- Email: [email protected]
A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma
Lung Cancer 140 (2020) 87–92
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A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma
T
Wei-Sen Lama,b,1, Jenette Creaneyb,c,g, Fred K. Chene, Wee Loong China,b,d,f, Sanjeevan Muruganandang, Sukanya Arunachalame, Mary S. Attiae, Catherine Readc, Kevin Murrayj, Michael Millwarda,f, Jon Spiroh, Aron Chakerai, Y.C. Gary Leec,f,g,2, Anna K. Nowaka,b,c,f,*,2 a
Department of Medical Oncology, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, Western Australia, 6009, Australia National Centre for Asbestos Related Diseases, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, Western Australia, 6009, Australia Institute for Respiratory Health, University of Western Australia, Sir Charles Gairdner Hospital Avenue, Nedlands, Western Australia, 6009, Australia d School of Biomedical Sciences, University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia, 6009, Australia e Centre for Ophthalmology and Visual Science (incorporating Lions Eye institute), The University of Western Australia, Nedlands, Western Australia, 6009, Australia f Medical School, University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia, 6009, Australia g Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, Western Australia, 6009, Australia h Department of Cardiology, Royal Perth Hospital, Wellington Street, Perth, Western Australia, 6000, Australia i Renal Unit, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, Western Australia, 6009, Australia j School of Population and Global Health, University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia, 6009, Australia b c
A R T I C LE I N FO
A B S T R A C T
Keywords: Fibroblast-growth-factor receptor Malignant pleural mesothelioma AZD4547 BAP1
Objectives: Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1–3 inhibitor, as a second or thirdline treatment. Materials and Methods: We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon’s two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients. Results: 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes. Conclusions: The FGFR 1–3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.
⁎ Corresponding author at: National Centre for Asbestos Related Diseases, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, Western Australia, 6009, Australia. E-mail addresses: [email protected] (W.-S. Lam), [email protected] (J. Creaney), [email protected] (F.K. Chen), [email protected] (W.L. Chin), [email protected] (S. Muruganandan), [email protected] (S. Arunachalam), [email protected] (M.S. Attia), [email protected] (C. Read), [email protected] (K. Murray), [email protected] (M. Millward), [email protected] (J. Spiro), [email protected] (A. Chakera), [email protected] (Y.C. Gary Lee), [email protected] (A.K. Nowak). 1 Present Address: Department of Medical Oncology, Fiona Stanley Hospital, 11 Robin Warren Dr, Murdoch, Western Australia, 6150. 2 These authors contributed equally to this work.
https://doi.org/10.1016/j.lungcan.2019.12.018 Received 4 November 2019; Accepted 30 December 2019 0169-5002/ © 2020 Elsevier B.V. All rights reserved.
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1. Introduction
studies with AZD4547 [18], so this study excluded patients with an active or previous history of PED, macular degeneration, and retinal vein occlusion. Based on preclinical safety data suggesting the risk of cardiac mineralization secondary to hyperphosphatemia [20], patients were also excluded if they showed clinical evidence of cardiac dysfunction, as demonstrated by significant QTc prolongation on ECG, a previous history of cardiac arrhythmias or a left ventricular ejection fraction < 50 % on functional studies. A complete list of inclusion and exclusion criteria can be found in Supplement A. All study patients provided written informed consent. The study protocol and all amendments were approved by local institutional review and conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the National Statement. The study was registered with the Australia New Zealand Clinical Trials Registry (ACTRN12615001291572)
Systemic chemotherapy remains the mainstay of treatment for patients with unresectable malignant pleural mesothelioma (MPM). In 2003, the EMPHACIS trial established cisplatin and pemetrexed as the standard of care for first-line treatment of advanced mesothelioma [1]. More recently, the MAPS trial provided the first randomised demonstration of efficacy of a targeted therapy in mesothelioma, with the addition of bevacizumab to cisplatin and pemetrexed chemotherapy providing a small incremental survival benefit over chemotherapy alone, increasing median survival from 16.1 to 18.8 months [2]. This regimen is not FDA approved and has therefore not been uniformly adopted. Currently, there is no clinical consensus about salvage therapy when patients relapse after first-line treatment. Treatment options postrelapse include reintroduction of a platinum and pemetrexed [3], single agent chemotherapy such as vinorelbine or gemcitabine [4], or checkpoint inhibitors including pembrolizumab [5] or nivolumab with/ without ipilimumab [6,7], although none of these have yet been demonstrated to improve survival in a randomised controlled trial. Nevertheless, only a small proportion of patients achieve a progression free survival of more than a year. These poor outcomes motivate the need for novel therapies for relapsed mesothelioma. In recent years, fibroblast growth factor receptor signalling has been recognised as increasingly important, both in cancer pathogenesis and as a potential therapeutic target [8,9]. There is strong preclinical data to suggest that fibroblast growth factor (FGF) signalling is important in mesothelioma. In mesothelial cell lines, FGFR1 and FGF2 are co-expressed and expression is significantly associated with sensitivity to FGFR-active tyrosine kinase inhibitor (TKI) [10]. Inhibiting FGF autocrine signalling using an FGF-ligand trap reduces proliferation in mesothelioma cell lines and reduces tumour growth in xenografts [11]. In our own work, FGFR-targeted tyrosine kinase inhibitors strikingly reduced tumour burden in three separate murine models of mesothelioma [12]. AZD4547 is a potent, orally bioavailable and highly selective FGFR1, 2, and 3 tyrosine kinase inhibitor [13]. Preclinical data, both from human tumour cell lines and patient-derived xenograft models, demonstrates that AZD4547 has anti-proliferative activity against a broad range of tumours, including gastric, pancreatic, colorectal and lung cancers [14–16]. Two phase I dose escalation studies have established a tolerable recommended dose (RD) of 80 mg twice daily. Clinical data on AZD4547 monotherapy demonstrates a consistent toxicity profile with dysgeusia, dry-mouth, stomatitis and hyperphosphatemia and fatigue as common side effects, which are generally well-tolerated [15,17,18]. The available preclinical and clinical data on AZD4547, combined with its strong scientific rationale in preclinical studies of mesothelioma made it an attractive candidate for a clinical trial in progressive disease.
