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Toxicity management of regorafenib in patients with gastro-intestinal stromal tumour (GIST) in a tertiary cancer centre

Toxicity management of regorafenib in patients with gastro-intestinal stromal tumour (GIST) in a... Background: Regorafenib is a multi‑kinase inhibitor approved as third line treatment for metastatic GIST. Dose limit ‑ ing toxicities are frequently seen and many patients require dose reductions. This study aimed to evaluate regorafenib toxicities and their management in a real‑ world GIST population. Methods: Retrospective review of a prospectively maintained database identified 50 patients with GIST treated with regorafenib at our centre between March 2013 and September 2018. Results: Median progression free survival (PFS) was 7.7 months [interquartile range (IQR) 2.8–14.4 months]. Median overall survival (OS) from start of regorafenib to death or last follow up was 15.7 months (IQR 9.2–28.4 months). Base‑ line median Eastern Cooperative Oncology Group (ECOG) performance status on starting regorafenib was 1. The main reason for discontinuing regorafenib was progressive disease (PD) (31/50 [62%]) rather than toxicity (10/50 [20%]). Grade 3–4 adverse events (AEs) were seen in 23/50 (46%) patients; palmar‑plantar erythrodysesthesia (PPE) was most frequently seen (9/50 (18%)). Two patients died whilst on treatment with regorafenib from multi‑ organ failure second‑ ary to sepsis (4%). Dose reductions were required in 19/50 patients (38%) and 8/50 (16%) patients started regorafenib at a lower dose band than the recommended dose (160 mg) due to comorbidities or concern over a higher individual risk of toxicity. Conclusion: Although PD was the main reason for discontinuing treatment, toxicity management and dosing of regorafenib remains critical. Median duration of treatment was longer compared to previous studies suggesting a durable clinical benefit with regorafenib with rigorous toxicity management. Keywords: Gastro‑intestinal stromal tumour, Regorafenib, Sarcoma, Soft tissue sarcoma, Toxicity management Background common in patients over the age of 60  years with equal Gastro-intestinal stromal tumour (GIST) is a rare male and female predilection [1]. Approximately 60% tumour, with approximately 900 new cases per annum in of all GIST tumours arise in the stomach and 30% from the United Kingdom [1]. These tumours arise from mes - the small bowel; however, they may arise in any part of enchymal cells of the gastrointestinal tract and are more the gastro-intestinal tract [2]. Presenting symptoms are mostly dependent on the primary tumour site and fre- quently include overt or occult bleeding and abdominal *Correspondence: florence.chamberlain@nhs.net pain, although 15% of patients are asymptomatic and Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London SW6 present incidentally [1]. Whilst approximately 80% pre- 3JJ, UK Full list of author information is available at the end of the article sent with localised disease, 20% have locally advanced or © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 2 of 8 metastatic disease [1, 3]. 90% of GIST tumours express participants experiencing at least one all grade AE. Grade gain-of-function mutations in either KIT or PDGFR 5 AEs were seen with seven patients in the regorafenib genes, which code the tyrosine kinase receptors responsi- arm (5.3% patients) of which in two patients (1.5%) this ble for cell survival and proliferation. The remaining 10% was considered to be drug related (cardiac arrest and of GIST, have no KIT or PGGFR mutations and comprise hepatic failure) [8]. a heterogeneous molecular group of tumours [1]. Aims Current management guidelines Given the high rates of dose modifications seen, the aim Chemotherapy is ineffective in GIST [4, 5]; however, of this study was to evaluate whether increased expe- the development of targeted treatments in the form of rience with regorafenib has improved toxicity man- tyrosine kinase inhibitors (TKIs) targeting KIT, PDGFR agement, enabling longer duration of treatment in a and BCR-ABL has dramatically improved outcomes for real-world GIST population. Additionally, we examine GIST patients over the past 20  years [6–8]. TKIs block whether there was a correlation between the rates of AEs the tyrosine kinase receptors encoded by the KIT or and response to treatment. PDGFR genes leading to tumour cell death. In localised disease, the current standard of care is surgical resection, Methods and for high risk disease adjuvant imatinib for 3 years is A retrospective review of the prospectively maintained recommended [9] The results of a large randomised study Royal Marsden Sarcoma Unit database was performed to which compares 3 vs. 5  years of adjuvant imatinib are identify GIST patients treated with regorafenib between awaited [10]. March 2013 and September 2018. Institutional approval In the United Kingdom, there are three TKIs which was obtained prior to commencing the study. Details are currently licensed for use in GIST, namely imatinib of baseline characteristics and treatment history were [6], sunitinib [7] and regorafenib [8]. Response rate to recorded such as tumour size, location, mutational status imatinib in advanced or metastatic GIST is approxi- as well as patient age, treatment history and performance mately 80%, and median PFS is 2  years [7, 8]. Patients status. The diagnosis was confirmed in all cases by an with imatinib resistance or failure are offered the TKI expert soft tissue pathologist. sunitinib [7]. Third line treatment in the United Kingdom Re-staging scans were routinely performed every 2–3 is with the multi-kinase inhibitor regorafenib [8]. Clinical cycles of regorafenib. Response to systemic therapy was trial options are considered at each stage of management. assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 [14]. Radiological images Regorafenib for all patients were re-reviewed for this study. Clinical Regorafenib (BAY 73-4506,  Stivarga ) is an oral multi- notes were reviewed for documentation of AEs, physical kinase inhibitor with anti-angiogenic (VEGFR 1-3 and examination findings, vital signs and laboratory assess - TEK), anti-stromal (PDGFR and FGFR) and anti-tumour- ment and severity was graded by Common terminology igenic (KIT, RET, RAF1 and BRAF) properties with effi - criteria for adverse events (CTCAE) version 4.0 version cacy in pre-clinical [11] phase I/II [12, 13] and phase III 4.0 [15]. Toxicity was managed according to standard clinical studies for GIST [8]. In the phase III GRID trial institutional guidelines. Descriptive statistics were used median PFS was 4.8  months (IQR 1.4–9.2). There was as well as Kaplan–Meier methods and Mann–Whitney U no significant difference in OS between the regorafenib test. and placebo arms (HR 0.77, 95% CI 0.42–1.41, p = 0.199) which may be attributed to the cross-over between pla- Results cebo and regorafenib [8]. We identified 50 GIST patients treated with regorafenib Dose modifications are frequently seen with at the Royal Marsden Hospital between March 2013 and regorafenib and many patients require dose reductions or September 2018. treatment interruptions/discontinuation. In the phase II trial of regorafenib in GIST, the starting dose was 160 mg Baseline characteristics once daily (OD) for 3 weeks followed by 1 week off treat - Baseline characteristics are shown in Table 1. The median ment [13]. However, 82% of patients had dose modifica - age at diagnosis was 56.0  years (IQR 46.0–66.5  years). tions with this dose and required dose reductions. The Median ECOG performance status (PS) at baseline was phase III GRID study also used an intermittent dosing 1 and all patients had a baseline ECOG PS of ≤ 2. Eight- schedule with a starting dose of 160  mg OD. Again, the een patients were female (36%) and 32 were male (64%). rate of dose modifications was high (72%) with patients Agents used prior to regorafenib included imatinib frequently requiring dose reductions and nearly all (98%) (n = 49, 98%), sunitinib (n = 48, 96%), avapritinib (n = 2, Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 3 of 8 Table 1 Baseline clinical characteristics of 50 GIST patients 4%), sorafenib (n = 1, 2%), dasatinib (n = 1, 2%), nilo- treated with regorafenib tinib (n = 1, 2%) and a phase I clinical trial agent (n = 1, 2%). All patients were pre-treated with at least two lines Characteristic Total, n = 50 of treatment; 38 patients (76%) received regorafenib in Age at diagnosis (years) the third line, 10 patients (20%) in the fourth line, and 2 Median (IQR) 56.0 years (46.0–66.5 years) patients (4%) in the fifth line or beyond. Gender Female 18 (36%) Tumour characteristics Male 32 (64%) Most tumours originated either from the stomach Primary site (n = 21, 42%) or from the small bowel (n = 21, 42%). Stomach 21 (42%) Other primary tumour sites included the rectum (n = 2, Small bowel 21 (42%) 4%), the mesentery (n = 2, 4%), the oesophagus (n = 2, Large bowel 2 (4.0%) 4%) and the large bowel (n = 2, 4%). Primary tumour size Rectum 2 (4.0%) was recorded in 47 patients (94%) and median tumour Mesenteric 2 (4.0%) size at presentation was 12.0  cm (IQR 8.0–17  cm); one Oesophageal 2 (4.0%) patient (2%) presented with metastatic disease, one Line of treatment (regorafenib) patient (2%) with tumour rupture at presentation and in 3rd line 38 (76%) one patient (2%) size was not available. 4th line 10 (20%) Most patients had tumours harbouring mutations ≥ 5th line 2 (4%) in KIT (n = 31, 62%), followed by PDGFR (n = 6, 12%) Tumour size (cm) and the remaining had no mutations in KIT or PDG- Median (IQR) 12.0 (8.0–17.0) FRA (n = 4, 8%) (the characteristics of these patients are Mutation profile found in Table  2). Mutational status was unknown in KIT 31 (62%) nine patients (18%) due to insufficient tissue in the biopsy Exon 9 4 (8%) specimen. Most tumours had KIT exon 11 mutations Exon 11 24 (48%) (n = 24, 48%), followed by PDGFR exon 18 (n = 5, 10%) Exon 11 + 13 1 (2%) and KIT exon 9 (n = 4, 8%). Tumour profiles are summa - Exon 11 + 17 2 (4%) rised in Table 1. PDGFR 6 (12%) Exon 18 5 (10%) Treatment schedule Exon 12 + 18 1 (2%) In our institution, regorafenib was prescribed in the rec- WT 4 (8%) ommended and licensed intermittent dosing schedule Unknown 9 (18%) (160 mg daily, 3 weeks on, followed by 1 week off ). None Reason for discontinuing regorafenib were treated with the continuous schedule.. Median Progressive disease 31 (62%) duration of regorafenib treatment was 7.6  months (IQR Toxicity 10 (20%) 3.1–12.9  months). Dose reductions were required in 19 New comorbidity/contraindication 3 (6%) patients (38%) of which 14 patients (28%) required a dose Death 2 (4%) reduction to 120  mg and five patients (10%) required a Surgery planned 1 (2%) dose reduction to 80  mg. Reasons for dose reductions Withdrawal of consent to treatment 1 (2%) included PPE (n = 11, 22%), fatigue (n = 6, 12%), diar- N/A—patient continues regorafenib 2 (4%) rhoea (n = 2, 4%), hepatotoxicity (n = 2, 4%) and hyper- AE tension (n = 2, 4%). Of all the patients treated, eight (16%) Grade ≥ 3 23 (46%) started regorafenib at a lower dose band at the clinician’s Best response as per RECIST 1.1 discretion due to concerns about potential higher risk Stable disease 35 (70%) of toxicity (n = 3 patients started on 120  mg OD, n = 5 Partial response 4 (8%) patients started on 80  mg OD). None of the patients Progressive disease 4 (8%) starting on a lower dose band required dose interrup- Complete response 0 (0%) tions or reductions and none had a dose escalation. Not evaluable 7 (14%) Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 4 of 8 Table 2 WT GIST patients Patient KIT mutation PDGFR BRAF mutation SDHB expression Duration Best response Reason mutation on regorafenib to regorafenib for discontinuing (months) as per RECIST 1.1 regorafenib 1 No No No Normal 3.6 PR Toxicity 2 No No Unknown Unknown 18.3 SD PD 3 No No Unknown Unknown 2.9 SD PD 4 No No No Normal 6.7 SD PD Survival distribuon funcon 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Survival from start of regorafenib to death or last follow up (months) Fig. 1 Overall survival from start of regorafenib to death or last follow up Treatment response and adverse events at the time of analysis. In the two patients (4%) that Median OS from start of regorafenib to death or last died whilst on treatment, both died from multi-organ follow up was 15.7  months (IQR 9.2–28.4  months) failure secondary to severe sepsis which was unlikely (Fig.  1). Median PFS was 7.7  months (IQR 2.8– to be related to regorafenib and likely to be related to 14.4  months) (Fig.  2). The main reason for discontinu - advanced disease. ing regorafenib was progressive disease (n = 31, 62%) Overall clinical benefit rate (stable disease, partial rather than toxicity (n = 10, 20%). Other reasons for response and complete response) as per RECIST 1.1 discontinuing treatment included death (n = 2, 4%) and [14] at first radiological assessment was 76% (n = 38). withdrawal of consent to treatment (n = 1, 2%). Three Seven patients (14%) were not evaluable due to discon patients developed a new co-morbidity or contraindi- tinuation of regorafenib prior to their first response cation to regorafenib; two patients (4%) had a cerebro- assessment. Best response as per RECIST 1.1 [14] was vascular accident and one patient (2%) was diagnosed partial response (n = 4, 8%), whilst stable disease was with metastatic angiosarcoma requiring systemic seen in a further 70% (n = 35) as best response. chemotherapy. One patient (2%) withdrew consent to Four patients (8%) had progressive disease as their treatment and one patient (2%) had a planned surgi- best response to regorafenib [mutation status KIT cal resection of their GIST and discontinued treatment exon 11 (n = 1), exon 18 (n = 1) and unknown (n = 2)]. after this. Two patients (4%) are still on regorafenib Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 5 of 8 Survival distribuon funcon 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 05 10 15 20 25 30 Progression free survival from start of regorafenib to first progression (months) Fig. 2 Progression free survival from start of regorafenib to first progression These four patients had prior treatment with imatinib at first radiological assessment was 65.2% (n = 15) in the (median duration of treatment 40.4  months (IQR grade 3–4 toxicity group and was lower than those who 15.0–70.3  months)) and sunitinib [median duration did not experience grade 3–4 toxicity (n = 24, 88.9%). In of treatment 42.9  months (IQR 26.7–69.0  months)]. those patients with grade 3–4 toxicity, 4 patients (17.4%) Median ECOG PS on starting regorafenib was 1 in this were not evaluable due to discontinuation of regorafenib cohort. Of these four patients, all required dose reduc- prior to their first response assessment and best response tions within the first two cycles due to grade ≥ 3 PPE as per RECIST 1.1 [14] was partial response (n = 1, 4.3%), (n = 3) and fatigue (n = 1). Despite small numbers, whilst stable disease was seen in a further 60.9% (n = 14) median OS in this cohort from start of regorafenib to as best response. Ten patients (20%) discontinued death was 12.2  months (IQR 12.1–40.7  months) and regorafenib due to toxicity of which sixty percent (n = 6) median OS from diagnosis to death was 9.9 years (IQR did so due to grade 3–4 toxicity; none of which had a 9.3–12.4 years). dose reduction to manage their toxicity. Of the remain- Grade 3–4 AEs were seen in 23 (46%) patients; PPE ing four patients (40%) who discontinued regorafenib was the most frequently seen (n = 9 (18%)), followed by due to toxicity, these patients discontinued due to grade fatigue (n = 7 (14%)), hypertension (n = 4 (8%)), hepato- 1–2 toxicity (fatigue (n = 2), diarrhoea and hyperten- toxicity (n = 1 (2%)), diarrhoea (n = 1 (2%)) and arthral- sion (n = 1), fatigue and PPE (n = 1)). None of these four gia (n = 1 (2%)). Two patients (4%) had overlapping grade patients had a dose reduction to manage toxicity, but one 3–4 toxicity; PPE and fatigue (n = 1, 2%), PPE, diar- patient had started regorafenib at a lower dose (120 mg) rhoea and fatigue (n = 1, 2%). There was no statistically due to previous toxicity with sunitinib. significant difference in median duration of treatment At the time of analysis, 43 patients had died of disease between those who experienced grade 3–4 AEs com- (86%) and five were alive with advanced/- or metastatic pared to those who did not (7.2  months vs. 8.2  months; disease (10%). One patient (2%) was alive with no evi- p = 0.878). Overall clinical benefit as per RECIST 1.1 [14] dence of disease and the status of one patient (1%) was unknown as they had left the United Kingdom. Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 6 of 8 Discussion early dose adjustments when patients experience adverse The management of advanced and metastatic GIST has events. Forty percent of patients discontinuing treatment improved significantly over the last 20  years following due to toxicities did so because of lower grade toxici- the introduction of oral TKIs with median OS improv- ties. Therefore, it is important to carefully manage lower ing from < 24  months in the pre-imatinib era [5] to grade toxicities, bearing in mind that these can become 45–53  months since imatinib was introduced [16, 17]. unbearable when treatment is administered continuously This success is due to international collaborative research or with only minor breaks. efforts supported by academic, pharmaceutical and In our cohort, the most frequently seen grade ≥ 3 tox- charitable organisations. This collaborative approach has icities included PPE (n = 9) and fatigue (n = 7). PPE enabled several novel oral TKIs to undergo randomised typically presents within the first month of regorafenib clinical trials for GIST, including avapritinib in the NAVI- treatment and therefore careful clinical monitoring can GATOR trial [18] and VOYAGER trial [19] and ripretinib enable early detection and management which in turn in both the INVICTUS trial [20] and INTRIGUE trial reduces the severity of the clinical course. Patients should [21]. be advised to apply emollients regularly and given advice Despite these successes, several TKIs have not demon- on reducing skin trauma and pressure. Topical steroids strated an improvement in PFS or OS in GIST. The phase and analgesic agents can be prescribed and in lesions II PAZOGIST study compared pazopanib with best sup- grade ≥ 3 as well as oral analgesics. Fatigue should be portive care to best supportive care alone in heavily pre- managed firstly by managing any underlying medical treated GIST. There was no significant difference in PFS conditions such as anaemias or vitamin D deficiency. in the pazopanib arm compared to best supportive care Patients should be given advice about graded exercise, alone (3.4 vs. 2.3  months, HR 0.59, p = 0.03) [22]. Addi- sleep hygiene and nutritional support but dose modifica - tionally, the phase III study of nilotinib compared to best tions may be required in grade ≥ 3 fatigue [25]. supportive care in pre-treated GIST did not demonstrate This study serves as an effective tool for clinicians statistically significant improvements in PFS, although in counselling patients about the side effect profile of post hoc analysis revealed a statistically significant regorafenib in a real-world population of patients with improvement in OS with nilotinib compared to best sup- GIST following pre-treatment with at least another two portive care [23]. TKIs. Additionally, effective patient education about the Notwithstanding the limitations of retrospective data risks and side effects of regorafenib is essential to improv - collection, to our knowledge, this is the largest-published ing adherence and managing the toxicities. Treatment study of regorafenib in GIST in a non-trial population to at specialised centres is critical as is the role of clinical date [24]. All patients had their tumour biopsy specimen nurse specialists, ensuring ongoing patient education in reviewed by an expert soft tissue pathologist and their the side effects and toxicity management of regorafenib imaging reviewed again for inclusion into the study. PD and other TKIs [26]. rather than toxicity was the main reason for discontinu- In our study we have used RECIST 1.1 [14] to assess ing regorafenib treatment. In our study, Grade ≥ 3 AEs response to regorafenib therapy, however, we recognise occurred in 23/50 