Rolf Stahel, Universitätsspital Zürich, Switzerland:

LBA37
Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma (MPM) with or without hemithoracic radiotherapy: final results of the randomized multicenter phase II trial SAKK17/04:

   

More Infos, ESMO Press Release & Abstract

LBA37
Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma (MPM) with or without hemithoracic radiotherapy: final results of the randomized multicenter phase II trial SAKK17/04:

Studies report new findings on treatment options for mesothelioma

  • High-dose radiotherapy adds no survival benefit after chemotherapy and radical surgery;
  • PD-L1 protein a possible immunotherapy target

Lugano/Madrid, 29 September 2014 -- Treating patients with high-dose radiotherapy after chemotherapy and surgery for malignant pleural mesothelioma does not achieve improvements in local relapse and overall survival, according to data from a prospective randomized phase II trial presented at ESMO 2014 Congress in Madrid.

“Mesothelioma remains a difficult disease to find better treatment options for, so we asked whether high-dose hemithoracic radiotherapy would decrease the rate or delay the time of local recurrence after chemotherapy and radical surgery,” says lead author Prof Rolf A. Stahel, from the Clinic and Policlinic for Oncology, at the University Hospital Zurich, Switzerland, and current President of the European Society for Medical Oncology.

The multicentre trial included 153 patients with surgically-treatable malignant pleural mesothelioma, who were first treated with three chemotherapy cycles of cisplatin and pemetrexed, followed by surgical removal of affected lung tissue, with the goal of complete removal of the cancerous areas of lung.

In a second part of the study, researchers randomly assigned 54 patients to receive either radiotherapy or no further treatment, with the primary endpoint being the duration of relapse-free survival.

While there had been preliminary evidence suggesting that the addition of radiotherapy might improve outcomes, the study failed to find any differences in relapse-free survival between patients treated with the additional radiotherapy, and those who were not.

Stahel says researchers were hoping for a more positive signal from the study. “We aimed for a six month delay in local recurrence, which would be meaningful because it’s an aggressive treatment for patients.”

In summary, Stahel says, “It demonstrates that, like in other solid tumours, when two modalities are not sufficient it’s very rare that the third modality added would make a benefit.”

Commenting on the results, Dr Paul Baas, from the Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, says the combined modality of chemotherapy followed by major surgery and irradiation of high volumes of the chest is one of the accepted treatments in very fit patients, however it is a combination associated with high morbidity.

“The study by Stahel et al. indicates that the contribution of radiation does not improve time to recurrence of the disease,” says Baas.

However he also stressed that the results did not lead him to conclude that there was no role for adjuvant radiation in this setting, pointing out that this was a phase II trial, and therefore not necessarily the final conclusion, and that selection of patients with differing pathology, stage and performance could influence outcome.

“Times are changing and this is also true for the way that radiation therapy can be administered to the patient, so new approaches (intensity modulated radiation) can improve the local control and reduce toxicity.”

Is PD-L1 a possible immunotherapy target in mesothelioma?

In a second study presented at the ESMO 2014 Congress, researchers report that about 20% of patients with malignant pleural mesothelioma have cancer cells that express a protein called programmed cell-death ligand 1 (PD-L1) that is associated with poorer outcomes.

The results suggest this population of patients could be treated with targeted therapies to PD-L1, researchers say.

The PD-L1 protein—which is part of the PD-1/PD-L1 immune pathway—is active in many different human cancers, where it is involved in suppressing the anti-tumor immune response and therefore hampering the immune system’s ability to attack the cancer.

Treatments that block this pathway are already showing considerable promise in other malignancies, such as melanoma and lung cancer, leading researchers to question whether this same pathway could be active in malignant pleural mesothelioma.

“We report that PD-L1 is expressed in 20% of malignant pleural mesothelioma patients and is associated with poor outcome, which suggests that this pathway could be targeted with PD-1/PD-L1 inhibitors,” says study author Dr Susana Cedres, from Vall d’Hebron Institute Oncology, Barcelona, Spain.

Researchers analysed tissue samples from 119 patients with malignant pleural mesothelioma using an anti-PD-L1 stain. PD-L1 expression intensity was scored on a scale of 0 to 3—with ‘0’ signifying no expression, ‘1’ signifying weak expression, ‘2’ moderate, and ‘3’ strong—and then compared the score with survival data and outcomes from those patients.

They found that overall, 20.7% of patients were positive for PD-L1 expression: 18.7% of these showed strong expression of PD-L1, 25% showed moderate expression, while 56.2% showed only weak expression of PD-L1.

Most importantly, patients who were negative for PD-L1 expression survived around 11 months longer than patients who were positive for PD-L1 expression (median survival 4.79 vs 16.3 months).