2.2. Treatment administration All patients received continuous, twice-daily dosing of 80 mg AZD4547 on a nominal 3-weekly cycle. Concurrent treatment with any experimental drugs or other anti-cancer therapy such as chemotherapy, radiotherapy, targeted therapies, immunotherapy or surgery was not allowed. Patients were reviewed 3-weekly with clinical history and examination, vital signs, recording of adverse events and concomitant medications, and haematology and biochemistry testing including serum phosphate. Patients were allowed up to two dose interruptions of no longer than 14 days for National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 grade 2 toxicities, with a mandatory dose reduction to 60 mg BD after the second event. Any subsequent events or any non-resolving toxicities (CTCAE grade 3 or above) beyond 21 days warranted permanent study discontinuation. To assess cardiac function, a gated sestamibi scan was performed at baseline, after the first 3 weeks of treatment, and 3monthly thereafter. In order to detect potential ophthalmological complications from the study drug, all patients underwent baseline ophthalmologic examination (including spectral domain optical coherence tomography (SD−OCT) scan) prior to initiation of study treatment and once every 3 weeks thereafter ( ± 1 week) until permanent discontinuation of AZD4547. 2.3. Outcomes and assessment of response The primary objective was 6-month progression free survival (PFS6), with progression assessed as per mRECIST. Secondary end points included overall survival (OS), objective tumour response by mRECIST, treatment duration and toxicities. Time to progression (TTP) was measured from the date of first dose to the first date of disease progression or death. Patients who died of MPM were regarded as having disease progression at death. Duration of response was measured from the first date of partial response (PR) to the first date of progression or death. Survival was defined as the time from day 1 of the first treatment cycle until death. An exploratory analysis was performed to correlate tumour BAP1 loss with outcomes. To assess response, a CT scan of the chest and upper abdomen was performed at baseline, every 6 weeks until 24 weeks, and then 12-weekly until progression. Adverse events were categorised, graded and recorded according to the NCI CTCAE version 4.03.
2. Materials and methods 2.1. Study design and participants This study was a single-center, open-label, single-arm phase II study of continuous single oral agent AZD4547. Patients were adults with a histologically or cytologically confirmed diagnosis of mesothelioma of any subtype, and evidence of measurable disease based on modified RECIST criteria for mesothelioma (mRECIST) [19]. Eligible patients had disease progression after one or two lines of systemic therapy, with the first line being a platinum (cisplatin or carboplatin) in combination with pemetrexed. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 with a minimum life expectancy of 12 weeks prior to commencement of treatment. Ophthalmological and cardiac comorbidities were key exclusion criteria in this study. Ophthalmological toxicity, including pigmented epithelium detachment (PED) has been identified in previous clinical
2.4. BAP1 immunohistochemistry Based on recent findings that loss of BAP1 expression was associated with FGFR inhibitor sensitivity [21], tumour cells were examined for BAP1 protein expression. Immunohistochemical staining for BAP1 was performed on archival tumour biopsy specimens at the PathWest Anatomical Pathology laboratory (QEII Medical Centre, Nedlands). Briefly, formalin fixed paraffin embedded biopsy or cell block samples were 88
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stained with anti-BAP1 mouse monoclonal antibody (Clone C4; Santa Cruz Biotechnology) at a dilution of 1:50, with an UltraView Universal DAB Detection Kit on a Ventana BenchMark ULTRA platform. Stromal and inflammatory cells served as an internal control. BAP1 negative MPM tissue was included on each slide as an external control. Each tumour sample was scored as having BAP1 retained or lost.
Table 1 Patient demographics and baseline characteristics.
2.5. FGF9 ELISA Serum, and where available pleural fluid was collected from subjects. Soluble FGF9 concentrations were determined in duplicate following the manufacturer’s instructions using a double determinant ELISA assay (R & D Systems, Minneapolis, MN). Concentrations were determined from a standard curve performed on each plate and expressed as ng/mL. 2.6. Statistical considerations A Simon’s optimal two-stage design was used to determine sample size. The null hypothesis that the true PFS6 was < 25 % was tested against a one-sided alternative. Based on this design, this study required a total recruitment of 55 patients and would be stopped if 7 or fewer patients from the first cohort of 26 were free from progression at 6 months. The study was to be declared positive if 17 or more patients from a total of 55 achieved 6-month progression-free survival. This design yielded a one-sided type I error rate of 0.1 and power of 0.90 when the true PFS6 is 45 %. The analysis of efficacy outcomes was performed on an intention to treat basis. The analysis of toxicity was performed on all participants who received at least one dose of study drug. PFS6, response and toxicities were analysed as a proportion of all patients eligible for that analysis. Time to event outcomes were analysed using Kaplan-Meier analysis with R version 3.6.0 [22].
