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J.F. Vansteenkiste
Moderator of
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SC22 - Selection and Monitoring of Patients for Immune Checkpoint Inhibitors (ID 346)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 4
- Moderators:G.V. Scagliotti, J.F. Vansteenkiste
- Coordinates: 12/06/2016, 16:00 - 17:30, Hall C8
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SC22.01 - How Do I Define Optimal Candidates for Immunotherapy in My Practice? (ID 6690)
16:00 - 17:30 | Author(s): J.F. Vansteenkiste, E. Wauters
- Abstract
- Presentation
Abstract:
Over the recent decade, we witnessed important progress in the treatment of patients with advanced NSCLC in three domains. First, cytotoxic chemotherapy, where histology-directed chemotherapy with cisplatin-pemetrexed, followed by pemetrexed maintenance therapy in appropriate candidates, has resulted in a median overall survival (OS) of 16.9 months in adenocarcinoma [1]. Second, the use of tyrosine kinase inhibitors (TKIs) in tumors driven by specific molecular pathways, such as EGFR, ALK and others, has largely improved progression-free survival (PFS) compared to the one with chemotherapy in randomized studies, and had led to OS times of several years in many of these patients [2]. Third, immunotherapy with immune checkpoint inhibitors (ICI) directed against the immunosuppressive molecules programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has been in clinical trials since 2009. At present, the anti-PD-1 antibodies nivolumab (a fully human IgG4 antibody) and pembrolizumab (an engineered humanized IgG4 antibody) have been approved for NSCLC by different regulatory agencies worldwide. EMA approved nivolumab for advanced NSCLC after prior chemotherapy, and pembrolizumab for advanced NSCLC in adults whose tumors express PD-L1 and who have received at least one prior chemotherapy regimen. At the time of writing of this contribution, there were no public randomized study data on the use of these agents in 1[st] line therapy, we will therefore concentrate on the relapse therapy setting. Despite the real progress made by ICI therapy, we must realize that at present only about 20% of the patients respond to single-agent ICI treatment, while 50% have early progression (Checkmate 017 [3]; Checkmate 057 [4]). Moreover, the cost of these drugs is considerable. Hence it is important to define optimal candidates in clinical practice. Elements in this decision are a) clinicopathological factors; b) possible predictive biomarkers; and c) the availability of other treatment choices. As for (a) clinicopathological factors, there is no evidence that age, gender or ethnicity determine activity of ICIs. Smoking history, on the other hand, is strongly associated with better response rate to ICI therapy. Although EGFR oncogene pathway activation has been linked to upregulation of PD-L1 in tumor cells, response rates to ICIs in these patients are generally reported to be lower. In e.g. Checkmate 057, the overall response rate was 19%. It was 22% in smokers vs. 9% in non-smokers, 18% in EGFR-wildtype vs. 11% in EGFR-mutant tumors. Further understanding and refinement of the use of ICIs in tumor with an oncogene driver is needed. (b) A multitude of potential predictive biomarkers of response to PD-1/PD-L1 pathway inhibitors have been reported. In particular, PD-L1 expression in tumor and/or immune cells, the presence of TILs (tumor-infiltrating lymphocytes, CD8+ T-cells in particular), and the overall mutational load in the tumor cells have been linked to activity of ICIs [5]. PD-L1 expression on tumor cells, determined by immunohistochemistry (IHC) staining is by far the one most close to clinical practice for selecting optimal candidates for immunotherapy. This biomarker is quite distinct and less powerful than e.g. EGFR mutation as predictor of efficacy of EGFR TKIs. EGFR mutation is limited to the tumor, it is located in a distinct pathway, and is a yes/no phenomenon. PD-L1 IHC, on the other hand, relates to the tumor and its micro-environment, is only one of the many checkpoints in a complex interaction, and is a gradual phenomenon. Nonetheless, as can be noted from the figure, in most datasets of phase III studies – except Checkmate 017 – PD-L1 IHC predicts efficacy of ICI therapy. We added the large phase I study Keynote 001 to the figure as a very illustrative example: Over the categories of PD-L1 expression, response rate increased from 8% in the lowest to 45% in the highest category [6]. In the Keynote 010 phase III study, the hazard ratio of OS versus chemotherapy was 0.76 in the low-, but 0.54 in the high-expression group [7]. In the Checkmate 057, the OS hazard ratio even was 1.00 in all patients with tumors having PD-L1 <10%. Thus, except for the Checkmate 017 dataset, PD-L1 IHC enriches the response rate and differential OS benefit vs. chemotherapy, and can be used to designate these expensive agents to the optimal candidates. (c) Docetaxel single-agent chemotherapy was the comparator in the phase III studies on relapse therapy. In the meanwhile, progress has been made in conventional relapse therapy as well. In the LUME-Lung 1 trial, the combination of docetaxel and the triple angiogenesis inhibitor nintedanib resulted in a significantly better OS than docetaxel alone – with a difference in median OS of 2.3 months – in patients with adenocarcinoma [8]. In the REVEL study, patients treated with docetaxel plus ramucirumab, a VEGF receptor 2 inhibiting monoclonal antibody, had significantly better OS than those treated with docetaxel alone across all NSCLC histologies [9]. In conclusion, the choice of ICI therapy for relapsing NSCLC needs to be considered in the available treatment options for these patients, and this can be based on clinicopathological factors, predictive biomarkers, and comparison of efficacy of various treatments in specific subgroups. While PD-L1 is not a biomarker with the strength such as e.g. EGFR mutation, it helps to optimize the response rate and differential OS benefit of ICI therapy vs. chemotherapy, and to and can be used to designate these expensive agents to the optimal candidates. Figure Figure 1 References 1. Paz-Ares LG, De Marinis F, Dediu M et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after first-line treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013; 31: 2895-2902. 2. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-957. 3. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous cell non-small cell lung cancer. N Engl J Med 2015; 373: 123-135. 4. Borghaei H, Paz-Ares L, Horn L et al. Nivolumab versus docetaxel in advanced nonsquamous non-small cell lung cancer. N Engl J Med 2015; 373: 1627-1639. 5. Rizvi NA, Hellmann MD, Snyder A et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348: 124-128. 6. Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med 2015; 372: 2018-2028. 7. Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016; 387: 1540-1550. 8. Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): A phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014; 15: 143-155. 9. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665-673.
