The following aims to estimate the expected use of the NICE positively appraised medicines afatinib, erlotinib, gefitinib and osimertinib in people with epidermal growth factor receptor (EGFR) positive advanced non-small-cell lung cancer (NSCLC).
Where these medicines have a licenced indication not positively appraised by NICE, usage has not been estimated. While this usage is expected to be small it may result in a lower expected usage when compared to observed usage.
1. Incidence of lung cancer
The SmPC states that these medicines are indicated in an adult population only.
Estimated incidence of lung cancer in adults aged 20 years or older was reported by the Office for National Statistics (2018), 2016 Cancer Registration Statistics for England.
|
Point estimate
|
Reference
|
Newly diagnosed lung cancers (C34 Malignant neoplasm of bronchus and lung)
|
38,352
|
(1)
|
2. Estimated number of people with non-small-cell lung cancer
The proportion of new cases of lung cancer that are non-small-cell lung cancer (NSCLC) in England is reported in the national lung cancer audit (2018) information sheet to be 88.4%. This proportion has been used to inform the upper and lower range and applied to the point estimate calculated in step 1.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people with non-small-cell lung cancer in England
|
33,903
|
33,903
|
33,903
|
(2)
|
3. Proportion of people presenting with stage IIIb (advanced) and stage IV (metastatic) NSCLC
The proportion of new cases of NSCLC that are diagnosed stage IIIb (advanced) or stage IV (metastatic) is reported in the national lung cancer audit for England information sheet to be 57.8%. This figure has been used to inform the upper and lower range. This proportion has been applied to the point estimate calculated in step 2.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people presenting with stage IIIb or stage IV NSCLC
|
19,596
|
19,596
|
19,596
|
(2)
|
4. Estimated proportion with stage IIIb/IV and PS 0–1 who receive systemic anticancer treatment
The proportion of people with good performance status (PS 0-1) and advanced or metastatic NSCLC who receive systemic anticancer treatment (SACT) in England is reported in the national lung cancer audit (2018) to be 62.5%. This proportion has been used to inform the upper and lower range and applied to the point estimate calculated in step 3.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people with stage IIIB/IV and PS 0–1 who receive SACT
|
12,248
|
12,248
|
12,248
|
(2)
|
5. Proportion of people with sufficient and insufficient sample for genotyping
The final appraisal determination produced for TA374 (NICE 2015) states that, to successfully test for EGFR mutation status, an adequate tissue sample and sufficient quality DNA is required. Zer (2014) estimated that between 15% and 35% of patients may not have sufficient samples for genotyping.
To calculate the proportion of people with sufficient samples for genotyping the inverse of these proportions has been applied. The midpoint (75%) has been applied to the point estimate and the proportions (65% and 85%) applied to the upper and lower range calculated in step 4.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people with sufficient samples for genotyping.
|
9,186
|
7,961
|
10,411
|
(3,4)
|
6. Proportion of people who test positive for EGFR mutation
The proportion who test EGFR mutation positive was reported in Li et al (2013). Li reported that between 10% and 20% of people defined by the authors as ‘white’ had tumours that were EGFR mutation positive.