N = 24
%
Sex Male
21
87.5
ECOG performance status 1
24
100.0
Histological subtype Epithelioid Sarcomatoid Biphasic
20 2 2
83.3 8.3 8.3
Number of lines of prior treatment 1 2
13 11
54.1 45.8
Previous systemic treatment agents 1st line treatment Cisplatin/Pemetrexed Carboplatin/Pemetrexed 2nd line treatment Vinorelbine Cisplatin/Gemcitabine PD1 inhibitor
14 10
58.0 42.0
8 1 2
33.3 4.2 8.3
Other prior non-systemic interventions Talc pleurodesis Radiotherapy
2 5
8.3 20.8
3.3. Toxicity and safety The maximum toxicities experienced for each patient across all cycles of treatment are summarised in Table 2. The six most common toxicities were xerostomia (62.5 %), hyperphosphatemia (54 %), retinopathy (50 %), mucositis (41 %), dysgeusia (38 %) and onycholysis (38 %), with no toxicity exceeding grade 2. These toxicities are compatible with those recorded in previous phase I studies of AZD4547. There were no hospital admissions secondary to drug toxicity and no grade 5 events from treatment. Although the adverse events were grade 1–2, side effects such as onycholysis, fatigue, mucositis, and palmar-plantar erythrodysesthesia effects were ongoing during continuous twice daily drug administration. Whilst quality of life was not formally measured, in this singlecentre study these adverse effects were observed to impact on patient wellbeing and to affect treatment compliance. Indeed, three patients (12.5 %) withdrew from the study due to toxicities. One patient had 3 full-dose cycles of 80 mg BD and 2 cycles at a lower dose level of 60 mg BD before ceasing the study drug. Another two patients voluntarily withdrew from the study after less than 3 cycles of full-dose treatment without attempting treatment at a lower dose level. In all these cases, the cumulative effect of multiple, ongoing grade 1 and 2 toxicities including fatigue, mucositis, and onycholysis proved too difficult for them to continue on the study drug. Significant hyperphosphatemia occurred in a single patient, requiring two dose interruptions, a low-phosphate diet and the addition of dietary calcium. Another seven patients experienced grade 2 hyperphosphatemia; all responded to oral calcium supplements alone. A female patient who received the longest duration of treatment (21 cycles) experienced ongoing hyperphosphatemia managed by low-phosphate diet and calcium supplementation, and subsequently experienced an atraumatic crush fracture of the T10 vertebra 6 months following cessation of treatment with AZD4547. There were three instances of liver function test abnormality, one instance of hypercalcemia and one instance of increased creatinine, none of which were considered clinically significant. Overall, no documented biochemical abnormalities aside from hyperphosphatemia were deemed clinically significant requiring dose interruption or study discontinuation.
3. Results Patient Characteristics: Between April 2016 and December 2018, 24 patients were recruited onto this study. 21 patients (87 %) were male; the median age of 69.5 years (range 53–84 years). Histological subtypes were epithelioid (83.3 %), biphasic (8.3 %), and sarcomatoid (8.3 %). Other patient characteristics are listed in Table 1. 3.1. Treatment delivered A total of 112 cycles of AZD4547 were administered to 24 patients. 110 (98 %) of these cycles were delivered at the full dose of 80 mg BD, whilst 2 cycles were given at a reduced dose of 60 mg BD. The median number of treatment cycles per patient was 4 (range 1–21). 3.2. Efficacy Three of 24 patients (12 %) were progression-free at 6 months. Based on the study design, the study fulfilled stopping criteria and warranted discontinuation. Continuing recruitment to achieve the primary end point of 7 responses by recruitment of 27 patients, even if the next three patients achieved 6 months without progression, would not have met the conditions for continuing to the second part of the study. Median progression free survival was 91 days (3.0 months, 95 % CI 69–180) and median overall survival was 220 days (7.3 months, 95 % CI 180–363) (Fig. 1). One patient (4 %) with epithelioid subtype mesothelioma had a 32 % reduction in tumour measurements at 6 weeks but experienced progressive disease at 12 weeks, hence having an unconfirmed partial response. 19 patients (79 %) had stable disease (SD) for at least 6 weeks, and 5 patients (21 %) had progressive disease as their best response (Fig. 2). 89
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Fig. 1. Kaplan Meier curves for AZD4547. (A) Progression free survival (PFS): N = 24, events = 20, median = 91 days, 95 % CI for median (69, 180). (B) Overall survival (OS): N = 24, events = 22, median = 220 days, 95 % CI for median (180, 363).
weeks after drug discontinuation. For the remaining 9 patients, longterm follow-up imaging was not available to determine if the fluid resolved after final dosing of the study drug.
No significant cardiac toxicities were reported. One patient experienced an asymptomatic reduction in ejection fraction to 53 % from > 70 %. However, the patient was clinically asymptomatic and this finding was not associated with ECG changes. Hence, this was not considered to be a clinically significant cardiac toxicity. Regarding ocular toxicities, 12 of 24 patients developed subretinal fluid in one, or more commonly both eyes, detected on OCT scans, emerging between 3 and 19 weeks following first dose of the study drug. All 12 patients remained asymptomatic and the presence of retinopathy did not require any dose interruptions or reductions. Furthermore, half of these patients had some reduction in the subretinal fluid despite continued administration of the study drug. Only 3 patients showed resolution of the subretinal fluid at the final ophthalmological examination. This was observed at the last dosing or 5 and 7
3.4. BAP1 immunohistochemistry and FGF9 biomarker analysis We tested both BAP1 immunohistochemistry and measured FGF9 concentrations, both known to confer sensitivity to FGFR inhibition [21]. Nineteen of 24 patients (79 %) were negative for BAP1 protein expression. The tumours of the five subjects who retained BAP1 expression were all of epithelioid histology. There was no difference in median PFS for the group which retained BAP1 (n = 5; 87 days, 95 %CI 58–134) compared to those that lost BAP1 expression (n = 19; 84 days, 95 %CI 62–139). The three subjects who achieved a PFS6 all lost BAP1
Fig. 2. Waterfall plot of best response to AZD4547. Two patients had progressive disease as best response (with % change < 20 % in measured sites) due to the development of new, non-target lesions (bilateral miliary lung lesions and brain lesions). PD: Progressive disease; SD: Stable disease. 90
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impact patient wellbeing. Due to lack of efficacy, the median duration of treatment in our cohort was short. Despite a sound preclinical rationale for targeting this pathway, this study does not support the role of FGFR targeting using AZD4547 as a single agent in pre-treated mesothelioma, or the role of BAP1 loss as a marker of potential efficacy. Further testing of similar drugs as single agents is unlikely to be fruitful in this disease. A single modest objective response was of short duration and does not support further efforts to identify a potential subset of responders to this agent.
Table 2 The ten most frequently documented toxicities, maximum grade per patient across all cycles of treatment. Toxicity
Grade 1 n (%)
Grade 2 n (%)
Grade 3/4 n (%)
Hyperphosphatemia Xerostomia Mucositis Dysgeusia Fatigue Onycholysis Hair loss Anorexia Dry Skin Subretinal fluid
6 (25 %) 13 (54.2 %) 6 (25 %) 8 (33.3 %) 6 (25 %) 5 (20.8 %) 4 (16.7 %) 4 (16.7 %) 6 (25.0 %) 12 (50.0 %)
7 2 4 1 2 4 0 0 0 0
0 0 0 0 0 0 – 0 0 0
(29.2 %) (8.3 %) (16.7 %) (4.2 %) (8.3 %) (16.7 %)
Funding
protein expression. FGF9 serum levels were uniformly low and were not further analysed. In contrast, FGF9 was detectable in all 4 patients with pleural fluid available for analysis. In the single patient with the unconfirmed partial response, pleural fluid FGF9 levels rose between 44 and 101 days on treatment.
