Hand-foot skin reaction (HFSR) and overall survival (OS) in the phase 3 RESORCE trial of regorafenib for treatment of hepatocellular carcinoma (HCC) progressing on sorafenib.

Bruix, Jordi; Merle, Philippe; Granito, Alessandro; Huang, Yi‐Hsiang; Bodoky, G.; Yokosuka, Osamu; Rosmorduc, Olivier; Breder, Valeriy Vladimirovich; Gerolami, René; Masi, Gianluca; Ross, Paul; Qin, Shukui; Song, Tianqiang; Bronowicki, Jean–Pierre; Ollivier-Hourmand, Isabelle; Kudo, Masatoshi; Xu, Lei; Baumhauer, Annette; Meinhardt, Gerold; Han, Guohong

doi:10.1200/jco.2018.36.4_suppl.412

Cited by 47 publications

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“…Regorafenib-related diarrhea was reported less frequently in this study than in CORRECT, perhaps related to dietary differences between populations. The relationship between HFSR and OS with regorafenib in this study confirms the findings of retrospective analyses from CORRECT in mCRC and RESORCE in HCC, in which patients who had HFSR had a greater treatment benefit with regorafenib than those without HFSR [23,24]. Although the development of HFSR has been associated with better outcomes with regorafenib and other multikinase inhibitors, oncologists should not pursue the occurrence of HFSR by increasing regorafenib dose intensity, but instead should follow the recommended dose modifications for grade 2 HFSR.…”

Section: Discussionsupporting

confidence: 86%

Regorafenib in Patients with Antiangiogenic-Naïve and Chemotherapy-Refractory Advanced Colorectal Cancer: Results from a Phase IIb Trial

et al. 2019

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Background Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy‐naïve chemotherapy‐refractory advanced colorectal cancer. Patients and Methods This single‐center, single‐arm, phase IIb study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy‐naïve. Patients received regorafenib 160 mg once daily for 3 weeks per 4‐week cycle. The primary endpoint was progression‐free survival (PFS) rate at week 8. Results Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1–64.3); median PFS was 3.5 months (95% CI, 1.8–3.6). Median OS was 7.4 months (95% CI, 5.3–8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib‐related grade ≥3 adverse events were hypertension (36%), hand–foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib‐related deaths. An exploratory analysis showed that patients with grade ≥2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0–1 (5.4 months). Conclusion These findings support the antitumor activity of regorafenib in antiangiogenic‐naïve patients with chemotherapy‐refractory mCRC. Implications for Practice The multikinase inhibitor regorafenib improved overall survival in the phase III CORRECT and CONCUR trials in heavily pretreated patients with treatment‐refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single‐center, single‐arm phase IIb study, regorafenib demonstrated antitumor activity in 59 antiangiogenic‐naïve patients with chemotherapy‐refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand–foot skin reaction.

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Section: Discussionsupporting

confidence: 86%

Regorafenib in Patients with Antiangiogenic-Naïve and Chemotherapy-Refractory Advanced Colorectal Cancer: Results from a Phase IIb Trial

et al. 2019

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“…Studies in renal cell carcinoma and thyroid carcinoma have reinforced the potential association between sorafenib‐related dermatologic adverse events and better overall survival . In addition, the impact of dermatologic adverse events has also been recently suggested in hepatocellular carcinoma and colorectal cancer patients treated with regorafenib . Untill now, sorafenib is the mainstay of systemic therapy for hepatocellular carcinoma even if immunomodulatory agents surpass it in the currently ongoing phase 3 trials, it will keep its relevant role in the treatment of this cancer.…”

Section: Introductionmentioning

confidence: 99%

Systematic review with meta‐analysis: the critical role of dermatological events in patients with hepatocellular carcinoma treated with sorafenib

