Open Access
`
`Editorial
`
`Immune checkpoint inhibitors in lung
`cancer: the holy grail has not yet been
`found…
`
`Satheesh Thungappa,1 Jose Ferri,1,2 Christian Caglevic,3 Francesco Passiglia,1,4
`Luis Raez,5 Christian Rolfo1,6
`
`Lung cancer is rich in molecular complex-
`ities and driven by different abnormal
`molecular pathways. Personalised medicine
`has begun to bring new hope for the treat-
`ment of patients with lung cancer, especially
`non-small cell lung cancer (NSCLC). The
`development of molecularly targeted therapy
`(small molecules and monoclonal anti-
`bodies) has significantly improved outcomes
`in the metastatic setting for patients with
`NSCLC whose tumours harbour activated
`oncogenes such as epidermal growth factor
`receptor (EGFR) and translocated genes like
`anaplastic lymphoma kinase (ALK). In addi-
`tion, immune checkpoint inhibitors have
`also dramatically changed the therapeutic
`landscape of NSCLC. In particular, mono-
`clonal antibodies targeting the programmed
`death-1 receptor (PD-1) /PD
`ligand 1
`(PD-L1) pathway have emerged as powerful
`new therapeutic tools in several clinical trials,
`and some of them are already approved by
`the Food and Drug Administration (FDA)
`and American Medical Association (AMA).
`Immunotherapy is a novel type of treat-
`ment that has been tested in patients with
`metastatic NSCLC. Two anti-PD-1 drugs
`(nivolumab and pembrolizumab) and one
`anti-PD-L1 drug (atezolizumab) have been
`approved as monotherapy for second-line
`treatment for NSCLC. Recent trials in first-
`line treatment of advanced or metastatic
`NSCLC with nivolumab and pembrolizumab
`have shown promising and also controversial
`results. The FDA has approved pembroli-
`zumab as a first-line treatment for patients
`with NSCLC whose tumours express PD-L1
`in more than 50% cells based on Keynote-
`024 trial.1 This high PD-L1 presence is
`only observed on about 30% of patients
`with NSCLC, limiting the use of the newly
`approved drug in less than one-third newly
`diagnosed patients.
`The results of nivolumab activity, in Check-
`mate-26 study, compared with chemotherapy
`
`were disappointing.2 We are still trying to
`understand the possible reasons for the disap-
`pointing progression-free survival (PFS) data
`and trying to find out how to improve survival
`with first-line immunotherapy. Either combi-
`nation with chemotherapy, immunotherapy
`or newer investigational agents and a good
`biomarker may be tried.
`if the addition of
`Keynote-021 tested
`pembrolizumab to the standard doublet
`chemotherapy (treatment with two chemo-
`therapy drugs, either pemetrexed + platinum
`in adenocarcinoma or gemcitabine + plat-
`inum in squamous cell lung carcinoma)
`improved outcomes compared with chemo-
`therapy doublet alone.3 The results were
`published in November and showed that the
`trial had met its primary overall response
`rate (ORR) endpoint, with 55% ORR in the
`combination treatment group versus 29%
`in
`the chemotherapy-alone group. This
`trial accrued patients with different levels of
`PD-L1 expression, and as might have been
`expected, those with PD-L1 in more than
`50% of tumour cells had better responses to
`pembrolizumab + chemotherapy. Data from
`the Checkmate-012 trial have many drug
`combinations, and also combined nivolumab
`with different chemotherapy regimens in
`different types of NSCLC. The best response
`rate (47%) was observed in patients who
`received a combination of nivolumab with
`carboplatin and paclitaxel. Overall survival
`was also significantly improved for patients
`who received this combination treatment.
`PD-L1 expression appeared to play no role in
`treatment responses as per this study.
`Several studies related to immunotherapy
`in NSCLC demonstrated
`that patients
`with EGFR mutations responded less to
`nivolumab and pembrolizumab. TATTON
`is a multi-arm phase Ib trial investigating
`osimertinib 80 mg
`in combination with
`durvalumab (anti-PD-L1 monoclonal anti-
`body) in EGFR-mutant NSCLC.4 Part A was a
`
`1
`
`To cite: Thungappa S,
`Ferri J, Caglevic C, et al. Immune
`checkpoint inhibitors in lung
`cancer: the holy grail has not
`yet been found…. ESMO Open
`2017;2:e000162. doi:10.1136/
`esmoopen-2017-000162
`
`ST and JF contributed equally.
