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C. Le Pechoux
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MINI 07 - ChemoRT and Translational Science (ID 110)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:D. Raben, B. Kavanagh
- Coordinates: 9/07/2015, 16:45 - 18:15, 201+203
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MINI07.08 - Mutation Profile Prognostic Value in Stage III Non Small Cell Lung Cancer (NSCLC) Patients Treated with Chemo-Radiotherapy (CRT) (ID 2262)
17:25 - 17:30 | Author(s): C. Le Pechoux
- Abstract
- Presentation
Background:
Molecular profiling is a standard procedure in advanced non squamous NSCLC. Gene alteration in EGFR, BRAF or ALK gene can lead to prescription of targeted therapies and prolongs survival. The influence of molecular abnormalities on the survival of stage III NSCLC patients definitely treated by CRT is unknown.
Methods:
We reviewed all consecutive patients that received CRT or RT with a curative intent for stage III NSCLC in a single institution. Paraffin embedded tissue block were collected. DNA was extracted for gene mutation analysis by next generation sequencing and ALK, ROS1 and RET rearrangements were detected by FISH analysis. Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method.
Results:
Between January2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Platinum-based chemotherapy was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Seventy-eight patients were evaluable for mutation profile, 20 (26%) were female, 47 (60%) were current smoker, 40 (51%) had adenocarcinoma and there were 47/31 stage IIIA/IIIB. Mutations were positive as follow: EGFR 12% (9/78), KRAS 15% (12/78), BRAF 5% (3/66), PI3KCA 2% (1/58), HER2 0% (0/65), NRAS 3% (1/32), CTNNB1 3% (1/32). FISH was positive for ALK in 5% (3/56) of the NSCLC. In 32 NSCLC for which the test was performed, there was no alteration in ROS1, RET, HRAS and AKT1. Median Follow-up was 3.1 years (minimum 0.9 year). EGFR mutated or ALK+ (EGFR/ALK) group (n=11) and other mutation group (n=17) had a poorer progression free survival (median 0.8[95%CI: 0.6 ; 0.9] year and 0.5 [0.4 ; 0.8] year ; multivariate hazard ratio (HR)= 1.8 [0.8 ; 3.8] and 2.8 [1.5 ; 5.1] respectively, p=0.004) compared to the wild group (n=50) (median 1 year [0.9;1.3]). There was no significant difference (p=0.23, multivariate Cox) in overall survival: median 2.4 years [1.3 ; NR] for EGFR/ALK group, 1.1 [0.6 ; 2.5] for other mutation group and 1.9 [1.5 ; 2.5] for wild type. In multivariate analysis, only the dose of radiotherapy was significantly associated with overall survival (HR=0.5 [0.3 ; 1.0], p=0.04 in contrast with performance status or stage.
Conclusion:
This study suggests that selected gene alterations could be associated with a poorer survival in stage III NSCLC patients treated by combined modality treatment or radiotherapy alone. Their prognostic and/or predictive value should be further evaluated in a larger population.
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ORAL 05 - Surgery (ID 97)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:P. Van Schil, F.(. Kong
- Coordinates: 9/07/2015, 10:45 - 12:15, 201+203
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ORAL05.02 - Quality of Resection in Pathological N2 NSCLC in the Phase 3 Lung Adjuvant Radiotherapy Trial (Lung ART): An Important Factor (ID 1001)
11:16 - 11:27 | Author(s): C. Le Pechoux
- Abstract
- Presentation
Background:
The main objective of the ongoing phase III Lung Adjuvant Radiotherapy Trial (Lung ART) is to study the impact of post-operative conformal radiotherapy (PORT) on disease-free survival (DFS) in a population of patients with completely resected pathologically proven N2 non-small cell lung cancer (NSCLC), with or without induction or adjuvant chemotherapy. Quality of surgical resection and extent of lymph node dissection are critically important in the interpretation of results.
Methods:
A surgical advisory committee composed of 4 international expert thoracic surgeons meets regularly in order to establish the quality of resection, taking into consideration the International Association for the Study of Lung Cancer and European Society of Thoracic Surgeons published guidelines. The committee reviews anonymized surgical and pathological reports, and establishes whether tumor resection can be considered complete (no residual tumor and adequate lymph node assessment), uncertain (highest mediastinal nodal station involved, incomplete nodal exploration, involved N2 removed in fragments) or incomplete (presence of residual tumor). Nodal exploration is evaluated according to recommendations and classified as sampling, selective dissection or extensive dissection.