Funding for study conduct was provided by grants from Cancer Australia (APP1121215) and icare Dust Diseases Board (5571/2014). Study drug was provided by AstraZeneca. Wei-Sen Lam and Wee Loong Chin were supported through funding from the Western Australian Cancer and Palliative Care network. Fred Chen is supported by NHMRC MRFF Career Development Fellowship (APP1142962). Jenette Creaney is supported in part by the Insurance Commission of Western Australia. Mary Attia and Sukanya Arunachalam are supported by the Miocevich Retina Fellowship.
4. Discussion
Declaration of Competing Interest All other authors have nothing to disclose.
Despite a strong biological rationale and promising pre-clinical data, this study of AZD4547 did not achieve its primary endpoint in patients with progressive pre-treated malignant pleural mesothelioma. Indeed, this result is compatible with the current clinical experience with FGFR inhibitors in other tumours, showing that only a small subset of patients will have an objective response [23]. Whilst one patient had an unconfirmed partial response, this was not durable. Although we did not identify a positive biomarker signal from our analysis, some important lessons emerged. Whilst previous studies in cell lines and xenografts have demonstrated that BAP1 loss confers sensitivity to FGFR inhibition [21], the high frequency of BAP1 protein loss and lack of any association with outcome in our study suggests that it is unlikely to serve as a stand-alone biomarker in clinical practice. The absence of interpretable FGF9 signal in patient serum, taken together with the dynamic changes to FGF9 levels in pleural fluid suggests that the type of sample and the timing of biomarker sampling are important considerations for any future study. In view of the lack of treatment efficacy, further study of biomarkers from this patient cohort is unlikely to be informative. In contrast to previous studies using AZD4547, we did not observe any patients with PED [18,28,29]. Instead, we observed localised and diffuse subretinal fluid accumulation of mild severity, with the distribution of fluid resembling the phenotype of mitogen-activated protein kinase (MEK) inhibitor-associated retinopathy (MEKAR) [24–27]. This is a distinct entity that mimics but differs from a common cause of serous retinal detachment unrelated to the targeted therapy, central serous retinopathy, which is also characterised by PED and often exposure to corticosteroid. Indeed, the spectrum of ocular toxicities from AZD4547 is likely to be more diverse than documented in previous clinical studies. Following expert re-evaluation of the OCT scans of patients treated with AZD4547 in another study, some of the cases that were originally graded as PEDs were re-classified as localised subretinal fluid accumulation which were mild in severity, had minimal impact on visual function and were reversible on treatment discontinuation (unpublished data, AZ investigators brochure publication in preparation). Our study reaffirms that regular ophthalmological review is required for patients undergoing treatment with this drug but treatment of these asymptomatic and self-limiting subretinal fluid may not be necessary. Our study is the first to describe the efficacy and toxicity profile of AZD4547 in a patient population with malignant mesothelioma. Overall, we found that AZD4547 was tolerable although prolonged use was associated with persistent low-grade toxicities that may potentially
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et al., Comprehensive pharmacogenomic profiling of malignant pleural mesothelioma identifies a subgroup sensitive to FGFR inhibition, Clin. Cancer Res. 24 (1) (2018) 84–94. R Core Team, R: a Language and Environment for Statistical Computing, R Foundation for Statistical Computing, Vienna, Austria, 2013http://www.R-project. org/. M. Touat, E. Ileana, S. Postel-Vinay, F. André, J.-C. Soria, Targeting FGFR signaling in Cancer, Clin. Cancer Res. 21 (June (12)) (2015) 2684–2694. J.H. Francis, L.A. Habib, D.H. Abramson, L.A. Yannuzzi, M. Heinemann, M.M. Gounder, et al., Clinical and Morphologic Characteristics of MEK InhibitorAssociated Retinopathy: Differences from Central Serous Chorioretinopathy, Ophthalmology 124 (12) (2017) 1788–1798. E.H.C. van Dijk, C.M.L. van Herpen, M. Marinkovic, H. JBAG, D. Amundson, G.P.M. Luyten, et al., Serous retinopathy associated with mitogen-activated protein kinase kinase inhibition (Binimetinib) for metastatic cutaneous and uveal melanoma, Ophthalmology 122 (September (9)) (2015) 1907–1916. M.L. Weber, M.C. Liang, K.T. Flaherty, J.S. Heier, Subretinal fluid associated with MEK inhibitor use in the treatment of systemic Cancer, JAMA Ophthalmol. 134 (August (8)) (2016) 855–862. E.H.C. van Dijk, W.H.J. Kruit, M.J. Jager, G.P.M. Luyten, J.R. Vingerling, C.J.F. Boon, Pimasertib-associated ophthalmological adverse events, Acta Ophthalmol. 96 (November (7)) (2018) 712–718. M. Seckl, P.D. Badman, X. Liu, I.R. MacPherson, I.H. Zubairi, R.D. Baird, et al., RADICAL trial: a phase Ib/IIa study to assess the safety and efficacy of AZD4547 in combination with either anastrozole or letrozole in ER positive breast cancer patients progressing on these aromatase inhibitors (AIs), J. Clin. Oncol. 35 (15suppl) (2017) 1059. H.-T. Arkenau, M. Saggese, A. Hollebecque, A. Mathewson, C.R. Lemech, D. Landers, et al., A phase 1 expansion cohort of the fibroblast growth factor receptor (FGFR) inhibitor AZD4547 in patients (pts) with advanced gastric (GC) and gastroesophageal (GOJ) cancer, J. Clin. Oncol. 32 (May (15suppl)) (2014) 2620.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma
T
Wei-Sen Lama,b,1, Jenette Creaneyb,c,g, Fred K. Chene, Wee Loong China,b,d,f, Sanjeevan Muruganandang, Sukanya Arunachalame, Mary S. Attiae, Catherine Readc, Kevin Murrayj, Michael Millwarda,f, Jon Spiroh, Aron Chakerai, Y.C. Gary Leec,f,g,2, Anna K. Nowaka,b,c,f,*,2 a
Department of Medical Oncology, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, Western Australia, 6009, Australia National Centre for Asbestos Related Diseases, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, Western Australia, 6009, Australia Institute for Respiratory Health, University of Western Australia, Sir Charles Gairdner Hospital Avenue, Nedlands, Western Australia, 6009, Australia d School of Biomedical Sciences, University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia, 6009, Australia e Centre for Ophthalmology and Visual Science (incorporating Lions Eye institute), The University of Western Australia, Nedlands, Western Australia, 6009, Australia f Medical School, University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia, 6009, Australia g Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, Western Australia, 6009, Australia h Department of Cardiology, Royal Perth Hospital, Wellington Street, Perth, Western Australia, 6000, Australia i Renal Unit, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, Western Australia, 6009, Australia j School of Population and Global Health, University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia, 6009, Australia b c
A R T I C LE I N FO
A B S T R A C T
Keywords: Fibroblast-growth-factor receptor Malignant pleural mesothelioma AZD4547 BAP1
Objectives: Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1–3 inhibitor, as a second or thirdline treatment. Materials and Methods: We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon’s two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients. Results: 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes. Conclusions: The FGFR 1–3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.
