Immune checkpoint inhibitors and response analysis: a tough challenge. A case report
Treatment of metastatic NSCLC patients with immune-checkpoint medicine is intriguing for the potential efficacy; however it may be difficult to evaluate the clinical response due to the lack of reliable immune-monitoring markers up to now and the possibility of radiological pseudo-progression.
Herein we report the case of a patient ex-smoker with adenocarcinoma of the lung, stage IV for liver metastases, in progression after cisplatin-based chemotherapy and treated with antiPD-L1 (MPDL3802-Roche Genentech) e.v. every 3 weeks in a clinical trial. Treatment with antiPD-L1 was well tolerated and CT scan after 6 weeks of treatment showed stabilization of mediastinal lymph nodes, while progression of liver metastases; liver progression only was confirmed by further CT-scans. Patient was asymptomatic and it was unclear if we faced a pseudo-progression in the liver or a real progression. Data about his PDL1 expression were not available because the patient was in a clinical trial. Eventually a biopsy of the liver metastasis confirmed that there was a massive neoplastic invasion with tumor infiltrating lymphocytes <5 %. We stopped anti-PD-L1 therapy due to progression.
Evaluation of response may be difficult with immune checkpoint inhibitors, in particular radiologic images may be a matter of debate; eventually we performed a biopsy to study tumor infiltrating lymphocytes to decide whether it was pseudo-progression or real progression.
KeywordsNSCLC Immune-checkpoint inhibitors Radiologic response
non-small cell lung cancer
epidermal growth factor receptor
anaplastic lymphoma kinase
thyroid transcription factor 1
computed tomography scan
response evaluation criteria in solid tumors
Response assessment during anticancer treatment is a strategic checkpoint to decide whether keep the patient on treatment or stop it and eventually change it. According to the RECIST system, dimensional criteria have driven such decision up to now; however, immune-checkpoint inhibitors have started a paradigm shift. There may be a dimensional increase of the tumor, without clinical deterioration and we do not know if refer it as pseudo-progression or real progression . Hodi et al. described two types of pseudo-tumor progression in melanoma, early and delayed, according to the timing of presentation , meaning an initial progression followed by a further shrinkage of the neoplastic disease, without changing of treatment. Although it is not a frequent phenomenon (the incidence of response with distinct immune-related patterns of response across several solid tumors is roughly 4 %), it is extremely important to recognize it avoiding inappropriate discontinuation of therapy [3, 4].
Response evaluation on immune-checkpoint inhibitors is a new and challenging issue for oncologists; although response rate is not the ultimate goal, it is a key tool to decide whether to keep the patient on treatment. Therefore we present our case, where the progression of disease was unclear at the beginning and a histological confirmation was necessary to understand the efficacy of the treatment.
To understand the underlying process, whether it was pseudo-progression or real progression, after 12 weeks of treatment with anti-PD-L1 we performed two biopsies of one liver metastasis; we chose to biopsy the liver localization, because it was easy to reach and in progression from the very beginning of treatment.
Surgical specimens were sampled according to current protocols. Formalin-fixed, paraffin-embedded tissue samples were obtained, 4-μm sections were stained with hematoxylin and eosin 2.5-μm sections were cut and immunohistochemical analysis was performed in an automated system (Benchmark-XT, Ventana, Tucson, AZ, US). The following primary antibodies were used: TTF-1 (monoclonal antibody, clone SP141, pre-diluted; Ventana, Tucson, AZ, US), CD45 (monoclonal antibody, clone 2B11&PD7/26; prediluted; Ventana, Tucson, AZ, US) and CD3 (monoclonal antibody, clone 2GV6; Ventana, Tucson, AZ, US). Color was developed with 3.3′-diaminobenzidine (DAB) and slides were counterstained with Meyer’s hematoxylin. Appropriate positive and negative controls were concurrently done.
Since we did not find any dense infiltrate of lymphocytes in the liver biopsies, we concluded that our patient had a real progression and stopped the treatment with anti PD-L1.
Up to now there are no available and reliable predictive factors for immune-checkpoint inhibitors neither dynamic predictive markers of efficacy; the tumoral response may be difficult to assess for the pseudo-progression phenomena .
Until a reliable clinical or biological predictor marker of activity for this new class of anticancer drugs is available and until radiological evaluation of response is based on dimension of cancer nodules, the analysis of response could be a real challenge in patients on treatment with immune-checkpoint inhibitors. In our case, the presence of an easily percutaneously accessible metastasis allowed a bioptic assessment to understand the real efficacy of the ongoing treatment.
AB and UT treated the patient, TP is the pathologist who analyzed the bioptic specimen, LC analyzed the radiologic images, EB is the study coordinator for the antiPD-L1, IS collected data. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Ethical approval and consent to participate
Written informed consent has been obtained from the patient for the publication of this case report and any accompanying images.
- 5.Di Giacomo AM, Danielli R, Guidoboni M, Calabro’ L, Carlucci D, Miracco CC, Volterrani L, Mazzei MA, Biagioli M, Altomonte M, Maio M. Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol Immunother. 2009;58:1297–306.CrossRefPubMedGoogle Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.