patients (46%) compared to 81/133 that there are several limitations in this tumour assess- patients (61%) in the 2012 GRID study. This demon - ment method in GIST. Many GISTs do not demonstrate strates that toxicity management may have improved any size reduction following initial treatment with TKIs with additional experience in using regorafenib in GIST. whereas there may be change in their density or enhance- Additionally, median duration of treatment was longer ment on imaging. Whilst RECIST 1.1 [14] only recog- in our cohort (32.9  weeks vs. 22.9  weeks) compared to nises a change in size and number of target lesions, the the GRID population. However, this may also reflect the Choi criteria [27] recognises changes in GIST lesion den- more stringent clinical study criteria for discontinuing a sity and enhancement. Therefore many centres use both trial treatment. RECIST 1.1 and Choi criteria to assess response to treat- Our data suggest that the safety profile of regorafenib ment [14, 27]. is acceptable, with AEs that can be managed through There are limited published data to confirm the optimal dose reductions, supportive medications and/or dose dosing schedule for regorafenib and in practice clinicians interruptions enabling sustained treatment in a non- use a range of different schedules (continuous dosing vs. trial population. Interestingly, in this cohort, none of the intermittent dosing). A single-centre retrospective review patients discontinuing regorafenib treatment due to tox- of post-marketing surveillance data of 28 patients treated icities had a dose reduction prior to discontinuation. This with regorafenib for GIST compared toxicity and efficacy might indicate that some of these discontinuations might of regorafenib amongst the different prescribing pat - have been preventable and emphasises the importance of terns. Despite small numbers, the study concluded that Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 7 of 8 Table 3 Grade ≥ 3 adverse events Grade ≥ 3 adverse events 2019 Royal Marsden % (n = 50) (%) 2017 study 2013 GRID study (n = 28) (%) (n = 132) (%) All grade ≥ 3 AEs 23 (46) 12 (42.9) 81 (61.4) PPE 9 (18) 5 (17.9) 26 (19.7) Fatigue 7 (14) 5 (17.9) 3 (2.3) Hypertension 4 (8) 2 (7.1) 31 (23.5) Hepatotoxicity 1 (2) 0 (0) 1 (0.8) Diarrhoea 1 (2) 2 (7.1) 7 (5.3) Arthralgia 1 (2) 0 (0) 1 (1%) Acknowledgements continuous dosing (120 mg OD) was more efficacious as The study authors would like to express their gratitude to the following for well as better tolerated compared to intermittent dos- the vital role they play in patient education and toxicity management for ing (160 mg OD for 3 weeks then 1 week off treatment). GIST patients: Melissa Balcorta—acute oncology advanced nurse practitioner; Elizabeth Barquin—lead sarcoma research nurse; Diego Bottero—sarcoma Median treatment duration was 7.3  months (range 0.9– research nurse; Alice Burridge—sarcoma research nurse; Alison Dunlop—sar‑ 18.8 months) [28]. Rates of toxicity were similar to those coma clinical nurse specialist; Steven Edmonds—sarcoma research nurse; Kelly in the GRID study [8] and are summarised in Table  3. McKibben—sarcoma clinical nurse specialist; Elaine Stephens—sarcoma clinical nurse specialist; Angela Teague—sarcoma clinical nurse specialist. In the randomised multicentre phase II ReDOS study of patients treated with regorafenib in advanced colorectal Authors’ contributions cancer, patients were randomised to four cohorts with FC, SF, CW‑S, CC, LC, OA‑M and DC: contributed to data collection. FC, SF, SM, BE contributed to data analysis and interpretation. All authors reviewed the different dosing strategies (80  mg OD with dose escala - manuscript and agreed on submission for publication. All authors read and tion, 160  mg OD, ± pre-emptive clobetasol propionate approved the final manuscript. cream). The study aimed at investigating if a dose esca - Funding lation, rather than de-escalation approach (with or with- Not applicable. out pre-emptive clobetasol propionate treatment) can improve toxicity management with regorafenib. The pri - Availability of data and materials The datasets used and/or analysed during the current study are available from mary endpoint was met for this study and a dose esca- the corresponding author on reasonable request. lation approach was found to increase the number of patients in each arm who completed 2 cycles of treat- Ethics approval and consent to participate Not applicable. ment without interruption in the absence of PD [29]. Consent for publication Not applicable. Conclusion Our experience in a tertiary sarcoma centre suggests that Competing interests RLJ: Receipt of honoraria and consultation fees (Adaptimmune; Blueprint; prolonged treatment with regorafenib following at least Clinigen; Eisai; Epizyme; Daichii; Deciphera; Immunedesign; Lilly; Merck; Phar‑ two lines of treatment can be achieved with careful tox- mamar). The rest of the authors declare that they have no competing interests. icity management. This includes the use of supportive Author details treatments, dose interruptions and dose modifications Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London SW6 3JJ, allowing for a durable clinical benefit. Patients should be 2 3 UK. The Institute of Cancer Research, London SW7 3RP, UK. University Hospi‑ provided with detailed information and education about tals Birmingham NHS Foundation Trust, Birmingham B15 2GW, UK. toxicity management and support from the wider multi- Received: 14 September 2019 Accepted: 10 December 2019 disciplinary team to enable this. Further studies into the different dosing strategies of regorafenib in GIST would be informative. References 1. Judson I, Bulusu R, Seddon B, Dangoor A, Wong N, Mudan S. UK clinical Abbreviations practice guidelines for the management of gastrointestinal stromal AE: adverse events; CI: confidence interval; CTCAE: common terminology tumours (GIST ). Clin Sarcoma Res. 2017;7(1):6. criteria for adverse events; ECOG: Eastern Cooperative Oncology Group; GIST: 2. Starczewska Amelio JM, Cid Ruzafa J, Desai K, Tzivelekis S, Muston D, gastro‑intestinal stromal tumour; HR: hazard ratio; IQR: interquartile range; Khalid JM, et al. 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Three versus five years of adjuvant imatinib as treatment tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol. of patients with operable GIST. U.S. Natl. Libr. Med. 2015 https ://clini caltr 2012;23(7):1680–7. ials.gov/ct2/show/NCT02 41373 6. Accessed 11 June 2019. 24. Mir O, Brodowicz T, Italiano A, Wallet J, Blay JY, Bertucci F, et al. Safety and 11. Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, et al. efficacy of regorafenib in patients with advanced soft tissue sarcoma Regorafenib (BAY 73‑4506): a new oral multikinase inhibitor of angio ‑ (REGOSARC): a randomised, double‑blind, placebo ‑ controlled, phase 2 genic, stromal and oncogenic receptor tyrosine kinases with potent trial. Lancet Oncol. 2016;17(12):1732–42. preclinical antitumor activity. Int J Cancer. 2011;129(1):245–55. 25. Krishnamoorthy SK, Relias V, Sebastian S, Jayaraman V, Saif MW. Manage‑ 12. Mross K, Frost A, Steinbild S, Hedbom S, Büchert M, Fasol U, et al. 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Springer Journals