Díaz-González

Sanduzzi‐Zamparelli

Sapena

et al. 2019

Aliment Pharmacol Ther

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Background: The positive results of the REFLECT trial in terms of survival (sorafenib vs lenvatinib) offer a new first-line option for hepatocellular carcinoma. Additionally, the expected results of immunotherapy could change the first-line treatment in hepatocellular carcinoma or the clinical trial design in first and second-line. Aims: To evaluate the impact of dermatologic adverse events under sorafenib in hepatocellular carcinoma patients as a clinical marker to predict prognosis and critically evaluate outcomes within trials. Methods: A systematic search of original articles published until October 2018 was performed using PubMed/MEDLINE and a meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.Results: A total of 393 studies were identified and 13 articles with 2035 patients (79.5% Child-Pugh-A, 73.2% BCLC-C) were selected for qualitative and quantitative analysis. The main type of dermatologic adverse events was hand-foot skin reaction (47.7%) but other dermatologic adverse events were reported in 31.7% of the cases.Presence of dermatologic adverse events was associated with a lower mortality when compared with those patients without them (pooled Hazard Ratio for the univariate analysis 0.45 (95% CI: 0.38-0.53) and there was no heterogeneity for the analysis (P = 0.511; I 2 = 0.0%). Refuting this association would require the future report of 1370 negative studies. Conclusions:This meta-analysis shows a clinically meaningful association between dermatologic adverse events and a higher probability of longer survival. These data support the use of dermatologic adverse events in the clinical decision-making when informing the prognosis and when systemic treatment is decided.

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“…The survival benefit of regorafenib was independent from the last dose of sorafenib (800 mg/day versus <800 mg/day but ≥400 mg/day) . This estimation is widely variable depending mostly on the pattern of progression, when regorafenib treatment is started, and on the development of early dermatologic AEs under sorafenib and regorafenib . According to our data, ≈35% of patients who have started sorafenib treatment will be candidates for regorafenib…”

Section: Second‐line Treatmentsmentioning

confidence: 77%

“…(54) This estimation is widely variable depending mostly on the pattern of progression, when regorafenib treatment is started, (27) and on the development of early dermatologic AEs under sorafenib and regorafenib. (47,55) According to our data, ≈35% of patients who have started sorafenib treatment will be candidates for regorafenib. (56) (44) EVOLVE (45) REACH (46) REACH-2 (7) METIV (47) CELESTIAL (5) RESORCE (4) Regorafenib has only recently received approval for the systemic treatment of HCC.…”

Section: Regorafenibmentioning

confidence: 95%

New Systemic Treatments in Advanced Hepatocellular Carcinoma

2019

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The principal advancements in the treatment of hepatocellular carcinoma (HCC) are the use of new systemic treatments, such as lenvatinib in first‐line treatment and regorafenib, cabozantinib, and ramucirumab in second‐line treatment, because of their benefits in terms of overall survival. In addition, nivolumab as a second‐line agent was approved by the US Food and Drug Administration in 2017 based on improved radiological response data. Physicians and patients alike will greatly benefit from this expanded arsenal of treatments once all these new drugs for the treatment of HCC finally become available. Unfortunately, in our review of the available data, we found a conspicuous lack of approved systemic treatments for HCC in the distinct setting of after liver transplantation (LT). Careful evaluation of the clinical trials for approved systemic treatments of HCC is crucial when considering the best options for those with HCC recurrence after LT. Although several first‐line or second‐line treatments have been shown to be effective for HCC, each of these trials was composed of its own specific populations, and those with HCC recurrence after LT were excluded. We have also summarized from a critical and clinical point of view the issues involved in the management of patients who are candidates for systemic treatment in this era of multiple drugs for the same indication.

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Hand-foot skin reaction (HFSR) and overall survival (OS) in the phase 3 RESORCE trial of regorafenib for treatment of hepatocellular carcinoma (HCC) progressing on sorafenib.

Cited by 47 publications

References 0 publications

Regorafenib in Patients with Antiangiogenic-Naïve and Chemotherapy-Refractory Advanced Colorectal Cancer: Results from a Phase IIb Trial

Regorafenib in Patients with Antiangiogenic-Naïve and Chemotherapy-Refractory Advanced Colorectal Cancer: Results from a Phase IIb Trial

Systematic review with meta‐analysis: the critical role of dermatological events in patients with hepatocellular carcinoma treated with sorafenib

New Systemic Treatments in Advanced Hepatocellular Carcinoma

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