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Cancer Drugs Fund Decision Summary
January 2015
Indication
Idelalisib plus rituximab for the treatment of
under
relapsed chronic lymphatic leukaemia
consideration
Clinical evidence
The application to the CDF was for the combination of idelalisib plus
rituximab to remain in the CDF for patients with chronic lymphatic
leukaemia (CLL) who cannot tolerate further chemotherapy.
The use of idelalisib plus rituximab in relapsed CLL is to be appraised
by NICE in 2015.
The evidence presented had been published in the NEJM in 2014 and
was a randomised comparison of idelalisib plus rituximab versus
placebo plus rituximab in 220 patients with CLL progressing on
chemotherapy within the previous 24 mo and who had
contraindications to further chemotherapy: severe neutropenia or
thrombocyctopenia caused by cumulative myelotoxicity from previous
therapies or estimated creatinine clearance of <60 msl/min or
significant comorbidities scoring >6 on the Cumulative Illness Rating
Scale (CIRS, range 0-56). Patients had to have been previously treated
with at least 1 CD20 antibody based therapy or 2 chemotherapy
regimens. Patients progressing on placebo plus rituximab could cross
over to idelalisib but within a separate study; patients progressing on
idelalisib plus rituximab could have their idelalisib dose increased. 85%
of patients had a CIRS score of >6 and 40% had a creatinine clearance
of <60 mls/min. 43% had adverse mutations [del(17p) or TP53] and
these adverse mutations were part of the stratification within the trial.
Previous treatments included rituximab (90%), cyclophosphamide
(67%), fludarabine (61%), bendamustine (56%) and chlorambucil
(26%).
Duration of the study was short because the study was stopped early
by the Data Monitoring Committee. At the time that the study was
ended, 81% remained on treatment with idelalisib plus rituximab vs
52% on placebo plus rituximab. The primary end point was progression
free survival (PFS) and this was significantly superior with idelalisib
plus rituximab, the median not being reached vs 5.5 mo. For the
adverse mutation group, the median PFS was also significantly greater
with idelalisib plus rituximab, being not reached vs 4.0 mo respectively.
The manufacturer claimed a median PFS of >14 mo with idelalisib plus
rituximab for all the patients and for the adverse mutation patients but
the CDF panel noted that the median duration of follow-up was 5-6 mo
and thus there were few patients at risk beyond 8 mo. The overall
survival was significantly greater with idelalisib plus rituximab than
placebo plus rituximab for all the patients and in the adverse mutation
group. The median OS figures for both groups had not been reached
Score
PFS = 7
OS = 0+
QoL= 0
Tox = -1
Unmet
need = 0
(see text)
and the CDF panel noted the very wide confidence intervals on these
OS comparisons.
Toxicity of WHO grade ≥3 was 56 vs 48%, grade ≥3 neutropenia 34 vs
22% and serious adverse events 40 vs 35%. No late onset diarrhoea
was observed with idelalisib but the CDF panel noted that follow-up in
the study was short. Data was also presented on quality of life
measurements that had been done in the study using the FACT-leu
questionnaire and this showed that global quality of life was greater in
the idelalisib plus rituximab arm. However, this data is only in abstract
form and has not yet been published in a peer reviewed journal.
The manufacturer also submitted an updated analysis of this study in
which the median duration of follow-up was 12 mo (this update was in
abstract form). The median PFS for the idelalisib arm was significantly
greater at 19.3 vs 7.3 mo for placebo (∆ 12.1 mo) and median OS was
also significantly prolonged, not reached vs 20.8, respectively. The
panel noted that there were few patients at risk beyond 16 mo. The
median duration of treatment was not stated but the manufacturer
indicated that it was close to the median duration of PFS. The median
PFS for the del 17p/TP53 group was 16.6 mo.
