The Committee endorsed the recommendations of the EML Cancer Medicine
Working Group with regard to the proposed threshold of four to six months of
overall survival benefit as a guiding principle for prioritizing cancer medicines
for inclusion on the EML, and applied this principle to the consideration of the
tyrosine kinase inhibitors afatinib, erlotinib and gefitinib.
The Committee noted that afatinib, erlotinib and gefitinib were all scored
as 4/5 on the ESMO-MCBS v1.1 for this indication.
The Expert Committee recommended the addition of erlotinib with a
square box to the complementary list of the EML for first-line treatment of EGFR
mutation-positive advanced non-small cell lung cancer. Afatinib and gefitinib
should be considered as therapeutically equivalent alternatives. The Committee
noted that these medicines are associated with relevant survival benefits for
patients, acceptable toxicity and improvements in quality of life compared to
The Committee also noted that since these medicines were considered
for inclusion on the EML in 2015, generic versions of these medicines are more
widely available, as are quality-assured diagnostic molecular tests for EGFR
The application requested the addition of epidermal growth factor receptor
(EGFR) tyrosine kinase inhibitors (TKIs) to the complementary list of the EML
for first-line treatment of EGFR mutation positive, non-small cell lung cancer.
EGFR TKIs have been considered and rejected for inclusion on the EML on
two previous occasions in 2015 and 2017. In each case, the Expert Committee
acknowledged that individual patients with a drug-sensitive EGFR mutation may
derive benefit from TKI therapy, which has been associated with similar efficacy
and more favourable tolerability compared to cytotoxic chemotherapy. However,
the requirements to screen patients for suitability for treatment must be taken
into account by health systems (1, 2).
Cytotoxic chemotherapy currently included on the EML for treatment
of non-small cell lung cancer (NSCLC) includes carboplatin, cisplatin, etoposide,
gemcitabine, paclitaxel and vinorelbine.
Public health relevance
Lung cancer is the most commonly diagnosed cancer globally, and the leading
cause of cancer death, with estimated 2 million new cases and 1.7 related deaths
in 2018. The economic impact of lung cancer has been estimated at around
US$ 8 billion in lost productivity in the BRICS countries (Brazil, Russia, India,
China and South Africa) (3).
Moreover, in the absence of wide coverage of effective screening
programmes on a global scale, lung cancer diagnoses occur in advanced stage
in more than 60% of cases, with highly regional variability (4, 5). The mutational
pattern of NSCLC varies across the different regions, with a higher prevalence in
Asia Pacific (up to 76% of patients) and the lowest registered in Oceania (12%).
Africa, Europe and North America registered the same rate of EGFR-mutated
NSCLC, at around 20% (6–8).
Non-squamous NSCLC has been linked to gene mutations in EGFR.
This disease, given its incidence, comprises a high burden and leads to a high
mortality. However, with advances in cancer gene-directed treatment, the
outcome of the disease has improved. The response rate doubled as compared
to chemotherapy, the progression free survival (PFS) doubled and the median
survival time increased to nearly three years if patients receive both the targeted
medicines and chemotherapy together (the median survival time for patient
receiving chemotherapy only is approximately 10 months, in historical series).
The application reported the findings and recommendations for EGFR-mutated
NSCLC from the 2018 European Society For Medical Oncology (ESMO) Clinical
Practice Guidelines for diagnosis, treatment and follow up of metastatic nonsmall
cell lung cancer (9).
The ESMO guidelines state that EGFR-TKIs are the standard of care for
first-line treatment for advanced EGFR-mutated NSCLC (level of evidence: I;
grade of recommendation: A).
EGFR mutation as an oncogenic target has proven predictive power in
NSCLC from multiple Phase III trials of EGFR-TKIs versus platinum-based
chemotherapy (10–15). The improvement in objective response rate (ORR)
and progression free survival (PFS) is consistent across all age groups, genders,
smoking status and performance status. However, none of the above studies
demonstrated an overall survival benefit for a EGFR-TKI over platinum-based
chemotherapy, likely due to the high level of crossover (16).