Factors such as gender, smoking, asbestos exposure and disease stage did not have an effect on whether patient’s disease was positive for PD-L1 expression, but researchers did find that expression of the protein was more common in non-epithelial tumours compared to epithelial tumours.

“The results of our study could offer new treatment to this population of patients, identifying a subset of malignant pleural mesothelioma who expressed PD-L1 and could be treated with targeted therapies to PD-L1,” Cedres says.

Commenting on the two studies, Baas says that finding a good treatment for mesothelioma has been a challenge for many years and has so far led to many disappointments, so there is a need for investigation into new pathways such as the use of immune checkpoint inhibitors that target the PD-1/PD-L1 pathway.

“Cedres and colleagues’ data are important because they might help in selecting the best patients for these kinds of (expensive) therapies,” Baas says.

Some key issues need to be addressed, such as identifying the best antibody and platform to find tumours with increased expression of PD-L1, and deciding which treatment approach to take.

“It is clear from these two studies that we still have a long way to go, but proper selection of patients, improved techniques in radiotherapy and new immunotherapy treatments will help us to fight this terrible disease.”

-END-

Notes to Editors

37LBA_PR: Neoadjuvant chemotherapy and extrapleural pneumonectomy (EPP) of malignant pleural mesothelioma (MPM) with or without hemithoracic radiotherapy: final results of the randomized multicenter phase II trial SAKK17/04

1556O_PR: Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM)

Disclaimer

Information contained in this press release was provided by the abstracts authors and reflects the content of the studies. It does not necessarily express ESMO's point of view.

Session info

37LBA_PR                            Monday, September 29, 2014 – 14:00 PM – 15:30 PM  - Hall Sevilla

1556O_PR                            Monday, September 29, 2014 – 14:00 PM – 15:30 PM  - Hall Sevilla

Abstract: 37LBA_PR

Neoadjuvant chemotherapy and extrapleural pneumonectomy (EPP) of malignant pleural mesothelioma (MPM) with or without hemithoracic radiotherapy: final results of the randomized multicenter phase II trial SAKK17/04

R.A. Stahel1, O. Riesterer2, X. Alexandros3, I. Opitz4, M. Beyeler5, A. Ochsenbein6, M. Früh7, R. Cathomas8, K. Nackaerts9, S. Peters10, C. Mamot11, A. Zippelius12, C. Mordasini13, K. Clemens14, K. Eckhardt5, R. Schmid15, W. Nagel16, D. Aebersold17, O. Gautschi18, W. Weder19
1Clinik of Oncology, Universitätsspital Zürich, Zurich, SWITZERLAND, 2Radio-onkologie, Universitätsspital Zürich, Zurich, SWITZERLAND, 3Biostatistics, SAKK Cordination Center, Bern, SWITZERLAND, 4Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 5SAKK Coordination Center, Bern, SWITZERLAND,6Medical Oncology, Inselspital Bern, Bern, SWITZERLAND, 7Medical Oncology, Kantonsspital St. Gallen, St. Gallen, SWITZERLAND, 8Medizinische Onkologie, Kantonsspital Graubünden, Chur, SWITZERLAND, 9Respiratory Oncology Unit, Univ Hospital Leuven, Leuven, BELGIUM,

10Oncology, Centre Hospitalier Universitaire Vaudois - CHUV, Lausanne, SWITZERLAND, 11Medical Oncology, Kantonsspital Aarau, Aarau, SWITZERLAND, 12Medical Oncology, University Hospital Basel, Basel, SWITZERLAND, 13Onkologie, Tifenau Spital, Bern, SWITZERLAND, 14Onkologie, Kantonsspital Baden, Baden, SWITZERLAND, 15SAKK Coordination Center, Bern, SWITZERLAND, 15Thoracic Surgery, Inselspital Bern, Bern, SWITZERLAND, 16Klinik für Chirurgie, Kantonsspital St. Gallen, St. Gallen, SWITZERLAND, 17Radio-onkologie, Inselspital Bern, Bern, SWITZERLAND, 18Klinik für Onkologie, Luzerner Kantonsspital, Lucerne, SWITZERLAND, 19Division of Thoracic Surgery, Universitätsspital Zürich, Zurich, SWITZERLAND

Aim: We have previously documented the feasibility of neoadjuvant chemotherapy and EPP in a multicenter trial of MPM (Weder, Ann Oncol 18: 1196, 2007). The objectives of the trimodality trial SAKK17/04 (NCT00334594) were to evaluate the time to loco-regional relapse with or without high dose hemithoracic radiotherapy in a prospective multicenter randomized phase II trial in patients with R0 and R1 resection after neoadjuvant chemotherapy and EPP.

