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Questions for Review 21st Expert Committee on Selection and Use of Essential Medicines Peer Review Report [Erlotonib, Gefitinib, Crizotinib] (1) Does the application adequately address the issue of the public health need for the medicine? Yes No Systemic chemotherapy is generally indicated for patients who present with advanced NSCLC, including those who present with metastases (stage IV) or recur following initial definitive treatment. The goals of patient management for patients with advanced NSCLC are to prolong survival and to maintain the quality of life for as long as possible, while minimizing the side effects due to treatment. Analysis for EGFR and ALK is indicated for the presence of a driver mutation for which a specific inhibitor is available, for all patients whose tumor contains an element of adenocarcinoma, regardless of the clinical characteristics of the tumor. Mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are observed in approximately 15 percent of NSCLC adenocarcinoma in the United States; and occur more frequently in never smokers/light smoker and females [1]. In the United States, the Lung Cancer Mutation Consortium analyzed samples using multiplex genotyping from 733 patients with adenocarcinoma at 14 centers in the United States, identifying a targetable driver mutation in 466 cases (64 percent). In Asian populations, the incidence of EGFR mutations is substantially higher, up to 62 percent. These studies underscore the potential clinical benefit and prognostic utility provided by large-scale utilization of molecular profiling in lung cancer. In the PIONEER study, tumor was analyzed from 1482 patients with adenocarcinoma in seven Asian regions (China, Hong Kong, India, Philippines, Taiwan, Thailand, Vietnam) [2]. The incidence of EGFR mutations ranged from 22 to 62 percent. Although EGFR mutations were more common in nonsmokers, the incidence still was 37 percent in regular smokers. The frequency of such mutations was higher in women than in men, but the difference was not significant after considering the frequency of smoking. With progressive availability of molecular profiling in developing regions of the world, targeted therapy is required to improve progression free survival and likely overall survival of this high burden disease community while maintaining their quality of life. (2) Have all important studies/evidence of which you are aware been included in the application? Yes No Please provide brief comments on any relevant studies that have not been included: Though EGFR tyrosine kinase inhibitors have been associated with significant prolongation of progression free survival in non-small cell lung cancer harbouring activating EGFR mutations, there is little or no benefit demonstrated in overall survival in large clinical trials. This likely reflects the effect post trial treatments have on OS, especially cross over to TKI upon progression on chemotherapy Data from 13 phase III trials comparing EGFR TKIs with platinum based chemotherapy are summarised in a large meta-analysis that includes data from 1475 EGFR mutation positive patients (2620 patients in total). PFS was significantly improved (HR-0.43), while no effect on OS was observed (HR-1.01) [3] ERLOTINIB: Erlotinib has been compared with chemotherapy in several randomized trials in patients with EGFR mutated lung cancer, all of which demonstrated a benefit in progression free survival, but not in overall survival some of which are summarized below: (cross over allowed in all trials) TRIAL PATIENT PFS (months) OS (months) NO erlotinib chemotherapy erlotinib chemotherapy Optimal 154 13.1 4.6 22.8 27.2 [4,5] Ensure 275 11 5.5 26.3 25.5 [6] Eurtac 157 9.7 5.2 19.3 19.5 [7] AFATINIB: Efficacy of Afatinib in treatment of EGFR mutation positive lung cancer has been demonstrated in 2 large phase III trials, LUX Lung 3 and LUX Lung 6. In a combined analysis of 2 trials, LUX lung 3 and LUX Lung 6 (n=709) comparing first line Afatinib with platinum based chemotherapy in previously untreated patients, despite a significant benefit in PFS there was no benefit in median overall survival in Afatinib treated patients. However, in a preplanned analysis based on specific EGFR mutation, OS was significantly longer for patients with del 19 positive tumours in Afatinib group than in chemotherapy group in both trials: in LUX lung 3, median OS was 33.3 months in afatinib vs 21.1 months in chemotherapy group (p value=0.00150, in LUX lung 6 it was 31.4 months vs 18.4 months (p value= 0.023) respectively. Similar benefit was not seen in patients with tumours harbouring EGFR L858R mutations. [8] GEFITINIB: The most robust data for gefitinib comes from IPASS trial which randomized 1271 patients to gefitinb or carbolplatin and paclitaxel. Progression free survival was significantly better with gefitinib as compared to chemotherapy (12 months median progression free rate 25 vs 7 percent, HR-0.74) though overall survival was not significantly different ( 18-8 months vs 1704 months , HR-0.9). 