Results:
As of April 15th 2015, 298 patients have been included in the Lung ART trial and 116 patients’ reports have been analyzed by the surgical advisory committee. The basic characteristics are specified in the following table:
Nodal dissection was performed according to lobar location specific recommendations in most patients: for instance, station 7 was explored in 91% patients and right inferior paratracheal station 4R in 93% of right side tumours. Nodal dissection was performed according to recommendations in 71% pts; 16% patients had sampling, 22% a selective dissection and 62% a systematic dissection. Resection was considered complete (R0) in 43%, uncertain in 42%, microscopically incomplete (R1) in 14% and macroscopically incomplete (R2) in 1 patient. The most frequent reason for “uncertain resection” was involvement of the highest mediastinal lymph node.Total n=116 Frequency Percent Induction chemotherapy no 89 77% yes 27 23% Type of surgery for right-side tumors 70 60% lobectomy 49 70% bilobectomy 9 13% pneumonectomy 5 7% other 7 10% for left-side tumors 46 40% lobectomy 34 74% pneumonectomy 10 22% other 2 4% Tumor Size (mm) Median size (range) 35 [0*-105] Number of mediastinal lymph nodes examined Median number (range) 10 [1-37] Number of mediastinal lymph nodes involved Median number (range) 1[0*-15] Number of mediastinal nodal stations involved 0* 5 4% 1 79 68% 2 20 17% >2 12 11% * patients with downstaging after induction chemotherapy
Conclusion:
Most adjuvant trials have included completely resected patients, without monitoring of the quality of nodal exploration and resection. This analysis outlines the importance of an external committee evaluating the quality of resection in stage IIIA-N2 NSCLC, and the findings of this audit will be useful in the interpretation of the results of the trial.
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ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:G. De Lima Lopes, V. Miller
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL06.05 - Molecular Tumor Board (MTB) in Non-Small Cell Lung Cancers (NSCLC) to Optimize Targeted Therapies: 4 Years' Experience at Gustave Roussy (ID 2563)
11:48 - 11:59 | Author(s): C. Le Pechoux
- Abstract
- Presentation
Background:
Molecular biology has changed the treatment of advanced NSCLC, leading to many small subgroups of patients (pts) eligible for targeted therapies, many of them being not approved. Since 2010 we created a monthly MTB dedicated to NSCLC pts with potential driving molecular abnormalitie(s). MTB includes expert physicians from the lung tumor board and phase I unit, radiation therapists, researchers, geneticists, pathologists and biologists. A medical report summarizes the findings and treatment recommendations for each pts. We report 4 years of activity of MTB at Gustave-Roussy.
Methods:
All consecutive files discussed in MTB for a NSCLC were reviewed. MTB included pts with at least one molecular alteration based on a 75 gene panel (NGS analysis and FISH for ALK, HER2, MET, FGFR1, ROS1 and RET). Tumor and pts characteristics were collected as well as treatments. Pts outcome was calculated from the MTB date. Kaplan-Meier methods, and Cox proportional hazards models were used for survival analysis, adjusting for sex, histology, smoking status, metastasis at diagnosis, number of line(s) before MTB.
Results:
502 files were discussed between 02/2010 and 09/2014. Median age was 60 yrs (25–88 yrs), 53% were male, 86% Caucasian, 26% never-smokers, and 93% had PS ≤1. Initial clinical stage was III-IV in 417 pts (84%) and 79%/10%/11% were adenocarcinomas/squamous cell carcinomas/others NSCLC. Median number of treatment-lines before MTB was 1 (0-10), 86% were previously treated by a platinum-based chemotherapy regimen, 17% in a therapeutic trial, and median time from diagnosis to MTB was 5 months. Biopsy for Molecular Analysis (MoA) mostly came from CT guided biopsies (62%), surgery (21%) or endoscopy (16%). Biopsy was repeated in 19% of pts to get enough material for MoA. The MoA results were ALK rearrangement in 11%, exon 18/19/20/21 EGFR mutation (mut) in 2/14/4/7% respectively, KRAS mut in 32%, PI3KCA mut in 3%, BRAF mut in 5%, HER2 mut (Exon 20) in 2%, HER2 amplification in 2%, FGFR1 amplification in 3%, MET amplification in 3% and other rare mutations in 27%. MTB recommended a targeted therapy in 344 pts (68%) either within clinical trials (57%), EMA approved therapy (23%), an off label drug (9%), or an expanded access program (11%). 162pts (47%) actually received the recommended therapy, 141 (41%) did not and 41 (12%) might receive it at the time of progression. Median follow-up was 24 months (1-24; follow-up censored after 24 months). Median OS was 13.1 months [95%CI: 8.8; 18.2] for non-oriented pts, and 14.3 months [11.5; 16.7] for oriented pts (p=0.39). We observed a significant difference between EGFR/ALK/ROS1 mutated/rearranged pts (median 23.8 months) vs. pts with KRAS (8.6 months) or others mutations (11.1 months) or non-oriented pts (13.1 m; p=0.0008, HR=0.56, 1.15 and 0.97 respectively compared to non-oriented).
