Sorafenib Tosylate, tablet, 200 mg (base), Nexavar November 2006
Public summary document for Sorafenib Tosylate, tablet, 200 mg (base), Nexavar November 2006
Page last updated: 16 March 2007
Public Summary Document
Product: Sorafenib Tosylate, tablet, 200 mg (base), Nexavar
Sponsor: Bayer Australia Ltd
Date of PBAC Consideration: November 2006
1. Purpose of Application
The submission requested an Authority Required listing for sorafenib for initial and continuing treatment of advanced renal cell carcinoma in patients who meet certain criteria.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Sorafanib was registered by the TGA on 25 September 2006 for the treatment of patients with advanced renal cell carcinoma.
4. Listing Requested and PBAC’s View
Authority required
Initial (up to 3 months) treatment of advanced (unresectable or metastatic) renal
cell carcinoma in patients with WHO performance status of 2 or less.
Continuing treatment of advanced renal cell carcinoma (beyond 3 months) in patients
with stable disease or responding disease (according to RECIST criteria).
The PBAC did not comment on the requested restriction.
5. Clinical Place for the Proposed Therapy
Renal cell carcinoma can often be cured if it is diagnosed and treated when still
localised to the kidney. When distant metastases are present, disease-free survival
is poor.
Palliative treatment is usually employed to help patients with advanced renal cell
carcinoma (kidney cancer) and help patients live without pain or distress.
Currently, only a small percentage of patients with advanced renal cell carcinoma
receive any active immunotherapy or chemotherapy, with the most commonly used agent
being interferon alfa. Patients may receive pain medication and/or radiotherapy for
symptom control (best supportive care).
Sorafenib is expected to be used alongside the current practice of best supportive
care and in the minority of cases it may replace immunotherapy or chemotherapy.
6. Comparator
The submission nominated placebo for best supportive care (BSC) as the main comparator.
The PBAC agreed that this is the appropriate comparator.
For further information on the PBAC’s views regarding the comparator see Recommendation
and Reasons.
7. Clinical Trials
The submission provided a comparison between sorafenib and placebo in two randomized
trials. Trial 11213 was a placebo controlled trial of 903 patients (pivotal trial),
and Ratain/2006 was a small randomized discontinuation trial of 65 patients who had
stable disease at the end of an open run-in period of 12 weeks on sorafenib.
These trials had been published at the time of submission as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Ratain et al |
Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. |
Journal of clinical oncology Jun 1 2006, 24 (16) p2505-12. |
|
Dhanda et al. |
Comparison of quality of life and symptoms in kidney cancer patients receiving sorafenib versus placebo. |
J. Clin Oncol 2006; 24 (18Suppl): Abstract 4534. |
|
Eisen et al. |
Trial of sorafenib in advanced renal cell carcinoma (RCC): impact of cross-over on survival” |
J. Clin Oncol 2006; 24 (18Suppl): Abstract 4524. |
|
Gao et al. |
Cost-effectiveness of sorafenib versus best supportive care in advanced renal cell carcinoma. |
J. Clin Oncol 2006; 24 (18Suppl): Abstract 4604 |
|
Escudier et al. |
Randomised phase III trial of the multikinase inhibitor sorafenib (bay 43-9006) in patients wit advanced renal cell carcinoma (RCC). |
Eur Urol. 2006; Suppl 5 (2): 287. |
|
Escudier et al. |
Randomised phase III trial of the multikinase inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). |
21st Annual Congress of the European-Association-of-Urology Paris, FRANCE April 05 -05, 2006; 20060405 |
|
Stehler et al. |
Randomized phase III trial of the multi-kinase inhibitor sorafenib (bay 43-9006) in patients with advanced renal cell carcinoma (RCC). |
Dtsch Krebskongress, Berlin, Germany, March 2006: Abstract |
|
Escudier et al. |
Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). |
J.Clin.Oncol. 2005; 23(16Suppl), Abstract 4510, 2005. |
|
Ratain et al. |
Final findings from a phase II, placebo-controlled, randomized discontinuation trial of sorafenib (bay 43-9006) in patients with advanced renal cell carcinaoma. |