Methods: Eligible patients had pathologically confirmed MPM, surgically resectable TNM stage (T1-3 N0-2 M0), PS0-1, ages 18-70 years. Part 1 had a phase II design, and included neoadjuvant chemotherapy with 3 cycles of cisplatin and pemetrexed, followed by restaging and EPP. The primary endpoint of part 1 was complete macroscopic resection (R0-1). Part 2 randomized consenting patients with R0-1 resection into two parallel phase II arms (control arm A and radiotherapy arm B). The primary endpoint for part 2 was loco-regional relapse-free survival (RFS). To detect a 1 year increase with 80% power and 10% alpha, 37 patients were needed for arm B. Secondary endpoints included operability, tolerability of chemotherapy and radiotherapy, survival, andtranslational research

Results: Because accrual of part 2 was slower than planned, the trial was stopped in 2013. Overall, 153 patients entered the trial, of whom 125 underwent surgery and 99 had a complete macroscopic resection (primary endpoint part 1). Of the later patients, 54 could be randomized 1:1 into each arm. Reasons for non-randomization included patient refusal in 24 and ineligibility or protocol deviations in 21. Of the 27 patients randomized to hemithoracic radiotherapy, 25 completed the treatment as planned. For part 1 the median RFS was 8.8 (95%CI: 7.3-10.7) and median OS was 15.0 (95%CI: 12.1-19.3) months. For part 2 the median local RFS for group A was 7.6 (95%CI: 5.5-10.7) and for group B 9.4 (95%CI: 6.5-11.9) months (primary endpoint part 2), while the overall RFS and OS for group A were 5.7 (95%CI: 3.5-8.8) and 16.9 (95%CI: 10.7-23.6) months and for group B 7.6 (95% CI:5.2-10.6) and 14.9 (95%CI: 7.0-17.6) months.

Conclusions: This study did not reach the primary endpoint which was defined as one-year increase in loco-regional relapse-free survival and thus does not support the routine use of hemithoracic RT after neoadjuvant chemotherapy and EPP.

Disclosure: All authors have declared no conflicts of interest.

Keywords: Hemothoracic radiotherapy, malignant pleural mesothelioma, extrapleural pneumonectomy, neo-adjuvant chemotherapy.

 

Abstract: 1556O_PR

Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM)

S. Cedres1, S. Ponce Aix2, J. Zugazagoitia2, A.B. Anguita3, I. Sansano4, A. Navarro Mendivil1, A. Martinez1, P. Martinez1, P. Fidalgo1, E. Felip1
1Medical Oncology, Vall d`Hebron University Hospital Institut d'Oncologia, Barcelona, SPAIN, 2Servicio de Oncologia Medica, University Hosptial 12 de OctubreMedical Oncology, Madrid, SPAIN, 3Servicio de Anatomia Patologica, University Hosptial 12 de Octubre Medical Oncology, Madrid, SPAIN, 4Pathology Department, Vall d`Hebron University Hospital Institut d'Oncologia, Barcelona, SPAIN

Aim: The increasing incidence and poor outcome associated with MPM requires to find effective treatment for this disease. PD1/PD-L1 pathway plays a central role in tumor immune evasion and appears to be predictive and prognostic marker. PD-L1 is expressed in many different human cancers but its role in MPM has yet to be established. The aim of this study is to evaluate the expression of PD-L1 in MPM

Methods: 119 MPM patients (p) from Vall d´Hebron University Hospital and 12 Octubre University Hospital between November 2002 and February 2014 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained with anti-PD-L1 (clone E1L3N™) and intensity was scored as 0 (negative), 1 (weak), 2 (moderate) and 3 (strong). Cases showing more than 1% expression of PD-L1 were considered positive. Survival data were calculated by the Kaplan-Meier method. The associations of PD-L1 expression with outcome were assessed with Cox regression models.

Results: Patient’s characteristics: median age 69 years (42-90 years), males:71.4%, PS 1:64.9%, asbestos exposure: 45%, stage III: 39%, epithelial subtype: 65.5%. PD-L1 was analyzed in 77 p and was positive in 20.7% p (14 samples in membrane, 16 in cytoplasm and 2 in immune infiltrate). PD-L1 intensity was weak in 56.2%, moderate in 25% and strong in 18.7% p. There was no significant relationship between PD-L1 expression and gender, smoking status, asbestos exposure, stage, and lymphocytic infiltration between PD-L1 positive and negative. We found differences in expression PD-L1 according to histology: PD-L1 expression was more frequent in no-epithelial tumor, 60% v 15% in epithelial; p=0.033. The median survival in all population was 13.8 months, and for PD-L1 analysis patients, median survival in p PD-L1 positive was 4.79 vs 16.3 months in p PD-L1 negative (p=0.012).

Conclusions: We have shown PD-L1 is expressed in 20% of p and is a prognostic marker in MPM. Our results suggest PD-L1 warrants further exploration in selecting p for immunotherapy

Disclosure: All authors have declared no conflicts of interest.

Keywords: PD-L1, malignant pleural mesothelioma, prognostic factor