Sorafenib tosylate, tablet, 200 mg (base), Nexavar®, July 2008
Public summary document for Sorafenib tosylate, tablet, 200 mg (base), Nexavar®, July 2008
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Public Summary Documents
Product: Sorafenib tosylate, tablet, 200 mg
(base), Nexavar®
Sponsor: Bayer Australia Ltd
Date of PBAC Consideration: July 2008
1. Purpose of Application
The submission sought an Authority required listing for sorafenib
for the treatment of advanced hepatocellular carcinoma in patients
with unresectable disease.
2. Background
Sorafenib for this indication had not previously been considered by
the PBAC.
3. Registration Status
Sorafenib was TGA registered on 25 February 2008 for:
Treatment of patients with advanced hepatocellular carcinoma.
Sorafenib was TGA registered on 27 September 2006 for:
Treatment of patients with advanced renal cell carcinoma.
4. Listing Requested and PBAC’s View
Authority required
Initial treatment of advanced hepatocellular carcinoma patients
with unresectable disease.
Continuing treatment of advanced hepatocellular carcinoma patients
with unresectable disease.
Treatment should continue as long as the patient is clinically
benefiting or until unacceptable toxicity occurs.
Note: No applications for increased maximum quantities and/or
repeats will be authorised
For PBAC’s view, see Recommendations and
Reasons.
5. Clinical Place for the Proposed Therapy
Hepatocellular carcinoma (HCC) is the fifth most common cancer
worldwide and the third commonest cause of cancer death. In most
instances, HCC is diagnosed only at intermediate to advanced stages
and best supportive care is the most widely used option for
patients with advanced HCC.
Sorafenib would be used in patients where curative treatment
options have been exhausted, and where surgery or loco-regional
therapy is not appropriate or has failed.
6. Comparator
The submission nominated placebo/best supportive care as the main
comparators which may include antibiotics, nutritional support,
correction of metabolic disorders, optimal symptom control and pain
management. The PBAC considered that this was appropriate.
7. Clinical Trials
The submission presented two randomised trials comparing sorafenib
with placebo/best supportive care in patients with advanced
hepatocellular carcinoma (HCC).
The trial published at the time of submission is as follows:
| Trial ID/First Author | Protocol title/ Publication title | Publication citation |
| Direct randomised trial | ||
| SHARP Trial Llovet et al. | Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial). | J Clin Oncology, ASCO Annual Meeting Proceedings Part I; 25 (18S). Abstract LBA1. |
8. Results of Trials
The results for overall survival in the comparative trials are summarised below:
| Analysis | Result (95% CI) | significance level needed* | |
| SHARP Trial – Cutoff date = 17 October 2006 Pre-specified interim analysis Time-to-death – 321 events (Sorafenib: 143 deaths, Placebo: 178 deaths) | |||
| Comparison of time-to-first event curves | 1-sided stratified log rank test | P=0.000583 | P=0.0073 |
| Median survival: sorafenib = 324 days (286, 405) placebo = 241 days (206, 276) | |||
| CPH | HR = 0.69 (0.55, 0.87) | NA | |
| Supplementary Asia Pacific Trial - Cutoff date = 19 March 2007 Non-pre-specified interim analysis Time-to-death – 128 events (Sorafenib: 79 deaths, Placebo: 49 deaths) | |||
| Comparison of time-to-first event curves | log rank test | P=0.040446 | NS |
| Median survival: sorafenib = 203 days (162, 235) placebo = 126 days (114, 166) | |||
| CPH | HR = 0.69 (0.48, 0.99) | NA | |
* Adjusted for alpha spending and any interim analyses
Abbreviations: NS=not specified, NA=not applicable, HR=hazard
ratio, CPH=Cox proportional hazard model
The overall survival of sorafenib treated patients was superior to
that of patients in the placebo arm, with a similar hazard ratio in
the SHARP and Asia Pacific trials.
The result for time-to-symptom -progression (TTSP) from the
comparative trials was not statistically significant.
The results for quality-of- life measures from the SHARP Trial were
not statistically significant.
There were more serious adverse events, drug related adverse
events, and Grade 3-4 hypertension, diarrhoea, oedema, and
hand-foot skin reaction, and thrombocytopenia, and hypophosphatemia
in sorafenib compared with BSC.
For PBAC’s comments on these results, see Recommendations
and Reasons.
9. Clinical Claim
The submission claimed sorafenib as superior in terms of
comparative effectiveness and inferior in terms of comparative
safety over best supportive care.
For PBAC’s view, see Recommendations and
Reasons.
10. Economic Analysis
A modelled evaluation was presented with four health states –
first line treatment/pre-progression, first line
treatment/post-progression, BSC/post progression, and death using a
ten year time horizon and one-monthly cycles. The model assumed
continued sorafenib treatment beyond progression in 54.5% of
patients for one month. Only treatment attributed adverse events of
grade 3 or 4 severity occurring in at least 10% of sorafenib
patients and considered to have cost consequences were included in
the model.
Treatment effect and duration, model time horizon, extent of
utility, and sorafenib price were the main drivers of the
model.
