Drugs Xagena
The Chemotherapy Clinical Reference Group ( CRG ) has reviewed drugs and drug indications for inclusion on the National cancer drugs fund list.
The decision summaries record how each drug/drug indication scored using the CDF prioritisation tool and include a summary of the CRG’s final decision.
1) Bendamustine [ Levact ]
Bendamustine for the treatment of patients with relapsed mantle cell lymphoma
The CDF panel’s scores for Bendamustine for patients with relapsed mantle cell lymphoma were as follows: 5 for progression free survival ( PFS 18 months, CDF score 10÷2 = 5, phase 2 study ); 0 for overall survival ( phase 2 study ); 0 for QOL ( phase 2 study, no data ); minus 1 for toxicity; 0 for unmet need.
It resulted in a total of 4D.
The CDF panel was aware that the value of Bendamustine use in mantle cell lymphoma ( MCL ) in England might not be reflected in the above evidence base but could only assess the clinical impact of the drug in mantle cell lymphoma on the basis of the clinical studies, submitted and described as above.
The Panel has suggested that the NHS England Chemotherapy Clinical Reference Group seeks information from the MCL community as to whether there is a clear role for Bendamustine beyond 1st line therapy, in which group
of patients such treatment would be appropriate, the evidence base behind such a potential policy and where this might sit in the treatment algorithm for mantle cell lymphoma.
The cost of Bendamustine for a 3-week cycle at the list price ( including VAT ) for a patient of body surface area 1.8m² is 1162 pounds.
Conclusion
The CDF Panel has considered the clinical benefits of treatment with Bendamustine in patients with relapsed mantle cell lymphoma to be insufficient to merit retention within current CDF funding.
Bendamustine for the treatment of patients with relapsed chronic lymphatic leukaemia
The CDF panel’s scores for Bendamustine for patients with relapsed chronic lymphatic leukaemia were as follows: 4 for progression free survival ( PFS was 15.2 months, CDF score 8÷2 = 4, phase 2 study ); 0 for overall survival ( phase 2 study ); 0 for QOL ( phase 2 study, no data ); minus 1 for toxicity; 0 for unmet need.
It resulted in a total of 3D.
The CDF panel was aware that the value of bendamustine use in chronic lymphatic leukaemia ( CLL ) in
England might not be reflected in the above evidence base but could only assess the clinical impact of the drug in chronic lymphatic leukaemia on the basis of the clinical studies, submitted.
The CDF panel recognised that Bendamustine is NICE-approved in the first line setting for chronic lymphatic leukaemia and has a toxicity profile which could aid patients with chronic lymphatic leukaemia elsewhere in the treatment pathway.
The Panel has suggested that the NHS England Chemotherapy Clinical Reference Group seeks information from the CLL community as to whether there is a clear role for Bendamustine beyond 1st line therapy, in which group of
patients such treatment would be appropriate, the evidence base behind such a potential policy and where this might sit in the treatment algorithm for chronic lymphatic leukaemia.
The cost of Bendamustine for a 4-week cycle at the list price ( including VAT ) for a patient of body surface area 1.8m² is 829 pounds.
Conclusion
The CDF Panel has considered the clinical benefits of treatment with Bendamustine in patients with relapsed chronic lymphatic leukaemia to be insufficient to merit retention within current CDF funding.
2) Bosutinib [ Bosulif ]
Bosutinib in the treatment of accelerated phase chronic myeloid leukaemia
The CDF Panel scored the impact of Bosutinib in accelerated phase chronic myeloid leukaemia ( AP CML ) as follows: 6 for progression free survival ( PFS of 22 months, CDF score 12 ÷ 2 = 6, phase 2 study ); 0 for overall survival ( phase 2 study ); 0 for QOL ( no comparative data ); minus 1 for toxicity; 0 for unmet need.
It resulted in a total score of 5D.
The CDF Panel examined the issue of whether there was a difference in patients resistant to Nilotinib [ Tasigna ] / Dasatinib [ Sprycel ] and intolerant of Nilotinib / Dasatinib. Although there was a theoretical difference in AP
( and of clinical relevance as noted in its considerations for chronic phase CML ), it noted that there had not been any applications for intolerant patients with AP CML in 2014/15. It thus considered that it was inappropriate to continue Bosutinib as an option for AP CML in intolerant patients as a cohort policy in the CDF.