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SC22.02 - How Do I Monitor for Efficacy? (ID 6691)
16:00 - 17:30 | Author(s): N. Rizvi
- Abstract
- Presentation
Abstract not provided
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SC22.03 - How Do I Monitor for and Treat Immune-Related Events? (ID 6692)
16:00 - 17:30 | Author(s): A. Spira
- Abstract
- Presentation
Abstract:
Immunotherapy (IT) has become one of the most potent new treatments for all cancers, particularly non small lung cancer. However, it has a unique toxicity profile different than most therapies (chemotherapy; biologic; targeted therapy) than most oncologists are familiar with, specifically immune related adverse events; irAE. These toxicities may be acute but also can occur weeks and months after starting or even stopping therapy. Given the prolonged duration that patients may be exposed to these drugs, they become important to manage over a short and long period. Further, given the responses and the relative milder toxicity compared with traditional chemotherapy agents, the older patient population may be exposed to these agents at a somewhat higher frequency. The use of immunomodulatory drugs to counter irAE toxicity will be discussed as to how it affects efficacy of immunotherapy. This lecture will focus on: Timeframe and monitoring for immune related toxicity (with special attention paid towards pulmonary, gastrointestinal and endocrinopathies) using the appropriate immunosuppressive drugs Management of toxicities related to IT Decision making on re-exposure to drug after iRAE Patient education Toxicities associated with combination IT drugs that may be used in the future or on clinical trials
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SC22.04 - How Can Immunotherapy Be Implemented in a Cost-Effective Strategy? (ID 6693)
16:00 - 17:30 | Author(s): C. Zielinski
- Abstract
- Presentation
Abstract:
“How Can Immunotherapy be Implemented In a Cost-Effective Strategy?” Christoph Zielinski, Director, Clinical Division of Oncology and Chairman, Department of Medicine I, and Comprehensive Cancer Center, Medical University Vienna – General Hospital, Vienna, Austria, Central European Cooperative Oncology Group (CECOG) When talking about immunotherapy and its cost-effectiveness, the story of disharmony between the magnitude of clinical benefit and the cost-effectiveness of certain drugs clearly emerges. I will try to illustrate this by the following arguments and data: The total health care costs of cancer per person varies widely within EU countries not only concerning outpatient and primary care, but also inpatient care and particularly drug expenditures. Cancer drug-related health care costs, thus differ between less than € 10.- per person up to over € 50.- per person. This divergence has been described previously and put into context with cancer outcomes (1) as well as cancer-associated mortality (2). Therefore, the European Society for Medical Oncology decided to create a magnitude of clinical benefit scale (ESMO-MCBS) “in order to promote high quality, rational, responsible and affordable cancer care wanting to highlight treatments which bring substantial improvements to the duration of survival and/or the quality of life of cancer patients” (3). It was intended that the scale was used for accelerated reimbursement evaluation. Factors taken into account for the ESMO-MCBS were particularly overall survival and/or progression-free survival as assessed by hazard ratios, quality of life, toxicity of the compound in question and the prognosis of the individual condition. Costs were not analysed in view of their significant heterogeneity across Europe. While generating two different scales for the curative versus the non-curative setting, a couple of rules were followed regarding the performed analyses: the priority was a strong level of evidence from large phase III studies with a careful analysis of each control arm and the identification of endpoints. For the required HR, the lower limit of the 95% CI was used to take into account the variability of the estimate. Before being published, the scale and its outcomes were broadly tested and evaluated in and by various institutions. The first full-length field testing (FT-MCBS) of the ESMO-MCBS was published recently (4) in which the results of non-small cell lung cancer (NSCLC) corresponded well with the original ESMO-MCBS. Regarding the use of the immune checkpoint inhibitor Nivolumab, the FT-MCBS generated the highest grade (i.e. “5”) for squamous NSCLC according to data generated within the Checkmate 017-Trial whereas a grade “4” was given for non-squamous NSCLC, as assessed in the Checkmate 057-Trial. Thus, the immune checkpoint inhibitor Nivolumab has acquired the highest or almost highest degree in the magnitude of clinical benefit, as assessed by the FT-MCBS scale. Soon after market introduction, concerns about the financial toxic dose of immune checkpoint inhibitors emerged leading to the rejection of NICE of Nivolumab in the second-line-treatment of NSCLC, whereas – in contrast - the Scottish authorities decided to include Nivolumab into their reimbursement strategies. Very recent analyses on this very topic showed that Nivolumab was not cost effective versus Docetaxel in the second-line-treatment of NSCLC based upon data generated in Checkmate 057-Trial. However, cost effectiveness could be very well reached by including and stratifying patients according to PD-L1 testing and the use of Nivolumab in PD-L1 overexpressing tumors on one side or – in statistical models - by the reduction of drug costs on the other. Either of these strategies would improve the cost effectiveness of Nivolumab (5, 6) Scientifically, however, the doubt remains to linger whether PD-L1 would be an optimal biomarker resulting in appropriate decision making for the choice of compound optimally suitable for the treatment of NSCLC without unjustly excluding patients who might have benefitted due to other factors from treatment: Thus, it is well known that certain somatic mutations occur more frequently in very special tumors than in others (7). Along this line, the efficacy of Nivolumab correlated with higher non-synonymous mutation burden in the Checkmate 063-Trial population (8). Therefore, it seems correct to conclude that we still have a long way to go to fully understand biomarkers predictive for the outcome of an optimal treatment of NSCLC with immune checkpoint inhibitors. Accordingly, appropriate analyses necessary for biomarker identification might translate into cost effectiveness. Such analyses might result in a primarily increased diagnostic cost, but lead to an ameliorated patient selection and, thus, ameliorated cost effectiveness in the appropriate use of immune checkpoint inhibitor treatment in NSCLC. In the meantime, the scientific community remains fascinated by the insights and results which are generated by the use of these compounds in a variety of diseases including NSCLC. References 1. Jedrzejewski M. et al., The Oncologist 20: 28, 2015; 2. .Ades F. et al., Ann. Oncol. 24: 2897, 2013; 3. N.I. Cherny et al., Ann. Oncol. 26: 1547, 2015; 4. B. Kiesewetter et al., ESMO Open 1: e000066, 2016; 5. K. Matter-Walstra et al., J. Thoracic Oncol., 2016, ePub.: http://dx.doi.org/10.1016/j.jtho.2016.05.032; 6. P.N. Aguiar et al., J. Clin. Oncol. 34, abstr. 9033, 2016; 7. L.B. Alexandrov et al., Nature. 22: 415, 2013; 8. N.A. Rizvi et al., Science 2015, ePub.: pii:aaa1348