The base case incremental cost effectiveness ratio (ICER) estimated
in the economic model was in the range of $45,000- $75,000 per
extra life year gained (LYG).
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be less
than 10,000 in Year 5.
The financial cost per year to the PBS was estimated to be less
than $10 million in Year 5. The PBAC noted that there would be
potential for use beyond progression in more patients and for
longer duration.
12. Recommendation and Reasons
The PBAC recommended the listing of sorafenib on the PBS as an
authority required benefit for advanced hepatocellular cancer (HCC)
in patients who meet certain criteria on the basis of high but
acceptable cost-effectiveness against best supportive care at the
price proposed in the pre-PBAC response.
The PBAC agreed that the data from the Sharp trial suggest
treatment with sorafenib is associated with a clinically meaningful
improvement in survival in patients with advanced Barcelona Liver
Clinic Cancer (BCLC) Stage C HCC, whose WHO performance status is 2
or less and who are Child Pugh class A. The Committee considered
that the PBS listing restriction should incorporate these criteria
for consistency with the Sharp trial.
Although the submission presented the results of the
cost-effectiveness analysis only in terms of life-years gained, the
Committee did not accept that it is appropriate to not quality
adjust the incremental cost-effectiveness ratio (ICER) in this
setting as this would imply an acceptance of the assumption that
treatment for end of life conditions can be valued entirely upon
the extent of survival benefit without consideration of any
potential trade-off in terms of quality of the life. The Committee
noted that although FACT-Hep (Functional Assessment of Cancer
Therapy- Hepatobiliary) response rate at 12 weeks was significantly
lower in the sorafenib arm of the SHARP trial compared with the
placebo arm (P=0.04), there was no difference between study arms in
FACT-Hep response rate at 12 weeks in the Asia-Pacific trial (24.4%
in the sorafenib arm and 26.9% in the placebo arm), despite almost
identical overall survival outcomes in the trials.
The FACT-Hep consists of the 27-item FACT-G (General), which
assesses generic health related quality of life (HRQL) concerns (in
four domains, covering Physical, Social & family, Emotional,
and Functional well-being), and the 18-item Hepatobiliary Subscale
(HS), which assesses disease-specific issues (Heffernan et al.
2002). A mapping algorithm was developed by Dobrez et al. (2007),
which found that the physical well being (PWB) and the functional
well being (FWB) subscale correlated with utility values elicited
using the time trade-off method. Although mapping could not be done
due to the limited data from the SHARP study, the PWB and FWB
subscales did not appear to be significantly different between the
two treatment arms (p=0.084 and p= 0.806 respectively).
In regard to the effect of treatment on patient symptoms, the
clinical status of subjects with HCC is often complicated by
concomitant liver disease, deterioration of liver function and
complications of underlying cirrhosis, clinical deterioration as a
result of HCC progression, and/or the side effects of therapy. The
Committee agreed that it is difficult to determine an appropriate
utility value in this case because the disutility associated with
the cancer per se cannot be reliably distinguished from any
disutility due to liver disease, with any deterioration of liver
function and complications of cirrhosis difficult to disentangle
from the adverse effects of sorafenib.
However, the PBAC was of the view that the utility of a patient
with advanced HCC would be less than 1, particularly as in the
group of patients who are Child-Pugh-A (as specified by the
restriction) liver function is not reduced at the beginning of
treatment.
The Committee notes the extremely conservative respecification of
the model suggested by the Economics Subcommittee (ESC) in which
the treatment effect ceases after 2 years while the time horizon of
the model was restricted to 5 years. However, the Committee
considered, in light of recent evidence published in the European
Journal of Cancer on the survival of patients with liver cancer
(2008, 44: 1000 – 1006), that the approach adopted initially
by the submission in which 10-year survival was modelled may not be
unreasonable . Thus the Committee considered that the
submission’s base case incremental cost-effectiveness ratio
of sorafenib over placebo in the range of $45,000 - $75,000 per
life year gained was reasonable, which when quality adjusted would
result in a ratio per quality-adjusted life-years gained more than
$75,000. Although high, this incremental cost-effectiveness ratio
was considered acceptable in light of the high clinical need given
the absence of any other treatment option for the patients
identified by the restriction, convincing clinical data from two
well designed clinical trials, and small financial expenditure of
less than $10 million in year 5.
Recommendation
SORAFENIB TOSYLATE, tablet, 200 mg (base)
Restriction Authority Required
Initial treatment, as the sole PBS subsidised agent, of advanced
(BCLC Stage C) hepatocellular carcinoma in a patient with a WHO
performance status of 2 or less and Child Pugh class A.
Authority Required
Continuing treatment, as the sole PBS subsidised agent, of advanced
hepatocellular carcinoma in a patient who has previously been
treated with PBS-subsidised sorafenib and who does not have
progressive disease.
NOTE: Sorafenib is not PBS-subsidised for
adjunctive treatment after resection, ablation or
chemoembolization.
Sorafenib is not PBS-subsidised for maintenance therapy after
disease progression.
No applications for increased maximum quantities and/or repeats
will be authorised
Maximum quantity: 120
Repeats: 2
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor chose not to comment.