The use of EGFR-TKI as first-line therapy has been associated with
a greater benefit than as second-line treatment after chemotherapy for PFS
(12.9 months vs 9.0 months (HR 0.78, 95%CI 0.61 to 0.98. p=0.034)), ORR
(67.8% and 55.6%, respectively, p=0.001). Overall survival in patients receiving
first-line TKI followed by second-line chemotherapy was longer than in patients
receiving TKI second-line after chemotherapy (30.7 months vs 27.2 months
(HR 0.69, 95%CI 0.50 to 0.94, p=0.02) (17).
Evidence supports the continuation of EGFR-TKI treatment beyond
radiological progression in patients who are clinically stable (18). EGFR-TKI
use in combination with local radiation therapy in patients with oligoprogressive
disease, has also been shown to be associated with significantly longer PFS (19).
The IMPRESS trial tested the continuation of gefitinib plus chemotherapy
with placebo plus chemotherapy in patients with EGFR mutation-positive
advanced NSCLC with progression after first-line gefitinib (20). The trial failed to
show a benefit of the continuation strategy of the EGFR-TKI as add-on strategy;
the continuation of gefitinib plus cisplatin and pemetrexed was detrimental to
OS when compared with placebo plus cisplatin and pemetrexed (hazard ratio
[HR] 1.44, 95%CI 1.07 to 1.94; p=0.016; median OS, 13.4 v 19.5 months).
Therefore, continuous use of EGFR-TKI in combination with chemotherapy is
The NEJ009 trial evaluated the efficacy of a combination of gefitinib
and carboplatin/pemetrexed in untreated advanced NSCLC patients with EGFR
mutations (21). Carboplatin/pemetrexed/gefitinib demonstrated better PFS
(mPFS: 20.9 vs 11.2 months, HR 0.49, 95%CI 0.39 to 0.62) and OS (mOS: 52.2 vs
38.8 months, HR 0.69, 95%CI 0.52 to 0.92) compared with gefitinib monotherapy
in advanced EGFR mutated NSCLC, representing a first-line therapy option.
The choice between first- (gefitinib or erlotinib, (reversible)) and
second-generation (afatinib, (irreversible)) EGFR-TKIs was investigated in
two randomized studies. The Phase IIB LUX-Lung 7 trial compared afatinib
with gefitinib (22). The study reported similar tumour ORR and a modest nonclinically
meaningful difference in PFS (mPFS 11.0 vs 10.9 months; HR 0.73,
95%CI 0.57 to 0.95, p=0.0165). OS was not statistically different (23). There was
no difference in OS in patients with EGFR exon 19 mutation, contrary to earlier
claims of benefit in this sub-group from the pooled analysis of LUX-Lung 3 and
LUX-Lung 6 studies (24).
ARCHER 1050 is a randomized Phase III study that compared
dacomitinib (a second-generation EGFR-TKI) with gefitinib in stage IV EGFRmutated
lung cancer patients without central nervous system (CNS) metastasis
(25, 26). The study showed an improved PFS in the dacomitinib arm (mPFS
14.7 vs 9.2 months; HR 0.59, 95%CI 0.47 to 0.74, p<0.0001). The mOS was
34.1 months with dacomitinib vs 26.8 months with gefitinib (HR 0.76, 95%CI
0.58 to 0.993, p<0.04). The OS probabilities at 30 months were 56.2% and 46.3%
with dacomitinib and gefitinib, respectively.
The toxicity profile of EGFR-TKIs is generally clinically manageable, with 6%
of toxicity-related treatment discontinuation reported in one pooled analysis
The use of EGFR-TKI was favoured over chemotherapy in quality of life
(QoL) analyses, reporting a longer time to clinical deterioration and maintained
overall QoL (29–31).