⁎ Corresponding author at: National Centre for Asbestos Related Diseases, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, Western Australia, 6009, Australia. E-mail addresses: [email protected] (W.-S. Lam), [email protected] (J. Creaney), [email protected] (F.K. Chen), [email protected] (W.L. Chin), [email protected] (S. Muruganandan), [email protected] (S. Arunachalam), [email protected] (M.S. Attia), [email protected] (C. Read), [email protected] (K. Murray), [email protected] (M. Millward), [email protected] (J. Spiro), [email protected] (A. Chakera), [email protected] (Y.C. Gary Lee), [email protected] (A.K. Nowak). 1 Present Address: Department of Medical Oncology, Fiona Stanley Hospital, 11 Robin Warren Dr, Murdoch, Western Australia, 6150. 2 These authors contributed equally to this work.
https://doi.org/10.1016/j.lungcan.2019.12.018 Received 4 November 2019; Accepted 30 December 2019 0169-5002/ © 2020 Elsevier B.V. All rights reserved.
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1. Introduction
studies with AZD4547 [18], so this study excluded patients with an active or previous history of PED, macular degeneration, and retinal vein occlusion. Based on preclinical safety data suggesting the risk of cardiac mineralization secondary to hyperphosphatemia [20], patients were also excluded if they showed clinical evidence of cardiac dysfunction, as demonstrated by significant QTc prolongation on ECG, a previous history of cardiac arrhythmias or a left ventricular ejection fraction < 50 % on functional studies. A complete list of inclusion and exclusion criteria can be found in Supplement A. All study patients provided written informed consent. The study protocol and all amendments were approved by local institutional review and conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the National Statement. The study was registered with the Australia New Zealand Clinical Trials Registry (ACTRN12615001291572)
Systemic chemotherapy remains the mainstay of treatment for patients with unresectable malignant pleural mesothelioma (MPM). In 2003, the EMPHACIS trial established cisplatin and pemetrexed as the standard of care for first-line treatment of advanced mesothelioma [1]. More recently, the MAPS trial provided the first randomised demonstration of efficacy of a targeted therapy in mesothelioma, with the addition of bevacizumab to cisplatin and pemetrexed chemotherapy providing a small incremental survival benefit over chemotherapy alone, increasing median survival from 16.1 to 18.8 months [2]. This regimen is not FDA approved and has therefore not been uniformly adopted. Currently, there is no clinical consensus about salvage therapy when patients relapse after first-line treatment. Treatment options postrelapse include reintroduction of a platinum and pemetrexed [3], single agent chemotherapy such as vinorelbine or gemcitabine [4], or checkpoint inhibitors including pembrolizumab [5] or nivolumab with/ without ipilimumab [6,7], although none of these have yet been demonstrated to improve survival in a randomised controlled trial. Nevertheless, only a small proportion of patients achieve a progression free survival of more than a year. These poor outcomes motivate the need for novel therapies for relapsed mesothelioma. In recent years, fibroblast growth factor receptor signalling has been recognised as increasingly important, both in cancer pathogenesis and as a potential therapeutic target [8,9]. There is strong preclinical data to suggest that fibroblast growth factor (FGF) signalling is important in mesothelioma. In mesothelial cell lines, FGFR1 and FGF2 are co-expressed and expression is significantly associated with sensitivity to FGFR-active tyrosine kinase inhibitor (TKI) [10]. Inhibiting FGF autocrine signalling using an FGF-ligand trap reduces proliferation in mesothelioma cell lines and reduces tumour growth in xenografts [11]. In our own work, FGFR-targeted tyrosine kinase inhibitors strikingly reduced tumour burden in three separate murine models of mesothelioma [12]. AZD4547 is a potent, orally bioavailable and highly selective FGFR1, 2, and 3 tyrosine kinase inhibitor [13]. Preclinical data, both from human tumour cell lines and patient-derived xenograft models, demonstrates that AZD4547 has anti-proliferative activity against a broad range of tumours, including gastric, pancreatic, colorectal and lung cancers [14–16]. Two phase I dose escalation studies have established a tolerable recommended dose (RD) of 80 mg twice daily. Clinical data on AZD4547 monotherapy demonstrates a consistent toxicity profile with dysgeusia, dry-mouth, stomatitis and hyperphosphatemia and fatigue as common side effects, which are generally well-tolerated [15,17,18]. The available preclinical and clinical data on AZD4547, combined with its strong scientific rationale in preclinical studies of mesothelioma made it an attractive candidate for a clinical trial in progressive disease.