The cost of Bosutinib per 4-weekly cycle is 4124 pounds ( including VAT ).
Conclusion
The estimated median drug cost of Bosutinib resulted in this indication scoring a value within the confidential CDF cost scoring system which when combined with the clinical score of 5 resulted in an overall score which was insufficient for a decision by the CDF panel to allow retention of the use of Bosutinib treatment in accelerated phase chronic myeloid leukaemia for patients who were resistant to Nilotinib / Dasatinib.
Bosutinib in the treatment of chronic phase chronic myeloid leukaemia
The CDF Panel scored the impact of Bosutinib in chronic phase chronic myeloid leukaemia ( CP CML ) as follows:
6.5+ for progression free survival ( PFS exceeded 24 months, CDF score of 13(+) ÷ 2 = 6.5+, phase I/II study ); 0 for overall survival ( phase I/II study ); 0 for QOL ( phase II study ); minus 1 for toxicity; 0 for unmet need.
It resulted in a total of 5.5+.
The CDF Panel examined the issue of whether there was a difference in patients resistant to Nilotinib / Dasatinib and intolerant of Nilotinib / Dasatinib. Since it was important for patients with CML to have had access to and been able to tolerate Imatinib ( Glivec ) and/or Nilotinib / Dasatinib, the CDF Panel considered that there was a difference
between resistance and intolerance in this place in the treatment pathway. It therefore endorsed its previous decision to potentially separate these two groups in its decision making.
The CDF Panel again observed the need for NHS England to have an approved treatment algorithm for the treatment of chronic phase CML and urged the Chemotherapy Clinical Reference Group to issue this as
soon as possible. It noted the need to incorporate the approved treatment options according to mutational status where there was sufficienty robust evidence in mutational status.
The cost of the Bosutinib per 4-weekly cycle is 4124 pounds ( including VAT ).
Conclusion
The CDF Panel recognised that the score for progression free survival was less than it could be as a consequence of the lack of maturity of follow-up.
In addition, the CDF Panel understood that the cost of Bosutinib would also rise as the likely duration of treatment was likely to be relatively close to the duration of follow-up. The estimated median drug cost of Bosutinib resulted in this indication scoring a value within the confidential CDF cost scoring system which when combined with the clinical score of 5.5+ resulted in an overall score which was insufficient for a decision by the CDF Panel to
allow retention of the use of Bosutinib treatment in CP CML for patients who were resistant to Nilotinib / Dasatinib.
However, for patients intolerant of Nilotinib / Dasatinib as set in the current CDF approval forms, and mindful inter alia of considerations of patient equity, the CDF panel wished to retain the use of Bosutinib in the CDF for CP CML as such patients had not had the chance of being fully treated with Nilotinib or Dasatinib, the former being NICE-approved and the latter already in the CDF.
3) Brentuximab [ Adcetris ]
Brentuximab for the treatment of patients with relapsed anaplastic large cell lymphoma
The CDF Panel’s scores for Brentuximab for patients with relapsed anaplastic large cell lymphoma reflected the single arm phase 2 study and the limitations of such a study.
The scores were as follows: 5.5 for progression free survival ( PFS of 20 months, CDF score of 11÷2 =5.5, phase 2
study ); 0 for overall survival ( phase 2 study ); 0 for QOL ( phase 2 study ); minus 1 for toxicity; 3 for unmet need.
It resulted in a total of 7.5D.
The CDF Panel recognised that Brentuximab might be curative for a proportion of patients but could not conclude that this was definitively so.
The cost of Brentuximab for a 3-weekly cycle and for a 75 kg patient at the list price ( including VAT ) is 9000 pounds.
Conclusion
The median drug cost of Brentuximab resulted in this indication scoring a value within the confidential CDF cost scoring system which when combined with the clinical score of 7.5 resulted in an overall score which was insufficient for a decision by the CDF Panel to allow retention of the use of Brentuximab treatment in
anaplastic large cell lymphoma ( ALCL ).