Conclusion:
MTB is feasible in daily practice with treatment recommendations in a majority of NSCLC pts (68%), enrichment in clinical trials or expanded access programs, and limitation of off-label drugs use. Benefit on survival for all oriented pts has to be clarified based on the type of molecular abnormality. Update results will be presented at the meeting.
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ORAL 36 - Translational Science/Radiation (ID 151)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:E. Vokes, B. Kavanagh
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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ORAL36.02 - Efficacy of Chemo-Radiotherapy (CRT) in Stage III Non-Small Cell Lung Cancer (NSCLC) and PD-L1 Expression (ID 2432)
16:56 - 17:07 | Author(s): C. Le Pechoux
- Abstract
- Presentation
Background:
Inhibition of the PD1/PD-L1 axis has been successfully developed in advanced NSCLC, and its role in locally advanced NSCLC is under investigation. The prognostic and predictive values of PD-L1 expression is still debated in advanced NSCLC and unknown in stage III NSCLC patients definitely treated by CRT
Methods:
We reviewed all consecutive patients that received CRT or RT with a curative intentfor stage III NSCLC in a single institution. Paraffin embedded tissue block were collected, immunohistochemistry was performed on a Ventana Benchmarck Ultra platform using the E1L3N clone (Cell Signaling Technologies). All tumors were centrally reviewed and tumor cells were scored accordingly (Herbst et al., Nature 2014).Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method
Results:
Between January 2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Chemotherapy, mostly based on doublets with platin salt was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Fifty NSCLC were evaluable for PD-L1 expression, 22 (44%) being positive. Fourteen (28%) were female, 24 (48%) were current-smoker, 17 (34%) had adenocarcinoma and there were 23/27 stage IIIA/IIIB. Evaluable and unevaluable populations for PD-L1 were not different. There were no clinical or pathological factors related to PD-L1 positivity. Median follow-up was 7.6 years (minimum: 0.7 year). Median OS was 1.1year(95% confidence interval (CI) 0.6-1.5) in PD-L1 positive (pos) and 2.0 years (95% CI 1.5-3.8) in PD-L1 negative (neg) (p=0.01), HR=2.3 (95% CI 1.2-4.5, p=0.01). Median PFS was 0.7 year (95% CI 0.6-0.8) in PD-L1pos and 1.0 year (95% CI 0.8-1.5) in PD-L1neg (p=0.04), HR=2.1 (95% CI1.1-4.0, p=0.03). There was no difference in terms of acute toxicity according to PD-L1 status (positive or negative):25 had oesophagitis (grade≥2) and 16 had pneumonitis (p=0.57 and p=0.23 respectively).
Conclusion:
PD-L1 positivity was associated to a poorer survival in stage III NSCLC patients treated by definitive chemo-radiotherapy. Its prognostic and/or predictive value should be further evaluated in this population.
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-019 - A Phase II Multicentre Study of Gefitinib in Combination with Irradiation Followed by Chemotherapy in Patients with Inoperable Stage III NSCLC (ID 2606)
09:30 - 09:30 | Author(s): C. Le Pechoux
- Abstract
Background:
Gefitinib is an oral EGFR TKI approved in first-line treatment for metastatic NSCLC patients with activating mutations of EGFR that may act as a radiosensitizer.
Methods:
This phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin 100 mg/m[2] once every 28 days and vinorelbine 25 mg/m[2] once per week for 3 weeks out of 4) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR status.
