TOPOTECAN,capsules, 0.25 mg and 1 mg (as hydrochloride), Hycamtin®, July 2010
Page last updated: 03 November 2010
Public Summary Document
Product: TOPOTECAN, capsules, 0.25 mg and 1 mg (as
hydrochloride), Hycamtin®
Sponsor: GlaxoSmithKline Australia Pty Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
The submission sought an Authority Required (STREAMLINED) listing
for treatment of relapsed or refractory small cell lung cancer
(SCLC) where intravenous (IV) therapy is inappropriate.
2. Background
Topotecan hydrochloride capsules had not previously been considered
by the PBAC.
3. Registration Status
Topotecan hydrochloride capsules 0.25 mg and 1 mg were TGA
registered on 26 August 2009 for treatment of patients with
relapsed small cell lung cancer for whom re-treatment with the
first-line regimen is not considered appropriate.
4. Listing Requested and PBAC’s View
The sponsor proposed a revised listing in the Pre-PBAC response as
follows:
Authority Required
Relapsed small cell lung cancer in a patient with ECOG performance status of 0, 1 or 2, where:
- Re-treatment with the first-line regimen is not considered appropriate, and;
- The combination of cyclophosphamide, doxorubicin and vincristine (CAV) is contraindicated.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Small cell lung cancer accounts for approximately 15% of all lung
cancers, and is the most aggressive type of lung cancer, with a
median survival in untreated patients of 2-4 months. Despite the
efficacy of first-line chemotherapy and radiotherapy, most patients
will eventually experience disease recurrence or progression, with
response to second-line therapy remaining consistently poor. For
many patients, second-line IV chemotherapy is not given due to
treatment refractory disease, co-existing morbidities, persistent
toxicities arising from first-line treatment, or patient preference
not to undergo further treatment. For these patients, the only
currently available option is best supportive care (BSC).
Oral topotecan is proposed as a treatment option for patients with
relapsed SCLC for whom second-line intravenous chemotherapy is
inappropriate.
6. Comparator
The submission nominated best supportive care for patients with
relapsed small cell lung cancer where IV treatment is considered
inappropriate as the comparator.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented one randomised open-label trial (Study
478) comparing oral topotecan (2.3 mg/m2/day for 5 days
in a 21-day cycle) plus BSC with BSC alone in patients with
relapsed SCLC for whom chemotherapy is considered
inappropriate.
The submission also presented an indirect comparison of three
randomised trials comparing oral topotecan with CAV using IV
topotecan as common reference. The submission did not include this
indirect comparison in the economic model.
Details of the trials published at the time of submission are
presented in the table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Direct comparison | ||
| Study 478 | ||
| O’Brien M, et al | Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. | Journal of Clinical Oncology 2006; 24: 5441-7 |
| Chen L, et al | Symptom assessment in relapsed SCLC: Cross-validation of the patient symptom assessment in lung cancer instrument. | Journal of Thoracic Oncology 2008; 3: 1137-45 |
| Indirect comparison | ||
| Oral topotecan | ||
| Study 065 | ||
| von Pawel J, et al | Phase II comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. | Journal of Clinical Oncology 2001; 19(6): 1746-1749 |
| Study 396 | ||
| Eckardt JR, et al | Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. | Journal of Clinical Oncology 2007; 25(15): 2086-92 |
| CAV | ||
| Study 090 | ||
| von Pawel J, et al | Topotecan versus cyclophosphamide, doxorubicin and vincristine for the treatment of recurrent small-cell lung cancer. | Journal of Clinical Oncology 1999; 17(2): 658-667 |
8. Results of Trials
Oral topotecan + BSC versus BSC alone
The primary outcome of Study 478 was overall survival. The main
secondary outcomes were response rate (topotecan plus BSC arm only)
and quality of life, assessed using the EQ-5D.
The PBAC noted that treatment with topotecan + BSC resulted in an
additional 12 weeks median survival (25.9 weeks; 95%CI: 18.3, 31.6)
when compared to BSC treatment (13.9 weeks; 95%CI: 11.1, 18.6). The
six months survival rate was also higher in the topotecan + BSC
group compared to the BSC group, however statistical significance
was not tested for this outcome.
For EQ-5D symptom scores from Study 478, the PBAC noted the mean
rate of change (decrease in quality of life score) from baseline
per three month interval was significantly greater for BSC compared
to topotecan + BSC treatment. The open-label nature of the trial
may have compromised these results.
Grade 3/4 haematological adverse events and diarrhoea occurred
significantly more often in patients treated with topotecan + BSC
compared with BSC alone. No other significant differences in Grade
3/4 adverse events were observed. In the topotecan + BSC group
three patients died due to haematological toxicity, while none of
the patients in the BSC group died due to this cause.
Indirect comparison oral topotecan vs. CAV
The submission stated that the meta-analysis of oral topotecan
versus CAV, using IV topotecan as a common reference, indicated
there was no statistically significant difference in tumour
response between oral and IV topotecan. The meta-analysis of Study
065 and Study 396 indicated there is heterogeneity for the primary
outcome. Due to different response rates and likely differences in
the patient populations in the trials, an additional indirect
comparison was performed during the evaluation, excluding Study 065
from the analysis. This analysis also found there to be no
statistically significant difference in tumour response between
oral topotecan and IV CAV using IV topotecan as common
reference.
The submission stated that while an indirect comparison was not
performed for overall survival, the point estimates from Study 065,
Study 396 and Study 090 suggest that there is unlikely to be a
difference between oral topotecan and CAV in terms of overall
survival.