2.2. Treatment administration All patients received continuous, twice-daily dosing of 80 mg AZD4547 on a nominal 3-weekly cycle. Concurrent treatment with any experimental drugs or other anti-cancer therapy such as chemotherapy, radiotherapy, targeted therapies, immunotherapy or surgery was not allowed. Patients were reviewed 3-weekly with clinical history and examination, vital signs, recording of adverse events and concomitant medications, and haematology and biochemistry testing including serum phosphate. Patients were allowed up to two dose interruptions of no longer than 14 days for National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 grade 2 toxicities, with a mandatory dose reduction to 60 mg BD after the second event. Any subsequent events or any non-resolving toxicities (CTCAE grade 3 or above) beyond 21 days warranted permanent study discontinuation. To assess cardiac function, a gated sestamibi scan was performed at baseline, after the first 3 weeks of treatment, and 3monthly thereafter. In order to detect potential ophthalmological complications from the study drug, all patients underwent baseline ophthalmologic examination (including spectral domain optical coherence tomography (SD−OCT) scan) prior to initiation of study treatment and once every 3 weeks thereafter ( ± 1 week) until permanent discontinuation of AZD4547. 2.3. Outcomes and assessment of response The primary objective was 6-month progression free survival (PFS6), with progression assessed as per mRECIST. Secondary end points included overall survival (OS), objective tumour response by mRECIST, treatment duration and toxicities. Time to progression (TTP) was measured from the date of first dose to the first date of disease progression or death. Patients who died of MPM were regarded as having disease progression at death. Duration of response was measured from the first date of partial response (PR) to the first date of progression or death. Survival was defined as the time from day 1 of the first treatment cycle until death. An exploratory analysis was performed to correlate tumour BAP1 loss with outcomes. To assess response, a CT scan of the chest and upper abdomen was performed at baseline, every 6 weeks until 24 weeks, and then 12-weekly until progression. Adverse events were categorised, graded and recorded according to the NCI CTCAE version 4.03.
2. Materials and methods 2.1. Study design and participants This study was a single-center, open-label, single-arm phase II study of continuous single oral agent AZD4547. Patients were adults with a histologically or cytologically confirmed diagnosis of mesothelioma of any subtype, and evidence of measurable disease based on modified RECIST criteria for mesothelioma (mRECIST) [19]. Eligible patients had disease progression after one or two lines of systemic therapy, with the first line being a platinum (cisplatin or carboplatin) in combination with pemetrexed. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 with a minimum life expectancy of 12 weeks prior to commencement of treatment. Ophthalmological and cardiac comorbidities were key exclusion criteria in this study. Ophthalmological toxicity, including pigmented epithelium detachment (PED) has been identified in previous clinical
2.4. BAP1 immunohistochemistry Based on recent findings that loss of BAP1 expression was associated with FGFR inhibitor sensitivity [21], tumour cells were examined for BAP1 protein expression. Immunohistochemical staining for BAP1 was performed on archival tumour biopsy specimens at the PathWest Anatomical Pathology laboratory (QEII Medical Centre, Nedlands). Briefly, formalin fixed paraffin embedded biopsy or cell block samples were 88
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stained with anti-BAP1 mouse monoclonal antibody (Clone C4; Santa Cruz Biotechnology) at a dilution of 1:50, with an UltraView Universal DAB Detection Kit on a Ventana BenchMark ULTRA platform. Stromal and inflammatory cells served as an internal control. BAP1 negative MPM tissue was included on each slide as an external control. Each tumour sample was scored as having BAP1 retained or lost.
Table 1 Patient demographics and baseline characteristics.
2.5. FGF9 ELISA Serum, and where available pleural fluid was collected from subjects. Soluble FGF9 concentrations were determined in duplicate following the manufacturer’s instructions using a double determinant ELISA assay (R & D Systems, Minneapolis, MN). Concentrations were determined from a standard curve performed on each plate and expressed as ng/mL. 2.6. Statistical considerations A Simon’s optimal two-stage design was used to determine sample size. The null hypothesis that the true PFS6 was < 25 % was tested against a one-sided alternative. Based on this design, this study required a total recruitment of 55 patients and would be stopped if 7 or fewer patients from the first cohort of 26 were free from progression at 6 months. The study was to be declared positive if 17 or more patients from a total of 55 achieved 6-month progression-free survival. This design yielded a one-sided type I error rate of 0.1 and power of 0.90 when the true PFS6 is 45 %. The analysis of efficacy outcomes was performed on an intention to treat basis. The analysis of toxicity was performed on all participants who received at least one dose of study drug. PFS6, response and toxicities were analysed as a proportion of all patients eligible for that analysis. Time to event outcomes were analysed using Kaplan-Meier analysis with R version 3.6.0 [22].