`
`Received 16 January 2017
`Accepted 19 January 2017
`
`1Phase I Early Clinical Trials
`Unit, Department of Oncology,
`Universitair Ziekenhuis
`Antwerpen, Edegem, Belgium
`2Consorci Hospital General
`Universitari de Valencia,
`Valencia, Comunitat Valenciana,
`Spain
`3Early Development Drugs Unit,
`Medical Oncology Department,
`Instituto Oncológico Fundación
`Arturo López Pérez, Santiago,
`Chile
`4Department of Oncology,
`Universita degli Studi di
`Palermo, Palermo, Sicilia, Italy
`5Thoracic Oncology Program,
`Memorial Cancer Institute,
`Memorial Health Care System,
`Pembroke Pines, Florida, USA
`6Center for Oncological
`Research (CORE), Antwerp
`University, Wilrijk, Belgium
`
`Correspondence to
`Professor Christian Rolfo;
`christian. rolfo@ uza. be
`
`
`
`Thungappa S, et al. ESMO Open 2017;2:e000162. doi:10.1136/esmoopen-2017-000162
`
`Genome Ex. 1028
`Page 1 of 3
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`dose escalation study in patients with advanced NSCLC
`who had received prior treatment with an EGFR-tyrosine
`kinase inhibitor (TKI). Part B was a dose expansion trial
`conducted in patients with advanced disease who were
`EGFR-TKI treatment-naive. Part A included 21 patients
`receiving combination osimertinib plus durvalumab.
`Partial response (PR) was achieved by 12 patients, 9
`of them had confirmed PR. Stable disease (SD) was
`achieved by other nine patients. In part B, of ten patients
`with evaluable data, eight patients achieved PR, which
`was confirmed in seven patients, and SD was observed
`in two patients. Responses were durable and translated
`into remarkable long-term survival. Both arms noticed
`increased incidence of adverse events ranging from
`35% to 55%. Immunotherapy with EGFR-TKI combina-
`tion appeared to have a good rational basis in terms of
`efficacy, relying on a presumption that a highly active
`therapy, such as an EGFR TKI in EGFR-mutant NSCLC,
`will lead to tumour apoptosis and enhanced immune
`priming, with resultant tumour lymphocytic infiltration
`and induced upregulation of PD-L1. But as explained
`by Gainor and colleagues from a limited number of
`patients with paired tumour specimens collected before
`and at the time of acquired resistance to TKI, they did
`not find clear changes in tumor-infiltrating lymphocytes
`(TILs) or PD-L1 expression.5 Besides, in the mentioned
`study of concomitant treatment with osimertinib and
`durvalumab, there was an increase in treatment-re-
`lated adverse events especially in terms of pneumonitis;
`hence, this trial was stopped.
`Regarding pharmacoeconomics in NSCLC, immu-
`notherapy has a high economic impact for any health
`system.6 It is currently unknown for how long patients
`need to receive ‘checkpoint inhibition therapy’ in order
`to develop and sustain the appropriate immunological
`response. Pembrolizumab was approved as first-line treat-
`ment for patients with metastatic NSCLC with high PD-1
`expression on October 24, becoming in 2016 the first
`immunotherapy drug to be ever approved as monotherapy
`for NSCLC. This approval has selected a restricted popu-
`lation with EFGR/ALK wild-type and PD-L1 expression
`more than 50% as biomarker when pembrolizumab is
`used. How economically feasible is immunotherapy in all
`patients with high PD-L1 expression in NSCLC outside a
`clinical trial? Future trials will be necessary to address this
`question. Simply continuing therapy indefinitely once a
`response is attained may not be necessary when being
`treated with novel immunotherapy agents, as opposed
`to the more traditional chemotherapy drugs that have a
`short PFS (<6 months).