J.Clin.Oncol. 2005; 23(16Suppl), Abstract 4544, 2005 |
|
Escudier et al. |
Randomized phase III trial of the multi-kinase inhibitor sorafenib (bay 43-9006) in patients with advanced renal cell carcinoma (RCC). |
EJC 2005. Suppl 3 (2): 226 Abstr 794. |
|
Eisen et al. |
Preliminary antitumor activity in metastatic renal cell carcinoma in a phase in randomized discontinuation trial. |
Symp Targeted Anticancer Ther, Mar 2005, Amsterdam |
|
Escudier et al. |
Randomized phase III trial of the raf kinase and vegfr inhibitor sorafenib (bay 43-9006) in patients with advanced renal cell carcinoma (RCC). |
J Clin Oncol 23 (16 PT 2): 1093 205 |
|
Ratain et al. |
Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT). |
J.Clin.Oncol.. 2004; 22 (14 Suppl): Abstract 4501. |
|
Ratain et al. |
A phase II study of BAY 43-9006 using the randomized discontinuation design in patients with advanced refractory cancer. |
Clin.Cancer Res. 2003; 9(16), 6265S-6266S. |
8. Results of Trials
The results of the key trial on progression-free survival, overall survival, Response
Evaluation Criteria In Solid Tumours (RECIST) categories and disease control rate
(proportion of patients with responding or stable disease), and Health Related Quality
of Life (HRQOL) measures are summarised in the tables below.
Progression-free survival results in Trial 11213 (as of 28 January 2005)
|
Analysis |
Event rate (progression or death) |
HR (95% CI) |
|---|---|---|
|
Progression-free survival |
147/384 (38.3%) vs 195/385 (50.6%) |
0.44 (0.35, 0.55) |
Note: An event is either progression or death prior to progression, so progression-free survival is the inverse of the event rates, i.e., 61.7% for sorafenib and 49.4% for placebo.
There was a statistically significant improvement representing a 56% reduction in
the hazard ratio of progression free survival (PFS) over placebo. This corresponds
to a median PFS of 167 days for sorafenib compared to 84 days for placebo. The submission
also presented the results for PFS as of 31 May 2005 as assessed by the investigators
rather than by independent review.
Overall survival results in Trial 11213 (as of 31 May 2005)
|
Analysis |
Event rate (death) |
HR (95% CI) |
|---|---|---|
|
Overall survival |
97/451 (21.5%) vs 123/452 (27.2%) |
0.72 (0.55, 0.95) |
Note: An event is death, so overall survival is the inverse of the event rates, i.e., 78.5% for sorafenib and 72.8% for placebo.
From this date, 31 May 2005, the trial was unblinded and placebo patients offered
sorafenib, so no subsequent analysis of overall survival would be uncertain and potentially
underestimate the value of therapy. See Recommendation and Reasons for the PBAC’s
view.
Sorafenib is associated with a variety of adverse events and laboratory findings including
dermatologic and gastrointestinal events, hypertension, sensory neuropathy, and neutropenia.
Additionally, a six-fold increase in cardiac ischemia/infarction was found in Trial
11213.
9. Clinical Claim
The submission claimed that sorafenib demonstrated benefits in survival and in progression-free
survival but also had more toxicity than best supportive care (BSC). The PBAC agreed
with this claim but considered that the extent of benefit for overall survival and
Health Related Quality of Life (HRQOL) to be unclear.
See Recommendation and Reasons for the PBAC’s view.
10. Economic Analysis
A preliminary economic evaluation was presented. The resources included were drug
costs, monitoring, and treatment of adverse events.
The submission estimated the base case modelled incremental discounted cost/discounted
extra life year gained or QALY to be in the range $15,000 - $45,000.
In its Pre-PBAC Response, the sponsor claimed that the base case cost per extra QALY
gained at 5 months as presented in the clinical secondary analysis was estimated to
be in the range $45,000 - $75,000.
The PBAC considered that the conservative base case incremental cost-effective ratio
(ICER) estimate in the range $45,000 - $75,000 to be high and uncertain, with the
possibility that the ICER being greater than $150,000.
11. Estimated PBS Usage and Financial Implications
The likely number of patients/year was estimated to be < 10,000 in Year 4 and the
financial cost/year to the PBS was estimated to be in the range $10 – 30 million in
Year 4.