The Panel noted the high cost of Brentuximab and the residual doubt as to whether patients with anaplastic large cell lymphoma treated with Brentuximab were cured. It knew that the high cost of Brentuximab might be justified if there was no doubt as to whether cures were achieved by such treatment but the panel was not able to make such a conclusion.
The CDF Panel urged NHS England to use its influence in order that Brentuximab in anaplastic large cell lymphoma is appraised by NICE as soon as possible.
Brentuximab for the treatment of patients with relapsed Hodgkin’s lymphoma
The CDF Panel’s scores for Brentuximab for patients with relapsed Hodgkin’s lymphoma reflected the single arm phase 2 study and the uncertainty as to longer term benefit.
The CDF panel’s scores were as follows: 2 for progression free survival ( PFS of 5.6 months, CDF score of 4÷2 = 2, phase 2 study, but tail on the PFS curve ); 0 for overall survival ( phase 2 study but tail on the OS curve ); 0 for QOL; minus 1 for toxicity; 3 for unmet need.
It resulted in a total of 4D without any consideration of the tails on the PFS curve and OS curves.
The CDF Panel recognised that Brentuximab might be curative for a small proportion of patients but could not conclude that this was definitively so.
The cost of Brentuximab for a 3-weekly cycle and for a 75 kg patient at the list price ( including VAT ) is 9000 pounds.
Conclusion
The median drug cost of Brentuximab resulted in this indication scoring a value within the confidential CDF cost scoring system which when combined with the clinical score of 4 resulted in an overall score which was insufficient for a decision by the CDF Panel to allow retention of the use of Brentuximab treatment in Hodgkin’s lymphoma. The panel noted the high cost of Brentuximab and the residual doubt as to whether patients with Hodgkin’s lymphoma treated with Brentuximab were cured. It knew that the high cost of Brentuximab might be justified if there was no doubt as to whether cures were achieved by such treatment but the panel was not able to make such a conclusion.
The CDF panel urged NHS England to use its influence in order to ensure that Brentuximab in Hodgkin’s lymphoma is appraised by NICE as soon as possible.
4) Dasatinib [ Sprycel ]
Dasatinib in the treatment of Philadelphia chromosome positive acute lymphoblastic leukaemia
The CDF Panel was aware that Dasatinib was the only product licensed for this indication. The CDF Panel knew that there were other treatments used in the treatment of Ph+ acute lymphoblastic leukaemia ( ALL ) and thus Dasatinib was not the only proven effective systemic therapy for Ph+ acute lymphoblastic leukaemia. The manufacturer had recognised this as being the case in its CDF presentation. The CDF Panel did not consider that Dasatinib in this indication with such a modest effect on progression free survival and with no evidence of benefit on overall survival represented a step change in the management of Ph+ acute lymphoblastic leukaemia. It therefore declined to award Dasatinib a positive score for unmet need.
On the information that was submitted to it, the CDF Panel scored the impact of Dasatinib in Ph+ acute lymphoblastic leukaemia as follows: 1.5 for progression free survival ( PFS 3-4 months, CDF score of 3 ÷ 2 = 1.5, phase 2 study ); 0 for overall survival ( phase 2 study ); 0 for QOL ( phase 2 study, no data ); minus 1 for toxicity; 0 for unmet need.
It resulted in a total score of 0.5D.
The cost of Dasatinib per 4-weekly cycle is 2806 pounds ( including VAT ).
Conclusion
The estimated median drug cost of Dasatinib resulted in this indication scoring a value within the confidential CDF cost scoring system which when combined with the clinical score of 0.5 resulted in an overall score which was insufficient for a decision by the CDF Panel to allow retention of the use of Dasatinib in patients with Ph+ acute lymphoblastic leukaemia.
The CDF Panel noted that there had been 4 applications to the CDF for use in Ph+ acute lymphoblastic leukaemia in the first 3 months of 2015 ( it was only since January 2015 that such applications were counted separately ). It recognised that some of these might have been in Imatinib-intolerant patients but given the very small numbers, it recognised that such a use of Dasatinib would be addressed by the Individual Funding Request system.
