Sunitinib malate, capsules, 12.5 mg (base), 25 mg (base) and 50 mg (base), Sutent®, July 2009
Public summary document for Sunitinib malate, capsules, 12.5 mg (base), 25 mg (base) and 50 mg (base), Sutent®, July 2009
Page last updated: 30 October 2009
Public Summary Document
Product: Sunitinib malate, capsules, 12.5 mg
(base), 25 mg (base) and 50 mg (base), Sutent®
Sponsor: Pfizer Australia Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
The submission sought a Section 85 Authority Required listing for
the initial and continuing treatment of gastrointestinal stromal
tumour (GIST) after failure of imatinib mesylate due to resistance
At the March 2007 meeting, the PBAC deferred consideration of a
submission for sunitinib pending the provision of further
information to demonstrate that sunitinib was a cost effective
treatment for GIST after failure of imatinib. The PBAC considered
that the submission’s cost-minimisation comparison with
imatinib was inappropriate because it rested on the inadequately
supported assumption that treatment with imatinib in eligible
patients was no better than placebo.
At the March 2008 meeting, the PBAC rejected a submission for an Authority required listing for GIST on the basis of an unacceptably high and uncertain ICER. The uncertainty was mainly due to the impact of continued sunitinib post-progression.
At its July 2008 meeting, the PBAC recommended listing of sunitinib for Stage IV clear cell renal cell carcinoma on the basis of acceptable cost-effectiveness compared with best supportive care. Listing was effective from 1 May 2009.
3. Registration Status
Sunitinib malate was registered by the TGA on 14 September 2006 for the treatment of:
- Advanced renal cell carcinoma;
- Gastrointestinal stromal tumour (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance.
4. Listing Requested and PBAC’s View
Initial PBS-subsidised treatment, as monotherapy, in a patient with gastrointestinal stromal tumour (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance.
Continuing PBS-subsidised treatment, as monotherapy, in a patient with gastrointestinal stromal tumour (GIST) who has previously been issued with an authority prescription for this drug and who does not have progressive disease.
The PBAC considered that the continuing criteria should state that there be no use of sunitinib beyond progression and that patients who had failed to respond or who were intolerant of imatinib cannot return to PBS-subsidised imatinib after progression on sunitinib and that this should also be included in the imatinib restriction for GIST. WHO performance status of 2 or less should be included in the initial criteria. Patients on the sunitinib compassionate program may be grandfathered onto PBS-subsidised sunitinib if they met the initial criteria and had failed imatinib treatment due to resistance or intolerance.
5. Clinical Place for the Proposed Therapy
Sunitinib will provide an alternative treatment for those patients
with GIST who cannot tolerate imatinib, or who have tumours that
are resistant to, or become resistant to imatinib.
The submission nominated best supportive care (placebo) as the main
comparator. This was previously suggested, and accepted by the
7. Clinical Trials
The final results of the key A618-1004 trial were presented in the
re-submission (maximum 4.35 years of follow-up). Previously only
the interim results were available (maximum of 12 months
follow-up). The A618-1004 trial was fully un-blinded shortly after
the interim analysis was conducted. Therefore the double-blind
period for both the interim and final results represented a similar
Given the trial was fully unblinded not long after the interim analysis and patients could switch from placebo to sunitinib, the results of the follow-up data were potentially biased towards the null. To overcome this issue, the submission had used a rank-preserving structural failure time (RPSFT) model, which was a version of randomised based efficacy estimator.
