The combination of sorafenib and modified FOLFOX demonstrated encouraging efficacy in a small phase II study, but some patients exhibited moderate hepatoxicity, according to investigators from the Massachusetts General Hospital Cancer Center.
Lipika Goyal, MD
The combination of sorafenib (Nexavar) and modified FOLFOX (oxaliplatin, 5-fluorouracil [5-FU], and leucovorin; mFOLFOX) demonstrated encouraging efficacy in a small phase II study, but some patients exhibited moderate hepatoxicity, according to investigators from the Massachusetts General Hospital Cancer Center, in Boston, Massachusetts.1
Although sorafenib is considered a standard first-line treatment for advanced hepatocellular carcinoma (HCC), the kinase inhibitor has demonstrated an overall response rate (ORR) of 2% to 3%, a time-to-progression (TTP) of up to 5.5 months, and a median overall survival (mOS) of up to 10.7 months, which fuels continuing research efforts by investigators.
In the study, the investigators emphasized that given the disappointing trials involving sorafenib combinations and sorafenib toxicity, immune checkpoint inhibitors are undergoing further research in HCC, especially with the approval of nivolumab (Opdivo) in advanced refractory HCC. PD-1 blockade used in combination with multikinase inhibitors have also shown promise in HCC (Table).
Table. PD-1 blockade + multikinase inhibitors in clinical trials.
NCT Trial Identifier
In addition, there is ongoing activity in this space, given that the FDA recently approved cabozantinib (Cabometyx) for the treatment of patients with hepatocellular carcinoma who previously received sorafenib. The approval was based on results from the phase III CELESTIAL trial.2
Lead author of this study Lipika Goyal, MD, said that the moderate toxicity of the combination of sorafenib and mFOLFOX suggests that the regimen may be suitable for select patients with robust liver function. Performing biomarker analysis may help identify potential candidates.
Eligible patients had histologically proven advanced HCC with no prior treatment with systemic therapy, Child-Pugh score of A5 or A6, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The median age of the patients was 65 years.
Patients received sorafenib 400 mg twice a day during a 2-week lead-in period, followed by concurrent mFOLFOX (5-FU 1200 mg/m2/day for 46 hours, leucovorin 200 mg/m2, and oxaliplatin 85 mg/m2) initiated on day 1 and 15 of each 28-day cycle. TTP was the primary endpoint and ORR, OS, safety and tolerability, and correlation of circulating cellular and plasma biomarkers with response were secondary endpoints. TTP was defined as the time from trial registration to evidence of either radiographic progression or clinical disease progression, whichever came first. Over the course of the trial, patients received a median of 8.0 cycles (range, 0-33) of sorafenib and 4.5 cycles (range, 0-25) of mFOLFOX.
“The study met its primary endpoint with a modest therapeutic index,” said Goyal, a hematologist in the Department of Hematology/Oncology at Massachusetts General Hospital. When investigators looked at modified RECIST (mRECIST) criteria, they found that 4 patients with stable disease by RECIST v1.1 converted to partial response, bringing the ORR by mRECIST up to 28%.
In the study, the sorafenib plus mFOLFOX combination had a TTP of 7.7 months (95% CI, 4.4-8.9 months), the mOS was 15.1 months (95% CI, 7.9-16.9), and ORR of 18% (95% CI, 7.5%-33.5%) in the first-line systemic treatment of advanced HCC. Although no unexpected toxicities emerged, discontinuation of treatment or withdrawal of consent was a noted outcome.
At the time of analysis, 37 patients in total had discontinued treatment because of radiologic progression (35%), clinical progression with stable disease (22%), withdrawal of patient consent (19%), physician’s decision (11%), and conversion to resection (3%). Dose reductions in sorafenib occurred in 74% of patients, and of the 35 patients who received at least 1 dose of mFOLFOX, 26 (74%) and 27 (77%) patients required dose reductions in 5-FU and oxaliplatin, respectively.
For the biomarker analysis, investigators reported that during the lead-in period when only sorafenib was administered, there was a significant increase in plasma VEGF, P1GF, VEGF-D, sMET, and TNF-alpha (at days 3 and 15); and sVEGFR1, CAIX, and the fraction of CD8-positive T cells (at day 15); decrease in plasma sVEGFR2 and the fraction of CD56Dim natural killer (NK) cells (at day 3); and plasma sVEGR2 and s-c-KIT (at day 15) compared with baseline.
The investigators observed an increase in plasma P1GF, sVEGFR1, CAIX, and VEGF-D on days 29 and 43, in circulating CD3-positive, CD3-positive CD4-positive, and CD3-positive CD8-positive lymphocyte fractions on day 28, IL12p70 on day 29, and TNF-alpha on day 43 during the combination treatment period.
“There was some association between time-to-progression and angiogenic and inflammatory biomarkers, consistent with previous reports, but which should be considered hypothesis generating,” Goyal said in an interview withTargeted Oncology.
“Most interestingly, correlative studies identified associations between poor outcomes with higher pretreatment sVEGFR1 and with increases in regulatory T cells after sorafenib alone,” said co-senior author Dan G. Duda, DMD, PhD, director of translational research in gastrointestinal radiation oncology, Department of Radiation Oncology at Massachusetts General Hospital.
Goyal noted that an ongoing study involving sorafenib in combination with capecitabine and oxaliplatin (SECOX) demonstrated an ORR of 16% in preliminary reports. This study has progressed to a phase II trial (NCT02716766). “SECOX might give oncologists some insight into how this regimen might fare in larger populations,” she said.