For afatinib, an extensive investigation of patient-reported symptoms and
health-related QoL benefits have been reported, showing that afatinib delayed
the time to deterioration for cough (HR 0.60, 95%CI 0.41 to 0.87; p=0.007)
and dyspnoea (HR 0.68, 95%CI 0.50 to 0.93; p=0.015), with more patients
on afatinib (64%) versus chemotherapy (50%) experiencing improvements in
dyspnoea scores (p=0.010), the cardinal symptom for lung cancer patients (32).
For erlotinib, a secondary analysis from the OPTIMAL (CTONG-0802) Phase
III clinical trial, showed that patients receiving erlotinib experienced clinically
relevant improvements in QoL compared with the chemotherapy group, across
different scales to assess general outcome and lung-specific subscales (33). Data
for gefitinib are still consistent with the findings for the other two EGFR-TKIs:
time to deterioration in physical and life well-being favoured gefitinib over
chemotherapy (HR of time to deterioration, 0.34, 95%CI 0.23 to 0.50; p<0.0001
and HR 0.43, 95%CI 0.28 to 0.65; p<0.0001, respectively) (29).
Cost / cost effectiveness
A cost-effectiveness analysis performed by the Institute for Clinical and Economic
Review showed that the use of each of the first-line EGFR-TKI regimens resulted
in a 0.84 life-year gain in survival relative to chemotherapy. Quality-adjusted
life-years (QALYs) gained versus chemotherapy were also very similar, ranging
from 0.60 for gefitinib to 0.62 for afatinib and erlotinib. Incremental costs
versus chemotherapy were lower for gefitinib (approximately US$ 66 000) than
for the other EGFR-TKIs, as a function of a shorter duration of time spent in
the progression-free state (and a consequently shorter duration of treatment).
Cost-effectiveness estimates were similar across the EGFR-TKIs, ranging from
approximately US$ 110 000 to US$ 150 000 per QALY gained (34).
In another cost-effectiveness analysis, two different strategies were
compared: the ‘EGFR testing strategy’, in which EGFR mutation testing was
performed before treatment and patients with EGFR mutations received gefitinib
while those without mutations received standard chemotherapy, to the ‘notesting
strategy,’ in which genetic testing was not conducted and all patients
were treated with standard chemotherapy. The authors concluded that the
combination use of gefitinib and EGFR testing can be considered a cost-effective
first-line therapy compared to chemotherapy such as carboplatin-paclitaxel for
the treatment for NSCLC in Japan (35).
Technology appraisal guidance issued by National Institute for Health
and Care Excellence (NICE) for first-line EGFR-TKIs gefitinib, erlotinib and
afatinib state that these medicines are recommended treatment options people
with locally advanced or metastatic EGFR mutation-positive NSCLC if the
manufacturers provide the drugs at agreed fixed or discounted prices (36–38).
Originator brands of afatinib, erlotinib and gefitinib are manufactured by Boehringer Ingelheim, Roche and AstraZeneca, respectively. Generic brands are becoming available.
Comments on the application were received from the WHO Department of
Management of NCDs, Disability, Violence and Injury Prevention. The technical
unit advised that it supported the inclusion of EGFR TKIs on the EML, stating
that there is sufficient evidence that these medicines are equivalent or superior
to existing listed medicines, based on updated meta-analysis and real-world data,
particularly in middle-income countries.
Based on the results of the LUX-Lung 3 study (14, 32), afatinib received a score
of 4 on the ESMO-Magnitude of Clinical Benefit Scale (MCBS, v1.1) for first-line
use in metastatic EGFR+ NSCLC (39).
Based on the results of the OPTIMAL (40) and EURTAC (13) studies,
erlotinib received a score of 4 on the ESMO-MCBS v1.1 for use in metastatic
EGFR+ NSCLC (39).
Based on the results of the IPASS study (10, 41), gefitinib received a score
of 4 on the ESMO-MCBS v1.1 for first-line use in metastatic EGFR+ NSCLC (39).
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