`The FDA previously approved pembrolizumab only
`in patients whose tumours showed the presence of the
`PD-L1 protein in more than 1% of their cells, whereas
`nivolumab was approved regardless of PD-L1 status in
`second-line settings. Finally, in first-line treatment for
`patients with metastatic NSCLC, nivolumab failed at its
`primary endpoint (PFS in patients who expressed 5%
`
`2
`
`PD-L1 or greater in tumour cells) when compared with
`pembrolizumab. The probable reasons are, first, the
`patients selected for participation in these trials were
`quite different from each other as more non-smokers
`were involved (11% vs 3%) in Checkmate-26 trial
`compared with Keynote-024. The second reason could
`be that the PD-L1 positivity (50% vs 30% in mentioned
`trails) cut-off values were different. Other reasons could
`be the variability of antibodies and immunohistochem-
`ical procedures for positive criteria, heterogeneity of
`PD-L1 expression and the dynamic expression of PD-L1
`itself. Another aspect to consider is that in both studies,
`Checkmate-012 and Keynote-001, responses were higher
`in patients with KRAS mutations,7 so it is interesting to
`know that KRAS mutations seem to have increased PD-L1
`staining.
`The FDA approval of two similar but distinct PD-L1
`immunohistochemistry (IHC) tests (22C3 pharmDx and
`28-8 pharmDx) acknowledges the potential of PD-L1
`as a predictive biomarker and helps physicians decide
`which checkpoint therapy to prescribe. Unfortunately,
`not all patients respond to these therapies, and evalua-
`tion of biomarkers associated with clinical outcomes is
`crucial and ongoing.8 Also, the interpretation of PD-L1
`(IHC) testing results can be tricky and challenging. In
`connection with technical difficulties, we should consider
`that multiple staining methods and primary antibodies
`exist, with multiple cut-off when determining test posi-
`tivity, and to all this preanalytical conditions must be
`added. This result in a high variability in staining perfor-
`mance and multiple readouts. Moreover, in regard
`to biological issues, there is controversy over whether
`to consider tumour cells or immune cells or both, and we
`should also take into account the dynamic heterogeneity
`of PD-L1 IHC across the tumour sample. This last issue
`causes a failure to capture tumour complexity, with all its
`microenvironment.9
`In their work Challenges & Perspective of Immuno-
`therapy Biomarkers, Ung and Kockx propose a systematic
`application of a methodology, the HistoOncoImmune,
`which harnesses histopathology data of the tumour with
`its corresponding molecular signatures.10 The selected
`biomarkers are rigorously validated and can be imple-
`mented across multiple clinical trials of various sizes
`and geographical locations. This system results in an
`integration of histopathology and molecular technology
`and provides investigators and physicians a method to
`understand the tumour microenvironment activity and
`its interface with the immune system. It offers a method-
`ology to attain a biomarker profile that predicts response
`or resistance to immune checkpoint therapy.
`In summary, considering the results of these trials,
`it seems that the place of immunotherapy in first-line
`treatment will be in combination with chemotherapy.
`Pembrolizumab has a definitive role in first-line treat-
`ment for EGFR/EML-ALK4 wild-type NSCLC with
`PD-L1 expression more than 50%. The predictive
`
`Open Access
`
`Thungappa S, et al. ESMO Open 2017;2:e000162. doi:10.1136/esmoopen-2017-000162
`
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`biomarkers that should be considered during single-
`agent immunotherapy of NSCLC are PD-L1 expression
`50%, smoking, EGFR and ALK status, and KRAS muta-
`tion positivity. To establish a clear cut-off value of PD-L1
`expression for appropriate immunological response
`and for new predictive biomarkers, further studies
`are required. Other important factors to be investi-
`gated in future trials are for how long a patient needs
`to receive ‘checkpoint inhibition therapy’ to address
`pharmacoeconomics and sustain an appropriate immu-
`nological response.
`
`Contributors All the authors have made substantial contribution to the idea,
`concept and writing of this publication, and have read and approved the
`manuscript.
`Competing interests None declared.
`Provenance and peer review Commissioned; internally peer reviewed.
`Open Access This is an Open Access article distributed in accordance with the
`Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
`permits others to distribute, remix, adapt, build upon this work non-commercially,
`and license their derivative works on different terms, provided the original work is
`properly cited and the use is non-commercial. See: http:// creativecommons. org/
`licenses/ by- nc/ 4. 0/
`© European Society for Medical Oncology (unless otherwise stated in the text of the
`article) 2017. All rights reserved. No commercial use is permitted unless otherwise
`expressly granted.
`
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`Open Access
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`Thungappa S, et al. ESMO Open 2017;2:e000162. doi:10.1136/esmoopen-2017-000162
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