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Copyright © 2020 by The Author(s)
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Biomedicine; Cancer Research; Oncology; Surgical Oncology
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10.1186/s13569-019-0123-4
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Abstract

Background: Regorafenib is a multi‑kinase inhibitor approved as third line treatment for metastatic GIST. Dose limit ‑ ing toxicities are frequently seen and many patients require dose reductions. This study aimed to evaluate regorafenib toxicities and their management in a real‑ world GIST population. Methods: Retrospective review of a prospectively maintained database identified 50 patients with GIST treated with regorafenib at our centre between March 2013 and September 2018. Results: Median progression free survival (PFS) was 7.7 months [interquartile range (IQR) 2.8–14.4 months]. Median overall survival (OS) from start of regorafenib to death or last follow up was 15.7 months (IQR 9.2–28.4 months). Base‑ line median Eastern Cooperative Oncology Group (ECOG) performance status on starting regorafenib was 1. The main reason for discontinuing regorafenib was progressive disease (PD) (31/50 [62%]) rather than toxicity (10/50 [20%]). Grade 3–4 adverse events (AEs) were seen in 23/50 (46%) patients; palmar‑plantar erythrodysesthesia (PPE) was most frequently seen (9/50 (18%)). Two patients died whilst on treatment with regorafenib from multi‑ organ failure second‑ ary to sepsis (4%). Dose reductions were required in 19/50 patients (38%) and 8/50 (16%) patients started regorafenib at a lower dose band than the recommended dose (160 mg) due to comorbidities or concern over a higher individual risk of toxicity. Conclusion: Although PD was the main reason for discontinuing treatment, toxicity management and dosing of regorafenib remains critical. Median duration of treatment was longer compared to previous studies suggesting a durable clinical benefit with regorafenib with rigorous toxicity management. Keywords: Gastro‑intestinal stromal tumour, Regorafenib, Sarcoma, Soft tissue sarcoma, Toxicity management Background common in patients over the age of 60  years with equal Gastro-intestinal stromal tumour (GIST) is a rare male and female predilection [1]. Approximately 60% tumour, with approximately 900 new cases per annum in of all GIST tumours arise in the stomach and 30% from the United Kingdom [1]. These tumours arise from mes - the small bowel; however, they may arise in any part of enchymal cells of the gastrointestinal tract and are more the gastro-intestinal tract [2]. Presenting symptoms are mostly dependent on the primary tumour site and fre- quently include overt or occult bleeding and abdominal *Correspondence: florence.chamberlain@nhs.net pain, although 15% of patients are asymptomatic and Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London SW6 present incidentally [1]. Whilst approximately 80% pre- 3JJ, UK Full list of author information is available at the end of the article sent with localised disease, 20% have locally advanced or © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 2 of 8 metastatic disease [1, 3]. 90% of GIST tumours express participants experiencing at least one all grade AE. Grade gain-of-function mutations in either KIT or PDGFR 5 AEs were seen with seven patients in the regorafenib genes, which code the tyrosine kinase receptors responsi- arm (5.3% patients) of which in two patients (1.5%) this ble for cell survival and proliferation. The remaining 10% was considered to be drug related (cardiac arrest and of GIST, have no KIT or PGGFR mutations and comprise hepatic failure) [8]. a heterogeneous molecular group of tumours [1]. Aims Current management guidelines Given the high rates of dose modifications seen, the aim Chemotherapy is ineffective in GIST [4, 5]; however, of this study was to evaluate whether increased expe- the development of targeted treatments in the form of rience with regorafenib has improved toxicity man- tyrosine kinase inhibitors (TKIs) targeting KIT, PDGFR agement, enabling longer duration of treatment in a and BCR-ABL has dramatically improved outcomes for real-world GIST population. Additionally, we examine GIST patients over the past 20  years [6–8]. TKIs block whether there was a correlation between the rates of AEs the tyrosine kinase receptors encoded by the KIT or and response to treatment. PDGFR genes leading to tumour cell death. In localised disease, the current standard of care is surgical resection, Methods and for high risk disease adjuvant imatinib for 3 years is A retrospective review of the prospectively maintained recommended [9] The results of a large randomised study Royal Marsden Sarcoma Unit database was performed to which compares 3 vs. 5  years of adjuvant imatinib are identify GIST patients treated with regorafenib between awaited [10]. March 2013 and September 2018. Institutional approval In the United Kingdom, there are three TKIs which was obtained prior to commencing the study. Details are currently licensed for use in GIST, namely imatinib of baseline characteristics and treatment history were [6], sunitinib [7] and regorafenib [8]. Response rate to recorded such as tumour size, location, mutational status imatinib in advanced or metastatic GIST is approxi- as well as patient age, treatment history and performance mately 80%, and median PFS is 2  years [7, 8]. Patients status. The diagnosis was confirmed in all cases by an with imatinib resistance or failure are offered the TKI expert soft tissue pathologist. sunitinib [7]. Third line treatment in the United Kingdom Re-staging scans were routinely performed every 2–3 is with the multi-kinase inhibitor regorafenib [8]. Clinical cycles of regorafenib. Response to systemic therapy was trial options are considered at each stage of management. assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 [14]. Radiological images Regorafenib for all patients were re-reviewed for this study. Clinical Regorafenib (BAY 73-4506,  Stivarga ) is an oral multi- notes were reviewed for documentation of AEs, physical kinase inhibitor with anti-angiogenic (VEGFR 1-3 and examination findings, vital signs and laboratory assess - TEK), anti-stromal (PDGFR and FGFR) and anti-tumour- ment and severity was graded by Common terminology igenic (KIT, RET, RAF1 and BRAF) properties with effi - criteria for