New promising options for advanced HCC and BC
A large international phase III study presented at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting in Chicago, Illinois, US demonstrated favourable data in first-line treatment of advanced hepatocellular carcinoma (HCC) with lenvatinib, which may potentially provide an effective alternative therapy in this setting. Two posters presented at the same meeting suggest an important role for eribulin in the management of advanced HER2-positive breast cancer (BC) and triple-negative BC (TNBC).
Lenvatinib in HCC: The REFLECT trial
With sorafenib being currently the only systemic therapy shown to extend overall survival (OS) in first-line treatment of HCC, there is a need for more effective therapeutic options. “Over the past decade, four global phase III trials of first-line sunitinib, brivanib, linifanib and erlotinib plus sorafenib failed to meet their primary endpoint of noninferiority or superiority vs sorafenib,” said Professor Ann-Lii Cheng from the National Taiwan University Hospital in Taipei, Taiwan, who reported the lenvatinib study results.
Lenvatinib, an oral multikinase inhibitor targeting VEGF receptors 1, 2 and 3, fibroblast growth factor (FGF) receptors 1, 2, 3 and 4, platelet-derived growth factor receptor alpha (PDGFRα), and the proto-oncogenes RET and KIT, has shown promising clinical activity in a previous phase II trial in advanced HCC patients. [J Gastroenterol 2017;52:512-519]
The REFLECT trial (study 304) was a global, randomized, open-label, phase III noninferiority trial of lenvatinib vs sorafenib in 954 patients with unresectable stage B or C HCC. All patients had received no prior systemic therapy for HCC, had ≥1 measurable target lesion per modified Response Evaluation Criteria in Solid Tumours (mRECIST), Child-Pugh score A, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1, and adequate organ function. Patients were stratified by region (Asia-Pacific or Western), microvascular invasion (MVI) and/or extrahepatic spread (EHS) (yes or no), ECOG PS (0 or 1) and body weight (BW) (<60 kg or ≥60 kg). Patient characteristics were well balanced between the two study arms in terms of gender, region, BW, ECOG PS, Child-Pugh score, presence of MVI, EHS or both, and HCC stage. Other features, such as aetiology of chronic liver disease, alpha fetoprotein (AFP) level and concomitant systemic antiviral therapy, were also similar in both arms.
Patients were randomized 1:1 to receive lenvatinib once daily (8 mg for BW <60 kg; 12 mg for BW ≥60 kg) or sorafenib 400 mg twice daily. The primary endpoint was OS, with a noninferiority margin set at 1.08 based on previous trials. Secondary endpoints included progression-free survival (PFS), time to progression (TTP), objective response rate (ORR) and quality of life. [ASCO 2017, abstract 4001]
“The study met its primary endpoint, with lenvatinib demonstrating noninferiority in OS within the set margin. Median OS was 13.6 months with lenvatinib vs 12.3 months with sorafenib [hazard ratio (HR), 0.92],” reported Cheng. “Lenvatinib is the first agent to demonstrate noninferiority to sorafenib in advanced HCC.” (Figure 1)
Subgroup analyses of OS consistently favoured lenvatinib over sorafenib regardless of age, gender, ECOG PS, BW, disease stage, AFP and HCC aetiology. “The only exceptions were Western populations and patients who had neither MVI nor EHS,” he pointed out.
In addition, lenvatinib achieved statistically significant and clinically meaningful improvements in the secondary endpoints, doubling sorafenib’s median PFS, TTP and ORR values. “Median PFS for lenvatinib was 7.4 months vs 3.7 months for sorafenib [HR, 0.66; p<0.00001]. The respective TTP values were 8.9 vs. 3.7 months [HR, 0.63; p<0.00001]. Again, subgroup analysis for PFS favoured lenvatinib in all study populations,” said Cheng. “The response rates were also significantly higher with lenvatinib.” (Table 1)
Cheng noted that the median duration of lenvatinib treatment was 5.7 months, and patients received 87.7 percent of the planned starting dose, compared with 3.7 months and 83 percent with sorafenib.