2 additional phase III trials, West Japan Oncology group trial 1712 and North East Japan study group trial 002 demonstrated similar magnitude of benefit. [9,10] COMPARISON OF EGFR TKIs: In one study, gefitinib demonstrated comparable efficacy with erlotinib [11]. The three EGFR TKIs have similar efficacy, choice is individualized based on patients’ and doctors’ preference. Some data suggest Afatinib may yield strongest tumor response but also causes most side effects while Gefitinib may be best tolerated. CRIZOTINIB: A group of patients with non-small cell lung cancer (NSCLC) have tumors that contain an inversion in chromosome 2 that juxtaposes the 5' end of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the 3' end of the anaplastic lymphoma kinase (ALK) gene, resulting in the novel fusion oncogene EML4-ALK. ALK gene rearrangements occur in up to 7% of NSCLC and are mutually exclusive with EGFR mutations.ALK rearranged lung cancers are “addicted“ to ALK fusion protein for their growth and are highly sensitive to treatment with an ALK inhibitor The efficacy of crizotinib has been demonstrated in randomized trials limited to patients whose tumors had the ALK rearrangement. A phase III trial randomly assigned 347 patients who had previously been treated to either crizotinib or single-agent pemetrexed or docetaxel [12]. At a median follow-up of 12 months, progression-free survival, the primary endpoint of the trial, was significantly increased with crizotinib compared with chemotherapy (median, 7.7 versus 3 months; HR for progression 0.49).There was no significant difference in overall survival (median, 20.3 versus 22.8 months; HR for death 1.02). The absence of an overall survival benefit presumably reflects subsequent treatment since 64 percent of chemotherapy- treated patients had crossed over to crizotinib after progressing on chemotherapy. Similar outcomes have been observed in chemotherapy-naïve patients [13]. (3) Does the application provide adequate evidence of efficacy/effectiveness of the medicine for the proposed use? Yes No (a) Briefly summarise the reported benefits (e.g. clinical versus surrogate) and comment, where possible, on the actual magnitude of benefit associated with use of the medicine: EGFR TKI therapy does prolong PFS in EGFR mutation positive patient and is associated with improved quality of life. In a meta-analysis comparing TKIs with chemotherapy the frontline HR for EGFR mutation positive tumours treated with EGFR TKIs is reported to be 0.43 and second line as HR-0.34. The clinically insignificant effect on overall survival is most likely related to cross over effect. Similarly, clinically significant progression free survival improvements are demonstrated with ALK inhibitors in ALK rearranged NSCLC. (b) Is there evidence of efficacy in diverse settings and/or populations? Please provide brief details: Yes There are large randomized studies conducted all over the globe including China, Singapore, Turkey, India, Taiwan and Japan (4) Has the application adequately considered the safety and adverse effects of the medicine? Are there any adverse effects of concern, or that may require special monitoring? Yes No Please provide brief details: Few additional but rare AEs include ocular complications (ulcerative keratitis and corneal perforation) serious dermatologic reaction (steven Johnson syndrome, toxic epidermal necrolysis) and pancreatitis. While on these medications, regular monitoring of liver function is required, however, no special/expensive testing is required. Most health care facilities will be able to cope with these monitoring requirements. (5) Please comment on the overall benefit to risk ratio of the medicine (e.g., favourable, uncertain etc). The EGFR TKIs (erlotinib, afatinib, gefitinib) and ALK inhibitor (Crizotinib) have a favorable benefit risk ratio. ADDITIONAL CONSIDERATIONS: (6) Are there special requirements or training needed for the safe, effective and/or appropriate use of the medicine? Yes No Please provide brief details: Prior to the initiation of these medications we need to establish mutational status of EGFR and ALK which can be done through Immunohistochemistry, FISH and RT-PCR. Among these immunohistochemistry is the most cost effective, sensitive and specific test. All of these medications are orally administered and can be taken by patients at home. (7) Are there any issues regarding the registration of the medicine by regulatory authorities? (e.g., recent registration, new indications, off-label use) Yes No Please provide brief details: (8) Is the medicine recommended for use in a current WHO GRC-approved Guideline (i.e., post 2008)? Yes No Please provide brief details: (9) Please comment briefly on issues regarding cost and affordability of this medicine. Generic of all the 3 drugs are available from South America, India & Mexico. The price range varies between $8 to $250 depending on the drug. At theses rates a vast majority of patients will be able to purchase these drugs a major advantage is these drugs do not have major side effects. Access to hospital care is less and overall cost medical care is decreased.
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