Erlotinib hydrochloride, tablet, 25 mg, 100 mg and 150 mg (base), Tarceva®
Public Summary Document for Erlotinib hydrochloride, tablet, 25 mg, 100 mg and 150 mg (base), Tarceva® March 2006.
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Public Summary Document
Product: Erlotinib hydrochloride, tablet, 25 mg, 100 mg and 150 mg (base), Tarceva®
Sponsor: Roche Products Pty Ltd
Date of PBAC Consideration: March 2006
1. Purpose of Application
To seek an authority required listing on the Pharmaceutical Benefits Scheme (PBS)
for erlotinib for the treatment of patients with locally advanced or metastatic non-small
cell lung cancer who have previously received chemotherapy.
2. Background
This drug had not previously been considered by the Pharmaceutical Benefits Advisory
Committee (PBAC).
3. Registration Status
Erlotinib is registered for the treatment of patients with locally advanced or metastatic
non-small cell lung cancer after failure of prior chemotherapy.
4. Listing Requested and PBAC’s View
Authority required
Treatment of patients with locally advanced or metastatic non-small cell lung cancer
who have previously received chemotherapy.
The PBAC’s view was that any restriction should stipulate use of erlotinib as monotherapy
for patients with locally advanced or metastatic non-small cell lung cancer with a
WHO status of 3 or less where disease progression has occurred following treatment
with at least one chemotherapy agent.
5. Clinical Place for the Proposed Therapy
Lung cancer is the fifth most commonly occurring cancer in Australia, accounting for
about 9% of all new cancer cases. It is the leading cause of death in men and the
second leading cause in women. The primary goal of therapy is to palliate symptoms
and prolong progression-free and overall survival.
After failure of first-line chemotherapy, additional second-line chemotherapy can
be beneficial. There are few therapeutic options available, other than supportive
care and palliative radiation, for patients whose disease has progressed following
second-line chemotherapy. Therefore, only a minority of these patients receive additional
cytotoxic therapy.
Erlotinib is a new oral agent which is indicated for the treatment of locally advanced
or metastatic non-small cell lung cancer who have previously received chemotherapy.
6. Comparator
The submission nominated docetaxel as the main comparator for patients receiving second-
or third-line chemotherapy for locally advanced or metastatic non-small cell lung
cancer. The submission also nominated best supportive care as a comparator for patients
who do not currently receive second- or third-line chemotherapy. The submission nominated
gefitinib as a secondary comparator.
The PBAC agreed that the appropriate comparators were docetaxel and best supportive
care (BSC). In addition, another comparator would be pemetrexed, which was listed
on a cost-minimisation basis compared with docetaxel and is replacing docetaxel in
the market place. The PBAC did not deem it necessary for mutational testing to access
erlotinib treatment and thus ruled out gefitinib as a comparator.
7. Clinical Trials
The submission presented a randomised placebo-controlled trial comparing erlotinib
150mg daily with best supportive care (BSC) in patients with locally advanced or metastatic
non-small cell lung cancer who have previously received chemotherapy, until disease
progression or unacceptable toxicity was documented and two indirect comparisons comparing
erlotinib (150mg/day) with docetaxel (75mg/m2) and with gefitinib (250mg/day), with
BSC as the common reference in patients with locally advanced or metastatic non-small
cell lung cancer who have previously received chemotherapy.
The list of studies that had been published at the time of submission is as follows:
|
Trial/First author |
Protocol/Publication title |
Publication citation |
|---|---|---|
|
Erlotinib vs BSC (randomised head-to-head trial) |
||
|
Study BR.21 |
A randomized, placebo-controlled study of OSI-774 (Tarceva™) in patients with incurable
stage IIIB/IV non-small cell lung cancer who have failed standard therapy for advanced
or metastatic disease. |
|
|
Erlotinib vs docetaxel (indirect comparison, BSC as the common reference) |
||
|
Shepherd (2000)
|
Prospective randomized trial of docetaxel versus best supportive care in patents with
non-small cell lung cancer previously treated with platinum-based chemotherapy. |
Journal of Clinical Oncology 18: 2095-103. |
|
Erlotinib vs gefitinib (Indirect comparison on efficacy, BSC as the common reference) |
||
|
ISEL trial |
FDA Oncologic Drugs Advisory Committee (ODAC) Meeting Briefing Document (2005). Drug Name: Iressa® (ZD1839, gefitinib) tables: 1-27 |
|
|
Gefitinib dose-finding studies (safety data, not placebo-controlled studies) |
||
|
IDEAL-1 trial |
Multi-institutional randomized phase II trial of gefitinib for previously treated
patients with advanced non-small-cell lung cancer. FDA Medical Review of a New Drug
Application (2003). Application Number: NDA 21-399. Drug Name: Iressa |
Journal of Clinical Oncology 21: 2237-46 |
|
IDEAL-2 trial |
Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine
kinase, in symptomatic patients with non-small cell lung cancer. FDA Medical Review
of a New Drug Application (2003). Application Number: NDA 21-399. Drug Name: Iressa®
(ZD1839) 250mg tablets: 1-129. |
Journal of the American Medical Association 290: 2149-58. |
8. Results of Trials
The randomised trial of erlotinib versus BSC demonstrated statistically significant
clinical benefits of erlotinib over BSC regarding all event rates, including overall
survival, 12-month survival rate, progression-free survival and overall response rate.