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ISS05 - Industry Supported Symposium: Orchestrating Progress for Patients with Squamous Cell Lung Cancer - Eli Lilly and Company (ID 439)
- Event: WCLC 2016
- Type: Industry Supported Symposium
- Track:
- Presentations: 1
- Moderators:S. Novello
- Coordinates: 12/05/2016, 07:30 - 08:30, Strauss 2
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ISS05.01 - Squamous Cell Lung Cancer – A Different Tune (ID 6859)
07:30 - 08:30 | Author(s): J.F. Vansteenkiste
- Abstract
Abstract not provided
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-025 - Evaluation of NGS and RT-PCR Methods for ALK Assessment in European NSCLC Patients: Results from the ETOP Lungscape Project (ID 5001)
14:30 - 15:45 | Author(s): J.F. Vansteenkiste
- Abstract
Background:
The reported prevalence of ALK rearrangement in NSCLC ranges from 2%-7%, depending on population and detection method. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proven to be a reproducible and sensitive technique. Reverse transcriptase-polymerase chain reaction (RT-PCR) has been advocated and most recently the advent of targeted Next-Generation Sequencing (NGS) for ALK and other fusions has become possible. This is one of the first studies comparing all 4 techniques in resected NSCLC from the large ETOP Lungscape cohort.
Methods:
96 cases from the ETOP Lungscape iBiobank (N=2709) selected based on any degree of IHC staining (clone 5A4 antibody, Novocastra, UK) were examined by FISH (Abbott Molecular, Inc.; Blackhall, JCO 2014), central RT-PCR and NGS. H-score 120 is used as cutoff for IHC+. For both RT-PCR and NGS, RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers were used covering the most frequent ALK translocations. For NGS, the Oncomine™ Solid Tumour Fusion Transcript Kit was used, allowing simultaneous sequencing of 70 ALK, RET and ROS1 specific fusion transcripts associated with NSCLC, as well as novel ALK translocations using 5’-3’ ALK gene expression ‘Imbalance Assay’.
Results:
NGS provided results for 90 cases, while RT-PCR for 77. Overall, 70 cases have results for all 4 methods, with fully concordant 60 (85.7%) cases (49 ALK-, 11 ALK+). Before employing the ‘Imbalance Assay', in 5 of the remaining 10 cases, NGS differs from the other methods (3 NGS-, 2 NGS+), while in the other 5, NGS agrees with RT-PCR in all, IHC in 2, and FISH in 1. Using the concordant result of at least two of the three methods as true negative/positive, the specificity and sensitivity of the fourth is 96/94/100/96% and 94/94/89/72% for IHC/FISH/RT-PCR/NGS, respectively (incorporating imbalance: NGS sensitivity=83%). Imbalance scores are presented here for 18 NGS- cases: 9 ‘NGS-/FISH+/IHC+’, 9 ‘NGS-/FISH-/IHC-‘. Among the ‘NGS-/FISH+/IHC+’, there is strong evidence of imbalance in 4 cases (score’s range: 0.0144-0.0555), uncertain in 5 (range: 0.0030-0.0087), and no evidence (scores≤0.0004) in the 9 negative cases.
Conclusion:
NGS is a useful screening tool for ALK rearrangement status, superior to RT-PCR when RNA yield is limited. When using NGS, it is critically important to integrate the 5’-3’ imbalance assay and to confirm with one or more additional methods in the ‘imbalance’ cases. Data further highlight the possibility of missing actionable rearrangements when only one screening methodology is available.
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P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.02-045 - Prognostic Value of Metabolic FDG-PET Response in Locally Advanced NSCLC: A Literature Review (ID 4781)
14:30 - 15:45 | Author(s): J.F. Vansteenkiste
- Abstract
Background:
It is still a matter of debate whether metrics of metabolic imaging by [18]F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) predict clinical outcome in non-small cell lung cancer (NSCLC). Pretreatment FDG uptake in the primary tumor has been shown to be a prognostic factor for survival. The prognostic role of FDG-PET in the evaluation of tumor response remains unclear and controversial. Hence, we conducted a comprehensive literature review to assess the prognostic value of FDG-PET/CT response monitoring along multimodality treatment in patients with locally advanced NSCLC.
Methods:
A systematic search of studies published in PubMed was performed using the keywords "positron emission tomography" or “PET”, "non-small cell lung cancer", and “response” or "outcome". References from adequate articles were checked for studies not retrieved by the search strategy. Inclusion criteria were: studies limited to locally advanced NSCLC containing >60% stage III patients, studies in which response monitoring with FDG-PET or PET/CT was performed, and studies that reported survival data.
Results:
Twenty-two studies (median 47 patients, range 15-545) published between 1998 and 2016 were included in the analysis. Ten studies used PET alone while recent trials used integrated PET/CT. PET based response evaluation was performed either after neoadjuvant chemotherapy prior to surgery or radiotherapy either after radical treatment consisting of (chemo)radiotherapy. Eight studies specifically addressed the prognostic value of early metabolic response measurement, either during induction chemo(radio)therapy (n=2) either early in the course of radical (chemo)radiotherapy (n=6). A heterogeneity between the studies was observed regarding timing of the repeat PET, thresholds to define metabolic response, and metrics of metabolic FDG imaging such as MRglu (metabolic rate of glucose), Total Lesion Glycolysis (TLG), Standardized Uptake Value (SUV), SUVmax, SUVpeak, SUVmean or Metabolic Tumor Volume (MTV). All studies showed a significant correlation between either the change in FDG uptake or the residual FDG uptake within the primary tumor and survival.
