Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial
Bruix J et al., Lancet. 2017 Jan 7;389(10064):56-66.
PubMed ID: 27932229
Regorafenib is an oral tyrosine kinase inhibitor that targets multiple kinases involved in tumorigenesis and was found in preclinical studies to have greater potency compared with sorafenib, standard of care in hepatocellular carcinoma (HCC). Researchers looked at the efficacy of regorafenib in HCC after disease progression on sorafenib in the phase III RESORCE trial.
- Patients: pathologically confirmed HCC or through non-invasive assessment according to the American Association for the Study of Liver Diseases criteria for patients with confirmed cirrhosis, BCLC stage 2 or 3, not eligible for resection, local ablation or chemoembolization and progressed on sorafenib (at least 20 days treatment prior to discontinuation), Child-Pugh A
- Study design: phase III, double-blind, placebo-controlled RCT
- Experimental: Regorafenib 160 mg PO for 3 wks. out of a 4-wk. cycle
- Control: Placebo
- Primary: OS
- Secondary: PFS, TTP, ORR, DCR, safety, HRQOL
- 573 patients randomized 2:1 to regorafenib (n=379) and placebo (n=194)
- Baseline patient characteristics: 88% male, median age 63 yrs., 62% rest of the world, 66% ECOG 0, 29% macrovascuar invasion, 73% extrahepatic disease, 82% macrovascular invasion and/or extrahepatic disease, 80% intrahepatic/extrahepatic growth or both on progression, 26% lung target lesion, 44% α-fetoprotein ≥400 ng/mL, 98% Child-Pugh A, 88% BCLC stage C, 38% cirrhosis due to Hepatitis B, 46% 2 target lesions, 1.4 mos. from sorafenib progression to start of study treatment, 7.8 mos. treatment with sorafenib, 0.9 mos. from discontinuation of sorefanib to start of study treatment
Table 1. Efficacy Endpoints
- Most common grade 3-4 adverse events: hypertension (15% vs. 5%), hand-foot skin reaction (13% vs. 1%), fatigue (9% vs. 5%), diarrhea (3% vs. 0)
Table 2. Adverse Events & Treatment Summary
- Most common adverse events leading to treatment discontinuation: elevated AST (2% vs. 2%), hand-foot skin reaction (2% vs. 0), increased ALT (1% vs. 0)
- HRQOL was similar in both arms, including changes from baseline.
- Among patients with HCC who progressed on first line sorafenib, regorafenib significantly improved OS by 2.8 mos. compared to placebo, with 37% reduction in the risk of death. Similarly, regorafenib doubled PFS and TTP. Clinical efficacy was observed in all prespecified subgroups.
- Regorafenib provided better ORR, DCR and tumor shrinkage vs. placebo. Most patients achieved stable disease (54% vs. 32%). Two patients on regorafenib had complete response by mRECIST.
- Adverse events occurred with more frequency in the regorafenib arm and subsequently resulted in higher rates of treatment interruption, dose reduction and discontinuation. Treatment duration was longer in the regorafenib arm compared to placebo (3.6 mos. vs. 1.9 mos.). Patient selection could explain the low rates of hepatic adverse events in both treatment arms.
- As with most trials of HCC systemic treatments Childs-Pugh A liver function was one of the inclusion criteria, therefore the results may not be generalizable to the population of HCC patients progressing on sorafenib with Childs-Pugh B liver function.
- Patients from North America, South America, Europe, Asia and Australia were included in this study which enhances the generalizability of these results to HCC patients around the world.
- In summary, regorafenib was associated with significant and clinically meaningful survival benefit and tumor response compared to placebo as 2nd line treatment for advanced HCC after failing sorafenib.
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Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial
Soulieres, D et al., Lancet Oncol. 2017 Mar;18(3):323-335.
PubMed ID: 28131786
Buparlisib (BKM120) is an oral pan-PI3K inhibitor that downregulates PI3K signaling in tumors. In a phase 1B study, buparlisib with paclitaxel demonstrated anti-tumor activity in solid tumors and after progression on taxane chemotherapy. Researchers further investigated the activity of buparlisib with paclitaxel in metastatic squamous cell carcinoma of the head and neck (mSCCH&N) in the phase II BERIL-1 trial.
- Patients: histologically or cytologically-proven recurrent/mSCCH&N after progression on platinum-based chemotherapy in recurrent, ≥ 2nd line or metastatic setting, previous cetuximab allowed, PS 0-1, CNS metastasis allowed if were asymptomatic.
- Study design: phase II double-blind, placebo controlled RCT
- Experimental (BP): Buparlisib 100 mg/d PO (continuous) + Paclitaxel 80 mg/m2 IV d1,8,15,22 q28d cycle
- Control (PP): Oral placebo + Paclitaxel 80 mg/m2 IV d1,8,15,22 q28d cycle
- Primary: PFS
- Secondary: OS, ORR, DCR, TTR, DOR, safety, QOL
- 158 patients randomized to BP (n=79) or PP (n=79)
- Baseline patient characteristics: median age 58.5 yrs., 84% males, 71% white, 64% ECOG 1, oral cavity primary 29%, oropharynx 29%, 73% HPV negative, 11% PI3K activated tumors, 58% previous surgery, 81% previous RT, 37% previous chemotherapy (adjuvant/neoadjuvant), 97% previous chemotherapy (recurrent/metastatic)
- Subsequent therapy: 28% buparlisib/paclitaxel (BP) vs. 32% paclitaxel/placebo (PP)
Table 1: Efficacy Outcomes
- PFS favoured BP in patients with cancer of the hypopharynx. However, no OS benefit was seen in HPV positive oropharyngeal tumors.
- No difference in QOL was observed between both arms.
- Most common grade 3-4 adverse events: hyperglycemia (22% vs. 3%), anemia (18% vs. 12%), neutropenia (17% vs. 5%), fatigue (8% vs. 10%)
Table 2: Adverse events & Treatment Summary
- In the phase II BERIL-1 study, the addition of buparlisib to paclitaxel significantly improved PFS compared to paclitaxel based on investigator's review in advanced SCCH&N after progression on platinum-based chemotherapy. Buparlisib with paclitaxel decreased the risk for disease progression or death by 35% and the risk of death by 28%.
- Response rates with buparlisib-paclitaxel more than doubled on investigator review, but did not double on central review. Disease control rate and time to response were comparable in both arms. Furthermore, response duration was longer in the paclitaxel-placebo arm.
- Combination treatment increased the rates of adverse events, particularly hyperglycemia, anemia and neutropenia. No treatment-related deaths were reported. Adverse events did not asignificantly affect QOL in both arms.
- Patients with HPV positive SCCH&N seemed to derive clinical activity with buparlisib-paclitaxel. However, due to small sample size in the phase II setting, requires further investigation in larger studies.
- In summary, BERIL-1 trial met its primary PFS objective, demonstrating significant improvement in survival and better response rates with 2nd line buparlisib in combination with paclitaxel. Adverse event rates were more frequent with combination therapy but were generally manageable with dose reductions and treatment interruptions. The addition of an oral pan-PI3K inhibitor to platinum chemotherapy is a novel therapeutic option as 2nd line treatment in advanced mSCCH&N..
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