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43rd Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / June 1-5, 2007

Identification and characterization of molecular pathways implicated in various cancers has opened up a new era of targeted anti-tumour agents. Among the many successes in this arena are sorafenib and sunitinib. As an oral Raf kinase inhibitor with activities against multiple growth factor receptors including VEGF-2, FLT-3 and PDGF, sorafenib affects the Ras/Raf/MEK pathway as well, while sunitinib inhibits c-KIT, FLT-3, PDGF-alpha and beta and VEGF-2. Both are approved for the treatment of advanced renal cell carcinoma (RCC) and studies reported here at ASCO suggest that these agents hold promise in other types of malignancies including hepatic cell carcinoma (HCC) and malignant melanoma.

Hepatocellular Carcinoma Breakthrough

Principal investigator Dr. Josep Llovet, Director, HCC Research, Mount Sinai School of Medicine, New York, New York (jointly appointed to the University of Barcelona, Spain), presented results of the SHARP (Sorafenib HCC Assessment Randomized Protocol) trial on a total of 602 patients with advanced disease who were treated with sorafenib 400 mg b.i.d. or placebo. Highly significant differences in median overall survival (OS) of 10.7 months vs. 7.9 months and median time to progression (TTP) of 5.5 months vs. 2.8 months between active treatment and placebo were observed. Active therapy also worked equally well in patients at all stages of Eastern Cooperative Oncology Group (ECOG) performance status, those with and without extra-hepatic spread and those with and without macroscopic vascular invasion.

However, it should be emphasized that these findings cannot be extrapolated to patients who are substantively different than those in the SHARP trial, including patients with advanced liver disease or poor liver function. As patients were accrued primarily in Europe, we are less certain that the benefits seen in SHARP will also apply to other ethnic groups and those with other etiologies giving rise to liver cancer. Thirteen per cent of actively treated patients developed drug-related treatment-emergent serious adverse events vs. 9% in placebo patients, the most common drug-related adverse events being diarrhea, most of it mild.

This study is the first in over 30 years of research to demonstrate significant activity for any systemic agent in advanced HCC and opens the door to a new treatment option. The next step will be to evaluate the compound in the adjuvant setting following surgery or other local therapies to determine whether it has even greater impact in earlier-stage disease.

Assessing TARGET Biomarkers

Previously published results from the pivotal phase III TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial) showed that sorafenib had excellent activity in advanced refractory RCC, leading to a significantly longer median progression-free survival (PFS) interval of 5.5 months vs. 2.8 months for placebo (N Engl J Med 2007;356(2):125-34). While median OS was not statistically significant at 17.8 months in the active treatment group vs. 15.2 months in placebo controls because of the effect of crossover from placebo to sorafenib, it did achieve significance in a pre-planned secondary analysis with censoring of the crossover patients (17.8 vs. 14.3 months, P=0.0287).

Updated biomarker findings from TARGET presented by Dr. Ronald Bukowski, Director of Experimental Therapeutics Program, Taussig Cancer Center, Cleveland, Ohio, showed plasma VEGF levels increased while plasma-soluble VEGF-2 levels decreased during active treatment. No change was reported in VEGF levels in placebo patients. Patients in the placebo cohort with higher baseline VEGF levels had a significantly shorter PFS of 2.7 months than those with low baseline VEGF levels at 3.3 months and trends were similar for OS. VEGF levels appear to have prognostic importance, and sorafenib-associated changes in VEGF and sVEGFR2 are consistent with inhibition of VEGF signalling. Investigators concluded that sorafenib was effective in patients with both low and high baseline VEGF levels.

Expanded Access Analysis

The ARCCS (Advanced Renal Cell Carcinoma Sorafenib) expanded access program allowed patients with advanced RCC access to sorafenib if they were not involved in any other clinical study. A total of 2502 patients were enrolled in the ARCCS program with both clear cell and non-clear cell histologies. There was one complete response (CR), a 4% partial response (PR) and 18% unconfirmed PRs to the agent among the ARCCS cohort but follow-up was very brief at 12.3 weeks, as the drug became commercially available. Disease stabilized in a large majority of patients (80%) and median duration of response was 24.1 weeks in PR patients, 28.6 weeks in unconfirmed PR patients and 27.1 weeks in patients with stable disease. Grade 3 and higher drug-related toxicities occurred in no more than one-third of ARCCS patients.