Conclusion:
Posttreatment FDG-PET/CT has been considered as a useful tool in determining prognosis and guiding therapy for patients with locally advanced NSCLC. Before implementation in routine clinical practice, there is however a need for standardization of PET data acquisition and analysis and a validation of a single definition for metabolic tumor response.
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P2.02-055 - Pathologic Mediastinal Nodal and Metabolic Tumor Response to Predict Overall Survival in Stage IIIA-N2 NSCLC after Neoadjuvant Chemotherapy (ID 5098)
14:30 - 15:45 | Author(s): J.F. Vansteenkiste
- Abstract
Background:
Neoadjuvant chemotherapy (NCT) is a therapeutic option that is used in patients with resectable stage IIIA-N2 NSCLC. We previously hypothesized that combined major histopathological mediastinal nodal response (≤10% residual tumor cells in nodal tissue) and metabolic FDG-PET response (ΔSUVmax ≥60%) on the primary tumor could be regarded as a powerful surrogate of overall survival (OS) in stage IIIA-N2 NSCLC given NCT and confirmed mediastinal nodal disease at diagnosis. This phase II prospective multicenter study aimed to validate the predictive power for OS of our restaging algorithm.
Methods:
Patients with resectable stage IIIA-N2 NSCLC having mediastinal nodal disease proven by endosonography and primary tumor SUVmax at least 2.5 were eligible. All patients were scheduled for 3 cycles of NCT followed by video-assisted mediastinoscopy (VAM). A standardized PET/CT was performed at baseline, after one and three cycles. The primary endpoint was the predictive power for longer OS of a major histopathological mediastinal nodal response at VAM combined with a pre-defined primary tumor SUVmax ≥60% at PET (good prognosis group) compared to all other situations (poor prognosis group). Under an assumption of a 2-year OS of 80% compared to 30% for the good versus poor prognosis group, respectively, 48 patients were required to have 80% power with 2-sided alpha of 0.05.
Results:
We enrolled 32 patients between 2009 and 2014. Two patients demonstrated stage IV at PET/CT after cycle one. All 3 cycles were given to 30 patients of whom 29 underwent VAM and 22 underwent surgical resection. Objective response rate (RECIST 1.1) was 44%. Complete pathological response occurred in 2 patients. Median OS was 26 months (all 2-year events occurred). In ITT, combined major histopathologic nodal and metabolic tumor response was associated with a trend towards longer OS (HR 0.29, 95%CI 0.14-1.09, P=0.07). Major histopathologic mediastinal nodal response was significantly associated with longer OS (HR 0.25, 95%CI 0.02-0.51, P=0.006), while metabolic ΔSUVmax ≥60% primary tumor response was only associated with a trend towards better OS (HR 0.41, 95%CI 0.17-1.27, P=0.14).
Conclusion:
Complete pathological response to NCT in stage IIIA-N2 NSCLC is infrequent and therefore not useful as a surrogate for OS. Combined major pathologic nodal and metabolic tumor response was associated with a trend towards longer OS. By contrast, a major histopathologic mediastinal nodal response with ≤10% residual tumor cells at VAM is well suited to be adopted as a surrogate of OS.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-031 - Impact of PD-L1 Status on Clinical Response in SELECT-1: Selumetinib + Docetaxel in KRASm Advanced NSCLC (ID 5040)
14:30 - 15:45 | Author(s): J.F. Vansteenkiste
- Abstract
Background:
Anti-PD-1/PD-L1 immunotherapy has delivered clinical benefit for patients with NSCLC, and PD-L1 has emerged as a predictive biomarker. In the Phase III SELECT-1 trial (NCT01933932), selumetinib (AZD6244, ARRY-142886), an oral, potent and selective, allosteric MEK1/2 inhibitor with a short half-life, plus second-line docetaxel did not provide clinical benefit for patients with KRAS-mutant (KRASm) NSCLC compared with placebo plus docetaxel (PBO+DOC). Although no incremental benefit was observed, it is important to evaluate biomarkers, such as PD-L1, to understand more about the biology of patients with KRASm NSCLC.
Methods:
In total, 510 patients with a prospectively, centrally confirmed KRAS mutation (cobas® KRAS Mutation Test, Roche Molecular Systems) were randomised 1:1 to selumetinib 75 mg BID, plus docetaxel 75 mg/m[2] q21d (SEL+DOC), or PBO+DOC. Evaluations included progression-free survival (PFS) by investigator assessment (RECIST 1.1; primary endpoint), and overall survival (OS). Association of tumour PD-L1 status with clinical responses was assessed as an exploratory objective. PD-L1 status was centrally determined using the PD-L1 IHC 28-8 pharmDx test (Dako) for all patients with sufficient tumour sample. Samples with a pre-specified cut-off of ≥5% tumour cell staining were considered PD-L1 positive.
Results:
SEL+DOC did not improve PFS or OS compared with PBO+DOC. PD-L1 status was determined for 385 (75%) patients: 224 (58%) samples were PD-L1 <5%, and 161 (42%) samples were PD-L1 ≥5%; the remaining 125 patients had unknown PD-L1 status due to insufficient tumour sample. Subgroups were balanced across treatments. PD-L1 subgroup analysis of PFS and OS is presented below.Subgroup Events (%) in SEL+DOC group Events (%) in PBO+DOC group HR (95% CI) PFS PD-L1 <5% 94/112 (84%) 101/112 (90%) 0.89 (0.67, 1.18) PD-L1 ≥5% 65/79 (82%) 71/82 (87%) 0.70 (0.50, 0.99) PD-L1 unknown 59/63 (94%) 57/62 (92%) 1.24 (0.86, 1.79) OS PD-L1 <5% 73/112 (65%) 74/112 (66%) 0.94 (0.68, 1.30) PD-L1 ≥5% 55/79 (70%) 58/82 (71%) 0.89 (0.61, 1.28) PD-L1 unknown 48/63 (76%) 38/62 (61%) 1.57 (1.02, 2.41)
Conclusion:
Prevalence of PD-L1 positive status in this KRASm cohort was similar to that reported for a pan-NSCLC cohort (Borghaei, NEJM 2015). No significant PFS or OS differences were observed between treatments in either PD-L1 positive or negative tumours. Additional biomarker analyses are planned for different KRAS codon mutations, and LKB1 and TP53 status.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-062 - Safety of Necitumumab and Abemaciclib Combination Therapy in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 4270)
14:30 - 15:45 | Author(s): J.F. Vansteenkiste
- Abstract
Background:
Trials of anti-EGFR necitumumab and the CDK4 and CDK6 inhibitor abemaciclib have demonstrated anti-tumor activity of each agent in patients with NSCLC. In a xenograft model of NSCLC, the addition of necitumumab to abemaciclib improved the anti-tumor efficacy compared to either monotherapy.