adverse events (CTCAE) version 4.0 version cacy in pre-clinical [11] phase I/II [12, 13] and phase III 4.0 [15]. Toxicity was managed according to standard clinical studies for GIST [8]. In the phase III GRID trial institutional guidelines. Descriptive statistics were used median PFS was 4.8  months (IQR 1.4–9.2). There was as well as Kaplan–Meier methods and Mann–Whitney U no significant difference in OS between the regorafenib test. and placebo arms (HR 0.77, 95% CI 0.42–1.41, p = 0.199) which may be attributed to the cross-over between pla- Results cebo and regorafenib [8]. We identified 50 GIST patients treated with regorafenib Dose modifications are frequently seen with at the Royal Marsden Hospital between March 2013 and regorafenib and many patients require dose reductions or September 2018. treatment interruptions/discontinuation. In the phase II trial of regorafenib in GIST, the starting dose was 160 mg Baseline characteristics once daily (OD) for 3 weeks followed by 1 week off treat - Baseline characteristics are shown in Table 1. The median ment [13]. However, 82% of patients had dose modifica - age at diagnosis was 56.0  years (IQR 46.0–66.5  years). tions with this dose and required dose reductions. The Median ECOG performance status (PS) at baseline was phase III GRID study also used an intermittent dosing 1 and all patients had a baseline ECOG PS of ≤ 2. Eight- schedule with a starting dose of 160  mg OD. Again, the een patients were female (36%) and 32 were male (64%). rate of dose modifications was high (72%) with patients Agents used prior to regorafenib included imatinib frequently requiring dose reductions and nearly all (98%) (n = 49, 98%), sunitinib (n = 48, 96%), avapritinib (n = 2, Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 3 of 8 Table 1 Baseline clinical characteristics of 50 GIST patients 4%), sorafenib (n = 1, 2%), dasatinib (n = 1, 2%), nilo- treated with regorafenib tinib (n = 1, 2%) and a phase I clinical trial agent (n = 1, 2%). All patients were pre-treated with at least two lines Characteristic Total, n = 50 of treatment; 38 patients (76%) received regorafenib in Age at diagnosis (years) the third line, 10 patients (20%) in the fourth line, and 2 Median (IQR) 56.0 years (46.0–66.5 years) patients (4%) in the fifth line or beyond. Gender Female 18 (36%) Tumour characteristics Male 32 (64%) Most tumours originated either from the stomach Primary site (n = 21, 42%) or from the small bowel (n = 21, 42%). Stomach 21 (42%) Other primary tumour sites included the rectum (n = 2, Small bowel 21 (42%) 4%), the mesentery (n = 2, 4%), the oesophagus (n = 2, Large bowel 2 (4.0%) 4%) and the large bowel (n = 2, 4%). Primary tumour size Rectum 2 (4.0%) was recorded in 47 patients (94%) and median tumour Mesenteric 2 (4.0%) size at presentation was 12.0  cm (IQR 8.0–17  cm); one Oesophageal 2 (4.0%) patient (2%) presented with metastatic disease, one Line of treatment (regorafenib) patient (2%) with tumour rupture at presentation and in 3rd line 38 (76%) one patient (2%) size was not available. 4th line 10 (20%) Most patients had tumours harbouring mutations ≥ 5th line 2 (4%) in KIT (n = 31, 62%), followed by PDGFR (n = 6, 12%) Tumour size (cm) and the remaining had no mutations in KIT or PDG- Median (IQR) 12.0 (8.0–17.0) FRA (n = 4, 8%) (the characteristics of these patients are Mutation profile found in Table  2). Mutational status was unknown in KIT 31 (62%) nine patients (18%) due to insufficient tissue in the biopsy Exon 9 4 (8%) specimen. Most tumours had KIT exon 11 mutations Exon 11 24 (48%) (n = 24, 48%), followed by PDGFR exon 18 (n = 5, 10%) Exon 11 + 13 1 (2%) and KIT exon 9 (n = 4, 8%). Tumour profiles are summa - Exon 11 + 17 2 (4%) rised in Table 1. PDGFR 6 (12%) Exon 18 5 (10%) Treatment schedule Exon 12 + 18 1 (2%) In our institution, regorafenib was prescribed in the rec- WT 4 (8%) ommended and licensed intermittent dosing schedule Unknown 9 (18%) (160 mg daily, 3 weeks on, followed by 1 week off ). None Reason for discontinuing regorafenib were treated with the continuous schedule.. Median Progressive disease 31 (62%) duration of regorafenib treatment was 7.6  months (IQR Toxicity 10 (20%) 3.1–12.9  months). Dose reductions were required in 19 New comorbidity/contraindication 3 (6%) patients (38%) of which 14 patients (28%) required a dose Death 2 (4%) reduction to 120  mg and five patients (10%) required a Surgery planned 1 (2%) dose reduction to 80  mg. Reasons for dose reductions Withdrawal of consent to treatment 1 (2%) included PPE (n = 11, 22%), fatigue (n = 6, 12%), diar- N/A—patient continues regorafenib 2 (4%) rhoea (n = 2, 4%), hepatotoxicity (n = 2, 4%) and hyper- AE tension (n = 2, 4%). Of all the patients treated, eight (16%) Grade ≥ 3 23 (46%) started regorafenib at a lower dose band at the clinician’s Best response as per RECIST 1.1 discretion due to concerns about potential higher risk Stable disease 35 (70%) of toxicity (n = 3 patients started on 120  mg OD, n = 5 Partial response 4 (8%) patients started on 80  mg OD). None of the patients Progressive disease 4 (8%) starting on a lower dose band required dose interrup- Complete response 0 (0%) tions or reductions and none had a dose escalation. Not evaluable 7 (14%) Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 4 of 8 Table 2 WT GIST patients Patient KIT mutation PDGFR BRAF mutation SDHB expression Duration Best response Reason mutation on regorafenib to regorafenib for discontinuing (months) as per RECIST 1.1 regorafenib 1 No No No Normal 3.6 PR Toxicity 2 No No Unknown Unknown 18.3 SD PD 3 No No Unknown Unknown 2.9 SD PD 4 No No No Normal 6.7 SD PD Survival distribuon funcon 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Survival from start of regorafenib to death or last follow up (months) Fig. 1 Overall survival from start of regorafenib to death or last follow up Treatment response and adverse events at the time of analysis. In the two patients (4%) that Median OS from start of regorafenib to death or last died whilst on treatment, both died from multi-organ follow up was 15.7  months (IQR 9.2–28.4  months) failure secondary to severe sepsis which was unlikely (Fig.  1). Median PFS was 7.7  months (IQR 2.8– to be related to regorafenib and likely to be related to 14.4  months) (Fig.  2). The main reason for discontinu - advanced disease. ing regorafenib was progressive disease (n = 31, 62%) Overall clinical benefit rate (stable disease, partial rather than toxicity (n = 10, 20%). Other reasons for response and complete response) as per RECIST 1.1 discontinuing treatment included death (n = 2, 4%) and [14] at first radiological assessment was 76% (n = 38). withdrawal of consent to treatment (n = 1, 2%). Three Seven patients (14%) were not evaluable due to discon patients developed a new co-morbidity or contraindi- tinuation of