These findings reflect both the toxicities and the efficacy seen in the phase III TARGET study and suggest the generalizability of TARGET findings to a less selected RCC patient population. When sorafenib was approved in December 2005 in the US, first-line patients enrolled at any site in the US became eligible to enter a six-month extension of the protocol.

A separate analysis of PFS for first-line patients in the extension phase presented by Dr. Christopher Ryan, Assistant Professor of Medicine, Oregon Health and Science University, Portland, showed that median PFS was 35.1 weeks. Confirmed and unconfirmed CRs occurred in five patients, while approximately 21% achieved either a confirmed or unconfirmed PR. Toxicity rates were remarkably similar to those reported in the phase III sorafenib trial. Investigators concluded that response rates in first-line patients and non-clear cell histologies were similar to those in the overall cohort.

However, we should exercise caution in interpreting responses to sorafenib in first-line patients, as there are conflicting results from other trials. General benefit was seen in several other subgroups of the ARCCS cohort, including patients with controlled brain metastases. Analysis of this subgroup did not reveal any additional risk or unexpected toxicities in this small group of patients (3% of the ARCCS cohort), nor was there any report of CNS-related hemorrhage.

Dose Escalation Tolerability and Sequencing Results

Normally given at the approved dose of 400 mg b.i.d., higher doses of sorafenib might provide greater antitumour activity if they prove tolerable. As presented by Dr. Robert Amato, Medical Director, Genitourinary Oncology Program, The Methodist Hospital Research Institute, Houston, Texas, a dose-escalating study involving 44 patients suggests that the majority of patients treated with escalating doses could tolerate between 1200 and 1600 mg daily.

At these high doses, a CR was achieved in 16% of patients, a PR in 39% of patients and disease stabilized for six months or more in 20%, for a 75% overall disease control rate in this small series of patients. These are investigator-determined responses which are currently undergoing an independent review. Median PFS was 8.4 months and median OS was 11.5 months. These findings suggest that certain patients may benefit from higher doses in terms of achieving good tumour control and they warrant further exploration.

Both sorafenib and sunitinib are indicated for advanced RCC; however, an evaluation of response rates achieved appears to vary according to the sequence of agents used.

In a retrospective analysis presented by Dr. Marie-Pierre Sablin, Institut Gustave Roussy, Villejuif, France, 68 patients with RCC received sorafenib first, while 22 others received sunitinib first.

After patients in each group progressed on the first inhibitor, they received the alternative agent. Following progression on sorafenib, a 20% PR was achieved with sunitinib while disease stabilized in 30% of the rest. Following progression on sunitinib, no PRs were attained with sorafenib but disease stabilized in 60% of remaining patients, although this was a much smaller cohort to evaluate. Approximately 30% of patients in each group experienced grade 3 or 4 toxicities.

The suggestion that the use of sorafenib first followed by sunitinib on disease progression may be the better sequence was echoed in another study led by Dr. Anu Dham, Comprehensive Cancer Center, University of Minnesota, Minneapolis. She and colleagues sought to determine overall disease control rates in 23 patients who received sorafenib first and then sunitinib on progression, and 14 others who received the reverse sequence.

Median TTP after the first treatment was not significantly different between the two agents. But when TTP after the second therapy was used as a measure of overall disease control, patients treated with sorafenib first had a median TTP of 69.4 weeks vs. a median of 36.1 weeks when they received sunitinib first. Overall disease control was also longer when patients received sorafenib first.

Both of these sequential studies were small and retrospective so no firm conclusions can be drawn, but it would be worth comparing the two sequences in a larger prospective trial to determine if one sequence is indeed associated with greater anti-tumour control than the other.

Reports of sorafenib being co-administered with several different cytotoxic agents for the treatment of metastatic melanoma were presented. The hope is that the combination of different chemotherapeutic agents plus this multi-targeted kinase inhibitor will extend median OS and improve the otherwise poor prognosis in this group of patients.

Summary

As a multi-targeted kinase inhibitor, sorafenib is proving to be a valuable new anti-tumour agent that is highly active in several advanced malignancies. It is also well tolerated, causing relatively few toxicities, the majority of them being grade 1 and 2. Further clinical trials evaluating the agent in earlier-stage disease may provide evidence that it has even greater anti-tumour activity when there is less tumour burden to eradicate. We strongly encourage the enrolment of patients into the planned and ongoing adjuvant trials in HCC and RCC, respectively. In the meantime, we welcome the advancement sorafenib has offered previously untreatable disease in this new era of targeted therapies.