In the indirect comparisons of erlotinib versus docetaxel and gefitinib, erlotinib
showed numerically similar effectiveness to docetaxel and superior (statistically
significant) evidence for effectiveness over gefitinib for median survival.
The results of the key trials are summarised in the tables below.
Results of the comparative randomised trial BR.21: Erlotinib vs BSC
|
Outcomes |
Erlotinib |
BSC |
ARD (erlotinib vs BSC) (95% CI) |
Hazard ratio (95% CI) |
|---|---|---|---|---|
|
Overall survival |
n=488 |
n=243 |
||
| Number (%) of patients who died |
378 (77.46) |
209 (86.01) |
-8.55 |
NC |
| Median duration of survival in months (95% CI) |
6.67 |
4.70 |
1.97 |
0.73 |
Results of the indirect comparisons
|
Trial |
Treatment effect (erlotinib vs BSC) |
Erlotinib |
Common reference BSC |
Main comparator |
Treatment effect (main comparator vs BSC) |
Indirect estimate of effect |
|---|---|---|---|---|---|---|
|
12-month survival rate (erlotinib vs docetaxel), n/N % |
||||||
| BR.21 |
RR: 1.49 |
150/488 (30.7%) |
BSC |
Relative ratio of RR: |
||
| Shepherd (2000) |
BSC75 |
D75 |
RR: 2.97 (1.30, 6.79) |
|||
| Fossella (2000) |
V/I |
D75 |
NR |
NR |
||
|
Median (95% CI) overall survival in months (erlotinib vs gefitinib) |
||||||
| BR.21 |
HR: 0.73 |
6.7 |
BSC |
NR |
||
| ISEL |
BSC |
Gefitinib |
HR: 0.89 |
|||
CI = confidence interval, BSC75 = best supportive care 75mg/m², D75 = docetaxel 75mg/m², V/I = vinorelbine/ifosfamide, RR = relative rate, HR = hazard ratio, NR = not reported, NC = not calculated
Post hoc analysis of data from the key Trial BR.21 suggested that erlotinib produced
a longer duration of survival in patients who were EGFR-positive; no survival benefit
was seen in EGFR-negative patients. However, the mutational status was unknown for
a significant proportion of the trial population; the trial confidence intervals for
the sub-groups were wide and overlapping; only 52% (11/21) of responders had the activating
gene; and a test for interaction based on the Trial BR.21 results showed that EFGR
status was not associated with survival (p value = 0.97). Thus, overall, the evidence
presented suggested that a PBS listing of erlotinib on the basis of EFGR status was
not required.
The clinical safety profile of erlotinib was typical of EGFR inhibitors. The incidence
of adverse events with erlotinib was similar to BSC, with the exception of rash and
diarrhoea. Unlike docetaxel, there was no evidence of bone-marrow toxicity, neutropenic
fever, septic complications or neurosensory toxicity associated with erlotinib. The
toxicity profile of erlotinib appeared similar to that of gefitinib.
For PBAC’s view of these results, see Recommendations and Reasons.
9. Clinical Claim
The submission claimed that erlotinib had similar effectiveness to docetaxel, but
a different toxicity profile which was not associated with the haematological toxicities;
and significant advantages in effectiveness over BSC, but having more toxicity. The
PBAC noted that the randomised trial data supported the second of these descriptions
against BSC. The indirect comparison against docetaxel showed no statistically significant
difference between docetaxel and erlotinib, however it favoured docetaxel such that
a statistically significant survival advantage for docetaxel could not be excluded.