Methods:
Single-arm, multicenter Phase 1b study to investigate the combination of necitumumab and abemaciclib in patients with stage IV NSCLC (NCT02411591). The safety interim population includes squamous and non-squamous patients treated with the recommended dose of necitumumab 800mg IV on days 1 and 8, every 21 days in combination with abemaciclib 150mg (dose identified in preceding dose escalation part of study) administered every 12 hours on days 1–21. Major eligibility criteria include: progression after platinum-based chemotherapy regimen and maximum 1 other prior chemotherapy for advanced and/or metastatic disease (prior treatment with EGFR-TKI and ALK inhibitors was mandatory in patients whose tumor has EGFR-activating mutations or ALK translocations, respectively); ECOG PS 0-1; tumor tissue availability for biomarker analysis and measurable disease. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent by the patient, or sponsor/investigator decision.
Results:
This safety interim includes 16 squamous and non-squamous patients treated at recommended dose (necitumumab 800mg + abemaciclib 150mg) and having completed 2 cycles of study treatment (or otherwise discontinued study treatment). The most common (>15% patients) adverse events (AEs) of any grade are shown in the Table. Grade ≥3 AEs were reported in 6 patients (diarrhea, nausea, vomiting, neutropenia, decreased appetite, hypophosphotaemia, dyspnoea were each reported in 1 patient and fatigue in 2 patients); grade ≥3 AEs were judged to be related to study treatment in 4 patients. No patients have discontinued the study due an AE. Figure 1
Conclusion:
The combination of necitumumab and abemaciclib in advanced NSCLC is well tolerated when administered according to recommended dosing schedules.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-087 - The Relationship of TILs and PD-L1 Expression in NSCLC Adenocarcinoma in Little to Non-Smokers with Driver Mutations and Outcome Parameters (ID 5410)
14:30 - 15:45 | Author(s): J.F. Vansteenkiste
- Abstract
Background:
Culminating evidence shows the importance of the immune response in NSCLC and other cancer types. TILs seem to be a marker of good prognosis in many different tumor types, including NSCLC. The prognostic importance of PD-L1 expression in NSCLC remains less clear. This study will contribute more information to this topic in NSCLC and will verify the influence of driver mutations on TILs levels and PD-L1 expression. In addition, the predictive role of TILs and PD-L1 expression in EGFR mutants, who received erlotinib, will be evaluated.
Methods:
Clinical data, genetic analysis and tumor biopsies of the FIELT-1 cohort (stage IIIb or IV NSCLC patients with little or non-smoking history) were retrospectively evaluated. PD-L1 expression was evaluated with a PD-1/PD-L1 IHC double staining. TILs were evaluated on H&E slides, using the method developed by an international working group under direction of R. Salgado.
Results:
Measuring stromal TILs on H&E slides proved to be reproducible (ICC=0.74). The measurement of intratumor TILs (ICC=0.16) did not reach the cut-off ICC of 0.70. There was no difference in stromal TILs counts in KRAS (p=0.454) and EGFR (p=0.962) mutant tumors compared to their respective wild type tumors, nor was there any difference in sTILs counts between KRAS and EGFR mutants (p=0.605). The median OS in the general population was 49 weeks. There was a significant difference in median OS between the stromal TILs high tumors and the stromal TILs low tumors (68 weeks vs. 35 weeks respectively; p=0.003). A similar observation was made in the KRAS mutant tumors (95 weeks vs. 12 weeks; p=0.003). In the EGFR mutants no significant difference in median OS could be found according to the stromal TILs counts (p=0.65). There was no difference in the stromal TILs counts of EGFR mutants who responded (p=0.160) or showed clinical benefit (p=0.621) after receiving erlotinib, compared to those who did not. The analysis of the PD-1/PD-L1 double staining has been postponed. Results will be available by the end of August 2016
Conclusion:
The results of the current study reinforce the prognostic role of TILs in NSCLC. Furthermore, this is the first study to confirm that the used scoring method on H&E slides is reproducible in NSCLC. This study is also the first to report about the relation between driver mutation and TILs, with results suggesting that the immune system plays a more crucial role in KRAS mutants than in EGFR mutants.
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P3.05 - Poster Session with Presenters Present (ID 475)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Palliative Care/Ethics
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.05-005 - Geriatric Assessment and Functional Decline in Older Patients with Lung Cancer (ID 4095)
14:30 - 15:45 | Author(s): J.F. Vansteenkiste
- Abstract
Background:
Physicians treating lung cancer are confronted with an expanding group of older patients. Treatment of these patients is complex and focusses on improving quality of life, maintenance of functional status (FS) and prolonging overall survival (OS). The present study aims to evaluate the role of geriatric assessment (GA) and the evolution of FS in older patients with lung cancer, and to identify predictors for functional decline and OS.
Methods:
Patients ≥70 years with a new diagnosis of lung cancer were included. At baseline, GA was performed, including FS measured by Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL). ADL and IADL were reevaluated 2-3 months after diagnosis. OS was collected. Determination of predictors of functional decline on ADL and IADL and of OS was performed by univariate and multivariable logistic and Cox regression.