regorafenib prior to their first response cation to regorafenib; two patients (4%) had a cerebro- assessment. Best response as per RECIST 1.1 [14] was vascular accident and one patient (2%) was diagnosed partial response (n = 4, 8%), whilst stable disease was with metastatic angiosarcoma requiring systemic seen in a further 70% (n = 35) as best response. chemotherapy. One patient (2%) withdrew consent to Four patients (8%) had progressive disease as their treatment and one patient (2%) had a planned surgi- best response to regorafenib [mutation status KIT cal resection of their GIST and discontinued treatment exon 11 (n = 1), exon 18 (n = 1) and unknown (n = 2)]. after this. Two patients (4%) are still on regorafenib Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 5 of 8 Survival distribuon funcon 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 05 10 15 20 25 30 Progression free survival from start of regorafenib to first progression (months) Fig. 2 Progression free survival from start of regorafenib to first progression These four patients had prior treatment with imatinib at first radiological assessment was 65.2% (n = 15) in the (median duration of treatment 40.4  months (IQR grade 3–4 toxicity group and was lower than those who 15.0–70.3  months)) and sunitinib [median duration did not experience grade 3–4 toxicity (n = 24, 88.9%). In of treatment 42.9  months (IQR 26.7–69.0  months)]. those patients with grade 3–4 toxicity, 4 patients (17.4%) Median ECOG PS on starting regorafenib was 1 in this were not evaluable due to discontinuation of regorafenib cohort. Of these four patients, all required dose reduc- prior to their first response assessment and best response tions within the first two cycles due to grade ≥ 3 PPE as per RECIST 1.1 [14] was partial response (n = 1, 4.3%), (n = 3) and fatigue (n = 1). Despite small numbers, whilst stable disease was seen in a further 60.9% (n = 14) median OS in this cohort from start of regorafenib to as best response. Ten patients (20%) discontinued death was 12.2  months (IQR 12.1–40.7  months) and regorafenib due to toxicity of which sixty percent (n = 6) median OS from diagnosis to death was 9.9 years (IQR did so due to grade 3–4 toxicity; none of which had a 9.3–12.4 years). dose reduction to manage their toxicity. Of the remain- Grade 3–4 AEs were seen in 23 (46%) patients; PPE ing four patients (40%) who discontinued regorafenib was the most frequently seen (n = 9 (18%)), followed by due to toxicity, these patients discontinued due to grade fatigue (n = 7 (14%)), hypertension (n = 4 (8%)), hepato- 1–2 toxicity (fatigue (n = 2), diarrhoea and hyperten- toxicity (n = 1 (2%)), diarrhoea (n = 1 (2%)) and arthral- sion (n = 1), fatigue and PPE (n = 1)). None of these four gia (n = 1 (2%)). Two patients (4%) had overlapping grade patients had a dose reduction to manage toxicity, but one 3–4 toxicity; PPE and fatigue (n = 1, 2%), PPE, diar- patient had started regorafenib at a lower dose (120 mg) rhoea and fatigue (n = 1, 2%). There was no statistically due to previous toxicity with sunitinib. significant difference in median duration of treatment At the time of analysis, 43 patients had died of disease between those who experienced grade 3–4 AEs com- (86%) and five were alive with advanced/- or metastatic pared to those who did not (7.2  months vs. 8.2  months; disease (10%). One patient (2%) was alive with no evi- p = 0.878). Overall clinical benefit as per RECIST 1.1 [14] dence of disease and the status of one patient (1%) was unknown as they had left the United Kingdom. Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 6 of 8 Discussion early dose adjustments when patients experience adverse The management of advanced and metastatic GIST has events. Forty percent of patients discontinuing treatment improved significantly over the last 20  years following due to toxicities did so because of lower grade toxici- the introduction of oral TKIs with median OS improv- ties. Therefore, it is important to carefully manage lower ing from < 24  months in the pre-imatinib era [5] to grade toxicities, bearing in mind that these can become 45–53  months since imatinib was introduced [16, 17]. unbearable when treatment is administered continuously This success is due to international collaborative research or with only minor breaks. efforts supported by academic, pharmaceutical and In our cohort, the most frequently seen grade ≥ 3 tox- charitable organisations. This collaborative approach has icities included PPE (n = 9) and fatigue (n = 7). PPE enabled several novel oral TKIs to undergo randomised typically presents within the first month of regorafenib clinical trials for GIST, including avapritinib in the NAVI- treatment and therefore careful clinical monitoring can GATOR trial [18] and VOYAGER trial [19] and ripretinib enable early detection and management which in turn in both the INVICTUS trial [20] and INTRIGUE trial reduces the severity of the clinical course. Patients should [21]. be advised to apply emollients regularly and given advice Despite these successes, several TKIs have not demon- on reducing skin trauma and pressure. Topical steroids strated an improvement in PFS or OS in GIST. The phase and analgesic agents can be prescribed and in lesions II PAZOGIST study compared pazopanib with best sup- grade ≥ 3 as well as oral analgesics. Fatigue should be portive care to best supportive care alone in heavily pre- managed firstly by managing any underlying medical treated GIST. There was no significant difference in PFS conditions such as anaemias or vitamin D deficiency. in the pazopanib arm compared to best supportive care Patients should be given advice about graded exercise, alone (3.4 vs. 2.3  months, HR 0.59, p = 0.03) [22]. Addi- sleep hygiene and nutritional support but dose modifica - tionally, the phase III study of nilotinib compared to best tions may be required in grade ≥ 3 fatigue [25]. supportive care in pre-treated GIST did not demonstrate This study serves as an effective tool for clinicians statistically significant improvements in PFS, although in counselling patients about the side effect profile of post hoc analysis revealed a statistically significant regorafenib in a real-world population of patients with improvement in OS with nilotinib compared to best sup- GIST following pre-treatment with at least another two portive care [23]. TKIs. Additionally, effective patient education about the Notwithstanding the limitations of retrospective data risks and side effects of regorafenib is essential to improv - collection, to our knowledge, this is the largest-published ing adherence and managing the toxicities. Treatment study of regorafenib in GIST in a non-trial population to at specialised centres is critical as is the role of clinical date [24]. All patients had their tumour biopsy specimen