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Pemetrexed chemotherapy as 2nd line treatment for patients with non- squamous non-small cell lung cancer: data are insufficiently robust


Cancer Drugs Fund ( CDF ) Panel has assessed the application for single agent Pemetrexed ( Alimta ) to remain in the CDF as 2nd line treatment for patients with non-squamous ( NS ) non-small cell lung cancer ( NSCLC ) who had not received Pemetrexed as part of 1st line combination chemotherapy.

The CDF Panel was aware that this indication for Pemetrexed has been appraised but not recommended by NICE. It also knew that since the early Pemetrexed trials, histology has been shown to predict for efficacy of Pemetrexed in the 1st line treatment of NSCLC: Pemetrexed’s licensed indications in NSCLC now state that it should only be used in NSCLC other than predominantly squamous cell histology ( the NS group ).

There was one randomised trial submitted by the manufacturer as the evidence base related to this indication. This randomised 571 patients with locally advanced or metastatic NSCLC previously treated with 1st line combination chemotherapy ( but not Pemetrexed-containing 1st line chemotherapy ) to receive Pemetrexed vs Docetaxel.
The primary end point was overall survival.
The trial was not stratified according to type of NSCLC histology.

Analysis on an intention to treat basis demonstrated that median progression free survival ( PFS ) was similar in both arms ( 2.9 months ) and overall survival ( OS ) was also not statistically significantly different ( 8.3 vs 7.9 months, hazard ratio, HR=0.97, 95% confidence interval ( CI ) 0.82-1.16 ).
The rate of median overall survival at 1 year was identical, being 30% in both arms.

A retrospective analysis of the trial data according to non-squamous histologies demonstrated that the median overall survival for Pemetrexed vs Docetaxel was 9.3 vs 8.0 months ( HR=0.78, 95% CI 0.61-1.00, p=0.048 ) and the median progression-free survival 3.1 vs 3.0 ( HR=0.82, 95% CI 0.66-1.02, p=0.08 ).

A similar retrospective analysis according to squamous histologies demonstrated that the median overall survival for Pemetrexed vs Docetaxel was 6.2 vs 7.4 months ( HR=1.56, 95% CI 1.08-2.26, p=0.018 ) and the median progression-free survival 2.3 vs 2.7 ( HR=1.40, 95% CI 1.01-1.96, p=0.046 ).

The Lung Cancer Symptom Scale was used in this trial to assess quality of life and an average symptom burden index created. There was no difference in general quality of life ( QOL ) scores between the two arms ( p=0.15 ) and thus QOL was maintained ( but not improved ) in the Pemetrexed arm.

Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events.
The CDF Panel examined the toxicities and consequences of these toxicities which would make a difference to patients in England ( for example colony stimulating factor support would not occur in England in this group of patients and abnormal alanine transaminase blood test results are rarely of any clinical consequence ).
The rate of 1 or more hospitalisations for febrile neutropenia was 2 vs 13% ( a statistically significant difference ), the rate of 1 or more hospitalisations for any other drug-related adverse events was 6 vs 11% and blood transfusions occurred in 17% vs 12%, respectively.
All grade fatigue occurred in 34% vs 36%, nausea 31% vs 17%, vomiting 16% vs 12%, neurosensory disorders 5% vs 16%, stomatitis 15% vs 17%, alopecia 6% vs 38% ( a statistically significant difference ), diarrhoea 13% vs 24%, rash 14% vs 6% and oedema 5% vs 8%.

The median duration of treatment in the Pemetrexed arm was four 3-weekly cycles.

The Panel noted that Pemetrexed was approved by NICE as part of induction chemotherapy in non-squamous NSCLC. It was also approved by NICE as maintenance treatment if the induction chemotherapy did not contain Pemetrexed ( in practice this meant induction chemotherapy was with Gemcitabine or Vinorelbine with Cisplatin or Carboplatin ).
Thus the Panel knew that the vast majority of patients with non-squamous NSCLC having 1st line / maintenance chemotherapy would receive Pemetrexed as part of this treatment.
It recognised that there are some patients who may not receive Pemetrexed as part of 1st line induction / maintenance chemotherapy.
There was no evidence submitted for the re-use of Pemetrexed as 2nd line treatment after 1st line Pemetrexed-containing induction / maintenance chemotherapy.

The Panel discussed the scoring of toxicity of Pemetrexed vs Docetaxel. It recognised the superiority of Pemetrexed in this regard compared with Docetaxel but noted that Pemetrexed still resulted in considerable toxicity in its own right.
It was aware too that the use of Pemetrexed necessitated the use of significant premedication to reduce its toxicities to the level observed in the clinical trial.
The Panel scored the reduced toxicity of Pemetrexed vs Docetaxel as plus 1.

The CDF Panel considered the issue of unmet need according to the CDF definition. It recognised that there were a number of treatment options available in non-squamous NSCLC and thus Pemetrexed did not fulfil the CDF definition of unmet need.
The Panel did not consider that 2nd line Pemetrexed represented a step change in the management of non-squamous NSCLC as it did not offer an increase in survival.

The Panel’s scores for Pemetrexed as 2nd line treatment in locally advanced or metastatic non-squamous NSCLC were as follows: 0 for progression-free survival ( whether on an intention to treat basis or in the post hoc non-squamous NSCLC subgroup ); 0 for overall survival ( whether on an intention to treat basis or in the post hoc non-squamous NSCLC subgroup ); 1 for quality of life; 1 for toxicity; 0 for unmet need, and resulted in a total of 2B.

In conclusion, the CDF Panel considered the clinical benefits of Pemetrexed in patients with locally advanced or metastatic non-squamous non-small cell lung cancer who had previously received chemotherapy to be insufficient to justify retention within the CDF. ( Xagena )

Source: Cancer Drugs Fund ( UK ), 2015

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