10. Economic Analysis
The submission presented a cost-effectiveness (vs BSC), a cost-minimisation (vs docetaxel)
and a cost-consequence (vs gefitinib) approach for the preliminary economic evaluations.
As PBAC had ruled gefitinib out as a comparator, no consideration was given to the
cost-consequence analysis.
In the preliminary economic evaluation against BSC, the trial-based incremental cost
per extra life-year gained was in the range of $75,000 - $105,000 over BSC. Using
differences in medians with 95% CI: the incremental cost per extra life-year gained
was in the range of $75,000 - $105,000 to > $200,000, thus reflecting a considerable
uncertainty around the incremental cost effectiveness ratio (ICER).
A modelled economic evaluation was presented. The base case modelled incremental discounted
cost per extra discounted life-years gained was in the range of $45,000 - $75,000.
The PBAC did not consider the cost-minimisation analysis against docetaxel to be appropriate.
For further information on PBAC’s view, see Recommendations and Reasons.
11. Estimated PBS Usage and Financial Implications
The net cost to the PBS was estimated to be < $10 million in year 4 of listing.
12. Recommendation and Reasons
The PBAC recalled that response to gefitinib correlates to presence of the activating
mutation (or mutations) of the epidermal growth factor receptor (EGFR) gene in tumour
material, whereas response to erlotinib also correlates to expression of the EGFR
gene (without mutation) and EGFR gene copy number. Any targeting of erlotinib would
need to take all three of these factors into account. The PBAC noted that the submission
postulated that erlotinib was effective against wild-type EGFR because of the ability
to achieve a higher plasma AUC with erlotinib than gefitinib, which was not active
against wild-type EGFR, but the PBAC considered this argument to be weak.
Further, post hoc analysis of data from the key Trial BR.21 suggested that erlotinib
produced a longer duration of survival in patients who were EGFR-positive; no survival
benefit was seen in EGFR-negative patients, although the analyses were not conclusive
because of wide and overlapping confidence intervals. However, it was also noted that
the mutational status was unknown for a wide proportion of the trial population; the
trial confidence intervals for the sub-groups were wide and overlapping; only 52%
(11/21) of responders had the activating gene; and a test for interaction based on
the Trial BR.21 results showed that EFGR status was not associated with survival (p
value = 0.97). Thus, overall, the evidence presented suggested that a PBS listing
of erlotinib on the basis of EFGR status was not required.
The randomised trial of erlotinib versus BSC demonstrated statistically significant
clinical benefits of erlotinib over BSC regarding all event rates, including overall
survival, 12-month survival rate, progression-free survival and overall response rate.
In the indirect comparisons of erlotinib versus docetaxel, erlotinib showed numerically
similar effectiveness to docetaxel. The PBAC noted that the submission claimed that
erlotinib was described as having similar effectiveness to docetaxel, but a different
toxicity profile which was not associated with the haematological toxicities; and
significant advantages in effectiveness over BSC, but having more toxicity. Randomised
trial data supported the second of these descriptions against BSC. The indirect comparison
against docetaxel showed no statistically significant difference between docetaxel
and erlotinib, however it favoured docetaxel such that a statistically significant
survival advantage for docetaxel cannot be excluded.
The PBAC considered that the cost-minimisation analysis of erlotinib with docetaxel
was inappropriate as both costs and effectiveness need to be taken into consideration
in assessing the cost-effectiveness of erlotinib.
In the preliminary economic evaluation against BSC, the trial-based incremental cost
per extra life-year gained was in the range of $75,000 to $105,000 over BSC. Using
differences in medians with 95% CI: the incremental cost per extra life-year gained
was in the range $75,000 - $105,000 to > $200,000, thus reflecting a considerable
uncertainty around the incremental cost effectiveness ratio (ICER). However, the base
case modelled incremental discounted cost per extra discounted life-years gained was
in the range of $45,000 - $75,000. The 95% CI of survival extrapolation, which did
not reflect the uncertainty over the estimate of the hazard ratio, were also in the
range $45,000 - $75,000. The PBAC also noted that the modelled ICER was sensitive
to the time horizon and health care resources. These cost-effectiveness ratios were
considered high and uncertain and would be even higher if quality adjusted.
The PBAC therefore rejected the submission because equi-effectiveness with docetaxel
had not been demonstrated and uncertain cost-effectiveness in comparison with BSC.
The PBAC considered that any re-submission should also present a comparison with pemetrexed.
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 is planning to resubmit an application for PBS listing for erlotinib.