The studies published at the time of submission are as follows:
|Trial/First author||Protocol title/Publication title||Publication citation|
|Chu TF, 2007||Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib||Lancet 2007; 370: 2011–19|
|Desai J, 2007||Sunitinib malate in the treatment of renal cell carcinoma and gastrointestinal stromal tumor: Recommendations for patient management||Asia–Pacific Journal of Clinical Oncology 2007; 3: 167–176|
|Khakoo AY, 2008||Heart failure associated with sunitinib malate: A multitargeted receptor tyrosine kinase inhibitor||Cancer 2008;112:2500–8|
|Rosenbaum SE, 2008||Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib.||Support Care Cancer 2008; 16: 557-566.|
|Telli ML, 2008||Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate||Annals of Oncology 2008; 19: 1613–1618, 2008|
|Houk B, 2008||An exposure-response-based meta-analysis of the efficacy of sunitinib in patients with gastrointestinal stromal tumor||Annals of Oncology 2008; 19 (Suppl 6): 12|
8. Results of Trials
The time to tumour progression, progression-free survival and overall survival for the ITT population in trial A618-1004 are summarised in the following table:
|Variable||Number of events||Hazard ratio (HR)||p-value|
|Sunitinib N = 243||Placebo N = 118|
|Time to tumour progression (double-blind period only)|
|TTP events; crude rate [n (%)]||91 (37.4)||73 (61.9)|
|TTP-free patients; crude rate [n (%)]||152 (62.6)||45 (38.1)|
|TTP median time to progression; weeks (95% CI)||26.6 (16.0, 32.1)||6.4 (4.4, 10.0)||0.339 (0.244, 0.472)||<0.001|
|Progression-free survival (double-blind period only)|
|PFS patients; crude rate [n (%)]||101 (41.6)||79 (66.9)|
|PFS median time to PFS-failure, weeks (95% CI)||22.9 (10.9, 28.0)||6.0 (4.4, 9.7)||0.347 (0.253, 0.475)||<0.001|
|Overall survival (double-blind and open-label periods)|
|Interim results (maximum 12 months follow-up)|
|Total deaths (any cause); crude rate [n (%)]||29 (14.0)||27 (25.7)|
|Alive patients; crude rate [n (%)]||178 (86.0)||78 (74.3)|
|Median time to death (any cause), weeks (95% CI)||Median not reached||Median not reached||0.491 (0.290, 0.831)||0.007|
|Final results (maximum 4.35 years follow-up)|
|Total deaths (any cause); crude rate [n (%)]||176 (72.4)||90 (76.3)|
|Alive patients; crude rate [n (%)]||67 (27.6)||28 (23.7)|
|Median time to death (any cause), weeks (95% CI)||72.7 (61.3, 83.0)||64.9 (45.7, 96.0)||0.876 (0.679, 1.129)||0.306|
|Median time to death (any cause), RPSFT model, weeks (95% CI)||72.7 (61.3, 83.0)||39.0 (28.0, 54.1)||0.505 (0.262, 1.134)||0.306|
Abbreviations: CI, confidence interval; OS, overall survival; RPSFT, rank-preserving
structural failure time; TTP, time-to-progression.
There were statistically significant differences in the median time-to-death between treatments at the interim analysis (HR 0.491, 95 % CI 0.290, 0.831) but not at the final analysis (HR 0.876, 95 % CI 0.679, 1.129). However both analyses of patient survival were confounded by patient crossover from placebo to sunitinib treatment (70 % of placebo patients had crossed-over to open-label sunitinib by Week 13, increasing to 87 % by Week 39). The RPSFT model estimated that the median time-to-death in the placebo arm would have decreased to 39 weeks if the patients had not crossed over to sunitinib treatment. A comparison of overall survival between treatments using the RPSFT model improved the estimated survival benefit of sunitinib (72.7 weeks vs. 39.0 weeks; HR 0.505, 95 % CI 0.262, 1.134).
The overall summary of adverse events in the as-treated population from the final analysis of trial A618-1004 was:
|Double-blind period||Open-label period N = 255||Sunitinib only treatment a N = 241|
|Sunitinib N = 228||Placebo N = 114|
|Subjects with at least 1 adverse event [n (%)]||223 (97.8)||110 (96.5)||254 (99.6)||239 (99.2)|
|Subjects with at least 1 serious adverse event [n (%)]||83 (36.4)||27 (23.7)||122 (47.8)||130 (53.9)|
|Subjects with at least 1 treatment-related adverse event [n (%)]||204 (89.5)||68 (59.6)||241 (94.5)||223 (92.5)|
|Subjects with at least 1 treatment-related serious adverse event [n (%)]||47 (20.6)||3 (2.6)||59 (23.1)||72 (29.9)|
|Subjects with grade 5 (fatal) treatment-related adverse event||4 (1.8)||2 (1.8)||4 (1.6)||5 (2.1)|
|Subjects with grade 4 (life-threatening or disabling) treatment-related adverse event||21 (9.2)||1 (0.9)||21 (8.2)||28 (11.6)|
|Subjects who withdrew due to adverse events [n (%)] b||32 (14.0)||10 (8.8)||68 (26.7)||69 (28.6)|
a The sunitinib-only analysis set includes safety results from both the double-blind
and open-label periods for patients randomised to sunitinib.
b Includes patients who withdrew due to the adverse event of disease progression.