The CDF Panel recognised that there may be some current use of Dasatinib post transplant for Ph+ acute lymphoblastic leukaemia in patients with molecular evidence of residual disease but no evidence was submitted of its benefit in this way.
The CDF Panel wished that evidence of such benefit ( if this use is indeed the case ) be requested with input
from the Bone Marrow Transplantation Clinical Reference Group in this regard.
5) Ibrutinib [ Imbruvica ]
Ibrutinib for the treatment of patients with relapsed mantle cell lymphoma
The CDF Panel’s scores for Ibrutinib for patients with relapsed mantle cell lymphoma in the single arm phase 2 study using the CDF prioritisation scoring tool could not reflect the uncertainty as to the obvious longer term benefit and treatment duration.
The scores were thus as follows for the phase 2 data: 3.5 for progression free survival ( PFS 13 months, CDF score of 7÷2 = 3.5, phase 2 study ); 0 for overall survival ( phase 2 study ); 0 for QOL; minus 1 for toxicity; 3 for unmet need.
It resulted in a total of 5.5D.
The CDF panel was aware that this score is likely to be a conservative one for the impact of Ibrutinib in mantle cell lymphoma but reflects the current published evidence base.
The Panel also scored the results of the unpublished randomised trial of Ibrutinib vs Temsirolimus and the overall total score using those results was 10B. ( As the data are academic in confidence the Panel cannot give a further breakdown at this time ).
The CDF Panel considered that that having concluded that Ibrutinib was a step change in the management of mantle cell lymphoma on the basis of the phase 2 study, it was appropriate to examine the comparative data of Ibrutinib vs Temsirolimus which would offer a more complete conclusion of the impact of Ibrutinib when assessed by the CDF Prioritisation scoring tool.
The CDF Panel recognised that this was an exceptional step in considering such unpublished evidence and considered this appropriate considering the exceptional circumstances of Ibrutinib in mantle cell lymphoma and the
recognition of Ibrutinib as a step change by the CDF Panel. The Panel thus preferred to use the scoring total of 10B rather than 5.5D.
The cost of Ibrutinib for a 4-week cycle at the list price ( including VAT ) is 6868 pounds.
Conclusion
The median drug cost of Ibrutinib resulted in this indication scoring a value within the confidential CDF cost scoring system which when combined with the clinical score of 10 resulted in an overall score which was insufficient for a decision by the CDF Panel to allow entry of the use of Ibrutinib treatment in mantle cell lymphoma.
Ibrutinib for the treatment of relapsed or refractory chronic lymphatic leukaemia
The CDF Panel recognised the difficulty in scoring Ibrutinib when follow-up was relatively short and when cross over had occurred in the RESONATE study. It knew the progression free survival ( PFS ) with Ibrutinib to be greater than 16 months but how much so was difficult to estimate. It also knew that the longer the median treatment duration was, the greater would be the cost score.
The CDF Panel scored the impact of Ibrutinib in comparison with Ofatumumab as follows: 5+ for progression free survival and scored on an intention to treat basis ( 16.0 months as this was the median duration of follow-up vs 8.1 months, delta 7.9 months ); 0+ for overall survival. The CDF recognised that OS was significantly greater with
Ibrutinib but follow-up was immature; 1 for QOL; minus 1 for toxicity; 3 for unmet need.
This gave an overall total score of 8+ B.
The CDF Panel wished this score to apply to all patients groups treated within this Ibrutinib study ( ie included those patients with del17p or TP53 mutations ).
The Panel also observed that treatments are potentially changing quickly in chronic lymphatic leukaemia ( CLL ) and wished to see the Chemotherapy Clinical Reference Group bring forward a treatment algorithm for CLL as soon as possible.
The CDF Panel also noted that Ibrutinib was licensed for the 1st line use of chronic lymphatic leukaemia in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemotherapy. The manufacturer had not sought this indication for entry into the CDF. In any case, the CDF Panel considered that on the evidence presented to it, the data was too preliminary.