Results:
245 patients with a median age of 76 years were included from October 2009 till January 2015. The majority of patients (58%) had stage IV disease. Treatment consisted of surgery in 20 patients (8%), radiotherapy in 105 patients (43%) and chemotherapy or targeted therapy in 125 patients (51%). At baseline, GA deficiencies were observed in all domains, most prominent for comorbidities (78%), fatigue (76%) and nutrition (76%). 240 patients (98%) had at least 2/10 abnormal domains with a median of 5. ADL and IADL impairments were detected in 51% and 63% of patients respectively. Follow-up ADL and IADL data were available for 145 patients. Functional decline for ADL was observed in 23% (95%CI 16,2; 29,9) and for IADL in 45% (95%CI 36,9;53,1) of patients. In multivariable analysis, radiotherapy was predictive for ADL decline. No other predictive factors for ADL or IADL decline were identified. In multivariable Cox regression, stage, gender and age were predictive for survival .
Conclusion:
Older patients with lung cancer are a high risk population with deficiencies in multiple geriatric domains. During treatment functional decline is observed in half of the patients, more prominently for IADL. Functional decline on ADL at 2-3 months is predicted by radiotherapy, possibly related to the acute toxicities of this treatment. None of the specific domains of the GA nor cumulative deficits on GA were predictive for functional decline or survival. Further research should focus on the role of interventions on evolution of quality of life.
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PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)
- Event: WCLC 2016
- Type: Plenary
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:J. Soria, C. Zhou
- Coordinates: 12/07/2016, 08:45 - 09:40, Hall D (Plenary Hall)
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PL04a.03 - Durvalumab in ≥3rd-Line Locally Advanced or Metastatic, EGFR/ALK Wild-Type NSCLC: Results from the Phase 2 ATLANTIC Study (Abstract under Embargo until December 7, 7:00 CET) (ID 5336)
08:45 - 09:40 | Author(s): J.F. Vansteenkiste
- Abstract
- Presentation
Background:
Treatment with anti-PD-1/PD-L1 antibodies has demonstrated meaningful clinical benefit in patients with advanced NSCLC. Patients that progress after 2 lines of chemotherapy have few treatment options and poor outcomes. Durvalumab is an engineered human IgG1 mAb targeting programmed cell death ligand-1 (PD-L1).
Methods:
ATLANTIC (NCT02087423) is a Phase 2, open-label, single-arm trial in patients with locally advanced or metastatic Stage IIIB–IV NSCLC (WHO PS 0 or 1; ≥2 prior systemic treatment regimens, including one platinum-based). There was no maximum number of prior treatments. The study initially enrolled all-comers and then was restricted to patients with PD-L1 high tumours (≥25% of tumour cells with membrane staining). The study includes three cohorts; here we report final results in Cohorts 2 and 3 that had EGFR/ALK wild-type or unknown status. Patients enrolled in Cohort 3 had ≥90% of tumour cells with PD-L1 staining. The primary endpoint is ORR (RECIST v1.1), based on independent central review. Secondary endpoints include DCR, DoR, PFS, OS, and safety (CTCAE v4.03).
Results:
As of 3 June 2016, in Cohorts 2/3, 265/68 patients (median age 62/61 years, 67/72% PS 1, 21/29% squamous histology; mean of 3.2/2.6 prior therapies) had received durvalumab (10 mg/kg i.v. q2w). Responses were durable; in Cohort 2, patients with PD-L1 ≥25%, the ORR was similar in patients with squamous and non-squamous histology.
Most AEs were low grade and resolved with treatment delay and/or immunosuppressive interventions. Overall, 10.2% of patients had Grade ≥3 treatment-related AEs and 2.7% had treatment-related AEs leading to discontinuation.Cohort 2 Cohort 3 PD-L1 high (≥25%) PD-L1 low/negative (<25%) PD-L1 ≥90% n=146 n=93 n=68 ORR,* %(95%CI) 16.4(10.8-23.5) 7.5(3.1-14.9) 30.9(20.2-43.3) DCR, %(95%CI) 28.8(21.6-36.8) 20.4(12.8-30.1) 38.2(26.7-50.8) mDoR, months(25[th], 75[th] percentile) 12.3(7.5-NR) NR(7.2-NR) NR; 18/21 responders progression free at DCO n=149 n=94 n=67 mPFS, months(95%CI) 3.3(1.9-3.7) 1.9(1.8-1.9) 2.4(1.8-5.5) mOS, months(95%CI) 10.9(8.6-13.6) 9.3(5.9-10.8) NR(5.9-NC) 1-year OS, %(95%CI) 47.7(39.3-55.5) 34.5(25.0-44.1) 50.8(36.9-63.2) mFollow-up for OS, months 9.4 9.3 7.0 *Confirmed response per independent central review. DCO=data cutoff; DCR=disease control rate (complete response, partial response or stable disease ≥24 weeks); DoR=duration of response; m=median; NC=not calculated; NR=not reached; ORR=objective response rate; OS=overall survival; PFS=progression-free survival
Conclusion:
Durvalumab was active and led to durable responses in a heavily pretreated metastatic NSCLC population; activity was numerically greater for patients whose tumours exceeded the 25% PD-L1 cutoff. The tolerability profile was manageable. Results are consistent with other anti-PD-1/PD-L1 therapies in metastatic, relapsed NSCLC and support further development of durvalumab.