NOTE: Patients randomised to treatment before the study was un-blinded without beginning study treatment until after un-blinding were excluded from the safety analysis of double-blind treatment (they are included in summaries of open-label treatment and, for subjects randomised to sunitinib, in the sunitinib-only analysis set).
The re-submission also presented additional safety data on the risk of congestive heart failure and skin reactions associated with sunitinib treatment. The proportion of individuals in the pivotal trial with congestive heart failure was 7.5 %.
9. Clinical Claim
The re-submission described sunitinib as superior in terms of
comparative effectiveness and inferior in terms of comparative
safety over placebo.
For PBAC's views see Recommendations and Reasons.
10. Economic Analysis
The result of the trial-based economic evaluation was that the
incremental cost/extra progression-free year gained was in the
range of $15,000 - $45,000.
An updated modelled economic evaluation was presented. Costs for the modelled economic evaluation include drug costs, management of adverse events costs, diagnostic imaging costs, acute progression management costs and palliative care costs. Based on the structure and assumptions used in the submission’s model, sunitinib treatment of GIST was associated with an incremental cost per life year gained in the range of $15,000 - $45,000 and an incremental cost per QALY gained in the range of $45,000 – $75,000 compared with placebo over a five-year time period.
The results of the sensitivity analyses indicated that the model was most sensitive to assumptions regarding the survival hazard ratio used to derive the placebo mortality rate in the model and assumptions regarding sunitinib use beyond tumour progression.
For PBAC’s views see Recommendations and Reasons
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was less than 100 patients
in Year 5.
12. Recommendation and Reasons
The PBAC recommended an extension to the listing of sunitinb on the
PBS to include the treatment of a metastatic or unresectable
malignant gastrointestinal stromal tumour on the basis of high
clinical need and a high but acceptable cost-effectiveness ratio
compared with best supportive care.
The PBAC considered that the continuing criteria should state that there be no use of sunitinib beyond progression and that patients who have failed to respond or who are intolerant of imatinib cannot return to PBS-subsidised imatinib after progression on sunitinib and that this should also be included in the imatinib restriction for GIST. WHO performance status of 2 or less should be included in the initial criteria. Patients on the sunitinib compassionate program may be grandfathered onto PBS-subsidised sunitinib if they meet the initial criteria and have failed imatinib treatment due to resistance or intolerance.
As previously agreed by the PBAC, best supportive care (placebo) was nominated as the main comparator.
The key difference between the March 2008 submission and the current was the presentation of the final analysis of the A0618-1004 trial with a maximum of 4.35 years follow-up. Previously only the interim results were available (maximum of 12 months follow-up).
The PBAC noted that the trial was fully unblinded not long after the interim analysis and patients could switch from placebo to sunitinib. The PBAC agreed that the crude overall survival hazard ratio of 0.876 was biased towards the null and that the rank-preserving structural failure time (RPSFT) modelled ratio, of 0.505, which was an attempt to estimate what the survival time would have been in the placebo arm if patients had not crossed-over, may be an overestimate. The PBAC noted that the base-case economic evaluation used the HR of 0.49 from the interim analysis. The PBAC considered that overall, sunitinib appeared to be clinically effective based on the primary endpoint of TTP and the available overall survival data. The size of the treatment effect is uncertain as demonstrated by the variability in the incremental cost-effectiveness ratio presented in sensitivity analyses and that the true result may be somewhere in between the RPSFT estimate and the base-case result. The PBAC agreed that the uncertainty around the incremental survival gain had been decreased by the provision of 4.35 years of survival data from the sunitinib arm. However, the survival estimate for the placebo group was still highly uncertain since it represented a modelled estimate and had not been measured directly.
