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Home , Afatinib, Crizotinib, Gefitinib

21st Expert Committee on Selection and Use of Essential Medicines

Peer Review Report

[Erlotonib, , ]

(1) Does the application adequately address the issue of the public health need for the medicine? Yes No

Systemic 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 , regardless of the clinical characteristics of the tumor. Mutations in the epidermal (EGFR) tyrosine 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 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 .

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 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 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: 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 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 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 are “addicted“ to ALK 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 or [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 , 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. Crizotonib is available as generics costing as low as $80,000 per month of therapy; therefore remains prohibitively expensive for many patients.

(10) Any additional comments?

(11) Please frame the decisions and recommendations that the Expert Committee could make. These drugs Erlotinib, Afatinib and Gefetinib should be approved as first line therapy for advanced adenocarcinoma lung with their EGFR positive mutation. Crizotinib should be approved for ALK positive advanced/metastatic adenocarcinoma lung cancers.

(12) References (if required)

1. Brambilla E, Travis WD. Lung cancer. In: World Cancer Report, Stewart BW, Wild CP (Eds), World Health Organization, Lyon 2014. 2. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, Heeroma K, Itoh Y, Cornelio G, Yang PCJ Thorac Oncol. 2014;9(2):154. 3. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis.Lee CK, Brown C, Gralla RJ, Hirsh V, Thongprasert S, Tsai CM, Tan EH, Ho JC, Chu da T, Zaatar A, Osorio Sanchez JA, Vu VV, Au JS, Inoue A, Lee SM, Gebski V, Yang JC J Natl Cancer Inst. 2013;105(9):595. 4. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study.Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C Lancet Oncol. 2011;12(8):735. 5. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small- cell lung cancer (OPTIMAL, CTONG-0802).Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C .Ann Oncol. 2015 Sep;26(9):1877-83. Epub 2015 Jul 3 6. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al.Lancet Oncol. 2012;13(3):239. 7. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Wu YL, Zhou C, Liam CK, Wu G, Liu X, et al. Ann Oncol. 2015;26(9):1883 8. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, et al.Lancet Oncol. 2015;16(2):14 9. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal (WJTOG3405): an open label, randomised phase 3 trial. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, et al. Lancet Oncol. 2010;11(2):121 10. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. Maemondo M, Inoue A, Kobayashi K, Sugawara S, et al.N Engl J Med. 2010;362(25):2380. 11. Randomized Phase III Study Comparing Gefitinib With Erlotinib in Patients With Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L.Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H,et al. J Clin Oncol. 2016;34(27):3248. 12. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. Shaw AT, Kim DW, Nakagawa K, Seto T, et al.N Engl J Med. 2013;368(25):2385. 13. First-line crizotinib versus chemotherapy in ALK-positive lung cancer.Solomon BJ, Mok T, Kim DW, Wu YL, et al.N Engl J Med. 2014 Dec;371(23):2167-77