and high unmet need for targeted therapeutic options. TIGER-3 will evaluate patients with T790M positive and negative status based on tumor biopsies and plasma, and biomarkers of response and/or resistance.
Methods:
Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC, with radiological progression on the most recent therapy will be enrolled in this phase 3, randomized, open-label study (NCT02322281). Patients must have documented evidence of a tumor with ≥1 EGFR activating mutations excluding exon 20 insertion, and prior treatment with an EGFR TKI and platinum-containing doublet chemotherapy. Patients will be randomized 1:1 to receive rociletinib twice daily (500 mg) or single agent cytotoxic chemotherapy (investigator choice specified before randomization) until disease progression according to RECIST 1.1. Patients will be stratified by presence or absence of brain metastases, ECOG performance status (0 vs 1), and race (Asian vs non-Asian). The primary endpoint is progression-free survival (PFS). Secondary endpoints include safety, objective response rates, duration of response, disease control rate, and overall survival. Kaplan-Meier methodology will assess time to event variables. The stratified log-rank and the hazard ratio will be used for comparing PFS distributions. Serial assessment of safety will be carried out based on standard adverse event reporting. Planned enrolment is 600 patients; enrolment has been open since March 2015. Sequist LV J Clin Oncol. 2014 Soria J-C EORTC-NCI-AACR 2014
Results:
Not applicable
Conclusion:
Not applicable
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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 - 09:30 | Author(s): F. Griesinger
- 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 - 09:30 | Author(s): F. Griesinger
- 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 - 09:30 | Author(s): F. Griesinger
- 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.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-005 - Discrepancies between ALK FISH and Capture Based NGS Test NEOplus and Clinical Outcome with ALK TKI Therapy (ID 2748)
09:30 - 09:30 | Author(s): F. Griesinger
- Abstract
Background:
Research in recent years has unraveled several gene fusions driving tumor development in lung cancer. Especially adenocarcinomas of the lung harboring ALK and ROS1 gene fusions exhibit striking sensitivity to ALK and ROS1 kinase inhibitors respectively, translating to dramatic responses in the clinic. Several different technologies are available to detect aberrant genomic structures. The most frequently used technologies include fluorescent in situ hybridization (FISH), currently considered as the “gold standard”, immunohistochemistry (IHC), RT-PCR based approaches and hybrid capture based NGS sequencing.
Methods:
Here, we describe a selection of tumor samples showing discrepant results between fluorescent in situ hybridization and hybrid capture based NGS sequencing. These included samples with positive FISH but negative NEOplus as well as negative FISH and positive NEOplus results. In addition, we used response data of targeted therapies to evaluate the true genetic phenotype of the tumor.
Results:
Overall, several lung adenocarcinomas showed discrepant results when FISH and NEOplus data were compared. First, one sample was tested positive for ALK rearrangement using FISH which was not confirmed using NEOplus. In line with this finding, the tumor did not respond to ALK TKI treatment. Second, a total of 4 cases were fusion negative by FISH but positive by NEOplus. Three out of 4 ALK positive cases showed clinical response to ALK kinase inhibition, the clinical results for case number 4 are pending. Interestingly, one of these responding tumors was also negative for ALK expression using IHC.
Conclusion:
In summary, we describe a selection of tumor samples with discrepant results for fusion detecting using FISH and NEOplus. Overall, in all of the cases for which clinical response data was available, tumor sensitivity was in line with the initial diagnosis generated by the NEOplus assay.
