Ratnayake_subbed.qxp 13/7/09 14:45 Page 80
Kidney Cancer
improved with the addition of bevacizumab to IFN-α (10.2 versus 5.4 comparing 400mg twice daily sorafenib with placebo as second-line
months; p=0.0001), and this pre-specified analysis was accepted for treatment (see Table 1).
34
More than 80% had received prior cytokine
regulatory submission. The PFS benefit was seen in all risk groups, and therapy. The sorafenib cohort had a superior PFS of 5.5 versus 2.8
was independent of the IFN-α dose. The Cancer and Leukemia Group B months (p<0.01) and greater PR rate (10 versus 2%; p<0.001).
(CALGB) 90206 phase III study randomized between IFN-α plus Subsequent analysis of OS again demonstrated the confounding
bevacizumab and IFN-α alone and reported a similar PFS benefit (8.5 influence of cross-over.
35
OS was not significantly different by intention-
versus 5.2 months; p<0.0001) and a significant improvement in ORR to-treat analysis, but censored analysis did demonstrate an OS benefit
(25.5 versus 13.1%; p<0.0001) (see Table 1).
24
Toxicities of the for sorafenib (HR 0.78, 95% CI 0.62–0.97; p=0.0287). Serious toxicities
combination in both phase III studies were manageable: grade 3 related to sorafenib included grade 3/4 hypertension (4 versus <1%;
hypertension, anemia, fatigue, and proteinuria, occurring more p=0.001) and cardiac ischemia or infarction (3 versus <1%; p=0.01).
frequently in the combination arm. The evidence for this combination is
persuasive; however, its use has been limited by the simultaneous First-line sorafenib was compared with IFN-α in a recently published
availability of effective oral therapies. randomized phase II trial.
36
The primary end-point of PFS was not
significantly different (5.7 versus 5.6 months; p=0.50), but sorafenib
Sunitinib provided better quality of life, fewer toxicities, and greater tumor
Sunitinib malate is an oral oxinodole tyrosine kinase inhibitor (TKI) of response rates. Dose escalation of sorafenib from 400mg twice daily to
the VEGF2, PDGF, c-KIT, and FLT-3 receptors.
25
It is orally administered 600mg twice daily on initial progression resulted in 41.9% response rate,
at a dose of 50mg once daily for four of every six weeks.
26
Phase II and was well-tolerated. The reason for the relative ineffectiveness of
studies reported response rates of 40–43%, with an additional 22–27% sorafenib as first-line treatment compared with sunitinib is unclear, but
having stable disease (SD) for more than three months.
27,28
Median TTP is postulated to be due to weaker inhibition of VEGFRs. The concept of
was 8.7 months (95% CI 5.5–10.7 months)
27
and median PFS 8.3 achieving greater efficacy from sorafenib by dose escalation is the
months (95% CI 7.8–14.5 months).
28
The most frequently observed subject of ongoing trials.
toxicities were fatigue and diarrhea.
Temsirolimus
A total of 750 clear-cell RCC patients were recruited into a randomized The mammalian target of rapamycin (mTOR) pathway has generated
multicentre phase III trial comparing first-line sunitinib with IFN-α (see significant interest in several tumor types, most notably in RCC. It is
Table 1)
29
. The primary end-point was PFS with secondary end-points downstream from several growth factor receptors, and when activated
including OS and ORR. Patients were of good or intermediate increases HIF-1α gene expression. Temsirolimus, an intravenous mTOR
performance status by the Memorial Sloan-Kettering Cancer Center inhibitor, demonstrated activity in the phase II setting. A clinical trial of
(MSKCC) risk criteria
30
and over 90% had undergone prior cytoreductive 111 patients, the majority of whom had received prior therapy, reported
nephrectomy. Sunitinib afforded a PFS advantage over IFN-α (11 versus a 7% ORR and a 51% SD rate.
37
Grade 3–4 hyperglycemia (17%),
5 months, HR 0.42, 95% CI 0.32–0.54; p<0.001) and improved ORR (31 hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%)
versus 6%; p<0.001). A subsequent OS analysis reported a non- were the most frequent side effects.
significant trend to superiority for sunitinib by intention-to-treat analysis
(26.4 versus 21.8 months; p=0.051). However, over 50% of the patients A phase III study recruited 626 systemic therapy-naïve patients with
randomized to IFN-α crossed over to sunitinib or other anti-VEGF poor-risk features (see Table 1).
38
Patients were randomized to one of
therapies. Analysis restricted to patients who did not receive second- three groups: IFN-α 9–18MU three times weekly alone, temsirolimus
line therapy demonstrated a substantial and statistically significant OS 25mg weekly alone, or temsirolimus 15mg weekly plus IFN-α 6MU
benefit for sunitinib (28.1 versus 14.1 months; p=0.0033).
31
Patients on three times weekly. Analysis of the efficacy of temsirolimus alone
sunitinib reported a significantly better quality of life (p<0.001). This versus IFN-α alone showed improved median OS (10.9 versus 7.3
landmark study led to sunitinib being widely adopted as standard first- months, HR for death 0.73, 95% CI 0.58–0.92; p=0.008) and better PFS
line treatment for advanced RCC in 2007. (3.8 versus 1.9 months investigator assessment and 5.5 versus 3.8
months by independent assessment; p<0.001) with temsirolimus.
Sorafenib Comparison between the combination arm and IFN-α alone revealed
Sorafenib tosylate similarly inhibits VEGF2 and 3, c-KIT, PDGF, and no significant difference in median OS (8.4 versus 7.3 months;
FLT-3 receptors, but also inhibits the serine/threonine kinases B-RAF p=0.70), and the ORR did not differ significantly between all three
and C-RAF of the RAF/MEK/ERK pathway.
32
Promising activity and safety groups. The toxicity profile of temsirolimus alone was more
data from phase I/II studies in metastatic RCC led to a phase II acceptable than IFN-α alone, but the combination arm resulted in
discontinuation study randomizing between either continued oral significantly greater toxicities. Therefore, single-agent temsirolimus
sorafenib after an initial 12 weeks of treatment or placebo.
33
The was established as standard first-line treatment in poor-risk patients.
authors demonstrated a significant PFS advantage with continued
sorafenib of 50 versus 18% at 24 weeks (p=0.0077) as the primary end- Everolimus
point. The sorafenib toxicity profile of fatigue, rash, and hand–foot Everolimus (RAD-001) is an orally bioavailable mTOR inhibitor. Clinical
syndrome was acceptable. A total of 903 patients of low and activity was initially demonstrated in an open-label trial of 25
intermediate MSKCC risk were recruited to the phase III Treatment metastatic RCC patients given 10mg daily continuous dosing.
39
The PR
Approach in Renal Cancer Global Evaluation Trial (TARGET) study rate was 32% and a further 51% had SD for greater than three months.
80 US ONCOLOGY
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100