nurse specialists, ensuring ongoing patient education in reviewed by an expert soft tissue pathologist and their the side effects and toxicity management of regorafenib imaging reviewed again for inclusion into the study. PD and other TKIs [26]. rather than toxicity was the main reason for discontinu- In our study we have used RECIST 1.1 [14] to assess ing regorafenib treatment. In our study, Grade ≥ 3 AEs response to regorafenib therapy, however, we recognise occurred in 23/50 patients (46%) compared to 81/133 that there are several limitations in this tumour assess- patients (61%) in the 2012 GRID study. This demon - ment method in GIST. Many GISTs do not demonstrate strates that toxicity management may have improved any size reduction following initial treatment with TKIs with additional experience in using regorafenib in GIST. whereas there may be change in their density or enhance- Additionally, median duration of treatment was longer ment on imaging. Whilst RECIST 1.1 [14] only recog- in our cohort (32.9  weeks vs. 22.9  weeks) compared to nises a change in size and number of target lesions, the the GRID population. However, this may also reflect the Choi criteria [27] recognises changes in GIST lesion den- more stringent clinical study criteria for discontinuing a sity and enhancement. Therefore many centres use both trial treatment. RECIST 1.1 and Choi criteria to assess response to treat- Our data suggest that the safety profile of regorafenib ment [14, 27]. is acceptable, with AEs that can be managed through There are limited published data to confirm the optimal dose reductions, supportive medications and/or dose dosing schedule for regorafenib and in practice clinicians interruptions enabling sustained treatment in a non- use a range of different schedules (continuous dosing vs. trial population. Interestingly, in this cohort, none of the intermittent dosing). A single-centre retrospective review patients discontinuing regorafenib treatment due to tox- of post-marketing surveillance data of 28 patients treated icities had a dose reduction prior to discontinuation. This with regorafenib for GIST compared toxicity and efficacy might indicate that some of these discontinuations might of regorafenib amongst the different prescribing pat - have been preventable and emphasises the importance of terns. Despite small numbers, the study concluded that Chamberlain et al. Clin Sarcoma Res (2020) 10:1 Page 7 of 8 Table 3 Grade ≥ 3 adverse events Grade ≥ 3 adverse events 2019 Royal Marsden % (n = 50) (%) 2017 study 2013 GRID study (n = 28) (%) (n = 132) (%) All grade ≥ 3 AEs 23 (46) 12 (42.9) 81 (61.4) PPE 9 (18) 5 (17.9) 26 (19.7) Fatigue 7 (14) 5 (17.9) 3 (2.3) Hypertension 4 (8) 2 (7.1) 31 (23.5) Hepatotoxicity 1 (2) 0 (0) 1 (0.8) Diarrhoea 1 (2) 2 (7.1) 7 (5.3) Arthralgia 1 (2) 0 (0) 1 (1%) Acknowledgements continuous dosing (120 mg OD) was more efficacious as The study authors would like to express their gratitude to the following for well as better tolerated compared to intermittent dos- the vital role they play in patient education and toxicity management for ing (160 mg OD for 3 weeks then 1 week off treatment). GIST patients: Melissa Balcorta—acute oncology advanced nurse practitioner; Elizabeth Barquin—lead sarcoma research nurse; Diego Bottero—sarcoma Median treatment duration was 7.3  months (range 0.9– research nurse; Alice Burridge—sarcoma research nurse; Alison Dunlop—sar‑ 18.8 months) [28]. Rates of toxicity were similar to those coma clinical nurse specialist; Steven Edmonds—sarcoma research nurse; Kelly in the GRID study [8] and are summarised in Table  3. McKibben—sarcoma clinical nurse specialist; Elaine Stephens—sarcoma clinical nurse specialist; Angela Teague—sarcoma clinical nurse specialist. In the randomised multicentre phase II ReDOS study of patients treated with regorafenib in advanced colorectal Authors’ contributions cancer, patients were randomised to four cohorts with FC, SF, CW‑S, CC, LC, OA‑M and DC: contributed to data collection. FC, SF, SM, BE contributed to data analysis and interpretation. All authors reviewed the different dosing strategies (80  mg OD with dose escala - manuscript and agreed on submission for publication. All authors read and tion, 160  mg OD, ± pre-emptive clobetasol propionate approved the final manuscript. cream). The study aimed at investigating if a dose esca - Funding lation, rather than de-escalation approach (with or with- Not applicable. out pre-emptive clobetasol propionate treatment) can improve toxicity management with regorafenib. The pri - Availability of data and materials The datasets used and/or analysed during the current study are available from mary endpoint was met for this study and a dose esca- the corresponding author on reasonable request. lation approach was found to increase the number of patients in each arm who completed 2 cycles of treat- Ethics approval and consent to participate Not applicable. ment without interruption in the absence of PD [29]. Consent for publication Not applicable. Conclusion Our experience in a tertiary sarcoma centre suggests that Competing interests RLJ: Receipt of honoraria and consultation fees (Adaptimmune; Blueprint; prolonged treatment with regorafenib following at least Clinigen; Eisai; Epizyme; Daichii; Deciphera; Immunedesign; Lilly; Merck; Phar‑ two lines of treatment can be achieved with careful tox- mamar). The rest of the authors declare that they have no competing interests. icity management. This includes the use of supportive Author details treatments, dose interruptions and dose modifications Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London SW6 3JJ, allowing for a durable clinical benefit. Patients should be 2 3 UK. The Institute of Cancer Research, London SW7 3RP, UK. University Hospi‑ provided with detailed information and education about tals Birmingham NHS Foundation Trust, Birmingham B15 2GW, UK. toxicity management and support from the wider multi- Received: 14 September 2019 Accepted: 10 December 2019 disciplinary team to enable this. Further studies into the different dosing strategies of regorafenib in GIST would be informative. References 1. Judson I, Bulusu R, Seddon B, Dangoor A, Wong N, Mudan S. UK clinical Abbreviations practice guidelines for the management of gastrointestinal stromal AE: adverse events; CI: confidence interval; CTCAE: common terminology tumours (GIST ). Clin Sarcoma Res. 2017;7(1):6. criteria for adverse events; ECOG: Eastern Cooperative Oncology Group; GIST: 2. Starczewska Amelio JM, Cid Ruzafa J, Desai K, Tzivelekis S, Muston D, gastro‑intestinal stromal tumour; HR: hazard ratio; IQR: interquartile range; Khalid JM, et al. 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Clinical Sarcoma ResearchSpringer Journals

Published: Dec 1, 2020

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