The manufacturer also had previously submitted some information
about longer term use of idelalisib. In a phase 1 study in CLL in which
the median PFS was 15.8 mo, the following WHO grade ≥3 toxicities
were observed: pneumonia 20%, febrile neutropenia 11% and
diarrhoea 6%. The CDF panel heard from experts that there is now a
much greater understanding about the diarrhoea associated with
idelalisib and this can be managed easily in the great majority of
patients.
In order to justify the use of rituximab in combination with placebo as
the comparator in this study and as indicative of standard treatment in
England, the manufacturer had previously submitted an EU survey of
which treatments were administered 3rd line; single agent rituximab
was given in 22% of patients. The CDF panel noted that this survey
reflected 3rd line use across all CLL patients and thus would have
included those who did not have any contraindications to
chemotherapy. The panel also observed that the PFS with placebo plus
rituximab was similar to the PFS seen in patients treated with
ofatumumab which might also have been regarded as an appropriate
comparator as it is currently available from the CDF.
The CDF panel discussed the issue as to whether the use of placebo
in combination with rituximab was an appropriate comparator in CLL
patients who had a contraindication to further chemotherapy. It
recognised that there were few options for patients in whom further
chemotherapy was contraindicated and thus treatment with an antiCD20 monoclonal antibody was reasonable. It noted that the PFS with
placebo plus rituximab in the study described above was similar to the
PFS observed with ofatumumab (another anti-CD20 antibody in
multiply relapsed CLL) and a drug available from the CDF. The CDF
panel thus considered that it was reasonable for the control arm in the
idelalisib trial to have been placebo plus rituximab.
The CDF panel recognised the difficulty of scoring idelaisib plus
rituximab when follow-up was still relatively immature and cross over
occurred. The CDF panel scored the combination of idelalisib plus
rituximab in comparison with placebo plus rituximab as follows: for PFS
the panel scored on an intention to treat basis and thus PFS score was
7; for OS, the score was 0+ although the CDF recognised that OS was
significantly greater with idelalisib; for QOL the score was 0 but if
confirmed and published in a peer reviewed journal (apparently
scheduled for quarter 2 in 2015), this score would change to 2; for
toxicity, the score was 0 on the randomised trial but the CDF panel
noted the short follow-up in this study and the greater grade 3 and 4
toxicity noted in the phase 1 Study which reflected longer term use. It
therefore scored the toxicity as minus 1; and for unmet need the score
was 0. This gave an overall score of 6+ B. The CDF panel wished this
score to apply to all patients groups treated within this idelalisib plus
rituximab study (ie included those patients with del17p or TP53
mutations).
The panel also observed that treatments are potentially changing
quickly in CLL and wished to see the Chemotherapy Clinical Reference
Group bring forward a treatment algorithm for CLL as soon as possible.
Total clinical score
6+B
Cost
The cost of idelalisib for a 4-week cycle at the list price (including
VAT) is £3489. The median duration of treatment was not stated
but the manufacturer indicated that it was close to the median
duration of PFS.
Conclusion
The median drug cost of idelalisib resulted in this indication
scoring a value within the confidential CDF cost scoring system
which when combined with the clinical score of 7 resulted in an
overall score which was sufficient for a decision by the CDF
panel to retain the use of idelalisib treatment in patients
ineleigible for further cytotoxic chemotherapy and who had
wished to access idelalisib as further treatment of their relapsed
CLL.
The CDF panel was not given any information as to the activity
of idelalisib following ibrutinib. In view of this, it restricted the use
of idelalisib to patients that had not previously been treated with
ibrutinib.
In addition, the CDF panel heard from experts that the
combination of idelalisib plus rituximab was generally preferred
to ibrutinib in patients on warfarin or if the pre-treatment platelet
count was less than 30 x 10⁹/l.
CDF criteria for As per current approved criteria
use
Key for strength of evidence:
Criteria
Grade
Two or more good quality Phase III Randomised
Controlled Trials, both published
A
One good quality Phase III Randomised Controlled
Trial, published
B
Comparative Phase II trial, published
C
Non-Comparative Phase II, published
D
Unpublished data (in abstract form only)1
U1
Unpublished data (in abstract form only)2
U2