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SC01 - Staging Before and After Induction Therapy for N2 Disease (ID 325)
- Event: WCLC 2016
- Type: Science Session
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:G. Mostbeck, E. Fadel
- Coordinates: 12/05/2016, 11:00 - 12:30, Lehar 3-4
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SC01.01 - The Importance of Mediastinal Down-Staging During Induction Therapy of N2 Disease (ID 6598)
11:00 - 12:30 | Author(s): J.F. Vansteenkiste
- Abstract
Abstract:
The importance of mediastinal downstaging during induction therapy of N2 disease P. De Leyn*, H. Decaluwe*, C. Dooms** and J. Vansteenkiste**. Department of Thoracic Surgery*, Department of Pneumology**, University Hospitals Leuven, Belgium Patients with preoperative pathological proven N2 disease have a dismal prognosis after surgery. Neoadjuvant chemotherapy or chemoradiotherapy is a therapeutic option that is used in patients with baseline resectable stage IIIA-N2 non-small cell lung cancer. Mediastinal downstaging is an important prognostic factor for long term survival. Different restaging techniques are available. The mediastinum can be restaged by CT scan, remediastinoscopy, VATS, PET-CT and EBUS-EUS fine needle aspiration. In primary staging, CT scan has proved to have a low accuracy. It is not surprising that the accuracy of CT scan in restaging the mediastinum is also low. In a Spanish study of 24 patients who underwent neoadjuvant chemotherapy for N2 non-small cell lung cancer, staging was performed by CT scan and remediastinoscopy (1). CT scan had a sensitivity of 41%, a specificity of 75% and an accuracy of 58%. In a prospective study of 93 patients who were restaged by integrated PET-CT after induction chemoradiotherapy, repeat PET-CT was found to be more accurate than CT alone for pathological stages. However, there were 20 false negative and 25 % false positive cases. So, in case of suspicion of residual mediastinal disease, nodal biopsies are still required (2). We evaluated in a prospective single center study repeat mediastinoscopy and PET-CT after induction chemotherapy for N2 disease. PET-CT had a sensitivity of 77% and a specificity of 88% (3). Repeat mediastinoscopy, technically much more difficult than the first procedure, offers the advantage of providing histological evidence of response after induction therapy. Although some centers obtain good results (4), most surgeons will accept that remediastinoscopy is technically difficult and often incomplete. We performed a prospective study to evaluate the accuracy of remediastinoscopy and PET-CT in restaging the mediastinum after mediastinoscopy proven N2 disease (3). The first mediastinoscopy was thoroughly performed with a mean lymph node level of 3.6 per patient biopsied. In our experience, remediastinoscopy was technically feasible, but inaccurate due to severe adhesions and fibrosis. The sensitivity to detect residual mediastinal lymph nodes was only 28,6% with an accuracy of 58,3%. Minimally invasive endoscopic technique EUS and EBUS also obtain histological diagnosis. Their accuracy is very good in baseline mediastinal staging. In the study Herth et al (5) EBUS-FNA was performed for restaging after induction chemotherapy or chemoradiotherapy for N2 disease in 124 patients. The sensitivity was 76% but the negative predictive value was as low as 20%. The largest series in the literature is reported by Szlubowski (6). They combined EBUS-EUS FNA for restaging N2 disease in 106 patients. Sensitivity was 67% with a negative predictive value of 73%. Some recent smaller studies showed better results for EBUS-EUS to prove persistent nodal disease. Most of the new lesions that appear after induction chemotherapy on PET-CT are not malignant (7). We know that some patients with minimal persistent N2 disease (mainly single level) can have a good prognosis after surgical resection (8). In a study published by Dooms et al (9) patients with less than 10% viable tumor cells in mediastinal lymph node sampled at mediastinoscopy and s with more than 60% decrease of SUV~max~ of primary tumor had a five year survival of over 60%. Therefore, we believe that a new staging algorithm could be used to select patients for radical therapy after induction chemotherapy for N2 disease. At baseline staging, pathological N2 disease should be proved by EBUS-EUS fine needle aspiration. PET-CT should be done to exclude distant metastasis and to evaluate SUV~max~ of the primary tumor. At restaging, mediastinoscopy with nodal dissection should be performed. Also repeat PET-CT should be done. In patients with major pathological response in lymph nodes and a major SUV drop of the primary tumor, surgery can be performed with good outcome. References (1)Mateu-Navarro M, Rami-Porta R, Bastus-Oiulats R, Cirera-Noqueras L, Gonzalez-Pont G. Remediastinoscopy after induction chemotherapy in non-small cell lung cancer. Ann Thorac Surg 2000;70:391-5. (2)Cerfolio R, Bryant A, Ojha B. Restaging patients with N2 (stage IIIa) non-small cell lung cancer after neoadjuvant chemoradiotherapy: a prospective study. J Thorac Cardiovasc Surg 2006;131(6):1229-1235. (3)De Leyn P, Stoobants S, Vansteenkiste J, Dewever W, Lerut A.. Prospective study of accuracy of redo videomediastinoscopy and PET-CT in detecting residual mediastinal disease after induction chemotherapy for NSCLC. Lung Cancer 2005;49 Suppl 2 : S3. (4)Rami-Porta R, Call S. Invasive staging of mediastinal lymph nodes: mediastinoscopy and remediastinoscopy. Thorac Surg Clin 2012: 22:177-89. (5)Herth F, Annema J, Eberhardt R, Yasufuku K, Ernst A, Krasnik M, Rintoul R. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer. J Clin Oncol 2008;26(20):3346-3350. (6)Szlubowski A, Zielinski M, Soja J, Filarecka A, Orzechowski S, Pankowski J, Obrochta A, Jakubiak M, Wegrzyn J, Cmiel A. Accurate and safe mediastinal restaging by combined endobronchial and endoscopic ultrasound-guided needle aspiration performed by single ultrasound bronchoscope. Eur J Cardiothor Surg 2014;46:262-266. (7)Collaud S, Lardinois D, Tischler V, Steinert H, Stahel R, Weder W. Significance of a new fluorodeoxyglucose-positive lesion on restaging positron emission tomography/computed tomography after induction therapy for non-small-cell lung cancer. Eur J Cardiothorac Surg 2012;41:612-616. (8)H. Decaluwé, P. De Leyn, J. Vansteenkiste, C. Dooms, D. Van Raemdonck, P. Nafteux, W. Coosemans, T. Lerut. Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothoracic Surg 2009 ;36 :433-9. (9)Dooms C, Verbeken E, Stroobants S, Nackaerts K, De Leyn P, Vansteenkiste J. Prognostic stratification of stage IIIA-N2 non-small-cell lung cancer after induction chemotherapy: a model based on the combination of morphometric-pathologic response in mediastinal nodes and primary tumor response on serial 18-fluoro-2-deoxy-glucose positron emission tomography. J Clin Oncol 2008;26(7):1128-1134.