The reported proportions have been applied to the upper and lower range and the midpoint (15%) applied to the point estimate for people with sufficient samples for genotyping calculated in step 5.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people expected to have a positive EGFR mutation status
|
1,378
|
796
|
2,082
|
(5)
|
7. Proportion of people who receive first line afatinib, erlotinib or gefitinib
It is expected that all the population in step 6 who test EGFR mutation positive will receive first line treatment with the tyrosine kinase inhibitors (TKIs) afatinib, erlotinib or gefitinib.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people who receive afatinib, erlotinib or gefitinib
|
1,378
|
796
|
2,082
|
(-)
|
8. Proportion of people who progress following first line treatment with afatinib, erlotinib or gefitinib (previously treated EGFR-positive)
The proportion of people who have disease progression after first-line treatment with afatinib, erlotinib or gefitinib is stated in the manufacturer’s submission for osimertinib TA416 (AstraZeneca 2016) to be 65% of the incident population. This proportion has been applied as a scaling factor to the point estimate and the lower and upper range summed in step 7.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people who progress following first line treatment
|
896
|
517
|
1,353
|
(6)
|
9. Proportion of people who harbour T790M mutation at progression (previously treated EGFR-population)
Based on genomic analysis, progression on a first-line EGFR TKI is characterised by an acquired secondary EGFR kinase domain mutation labelled T790M, causing resistance to the first-line EGFR TKI. The proportion of people who harbour T790M mutation at progression is reported in Mazza (2017) to be between 50% and 60%. The midpoint (55%) has been applied to the point estimate and the proportions (50% and 60%) applied to the upper and lower range calculated in step 8.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people who harbour T790M mutation at progression
|
493
|
259
|
812
|
(7)
|
10. Proportion of people who receive osimertinib (previously treated EGFR-population)
It is assumed that all the people who harbour T790M mutation at progression (step 9) will receive osimertinib.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people receiving osimertinib
|
493
|
259
|
812
|
(-)
|
11. Number of people with insufficient sample for genotyping (unidentified EGFR status)
The final appraisal determination produced for TA374 (NICE 2015) states that, to successfully test for EGFR mutation status, an adequate tissue sample and sufficient quality DNA is required. Zer (2014) estimated that between 15% and 35% of patients may not have sufficient samples for genotyping.
To calculate the proportion with inadequate tissue sample, the midpoint (25%) has been applied to the point estimate and the proportions (15% and 35%) applied to the upper and lower range calculated in step 4.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people with inadequate tissue sample or unsuccessful DNA test
|
3,062
|
1,837
|
4,287
|
(3,4)
|
12. Proportion of people who will receive second line therapy (unidentified EGFR status)
The proportion of the population expected to receive any second line therapy was stated in Zer (2014) to be between 30% and 50% of the eligible population. These proportions have been used to inform the upper and lower range and a mid-point (40%) has been applied to the point estimate calculated in step 11.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated number of people with inadequate tissue sample or unsuccessful DNA test
|
1,225
|
551
|
2,144
|
(3,4)
|
The final appraisal determination produced for TA374 (NICE 2015) states that an element of clinical judgement is needed when treating these patients. Patients in whom the disease has progressed after non-targeted chemotherapy may have erlotinib if their patient characteristics suggest that their tumour may be mutation-positive (for example, people who have never smoked or are light smokers, women, people of Asian family origin and people with adenocarcinoma histology). The proportion that will be identified is uncertain and is not calculated here. In clinical practice this may reduce the expected treatment population.
13. Treatment population for afatinib, erlotinib, gefitinib and osimertinib
The total treatment population for first line afatinib, erlotinib or gefitinib has been taken from step 7. The treatment population for second line osimertinib has been taken from step 10. The treatment population for second line erlotinib has been taken from step 12.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated treatment population first line afatinib, erlotinib, gefitinib
|
1,378
|
796
|
2,082
|
(-)
|
Estimated treatment population second line osimertinib
|
493
|
259
|
812
|
|
Estimated treatment population second line erlotinib
|
1,225
|
551
|
2,144
|
|
14. Calculate estimated usage volume
Defined Daily Doses (DDDs) were not available for afatinib, erlotinib, gefitinib and osimertinib so daily doses calculated from the SmPC have been used.
The SmPC recommended daily dose for afatinib is 40mg, for erlotinib is 150mg, for gefitinib is 250mg and for osimertinib is 80mg. The estimated treatment population (calculated in step 13) has been multiplied by estimated median progression-free survival per year to produce an expected volume of medicine per year in daily doses.
14a. Calculate estimated usage volume – first line afatinib, erlotinib and gefitinib
The total estimated treatment population for first line afatinib, erlotinib and gefitinib has been taken from step 13. Scluier et al (2015) reported that across 6 RCTs assessing the TKIs afatinib, erlotinib and gefitinib, compared with chemotherapy in people with NSCLC with active EGFR mutations, median progression free survival ranged between 9.2 and 13.1 months. To develop this estimate, the midpoint between this range was calculated (11 months) and applied to estimate the median progression free survival per year (11 months x 365/12 = 335 days).