N = 24
%
Sex Male
21
87.5
ECOG performance status 1
24
100.0
Histological subtype Epithelioid Sarcomatoid Biphasic
20 2 2
83.3 8.3 8.3
Number of lines of prior treatment 1 2
13 11
54.1 45.8
Previous systemic treatment agents 1st line treatment Cisplatin/Pemetrexed Carboplatin/Pemetrexed 2nd line treatment Vinorelbine Cisplatin/Gemcitabine PD1 inhibitor
14 10
58.0 42.0
8 1 2
33.3 4.2 8.3
Other prior non-systemic interventions Talc pleurodesis Radiotherapy
2 5
8.3 20.8
3.3. Toxicity and safety The maximum toxicities experienced for each patient across all cycles of treatment are summarised in Table 2. The six most common toxicities were xerostomia (62.5 %), hyperphosphatemia (54 %), retinopathy (50 %), mucositis (41 %), dysgeusia (38 %) and onycholysis (38 %), with no toxicity exceeding grade 2. These toxicities are compatible with those recorded in previous phase I studies of AZD4547. There were no hospital admissions secondary to drug toxicity and no grade 5 events from treatment. Although the adverse events were grade 1–2, side effects such as onycholysis, fatigue, mucositis, and palmar-plantar erythrodysesthesia effects were ongoing during continuous twice daily drug administration. Whilst quality of life was not formally measured, in this singlecentre study these adverse effects were observed to impact on patient wellbeing and to affect treatment compliance. Indeed, three patients (12.5 %) withdrew from the study due to toxicities. One patient had 3 full-dose cycles of 80 mg BD and 2 cycles at a lower dose level of 60 mg BD before ceasing the study drug. Another two patients voluntarily withdrew from the study after less than 3 cycles of full-dose treatment without attempting treatment at a lower dose level. In all these cases, the cumulative effect of multiple, ongoing grade 1 and 2 toxicities including fatigue, mucositis, and onycholysis proved too difficult for them to continue on the study drug. Significant hyperphosphatemia occurred in a single patient, requiring two dose interruptions, a low-phosphate diet and the addition of dietary calcium. Another seven patients experienced grade 2 hyperphosphatemia; all responded to oral calcium supplements alone. A female patient who received the longest duration of treatment (21 cycles) experienced ongoing hyperphosphatemia managed by low-phosphate diet and calcium supplementation, and subsequently experienced an atraumatic crush fracture of the T10 vertebra 6 months following cessation of treatment with AZD4547. There were three instances of liver function test abnormality, one instance of hypercalcemia and one instance of increased creatinine, none of which were considered clinically significant. Overall, no documented biochemical abnormalities aside from hyperphosphatemia were deemed clinically significant requiring dose interruption or study discontinuation.
3. Results Patient Characteristics: Between April 2016 and December 2018, 24 patients were recruited onto this study. 21 patients (87 %) were male; the median age of 69.5 years (range 53–84 years). Histological subtypes were epithelioid (83.3 %), biphasic (8.3 %), and sarcomatoid (8.3 %). Other patient characteristics are listed in Table 1. 3.1. Treatment delivered A total of 112 cycles of AZD4547 were administered to 24 patients. 110 (98 %) of these cycles were delivered at the full dose of 80 mg BD, whilst 2 cycles were given at a reduced dose of 60 mg BD. The median number of treatment cycles per patient was 4 (range 1–21). 3.2. Efficacy Three of 24 patients (12 %) were progression-free at 6 months. Based on the study design, the study fulfilled stopping criteria and warranted discontinuation. Continuing recruitment to achieve the primary end point of 7 responses by recruitment of 27 patients, even if the next three patients achieved 6 months without progression, would not have met the conditions for continuing to the second part of the study. Median progression free survival was 91 days (3.0 months, 95 % CI 69–180) and median overall survival was 220 days (7.3 months, 95 % CI 180–363) (Fig. 1). One patient (4 %) with epithelioid subtype mesothelioma had a 32 % reduction in tumour measurements at 6 weeks but experienced progressive disease at 12 weeks, hence having an unconfirmed partial response. 19 patients (79 %) had stable disease (SD) for at least 6 weeks, and 5 patients (21 %) had progressive disease as their best response (Fig. 2). 89
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Fig. 1. Kaplan Meier curves for AZD4547. (A) Progression free survival (PFS): N = 24, events = 20, median = 91 days, 95 % CI for median (69, 180). (B) Overall survival (OS): N = 24, events = 22, median = 220 days, 95 % CI for median (180, 363).
weeks after drug discontinuation. For the remaining 9 patients, longterm follow-up imaging was not available to determine if the fluid resolved after final dosing of the study drug.
No significant cardiac toxicities were reported. One patient experienced an asymptomatic reduction in ejection fraction to 53 % from > 70 %. However, the patient was clinically asymptomatic and this finding was not associated with ECG changes. Hence, this was not considered to be a clinically significant cardiac toxicity. Regarding ocular toxicities, 12 of 24 patients developed subretinal fluid in one, or more commonly both eyes, detected on OCT scans, emerging between 3 and 19 weeks following first dose of the study drug. All 12 patients remained asymptomatic and the presence of retinopathy did not require any dose interruptions or reductions. Furthermore, half of these patients had some reduction in the subretinal fluid despite continued administration of the study drug. Only 3 patients showed resolution of the subretinal fluid at the final ophthalmological examination. This was observed at the last dosing or 5 and 7
3.4. BAP1 immunohistochemistry and FGF9 biomarker analysis We tested both BAP1 immunohistochemistry and measured FGF9 concentrations, both known to confer sensitivity to FGFR inhibition [21]. Nineteen of 24 patients (79 %) were negative for BAP1 protein expression. The tumours of the five subjects who retained BAP1 expression were all of epithelioid histology. There was no difference in median PFS for the group which retained BAP1 (n = 5; 87 days, 95 %CI 58–134) compared to those that lost BAP1 expression (n = 19; 84 days, 95 %CI 62–139). The three subjects who achieved a PFS6 all lost BAP1
Fig. 2. Waterfall plot of best response to AZD4547. Two patients had progressive disease as best response (with % change < 20 % in measured sites) due to the development of new, non-target lesions (bilateral miliary lung lesions and brain lesions). PD: Progressive disease; SD: Stable disease. 90
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impact patient wellbeing. Due to lack of efficacy, the median duration of treatment in our cohort was short. Despite a sound preclinical rationale for targeting this pathway, this study does not support the role of FGFR targeting using AZD4547 as a single agent in pre-treated mesothelioma, or the role of BAP1 loss as a marker of potential efficacy. Further testing of similar drugs as single agents is unlikely to be fruitful in this disease. A single modest objective response was of short duration and does not support further efforts to identify a potential subset of responders to this agent.
Table 2 The ten most frequently documented toxicities, maximum grade per patient across all cycles of treatment. Toxicity
Grade 1 n (%)
Grade 2 n (%)
Grade 3/4 n (%)
Hyperphosphatemia Xerostomia Mucositis Dysgeusia Fatigue Onycholysis Hair loss Anorexia Dry Skin Subretinal fluid
6 (25 %) 13 (54.2 %) 6 (25 %) 8 (33.3 %) 6 (25 %) 5 (20.8 %) 4 (16.7 %) 4 (16.7 %) 6 (25.0 %) 12 (50.0 %)
7 2 4 1 2 4 0 0 0 0
0 0 0 0 0 0 – 0 0 0
(29.2 %) (8.3 %) (16.7 %) (4.2 %) (8.3 %) (16.7 %)
Funding
protein expression. FGF9 serum levels were uniformly low and were not further analysed. In contrast, FGF9 was detectable in all 4 patients with pleural fluid available for analysis. In the single patient with the unconfirmed partial response, pleural fluid FGF9 levels rose between 44 and 101 days on treatment.