The PBAC considered that the estimates of usage may result in net costs ≥ $10 million/year
to the PBS in the first year of listing at least.
12. Recommendation and Reasons
The PBAC agreed that placebo for best supportive care to be the appropriate comparator
and noted, given the shortage of treatment options for renal cell carcinoma, that
some patients are being treated with newer agents under clinical trial conditions.
The PBAC accepted that there is a clinical need for additional treatment options in
this group of patients.
The Committee agreed that the data presented in the submission demonstrated that sorafenib
is associated with an overall survival gain, but the extent of this gain is uncertain.
The Committee noted the influence that the cross over to sorafenib treatment in the
pivotal trial (Trial 11213), had on the ability of the submission to demonstrate efficacy
in terms of the extent of overall survival gain compared to placebo. The Committee
considered that the extent of overall survival gain is not quantifiable, due to the
corruption of the data resulting from the need to cross patients over to active treatment
in the clinical trial. The sponsor’s comments in its Pre-PBAC Response regarding this
issue was noted, including the pre-specified secondary analysis that was conducted
to understand the impact of the cross-over on overall survival in placebo patients.
The Committee felt that the sponsor’s estimated 5 months overall survival gain of
sorafenib over placebo, remained debatable, and noted that statistical significance
had not been reached.
The PBAC agreed that the data supports that sorafenib improves progression free survival,
however considered that the clinical relevance of this gain had not been demonstrated
in the submission, either in terms of symptoms of renal cell carcinoma or prediction
of survival. The PBAC noted that once patients had progressed in Trial 11213, they
were only followed up for vital status and that no data directly describing the relation
of progression to symptoms were presented.
The PBAC noted that in the pivotal trial, only 9.5% of patients achieved a partial
response to sorafenib as compared to 1.8% for placebo, in the comparison of RECIST
categories determined by the investigator. The clinical rationale for patients not
achieving a partial response is unknown. There was no statistically significant difference
in patients achieving a complete response and 73.8% of patients achieved stable disease
with sorafenib compared with 52.9% with placebo. All three categories were included
in the requested restriction.
The PBAC noted that sorafenib is associated with a variety of adverse events and laboratory
findings including dermatologic and gastrointestinal events, hypertension, sensory
neuropathy, and neutropenia. Additionally, a six-fold increase in cardiac ischemia/infarction
was found in Trial 11213. Diarrhoea, rash, fatigue, hand-foot syndrome, alopecia and
nausea were reported in >20% patients.
The key concern raised by the modelled economic evaluation related to the time horizon.
The assumptions resulted in the model predicting an incremental survival in excess
of the survival shown in the results of the clinical trial.
The PBAC considered that the conservative base case incremental cost-effective ratio
(ICER) estimate in the range $45,000 - $75,000 to be high and uncertain, with the
possibility of the ICER being greater than $150,000.
The PBAC agreed that the revised estimates of usage may be an underestimate due to
uncertainties relating to prevalence and possible increased rate of referral resulting
from the availability of subsidised sorafenib. The sponsor’s pre-PBAC response regarding
expected uptake was noted by the Committee, with the final estimate of total cost
to government to be in the range $10 - $30 million in year 4 of PBS listing.
Overall, the PBAC accepted that there is a clinical need for additional treatment
options for the management of renal cell carcinoma but that the data presented in
the submission did not present, with an adequate degree of certainty, the extent of
benefit that would be realised should sorafenib be listed on the PBS. The Committee
considered that the conservative base case ICER estimate in the range $45,000 - $75,000
to be high and uncertain, with the possibility of the ICER being greater than $150,000.
The PBAC therefore rejected the submission on the basis of uncertainty of the extent
of gain in overall survival, and the resulting high and uncertain cost-effectiveness
ratio.
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
Bayer Australia Ltd continues to be concerned that the current treatment options for
advanced renal cell carcinoma are limited and is committed to securing a PBS listing
for sorafenib. The sponsor is planning to resubmit an application.
In the meantime, Bayer Australia Ltd suggests that patients with advanced renal cell
carcinoma speak to their clinicians about treatment options.
