Hypoxia is a known feature of many tumors including HCC and RCC. Tumor cells have the capability to survive and thrive in the setting of hypoxia through metabolic reprogramming(27-29), gene expressions that suppress apoptosis(30) and enhancing receptor tyrosine kinase signaling (31) among many other key mechanisms. Through these mechanisms, hypoxic regions of tumor play an important role in tumor progression and development of aggressive phenotypes and are implicated in resistance to therapy.(32) Several bioreductive prodrugs have been designed to target tumor hypoxia for the treatment of cancer(33); however, results have been disappointing.(34-36)
Antiangiogenics are established therapeutics in HCC and RCC. One major drawback includes exacerbating hypoxia due to reduction in tumor vasculature. HAPs such as TH-302 can overcome this limitation by targeting hypoxic regions. In this phase I trial, we evaluated the safety and dose-limiting toxicity of the combination of sorafenib and Evo in patients with advanced HCC and RCC. Results from this study established sorafenib dosing of 200 mg BID and evosfosfamide of 340 mg/m2 as the MTD.
The combination from this study is feasible in patients with HCC and RCC after first-line therapy. The most common side effects included fatigue, hand-foot syndrome, hypertension, nausea/vomiting, weight loss, oral mucositis, diarrhea, and rash. These are consistent with side effects seen previously with single agent sorafenib(2) and Evo.(37) Grade 3 or higher AEs (regardless of attribution) were observed in 29% of patients receiving MTD dose and were manageable. The rate of treatment discontinuation in this study was 44%, similar to that of single agent use of sorafenib at 38%.(2) The recommended phase II dose was established at Evo 240 mg/m2 and sorafenib 200 mg bid, 1 level below MTD. This dose level was more tolerable, as more patients were able to stay on treatment longer with median of 3.5 cycles of treatment with range from 1-6. Patients on MTD level stayed on treatment for a median of 2 cycles (range from 1-11).
The efficacy results from this study are encouraging, with 11% having a partial response and a disease control rate of 55%. Median progression-free survival was 7.8 months and 3.6 months for MTD and RP2D cohorts, respectively. Median OS was 13.4 months for MTD cohort and 18.5 months for RP2D. These results are consistent with survival outcomes seen in other second-line therapy in HCC.(5-7) This study demonstrates preliminary safety and tolerability of the combination sorafenib with TH-302 in patients with HCC and RCC. Efficacy was observed and there is a rationale for continuation to the phase II portion at the RP2D.
Since the completion of this trial, the treatment paradigm for HCC has changed, with the U.S. Food and Drug Administration approval of atezolizumab in combination with bevacizumab as the standard first-line therapy. This presents new opportunities for novel combinations. Evosfosfamide has successfully been combined with a number of other antiangiogenic agents including pazopanib(38), bevacizumab(39), and sunitinib(40). Preclinical data suggest synergism when evosfosfamide is combined with immune checkpoint inhibitors in solid tumors.(41) Studies in preclinical mouse models showed decreased frequency and density of myeloid-derived suppressor cells with reduction of hypoxia. Indirect and direct tumor-infiltrating T cells benefits were observed with increased proliferation, cytotoxicity, cytokine production and survival. The combination of evosfosfamide and ipilimumab, a CTLA-4 inhibitor, is currently being evaluated across solid tumors in clinical trials (NCT03098160). Based on this rationale, future combinations could be considered with evosfosfamide, atezolizumab with bevacizumab in the first-line setting in HCC.
In parallel, the treatment landscape for RCC has also changed dramatically with the addition of the combinations pembrolizumab plus axitinib, avelumab plus axitinib, and ipilimumab plus nivolumab as front line therapies for both favorable and unfavorable risk groups.(11, 12, 42) More recently, tivozanib, a selective inhibitor of VEGFR, improved PFS in patients previously treated with checkpoint inhibitor plus VEGFR TKI or VEGFR TKIs alone.(43) Given the preclinical data suggesting synergism when evosfosfamide is combined with immune checkpoint inhibitors, the next step is to either combine evosfosfamide with immune checkpoint inhibitors plus anti-VEGFR in the front-line setting or combine evosfosfamide with tivozanib in the refractory renal cell carcinoma setting.
Given these advances in the therapeutic paradigm for advanced HCC and RCC, future development of HAPs such as evofosfamide would need to be in post-immune checkpoint inhibitor settings if doublets with antiangiogenics are evaluated further. In the first-line setting, feasibility would need to be established with triplet combinations involving HAPs, antiangiogenic and immune checkpoint inhibitors, and further development would be contingent on safety feasibility and meaningfully robust signals over established efficacy benchmarks in those settings.
ClinicalTrials.gov Identifier: NCT01497444