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SC22 - Selection and Monitoring of Patients for Immune Checkpoint Inhibitors (ID 346)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G.V. Scagliotti, J.F. Vansteenkiste
- Coordinates: 12/06/2016, 16:00 - 17:30, Hall C8
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SC22.01 - How Do I Define Optimal Candidates for Immunotherapy in My Practice? (ID 6690)
16:00 - 17:30 | Author(s): J.F. Vansteenkiste
- Abstract
- Presentation
Abstract:
Over the recent decade, we witnessed important progress in the treatment of patients with advanced NSCLC in three domains. First, cytotoxic chemotherapy, where histology-directed chemotherapy with cisplatin-pemetrexed, followed by pemetrexed maintenance therapy in appropriate candidates, has resulted in a median overall survival (OS) of 16.9 months in adenocarcinoma [1]. Second, the use of tyrosine kinase inhibitors (TKIs) in tumors driven by specific molecular pathways, such as EGFR, ALK and others, has largely improved progression-free survival (PFS) compared to the one with chemotherapy in randomized studies, and had led to OS times of several years in many of these patients [2]. Third, immunotherapy with immune checkpoint inhibitors (ICI) directed against the immunosuppressive molecules programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has been in clinical trials since 2009. At present, the anti-PD-1 antibodies nivolumab (a fully human IgG4 antibody) and pembrolizumab (an engineered humanized IgG4 antibody) have been approved for NSCLC by different regulatory agencies worldwide. EMA approved nivolumab for advanced NSCLC after prior chemotherapy, and pembrolizumab for advanced NSCLC in adults whose tumors express PD-L1 and who have received at least one prior chemotherapy regimen. At the time of writing of this contribution, there were no public randomized study data on the use of these agents in 1[st] line therapy, we will therefore concentrate on the relapse therapy setting. Despite the real progress made by ICI therapy, we must realize that at present only about 20% of the patients respond to single-agent ICI treatment, while 50% have early progression (Checkmate 017 [3]; Checkmate 057 [4]). Moreover, the cost of these drugs is considerable. Hence it is important to define optimal candidates in clinical practice. Elements in this decision are a) clinicopathological factors; b) possible predictive biomarkers; and c) the availability of other treatment choices. As for (a) clinicopathological factors, there is no evidence that age, gender or ethnicity determine activity of ICIs. Smoking history, on the other hand, is strongly associated with better response rate to ICI therapy. Although EGFR oncogene pathway activation has been linked to upregulation of PD-L1 in tumor cells, response rates to ICIs in these patients are generally reported to be lower. In e.g. Checkmate 057, the overall response rate was 19%. It was 22% in smokers vs. 9% in non-smokers, 18% in EGFR-wildtype vs. 11% in EGFR-mutant tumors. Further understanding and refinement of the use of ICIs in tumor with an oncogene driver is needed. (b) A multitude of potential predictive biomarkers of response to PD-1/PD-L1 pathway inhibitors have been reported. In particular, PD-L1 expression in tumor and/or immune cells, the presence of TILs (tumor-infiltrating lymphocytes, CD8+ T-cells in particular), and the overall mutational load in the tumor cells have been linked to activity of ICIs [5]. PD-L1 expression on tumor cells, determined by immunohistochemistry (IHC) staining is by far the one most close to clinical practice for selecting optimal candidates for immunotherapy. This biomarker is quite distinct and less powerful than e.g. EGFR mutation as predictor of efficacy of EGFR TKIs. EGFR mutation is limited to the tumor, it is located in a distinct pathway, and is a yes/no phenomenon. PD-L1 IHC, on the other hand, relates to the tumor and its micro-environment, is only one of the many checkpoints in a complex interaction, and is a gradual phenomenon. Nonetheless, as can be noted from the figure, in most datasets of phase III studies – except Checkmate 017 – PD-L1 IHC predicts efficacy of ICI therapy. We added the large phase I study Keynote 001 to the figure as a very illustrative example: Over the categories of PD-L1 expression, response rate increased from 8% in the lowest to 45% in the highest category [6]. In the Keynote 010 phase III study, the hazard ratio of OS versus chemotherapy was 0.76 in the low-, but 0.54 in the high-expression group [7]. In the Checkmate 057, the OS hazard ratio even was 1.00 in all patients with tumors having PD-L1 <10%. Thus, except for the Checkmate 017 dataset, PD-L1 IHC enriches the response rate and differential OS benefit vs. chemotherapy, and can be used to designate these expensive agents to the optimal candidates. (c) Docetaxel single-agent chemotherapy was the comparator in the phase III studies on relapse therapy. In the meanwhile, progress has been made in conventional relapse therapy as well. In the LUME-Lung 1 trial, the combination of docetaxel and the triple angiogenesis inhibitor nintedanib resulted in a significantly better OS than docetaxel alone – with a difference in median OS of 2.3 months – in patients with adenocarcinoma [8]. In the REVEL study, patients treated with docetaxel plus ramucirumab, a VEGF receptor 2 inhibiting monoclonal antibody, had significantly better OS than those treated with docetaxel alone across all NSCLC histologies [9]. In conclusion, the choice of ICI therapy for relapsing NSCLC needs to be considered in the available treatment options for these patients, and this can be based on clinicopathological factors, predictive biomarkers, and comparison of efficacy of various treatments in specific subgroups. While PD-L1 is not a biomarker with the strength such as e.g. EGFR mutation, it helps to optimize the response rate and differential OS benefit of ICI therapy vs. chemotherapy, and to and can be used to designate these expensive agents to the optimal candidates. Figure Figure 1 References 1. Paz-Ares LG, De Marinis F, Dediu M et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after first-line treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2013; 31: 2895-2902. 2. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-957. 3. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous cell non-small cell lung cancer. N Engl J Med 2015; 373: 123-135. 4. Borghaei H, Paz-Ares L, Horn L et al. Nivolumab versus docetaxel in advanced nonsquamous non-small cell lung cancer. N Engl J Med 2015; 373: 1627-1639. 5. Rizvi NA, Hellmann MD, Snyder A et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348: 124-128. 6. Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med 2015; 372: 2018-2028. 7. Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016; 387: 1540-1550. 8. Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): A phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014; 15: 143-155. 9. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665-673.
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