Funding for study conduct was provided by grants from Cancer Australia (APP1121215) and icare Dust Diseases Board (5571/2014). Study drug was provided by AstraZeneca. Wei-Sen Lam and Wee Loong Chin were supported through funding from the Western Australian Cancer and Palliative Care network. Fred Chen is supported by NHMRC MRFF Career Development Fellowship (APP1142962). Jenette Creaney is supported in part by the Insurance Commission of Western Australia. Mary Attia and Sukanya Arunachalam are supported by the Miocevich Retina Fellowship.
4. Discussion
Declaration of Competing Interest All other authors have nothing to disclose.
Despite a strong biological rationale and promising pre-clinical data, this study of AZD4547 did not achieve its primary endpoint in patients with progressive pre-treated malignant pleural mesothelioma. Indeed, this result is compatible with the current clinical experience with FGFR inhibitors in other tumours, showing that only a small subset of patients will have an objective response [23]. Whilst one patient had an unconfirmed partial response, this was not durable. Although we did not identify a positive biomarker signal from our analysis, some important lessons emerged. Whilst previous studies in cell lines and xenografts have demonstrated that BAP1 loss confers sensitivity to FGFR inhibition [21], the high frequency of BAP1 protein loss and lack of any association with outcome in our study suggests that it is unlikely to serve as a stand-alone biomarker in clinical practice. The absence of interpretable FGF9 signal in patient serum, taken together with the dynamic changes to FGF9 levels in pleural fluid suggests that the type of sample and the timing of biomarker sampling are important considerations for any future study. In view of the lack of treatment efficacy, further study of biomarkers from this patient cohort is unlikely to be informative. In contrast to previous studies using AZD4547, we did not observe any patients with PED [18,28,29]. Instead, we observed localised and diffuse subretinal fluid accumulation of mild severity, with the distribution of fluid resembling the phenotype of mitogen-activated protein kinase (MEK) inhibitor-associated retinopathy (MEKAR) [24–27]. This is a distinct entity that mimics but differs from a common cause of serous retinal detachment unrelated to the targeted therapy, central serous retinopathy, which is also characterised by PED and often exposure to corticosteroid. Indeed, the spectrum of ocular toxicities from AZD4547 is likely to be more diverse than documented in previous clinical studies. Following expert re-evaluation of the OCT scans of patients treated with AZD4547 in another study, some of the cases that were originally graded as PEDs were re-classified as localised subretinal fluid accumulation which were mild in severity, had minimal impact on visual function and were reversible on treatment discontinuation (unpublished data, AZ investigators brochure publication in preparation). Our study reaffirms that regular ophthalmological review is required for patients undergoing treatment with this drug but treatment of these asymptomatic and self-limiting subretinal fluid may not be necessary. Our study is the first to describe the efficacy and toxicity profile of AZD4547 in a patient population with malignant mesothelioma. Overall, we found that AZD4547 was tolerable although prolonged use was associated with persistent low-grade toxicities that may potentially
Acknowledgement We thank pathologist Dr Amber Louw for her help with tumour BAP1 immunohistochemistry. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.lungcan.2019.12.018. References [1] N.J. Vogelzang, J.J. Rusthoven, J. Symanowski, C. Denham, E. Kaukel, P. Ruffie, et al., Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma, J. Clin. Oncol. 21 (July (14)) (2003) 2636–2644. [2] G. Zalcman, J. Mazieres, J. Margery, L. Greillier, C. Audigier-Valette, D. MoroSibilot, et al., Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial, Lancet 387 (April (10026)) (2016) 1405–1414. [3] A.R.A. Razak, K.J. Chatten, A.N. Hughes, Retreatment with pemetrexed-based chemotherapy in malignant pleural mesothelioma (MPM): a second line treatment option, Lung Cancer 60 (May (2)) (2008) 294–297. [4] M.G. Zauderer, S.L. Kass, K. Woo, C.S. Sima, M.S. Ginsberg, L.M. Krug, Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma, Lung Cancer 84 (June (3)) (2014) 271–274. [5] E. Alley, J. Lopez, A. Santoro, A. Morosky, S. Saraf, B. Piperdi, et al., OA13.03 longterm overall survival for patients with malignant pleural mesothelioma on pembrolizumab enrolled in KEYNOTE-028, J. Thorac. Oncol. 12 (January (1)) (2017) S294. [6] M.J. Disselhorst, J. Quispel-Janssen, F. Lalezari, K. Monkhorst, J.F. de Vries, V. van der Noort, et al., Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial, Lancet Respir. Med. 7 (March (3)) (2019) 260–270. [7] A. Scherpereel, J. Mazieres, L. Greillier, S. Lantuejoul, P. Dô, O. Bylicki, et al., Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial, Lancet Oncol. 20 (February (2)) (2019) 239–253. [8] A. Beenken, M. Mohammadi, The FGF family: biology, pathophysiology and therapy, Nat. Rev. Drug Discov. 8 (March (3)) (2009) 235–253. [9] M. Katoh, H. Nakagama, FGF receptors: cancer biology and therapeutics, Med. Res. Rev. 34 (March (2)) (2014) 280–300. [10] L.A. Marek, T.K. Hinz, A. von Mässenhause, K.A. Olszewski, E.K. Kleczko, D. Böhm, et al., Non-amplified FGFR1 is a growth driver in malignant pleural mesothelioma, Mol. Cancer Res. 12 (October (10)) (2014) 1460–1469. [11] C. Blackwell, C. Sherk, M. Fricko, G. Ganji, M. Barnette, B. Hoang, et al., Inhibition of FGF/FGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP1039/GSK3052230, Oncotarget 7 (June (26)) (2016) 39861–39871.
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