Treatment-related adverse events (AEs) of grade ≥3 were more common with lenvatinib vs sorafenib (57 vs 49 percent). However, the rates of dose reductions, interruptions and discontinuations due to treatment-related AEs were similar in both treatment arms (37 vs 38 percent, 53 vs 50 percent and 9 vs 7 percent, respectively), while palmar-plantar erythrodysesthesia was much more common in patients receiving sorafenib (27 vs 52 percent). “Generally, the safety profiles of both drugs appeared consistent with those reported previously in HCC patients,” Cheng said.
According to health-related quality of life questionnaires, role functioning, pain, diarrhoea and body image scores worsened earlier in patients receiving sorafenib vs lenvatinib.
“Based on the REFLECT trial results, lenvatinib may be a potential first-line treatment option for patients with advanced HCC,” concluded Cheng.
Eribulin in HER2-positive advanced BC
The addition of pertuzumab to trastuzumab and docetaxel has demonstrated PFS and OS benefits in first-line treatment of advanced or recurrent HER2-positive BC. [N Engl J Med 2012;366:109-119; Lancet Oncol 2013;14:461-472] However, in the long term, docetaxel-associated toxicity may limit the dose that can be administered.
A Japanese single-arm, open-label phase II trial was designed to evaluate the efficacy and safety of eribulin – a well-tolerated cytotoxic agent – in combination with pertuzumab and trastuzumab as first- and second-line therapy in 49 patients with metastatic or advanced BC with adequate organ function who had received prior therapy including trastuzumab and a taxane. The primary endpoint was PFS. [ASCO 2017, abstract 1025]
Eight and 41 patients were treated in first- and second-line settings, respectively. Treatment consisted of eribulin on days 1 and 8 of a 21-day cycle, and trastuzumab plus pertuzumab every 3 weeks. At the end of eight cycles, 28 patients continued the protocol therapy.
“Median PFS was not yet reached. Among 46 patients included in the full analysis, the ORR by RECIST version 1.1 was 56.5 percent [87.5 percent in first line and 50.0 percent in second line],” reported Dr Kazutaka Narui of the Yokohama City University Medical Centre, Yokohama, Japan. (Table 2)
The relative dose intensity of eribulin over eight cycles was 93.3 percent. Grade 3/4 AEs included leukopenia, neutropenia, febrile neutropenia and hypertension (4.1, 10.2, 4.1 and 6.1 percent, respectively).
“Eribulin in combination with pertuzumab plus trastuzumab was well tolerated, and could be an alternative to docetaxel-based combination therapy for HER2-positive advanced BC,” Narui suggested.
Eribulin in advanced TNBC
An Italian open-label phase II trial evaluated the combination of eribulin plus gemcitabine as either first- or second-line therapy for locally advanced or metastatic TNBC. The combination could potentially provide synergistic effects in inducing tumour cell death in malignancies characterized by high cell proliferation and chemoresistance, such as TNBC. [ASCO 2017, abstract 1095]
Eighty-three evaluable patients were enrolled (66 patients for first-line and 17 for second-line treatment). All patients were previously treated with an anthracycline and/or a taxane. The primary endpoint was ORR.
After a median of six treatment cycles, the ORR was 37.4 percent. Complete response, partial response and stable disease rates were 2, 35.4 and 11.4 percent, respectively, accounting for a clinical benefit rate of 48.8 percent.
With a median follow-up of 20.1 months, median PFS was 5.1 months, and median OS was 14.8 months. The most common grade 3/4 AEs (>10 percent of patients) were neutropenia and liver toxicity.
A prospective molecular correlative study to assess the role of BRCA mutations in predicting treatment efficacy and toxicity was carried out in 68 genotyped patients. BRCA1/2 mutations were observed in 15 patients (22 percent) and were associated with worse ORR, PFS and OS than those with wild-type BRCA1/2. (Table 3)
“The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC,” the authors concluded.