Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement

Our plain-English summary of Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement, by G. Bronte, A. Delmonte, M.A. Burgio, et al (Lung Cancer, 2020).

The study

• Authors: G. Bronte, A. Delmonte, M.A. Burgio, A. Verlicchi, M. Puccetti, S. Bravaccini, P. Cravero, M.M. Tumedei, D. Diano, G. Rossi, P. Ulivi, G. Martinelli, L. Crinò
• Journal: Lung Cancer
• Published: 2020;142:47-50
• Type of article: Case report
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Treatment options for malignant pleural mesothelioma (MPM) are limited but some studies on immune checkpoint inhibitors (ICIs) in MPM have reported antitumor activity. Very little is known about immune-related predictive factors.

Materials And Methods: Here we report the case of a 45-year-old woman presenting with dyspnea and evidence of pleural effusion. She was diagnosed with malignant epithelioid pleural mesothelioma with brain metastasis and peritoneal carcinosis, refractory to initial standard chemotherapy treatment. Because of high PDL1 expression (100 %), she was treated with the anti-PD1 agent, pembrolizumab.

Results: Chemotherapy with cisplatin and pemetrexed was started, imaging studies showing stable disease after 3 treatment cycles. The patient underwent pleural decortication but rapidly progressed and thus started chemotherapy with carboplatin and gemcitabine. After 2 cycles she experienced seizures caused by a brain metastasis. This secondary lesion was surgically removed and confirmed as a metastasis from mesothelioma. Samples from both the primary tumor and the metastasis were molecularly characterized, the pleural sample proving ALK-positive and the brain sample, ALK-negative. PD-L1 was positive in 10 % of tumor cells in the pleural biopsy and 100 % in the brain lesion. Next generation sequencing analysis was negative for both samples. It was decided to start alectinib. Disease progression (peritoneal carcinosis and liver metastases) was documented after one month followed by complete bowel obstruction and recurrence in the site of the brain surgery. Alectinib was stopped and supportive care begun with parenteral nutrition via nasogastric tube. Pembrolizumab was started and after 15 days the patient's condition had significantly improved, enabling recanalization and restoration of enteral nutrition. Imaging displayed complete response of the brain metastasis, peritoneal carcinosis, bone lesions and mediastinal nodal metastases. A partial response was documented in the pleural and pulmonary nodules, with stable liver metastases. The patient is still undergoing immunotherapy and has no cancer-related symptoms.

Conclusions: Our findings indicate that the use of immunotherapy in MPM warrants further investigation. Furthermore, the impressive clinical response obtained by our patient suggests that immune checkpoint inhibitors could help in the management of the disease after the failure of other treatments.

Copyright © 2020 Elsevier B.V. All rights reserved.

In plain English

This is a case report about one patient, a 45-year-old woman diagnosed with malignant epithelioid pleural mesothelioma whose symptoms began in November 2017. The article does not say whether she had been exposed to asbestos. Her disease progressed despite chemotherapy (cisplatin and pemetrexed, then carboplatin and gemcitabine) and surgery, and it spread to bone and the brain. Pleural tumor tissue carried an EML4-ALK gene rearrangement in 18% of tumor cells, but the brain tumor did not. The protein PD-L1 was found in 10% of pleural tumor cells and 100% of brain tumor cells. After one month on the ALK-targeted drug alectinib, the cancer had spread further and her bowel was completely blocked. She was then given the immunotherapy drug pembrolizumab. Scans showed complete response in the brain, peritoneum, bone and mediastinal lymph nodes, partial response in the pleura and lung, and stable liver disease. A liver biopsy showed two different tumor cell populations. She remained on immunotherapy without cancer-related symptoms. The authors concluded that immunotherapy in pleural mesothelioma warrants further investigation. They noted that high PD-L1 may not explain the outcome.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case report (a single patient)
• Who was studied: One 45-year-old woman, a former light smoker (printed as 2 packs/year), with malignant epithelioid pleural mesothelioma. Her symptoms began in November 2017 and the report follows her through April 2019. The authors are at institutions in Italy.
• Exposure: The article does not report the patient's asbestos exposure. The case concerns treatments: cisplatin plus pemetrexed, then carboplatin plus gemcitabine, then alectinib 600 mg twice daily, then pembrolizumab 2 mg/kg every 21 days.
• Main results:
  • In the pleural tumor sample, EML4-ALK translocation was confirmed by FISH in 18% of tumor cells. The brain metastasis sample was negative for ALK expression.
  • PD-L1 was positive in 10% of tumor cells in the pleural biopsy and in 100% in the brain lesion.
  • After one month of alectinib, CT showed peritoneal carcinosis and 2 liver metastases, and complete bowel obstruction developed.
  • Fifteen days after starting pembrolizumab, the patient's condition had improved enough to restart enteral nutrition.
  • On pembrolizumab, imaging showed complete response of the brain metastasis, peritoneal carcinosis, bone lesions and mediastinal nodal metastases. There was partial response in the pleural and pulmonary nodules and stable disease in the liver metastases.
  • A biopsy of the liver metastases showed two clonal cell populations, with ALK translocation in 18% of tumor cells and PD-L1 expression in 70% of tumor cells.
  • The patient was still undergoing immunotherapy with no cancer-related symptoms. The liver lesions were treated with radiofrequency thermoablation in April 2019.
• The authors' conclusion: The authors concluded that the case highlights the need for further investigation of immunotherapy in malignant pleural mesothelioma. In their view, the response supports the hypothesis that immune checkpoint inhibitors could be a valid alternative after other treatments fail. They also said the varying PD-L1 and ALK results indicate wide tumor heterogeneity within one patient.
• Limitations the authors state:
  • The authors note that high PD-L1 expression may not have been responsible for the outcome.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Epithelioid, Mesothelioma, PD-L1, Pleural Mesothelioma, checkpoint inhibitors, Dyspnea, Pleural Effusion, Metastasis.

Related studies

• Tumor PD-L1 expression in malignant pleural and peritoneal mesothelioma by Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx assays — D.B. Chapel, R. Stewart, et al. (2019)
• Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial — B. Geoerger, H.J. Kang, et al. (2020)
• Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: A RENAPE study — S. Valmary-Degano, P. Colpart, et al. (2017)
• Molecular and immunological features of a prolonged exceptional responder with malignant pleural mesothelioma treated initially and rechallenged with pembrolizumab — A. Minchom, W. Yuan, et al. (2020)
• Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial — E.W. Alley, J. Lopez, et al. (2017)
• Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort — S. Brosseau, C. Danel, et al. (2019)

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