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FROM THE LITERATURE
MELANOMA:
Improved Outcome for Locally Advanced Disease
The final results of EORTC 18991, a randomized phase III trial evaluating adjuvant
therapy with pegylated interferon alfa-2b versus observation alone in resected stage
III melanoma were published in a recent issue of The Lancet along with
an editorial. The aim of the trial was to determine whether pegylated interferon
(pegIFN) alfa-2b can facilitate prolonged exposure (a maximum of 5 years) while
maintaining patient tolerability. Patients (N=1256) were randomized to observation
(N=629) or pegIFN alfa-2b (N=627) 6mcg/kg per week for 8 weeks (induction) then
3mcg/kg per week (maintenance) for an intended duration of 5 years and stratified
for microscopic (N1) vs macroscopic (N2) nodal involvement, number of positive nodes,
ulceration and tumor thickness. Primary endpoint was recurrence-free survival (RFS).
Median length of treatment with pegIFN alfa-2b was 12 months. At 3.8 years median
follow-up there were 328 recurrences in pegIFN group vs 368 in observation group
(HR 0.82; p=0.01); the 4-year rate of RFS was 45.6% in the IFN groups vs 38.9% in
the observation groups. There was no difference in OS between the groups. Grade
3 adverse events (A/E) occurred in 40% of patients receiving IFN vs 10% A/E in the
observation group; grade 4 A/Es were seen in 5% of the IFN group vs 2% in observation
group. Most common Grade 3 or 4 A/Es in pegIFN alfa-2b group were fatigue (16%),
hepatotoxicity (11%), and depression (6%). Treatment with pegIFN was discontinued
due to toxicity in 31% of patients.
Interpretation (of authors): Adjuvant pegIFN alfa-2b for stage III melanoma has
a significant, sustained effect on RFS.
Discussion (authors):
- Toxicity did not seem to increase with longer duration of treatment.
- In the N1 (microscopic nodal disease) population, the Kaplan-Meier
curves for RFS in the IFN and observation groups separate from one another increasingly
over time, suggesting that prolonged administration of pegIFN alfa-2b could be of
value.
Editorial Comments:
- More and more patients with stage III melanoma are now diagnosed
worldwide with N1 disease and these findings represent a very relevant subset for
therapy.
- The observation that primary tumor ulceration was associated with
benefit from pegylated IFN is particularly intriguing, and must be evaluated.
- In the near future, the prospects of combining pegIFN alfa-2b with
other agents in the adjuvant setting and evaluating it for maintenance use are real
possibilities.
- Further follow-up might show a significant survival advantage for
the N1 population; that would represent the real advance we have been waiting for.
Eggermont AMM, Suciu S, Santinami M, et al. Adjuvant therapy
with pegylated interferon alfa-2b versus observation alone in resected stage III
melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet.
2008;372:117-126.
RENAL CELL CARCINOMA:
mTOR Inhibition Produces Impressive Results After Disease Progression
on VEGF TKIs
RAD001 (with the proposed brand name of Afinitor) is an orally administered inhibitor
of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic
renal cell carcinoma (mRCC). Results of a phase III, double-blind, randomized, placebo-controlled
trial of everolimus in 410 patients with mRCC whose disease had progressed on treatment
with VEGF receptor tyrosine kinase inhibitors (sunitinib, sorafenib, or both) have
demonstrated that treatment with everolimus prolongs PFS (the primary endpoint)
relative to placebo in this patient population. The study drug and the placebo were
given in conjunction with best supportive care. Findings: Results of the second
interim analysis indicated a significant difference in efficacy between arms and
the trial was halted early after 191 progression events were observed, 37% events
in everolimus group and 65% in the placebo group (HR 0.30, p<0.0001); median
PFS 4.0 months vs. 1.9 months favoring everolimus. At the time of the analysis,
median OS had not been reached for the everolimus group. As anticipated, A/Es were
more frequently reported for everolimus but these were mostly grade 1 or 2.
Treatment with VEGF receptor tyrosine kinase inhibitors has provided a significant
benefit to patients with mRCC but the therapy is not curative and a therapeutic
option was lacking after progression on these agents. On the basis of the results
of this trial, the authors feel that everolimus should now be considered as the
standard-of-care for this population of mRCC patients.
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal
cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
Lancet. 2008;372:449-456.
HEPATOCELLULAR CARCINOMA:
Improved Survival Seen In Advanced Disease with Sorafenib
The incidence of HCC is increasing in the U.S. and Europe, and it is the third highest
cause of cancer-related death globally, behind only lung and stomach cancers. No
systemic therapy has improved survival in patients with advanced HCC. A preliminary
study suggested that sorafenib (Nexavar), an oral multikinase inhibitor of the vascular
endothelial growth factor receptor (VEGFR), the platelet-derived growth factor receptor
β (PDGFR-β), and Raf may be effective in HCC. Results of this uncontrolled phase
II trial of a single-agent sorafenib demonstrated a median OS of 9.2 months and
a median time to progression (TTP) of 5.5 months.
On the basis of these data, investigators conducted a large (602 patient) phase
III, randomized, double blind, placebo-controlled trial to assess the efficacy and
safety of sorafenib in patients with advanced HCC who had not received previous
systemic treatment. Patients received either sorafenib 400 mg PO twice daily or
placebo. Primary outcomes were OS and the time to symptomatic progression. Secondary
outcomes were time to radiologic progression and safety.
At the second planned interim analysis, 321 deaths had occurred, and the study was
stopped. Median OS was 10.7 months in the sorafenib group and 7.9 months in placebo
patients (HR in sorafenib group, 0.69; p<0.001). There was no significant difference
between the two groups in the median time to symptomatic progression (4.1 months
vs. 4.9 months; p=0.77). The median time to radiologic progression was 5.5 months
in the sorafenib group and 2.8 months in the placebo group (p<0.001). Seven patients
in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial
response; no patients had a complete response. Diarrhea, weight loss, hand-foot
skin reaction, and hypophosphatemia were more frequent in the sorafenib group.
Conclusions/Summary:
- This study showed that sorafenib prolonged median survival and the
time to progression by nearly 3 months in patients with advanced HCC.
- Future studies are warranted to evaluate sorafenib as an adjuvant
therapy after curative or locoregional therapies.
- Studies are needed to evaluate sorafenib in
combination with other molecular targeted therapies.
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in Advanced Hepatocellular Carcinoma.
N Engl J Med. 2008;378-390.
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