The incremental cost per QALY gained was estimated to be between $45,000 and $75,000 compared with placebo over a five-year time period. This was compared with ICERs of between $75,000 and $105,000 per extra LYG and $105,000 to $200,000 per extra QALY estimated in the March 2008 submission. The PBAC noted that the difference between submissions related to differences in the estimation of survival benefit which had more than doubled in this submission from 15 weeks in March 08 to 36 weeks in July 09 because the survival in the sunitinib arm had increased. The survival in the placebo arm was also better. The PBAC considered that the QALY was more certain than the QALY in the March 2008 submission.
The PBAC noted that the claimed survival benefit of sunitinib versus placebo (i.e. the hazard ratio) was assumed to continue undiminished for the 5-year duration of the model and that data from these sunitinib treated patients were used to establish the “reference survival curve”. The PBAC accepted the reference curve but did not agree that the HR (0.49, 95 % CI 0.290, 0.831) remained constant over time as the confidence interval is wide.
The PBAC noted that the results of the sensitivity analyses indicated that the model was most sensitive to assumptions regarding the survival hazard ratio used to derive the placebo mortality rate in the model and assumptions regarding sunitinib use beyond tumour progression. If the upper 95 % CI was used then the ICER was estimated to be between $105,000 and $200,000/QALY.
The PBAC agreed that the duration of sunitinib treatment beyond tumour progression (2 treatment cycles) was likely to be an underestimate. The estimate was based on the median number of treatment cycles post-progression in the A618-1004, and although the data may be skewed, the mean number of 6 treatment cycles was likely to be a more informative estimate of the costs across all patients. The PBAC considered that the mean treatment cycles post progression from the study of 5.85 should be used, which resulted in an ICER of between $45,000-$75,000/QALY.
SUNITINIB MALATE, capsules, 12.5 mg (base), 25 mg (base) and 50 mg (base)
Extend the current restriction to include:
Any queries concerning the arrangements to prescribe sunitinib malate may be directed to Medicare Australia on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday to Friday).
Prescribing information (including Authority Application forms) is available on the Medicare Australia website at www.medicareaustralia.gov.au.
Any queries concerning patients who are enrolled on the Sunitinib Compassionate Program may be directed to Medicare Australia on
1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday to Friday).
Written applications for authority to prescribe sunitinib malate should be forwarded to:
Prior Written Approval of Specialised Drugs
Reply Paid 9826
GPO Box 9826
HOBART TAS 7001
No applications for increased maximum quantities and/or repeats will be authorised.
Sunitinib malate is not PBS-subsidised for the treatment of patients with resectable malignant gastrointestinal stromal tumours.
Initial PBS-subsidised treatment as monotherapy of a patient with WHO performance status of 2 or less with metastatic or unresectable malignant gastrointestinal stromal tumour after failure of imatinib mesylate treatment due to resistance or intolerance.
Applications for authorisation must be in writing and must include:
- a completed authority prescription form;
- a completed Sunitinib Malate (Sutent) PBS Authority Application for Use in the Treatment of Gastrointestinal Stromal Tumour – Supporting Information Form [may be downloaded from the Medicare Australia Website (www.medicareaustralia.gov.au)]; and
- a signed patient acknowledgement.
Patients who have failed to respond or are intolerant to imatinib
are no longer eligible to receive PBS-subsidised imatinib.Max qty:
28 (all strengths)
Restriction: Authority Required
Continuing PBS-subsidised treatment as monotherapy of a patient with WHO performance status of 2 or less with a metastatic or unresectable malignant gastrointestinal stromal tumour who has previously been issued with an authority prescription for sunitinib and who does not have progressive disease.
Applications for continuing treatment may be made by telephone (1800 700 270, hours of operation 8 a.m. to 5 p.m. EST Monday to Friday).
Patients who have failed to respond or who are intolerant to imatinib are no longer eligible to receive PBS-subsidised imatinib.
Patients who have progressive disease on sunitinib are no longer eligible for PBS-subsidised sunitinib.Max qty 28 (all strengths)
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
Pfizer Australia welcomes the positive recommendation of the PBAC and looks forward to finalising the listing of sunitinib on the PBS for the treatment of metastatic or unresectable malignant gastrointestinal stromal tumour.