The CDF Panel was aware that NICE had issued provisional guidance which had requested further analyses as to the use of Idelalisib ( Zydelig ) plus Rituximab ( MabThera ) for CLL patients whose disease is refractory and re-treatment
with previous chemotherapy regimes is not considered appropriate. The CDF Panel was aware that if NICE subsequently issued a positive recommendation in its final guidance for Idelalisib plus Rituximab then this would trump Ibrutinib from the CDF.
The Panel noted that NICE guidance on Ibrutinib will not be issued until 2016. The CDF Panel knew that it had decided to retain the availability of Idelalisib plus Rituximab in the treatment of chronic lymphatic leukaemia when further chemotherapy is inappropriate.
The cost of Ibrutinib for a 4-week cycle at the list price ( including VAT ) is 5151 pounds.
Conclusion
For the patients with previously treated chronic lymphatic leukaemia in whom purine analogue-based treatment is not appropriate, the median drug cost of Ibrutinib resulted in this indication scoring a value within the confidential CDF cost scoring system which when combined with the clinical score of 8+ resulted in an overall score which was
insufficient for a decision by the CDF Panel to retain the use of Ibrutinib treatment in patients ineligible for purine analogue-based treatment and who had wished to access Ibrutinib as further treatment of their relapsed chronic lymphatic leukaemia.
The only exception to this policy would be for those CLL patients in whom either Idelalisib plus Rituximab is contraindicated ( eg those patients with bowel comorbidities ) or those patients who have to discontinue Idelalisib on account of toxicity in the first 3 months of treatment and have not progressed at the time of discontinuing Idelalisib.
6) Lenalidomide [ Revlimid ]
Lenalidomide as 2nd line treatment for patients with relapsed myeloma
The CDF Panel’s scores for Lenalidomide according to the intention-to-treat analysis for patients with relapsed myeloma were as follows: 5 for time to progression ( 13.4 vs 4.6 months, delta 8.8 months ); 4 for overall survival ( 38.0 vs 31.6 months, delta 6.4 months ); 0 for QOL; minus 1 for toxicity; 0 for unmet need.
It resulted in a total of 8A.
The Panel regarded this score as being the best possible score ( despite the cross over ) in the light of the minority of patients treated with previous Bortezomib ( Velcade ) or Thalidomide. The CDF Panel considered the changes to the myeloma treatment pathways and recognised the increased opportunities for use of 1st and 2nd line Bortezomib provided by NICE guidance and thus could see increasing potential opportunities for the use of Lenalidomide as 2nd line therapy ( for which NICE guidance is awaited ).
It also recognised the importance of the myeloma treatment algorithms drawn up by the NHS England Chemotherapy Clinical Reference Group in setting out how baseline commissioning should address the continually changing influences of evidence-based practice and NICE guidance.
The cost of Lenalidomide for a 4-week cycle at the list price ( including VAT ) is 5242 pounds.
Conclusion
The median drug cost of Lenalidomide resulted in this indication scoring a value within the confidential CDF cost scoring system which when combined with the clinical score of 8 resulted in an overall score which was insufficient for a decision by the CDF Panel to retain the use of Lenalidomide chemotherapy in patients who had wished to access Lenalidomide as 2nd line treatment for their myeloma.
7) Pomalidomide [ Imnovid ]
Pomalidomide as at least 3rd line treatment for patients with relapsed myeloma
The panel’s scores for Pomalidomide according to the intention-to-treat analysis for patients with relapsed and refractory myeloma were as follows: 2 for progression free survival ( 4.0 vs 1.9 months, delta 2.1 months ); 3 for overall survival ( 12.7 vs 8.1 months, delta 4.6 months ); 2 for QOL; minus 1 for toxicity; 0 for unmet need.
It resulted in a total of 6B.
The cost of Pomalidomide for a 4-week cycle at the list price ( including VAT ) is 10661 pounds.
Conclusion
The median drug cost of Pomalidomide resulted in this indication scoring a value within the confidential CDF cost scoring system which when combined with the clinical score of 6 resulted in an overall score which was insufficient for a decision by the CDF Panel to retain the use of Pomalidomide chemotherapy in patients who had wished to access Pomalidomide as at least 3rd line treatment for their relapsed and refractory myeloma. ( Xagena )
Source: NHS, 2015
XagenaMedicine_2015
