Cancer Drugs Fund ( CDF ) Panel has assessed the application was for single agent Pemetrexed ( Alimta ) to remain in the CDF as maintenance treatment for patients with locally advanced or metastatic non-squamous ( NS ) non-small cell lung cancer ( NSCLC ) who had received induction chemotherapy with Cisplatin and Pemetrexed and had not progressed on that induction chemotherapy.
The CDF Panel was aware that this indication for Pemetrexed has been appraised but not recommended by NICE ( National Institute for Health and Care Excellence ).
There was one randomised trial ( PARAMOUNT study ) submitted by the manufacturer as the evidence base related to this indication.
This randomised 539 patients with locally advanced or metastatic non-squamous NSCLC previously treated with the combination of Cisplatin and Pemetrexed and whose disease had not progressed to receive maintenance Pemetrexed plus best supportive care versus placebo plus best supportive care ( BSC ).
The primary end point was progression free survival ( PFS ) as assessed by the investigators.
Updated analysis ( with a median duration of follow-up of 24.3 months for alive patients ) and on an intention to treat basis demonstrated that progression-free survival was significantly greater in the maintenance Pemetrexed arm ( 4.4 vs 2.8 months, difference [ delta ] 1.6 months, hazard ratio [ HR ] 0.60, 95% confidence interval 0.50-0.73, p less than 0.001 ).
This updated analysis of overall survival ( OS ) showed that overall survival was also significantly greater ( 13.9 vs 11.0 months, delta 2.9 months, HR=0.78, 95% CI 0.64-0.96, p=0.02 ), respectively.
Overall survival at 2 years was 32 vs 21% respectively but the Panel noted the small numbers of patients at risk at the 2 year Overall survival time.
Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Toxicity was increased in the Pemetrexed plus BSC arm, 41% of patients having 1 or more all grade non-laboratory adverse events with Pemetrexed plus BSC vs 27% with placebo plus BSC.
Updated all grade toxicities were as follows: fatigue 22% vs 12% ( a statistically significant difference ), nausea 14% vs 2% ( a statistically significant difference ), vomiting 8% vs 1% ( a statistically significant difference ), oedema 7% vs 3%, mucositis 5% vs 1% ( a statistically significant difference ), watery eyes 4% vs 1% ( a statistically significant difference ) and anaemia 14% vs 4% ( a statistically significant difference ), respectively.
The CDF Panel noted that patients on maintenance Pemetrexed required more blood transfusions ( 13% vs 5%, a statistically significant difference, p=0.003 ), anti-infective agents ( 25% vs 17%, a statistically significant difference, p=0.03 ) and hospitalisations because of study drug ( 8% vs 3%, a statistically significant difference, p=0.03 ).
Quality of life was assessed using the EuroQol 5-dimensional scale ( EQ-5D ) and analysis of the results had been published in a peer reviewed journal. There was no difference in general quality of life ( QOL ) scores between the two arms and thus QOL was maintained in the maintenance Pemetrexed arm.
The median duration of treatment in the Pemetrexed plus BSC arm was four 3-weekly cycles.
The CDF Panel recognised that the comparator of placebo plus BSC was the correct comparator in order to assess the impact of maintenance Pemetrexed on patients with non-squamous NSCLC in England.
It recognised that Cisplatin plus Pemtrexed was a standard induction regimen in non-squamous NSCLC and that BSC was a standard treatment policy if maintenance Pemetrexed was not employed.
It also considered that BSC represented active treatment in the trial as patients were seen 3-weekly in the maintenance phase and this allowed opportunity for symptomatic and supportive care to be given.
The Panel discussed the scoring of toxicity of Pemetrexed plus BSC vs BSC. It recognised the greater side-effects in the Pemetrexed plus BSC arm and considered this in relation to the control arm which had no chemotherapy.
Although there were many statistically significant increases in toxicities with maintenance Pemetrexed, it observed that these differences applied to modest percentages of the trial populations.
The Panel thus scored the increased toxicity as minus 1.
The CDF considered the issue of scoring for the CDF definition of unmet need. It recognised that maintenance Pemetrexed was one of a number of systemic therapies which are available for patients with non-squamous NSCLC as 1st, 2nd and sometimes 3rd line therapies and was also aware of the NHS England Chemotherapy Clinical Reference Group draft lung cancer algorithms. It thus concluded that maintenance Pemetrexed did not fulfil the definition of unmet need as set out in the CDF scoring tool and the CDF Standard Operating Procedures.
The Panel observed that its interpretation of the definition of unmet need had been consistent since it had first been convened in 2013.
It noted that Pemetrexed was the only systemic therapy licensed for maintenance treatment in non-squamous NSCLC but was by no means the only treatment available for non-squamous NSCLC when considered as a disease.
The CDF Panel considered whether maintenance Pemetrexed represented a step change in the management of non-squamous NSCLC. With a survival benefit of less than 3 months coming at the expense of increased toxicity, the Panel did not consider that maintenance Pemetrexed provided a step change in outlook for patients with advanced non-squamous NSCLC.
The CDF Panel was aware of the clinical support for the use of maintenance Pemetrexed after induction chemotherapy with the combination of Cisplatin and Pemetrexed as the manufacturer’s business unit had organised and submitted a petition containing 338 signatories from a variety of NHS personnel.
The CDF Panel knew of this clinical support in any case in view of the number of applications to the CDF for this particular use of Pemetrexed.
It nevertheless recognised that the CDF has to be fair to all cancers whether they are common ( and thus may have many personnel involved in their care or attract large numbers of CDF individual patient applications ) or rare ( and thus have few personnel involved in their care or result in few individual patient applications to the CDF ).
The CDF Panel’s scores for Pemetrexed as maintenance treatment in locally advanced or metastatic non-squamous NSCLC after induction chemotherapy with Cisplatin plus Pemetrexed were as follows: 0 for progression-free survival ( difference less than 2 months vs placebo plus BSC ); 2 for overall survival ( difference 2.9 months vs placebo plus BSC ); 1 for quality of life ( QOL no difference ); minus 1 for toxicity; 0 for unmet need; and this resulted in a total of 2B.
In conclusion the CDF Panel considered the clinical benefits of maintenance Pemetrexed in patients with locally advanced or metastatic non-squamous non-small cell lung cancer who had previously not progressed on chemotherapy with the combination of Cisplatin and Pemetrexed to be insufficient to justify retention within the Cancer Drugs Fund. ( Xagena )
Source: Cancer Drugs Fund ( UK ), 2015