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated treatment population first line afatinib, erlotinib, gefitinib
|
1,378
|
796
|
2,082
|
(-)
|
Estimated median progression-free survival (days)
|
335
|
335
|
335
|
(8)
|
Total estimated annual usage (daily doses)
|
461,630
|
266,660
|
697,470
|
|
14b. Calculate estimated usage volume – subsequent osimertinib
The total estimated treatment population for subsequent osimertinib use has been taken from step 13. The committee for TA416 (NICE 2016) noted the pooled AURA dataset (AURA extension and AURA2) for people having osimertinib as second and later lines of treatment. It noted that the estimate of median progression-free survival from this analysis was 11.0 months (335 days).
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated treatment population subsequent osimertinib
|
493
|
259
|
812
|
(-)
|
Estimated median progression-free survival (days)
|
335
|
335
|
335
|
(6)
|
Total estimated annual usage (daily doses)
|
165,155
|
86,765
|
272,020
|
|
14c. Calculate estimated usage volume – second line erlotinib
The total treatment population for second line erlotinib has been taken from step 13. Cappuzzo (2010) reported a multicentre, randomised, placebo-controlled phase 3 study on second line erlotinib. Progression free survival was reported as 12.3 weeks (86 days).
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Estimated treatment population second line erlotinib
|
1,225
|
551
|
2,144
|
(-)
|
Estimated median progression-free survival (days)
|
86
|
86
|
86
|
(9)
|
Total estimated annual usage (daily doses)
|
105,350
|
47,386
|
184,384
|
|
14d. Total estimated usage volume – afatinib, erlotinib, gefitinib and osimertinib
The total volume in daily doses for afatinib, erlotinib, gefitinib and osimertinib has been summed from steps 14a, 14b and 14c.
|
Point estimate
|
Lower range
|
Upper range
|
Reference
|
Total estimated annual usage (daily doses)
|
732,135
|
400,811
|
1,153,874
|
(-)
|
References
- Office for National Statistics (2018) Cancer Registration Statistics, England: 2016. ONS: Newport. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/datasets/cancerregistrationstatisticscancerregistrationstatisticsengland [Accessed: 12/03/2018]
- National Cancer Registration and Analysis Service (2018). Royal College of Physicians. National lung cancer audit 2018 (for the audit period 2016). London: RCP, 2017. Available from https://www.rcplondon.ac.uk/projects/outputs/nlca-annual-report-2017 [Accessed 03/04/2018]
- TA374 (2015) Erlotinib and gefitinib for treating non-small-cell lung cancer that has progressed after prior chemotherapy. Final appraisal determination, section 4.3.6. Available from https://www.nice.org.uk/guidance/ta374 [accessed 29/01/2018]
- Zer A, Natasha B. Leigh l. Second-Line Therapy in Non–Small-Cell Lung Cancer: The DELTA Between Different Genotypes Widens. Journal of Clinical Oncology 32, no. 18 (June 2014) 1874-1881.
- Li T, Kung H, Mack P et al. (2013). Genotyping and Genomic Profiling of Non–Small-Cell Lung Cancer: Implications for Current and Future Therapies. Journal of clinical oncology. Vol 31, number 8. March 2013.
- TA416 (NICE 2016). Manufacturers submission (AstraZeneca 2016) Available from https://www.nice.org.uk/guidance/ta416/chapter/3-Evidence [Accessed 29/01/2018]
- Mazza V, Cappuzzo F. Treating EGFR mutation resistance in non-small cell lung cancer – role of osimertinib. The Application of Clinical Genetics. 2017; 10:49-56. doi:10.2147/TACG.S103471.
- Scluier J, Berghmans T, Meert A (2015) Advances in target therapy in lung cancer. European respiratory review 24: 23-29. Journal of Clinical Oncology 32, no. 18 (June 2014) 1874-1881.
- Cappuzzo F, Ciuleanu T, Stelmakh L (2010). Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. The Lancet Oncology. Volume 11, Issue 6, June 2010, Pages 521-529
- WHO (2017) ATC/DDD Index 2017. [WWW] WHO. Available from: https://www.whocc.no/atc_ddd_index/ [Accessed: 17/01/2018]
- Datapharm Communications Limited (2017) The Electronic Medicines Compendium [WWW]. Available from: https://www.medicines.org.uk:443/emc/ [Accessed: 17/01/2018]