Title: A Phase I/II Study of mTOR Inhibitor Temsirolimus in Patients with Unresectable Hepatocellular Carcinoma (HCC)
Abstract: Background: HCC is a common cause of cancer morbidity and mortality. The oncogenic PI3K/Akt/mTOR pathway is frequently activated in HCC. Preliminary studies on mTOR inhibitors such as temsirolimus show promising results but there is limited data on the efficacy and toxicities in HCC patients who have concomitant chronic liver disease. Methods: This phase I/II study examined the use of temsirolimus in advanced HCC. Major eligibility criteria included histologically confirmed HCC that is not amenable to curative treatment; ECOG ≤ 2; adequate hematological and liver function. Phase I portion identified 25 mg weekly every 3 weeks to be the maximum tolerated dose. Phase II adopts a single arm design, the primary endpoint is PFS. The secondary end points are to define response rate, disease stabilization and overall survival. Overall survival and PFS were calculated using the Kaplan-Meier method. Reassessment CT scans were done every 6 weeks. All adverse events were reported using CTCAE v3. Results: A total of 36 patients (10 from phase I and 26 from phase II) were enrolled. The median follow-up was 17.0 months. The median age was 56.0 years (range 26-77). 31 (86.1%) were male and 24 (66.7%) had ECOG 0. All had Child's A cirrhosis. 29 patients (80.5%) had received prior treatment for HCC; 19 of them (52.8%) had received prior local or locoregional therapies and 19 (52.8%) received ≥1 line of prior systemic therapies. 24 (66.7%) had vascular involvement and 21 (58.3%) had extrahepatic metastases. Amongst the evaluable pts, the PR and SD rate was 2.8% (1/35) and 57.1% (20/35) respectively. The median PFS was 2.83 months and the median OS was 8.88 months. Disease stabilization (PR, CR or SD ≥12 weeks) was 38.9% (14 of 36 pts had confirmed SD). At the time of data cutoff, 25 patients (69.4%) were death; 24 were due to progressive disease and one was due to liver failure. Grade 3 causally-related toxicities included: raised ALT 1 (2.8%), raised ALP 3 (8.3%), raised bilirubin 1 (2.8%), cough 1 (2.8%), creatinine 1 (2.8%), diarrhea 1 (2.8%), fatigue 1 (2.8%), anemia 2 (5.6%), hypokalemia 1 (2.8%), leucopenia 1(2.8%), oral mucositis 1 (2.8%), thrombocytopenia 4 (11.1%), pneumonitis 1 (2.8%); there was no grade 4 or 5 toxicities. Conclusion: In this patient population whom over half had prior systemic therapy for advanced HCC, temsirolimus demonstrates tumor stabilization despite lack of tumor shrinkage. The agent is generally well-tolerated. Further studies to identify patient subgroup that will benefit from this agent are warranted. Sponsor: Pfizer Corporation Inc.