Results:
Due to a low recruitment rate in this study, the sample size (n=50) was not reached. Sixteen patients were included in four centers between 2004 and 2006, 50% had adenocarcinoma and 75% were male. Molecular analysis (n=10) revealed that 2, 2, and 4 patients had positive biopsies for pERK, pAKT, and EGFR, respectively. EGFR mutation status was not explored at this time. Four weeks after radiotherapy, 3 patients (19%) had a PR, 6 (38%) had a SD, and 9 had PD (56%).Median OS was 11 months and median TTP was 5 months. At the time of the last contact, 5 patients (31%) were still alive. Compliance was good and all patients completed the combination of gefitinib and radiotherapy. Main toxicities were gastrointestinal (81%), cutaneous (81%), General (56%), and respiratory (50%). Seven (47%) patients had at least one grade 3-4 related adverse event.
Conclusion:
Gefitinib (250 mg daily) in combination with RT is feasible but its impact on outcomes remains to be determined, especially in EGFR mutated patients.
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PC 03 - Pro vs Con: Prophylactic Cranial Irradiation (PCI) Post Chemotherapy Response / Pro vs Con: Is There a Role for Radiation in Oligometastatic Disease? (ID 49)
- Event: WCLC 2015
- Type: Pro Con
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:A. Brade, K. Rosenzweig, A. Bezjak, J.S. Lee
- Coordinates: 9/09/2015, 14:15 - 15:45, 708+710+712
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PC03.03 - Is There a Role for Radiation in Oligometastatic Disease? - Pro (ID 2036)
15:00 - 15:20 | Author(s): C. Le Pechoux
- Abstract
- Presentation
Abstract:
Fewer than 20% of all lung cancers are small cell lung carcinomas (SCLCs). As SCLC is an aggressive tumor because of its high and early risk of dissemination, most patients (60-70%) have metastatic disease at diagnosis. Given the high propensity of SCLC for early metastatic dissemination, chemotherapy has been and still is the cornerstone of treatment based on etoposide and platinum, but SCLC is also very sensitive to radiotherapy. Median survival for patients with non-metastatic disease for whom the standard treatment is combined chemotherapy and thoracic radiotherapy, as well as prophylactic cranial irradiation (PCI), is currently 15–20 months, with 20–40% surviving to 2 years, and 25% surviving at 5 years in the best series. For metastatic patients, median survival is 8–13 months and 2 year survival is around 5%. Recent advances in SCLC management derive mostly from a better integration of chemotherapy and radiotherapy. So patients with a limited number of metastases in number and location may have an intermediate outcome; and local treatment of both the primary tumor as well as oligometastatic disease could be discussed. Such an approach is supported by the fact that many patients in early studies that established the role of thoracic radiation therapy in limited disease would now be considered as having metastatic disease. The percentage of such metastatic patients seems to have increased partly because of stage migration with the more frequent use of PET scan and brain MRI. Thus there is a category of patients with oligometastatic disease for whom local treatment may be envisaged. The oligometastatic status was first described by Hellman and Weichselbaum as an intermediate clinical state between locoregionally confined and widespread cancer in 1995. There has been strong interest lately in this subgroup of non-small cell lung cancer oligometastatic patients, with the development of stereotactic ablative radiotherapy. Until recently, there were few data supporting the role of radiation therapy in metastatic small cell lung cancer, except PCI. As there are few therapeutic options in second line, local treatment approaches have been evaluated in extensive disease. Prophylactic cranial irradiation is now part of the standard treatment in responders and more recently a phase III trial has shown that consolidation thoracic radiotherapy could improve outcome. The 2-year survival rate was 13% in the investigational arm versus 3% in the control arm where patients had 4-6 cycles of chemotherapy and PCI [Auperin, 1999; Slotman 2007; Slotman, 2015]. A randomized phase II trial (RTOG 0937) went further in the local approach of metastatic disease after systemic chemotherapy and really addressed the issue of oligometastatic disease [Gore, RTOG 0937]. It compared PCI to PCI and consolidative radiation therapy not only to the primary intrathoracic disease but also to residual extracranial metastatic lesions (1-4 extracranial metastases who achieve a CR/PR following chemotherapy). The trial has included 96 patients and has closed recently after a planned protocol interim analysis. Results are eagerly awaited. Even if there are studies supporting the role of radiotherapy in metastatic SCLC, new strategies are needed for this category of patients. There are promising preclinical data showing a strong synergy between radiotherapy and immune treatments. Such approaches are starting to be explored in SCLC in prospective studies.
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