The indirect comparison indicated that, compared with CAV
treatment, oral topotecan was associated with significantly less
neutropenia and more thrombocytopenia, anaemia and diarrhoea. Using
the odds ratio (OR), the result for neutropenia was not
statistically significant. Both oral topotecan and CAV treatment
were associated with death due to haematological toxicity.
For PBAC’s views on these results, see Recommendation and
Reasons.
9. Clinical Claim
Oral topotecan + BSC versus BSC alone
The submission described topotecan plus BSC as superior in terms of comparative effectiveness
and inferior in terms of comparative safety compared with BSC for the treatment of
patients with relapsed SCLC where further intravenous chemotherapy is inappropriate.
Indirect comparison oral topotecan vs. CAV The submission described oral topotecan
as non-inferior in terms of comparative effectiveness and having a different safety
profile over CAV treatment.
For PBAC’s view, see Recommendation and Reasons.
10. Economic Analysis
Oral topotecan + BSC versus BSC alone
A trial-based economic evaluation was presented, based on the
direct randomised trial (Study 478).
A stepped analysis was presented in which health outcomes were
presented as life years gained and then as quality-adjusted life
years (QALY) gained.
The time horizon in the modelled economic evaluation was the
maximum duration of follow-up of the individual patients in the
trial, which was up to 71 cycles (4.08 years).
The economic evaluation estimated the incremental cost/extra life
year gained (discounted) and the incremental cost/extra QALY gained
(discounted) to both be in the range of $15,000 and $45,000.
The submission presented sensitivity analyses which considered
variations in the base case assumptions used and patient subgroups
as defined in Study 478 namely gender, presence of liver
metastases, performance status and time to relapse.
For PBAC’s view, see Recommendation and
Reasons.
Indirect comparison oral topotecan vs. CAV
The submission did not provide a cost-effectiveness analysis
comparing oral topotecan with CAV treatment, on the basis that it
requested listing for patients for whom IV chemotherapy is
considered inappropriate.
During the evaluation an indicative cost-minimisation analysis was
performed, including only drug costs and infusion costs. In this
analysis the average dose of topotecan per cycle was used for the
calculations. The indicative cost-minimisation analysis showed that
oral topotecan is more expensive than IV CAV therapy.
11. Estimated PBS Usage and Financial Implications
The submission estimated the financial cost per year to the PBS to
be less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC noted the revised restrictions proposed in the
sponsor’s Pre-Sub-Committee Response and the Pre-PBAC
response and considered that it would be difficult to define
“contraindication to CAV”. In addition, it would also
be difficult to define “patients for whom IV therapy is
inappropriate” as proposed in the original restriction. The
PBAC considered that despite the revised restrictions, topotecan
was likely to be used in some patients who prefer oral rather than
IV treatment and therefore oral etoposide would also be an
appropriate comparator. Further, the submission and clinical trial
report did not provide a well defined description of the inclusion
criterion “patients not considered suitable for further IV
chemotherapy” and therefore it could not be ascertained
whether the term would include the same patients in the proposed
population compared with the clinical trial.
The PBAC considered that the requested restriction did not match
the trial population as some patients in the trial received further
intravenous chemotherapy. The PBAC considered that by only
comparing topotecan with best supportive care and not with other
treatments that topotecan was likely to replace, it was difficult
to define its place in therapy. The PBAC noted that for most
patients (70%) in the clinical trial the time to progression was
greater than 60 days and therefore patients may be eligible for
treatments such as oral etoposide, repeat first line therapy
(cisplatin/carboplatin and etoposide) or CAV. The PBAC also noted
that 38% of patients had limited disease which may enable treatment
with a tolerable radiation field and therefore topotecan may have
been used in this setting as additional “adjuvant
therapy” or maintenance therapy.
The PBAC noted that an indirect comparison of topotecan versus CAV
was presented but considered that this may not be appropriate due
to differences in baseline patient characteristics across the three
trials and between each of the treatment arms within the trials. It
also appeared that oral topotecan might be associated with more
toxicity compared with CAV treatment.
The PBAC agreed that based on supporting data the clinical claim
that topotecan plus BSC is superior in terms of comparative
effectiveness and inferior in terms of comparative safety compared
with BSC for the treatment of patients with relapsed SCLC where
further intravenous chemotherapy is inappropriate was reasonable.
However, the PBAC again noted that the term “IV
appropriate” was not well defined in the clinical trial and
could include patients who prefer not to undergo further IV
chemotherapy.
The PBAC noted the sponsor’s Pre-Sub-Committee Response
regarding a decision of cost-effectiveness being made on the basis
of the cost per life year gained but considered that in this case
it would not reduce the uncertainty associated with the quality of
life outcomes. The PBAC preferred quality adjusted life years and
this was the preferred basis of all decisions by the PBAC.
The trial-based economic evaluation based on the direct randomised
trial (Study 478) estimated the incremental cost effectiveness
ratio to be between $15,000 and $45,000 /LYG (discounted) and
between $15,000 and $45,000/QALY (discounted). The PBAC noted that
the results of the sensitivity analyses indicate that the model is
most sensitive to variation in the assumptions used for calculating
the utility values and the subgroup analyses assessing the effect
of male gender and the presence of liver metastases. There was a
difference in ICER between men ($75,000 – $105,000/QALY) and
women (less than $15,000/QALY). Given that 73% of the population
are males, the PBAC considered that the base case ICER should
probably be closer to the male not the female figure.
The PBAC therefore rejected the submission on the basis of
uncertain clinical benefit and a high and uncertain incremental
cost-effectiveness ratio.
The PBAC noted that the submission meets the criteria for an
independent review.
Recommendation:
Reject
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
GSK is disappointed with the outcome and is considering options to
make the product available to patients.
