non-small cell lung cancer - world health organization · vinca alkaloids, and severe allergic...

NON-SMALL CELL LUNG CANCER Union for International Cancer Control

2014 Review of Cancer Medicines on the WHO List of Essential Medicines

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NON-SMALL CELL LUNG CANCER

Executive Summary In 2012, an estimated 1.8 million people were diagnosed with lung cancer resulting in 1.6 million deaths (http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx). Lung cancer is the leading malignant cause of death in 93 countries accounting for a fifth of the total global burden of disability-adjusted life years from cancer.1 Non-small cell lung cancer (NSCLC) comprise 85% of all lung cancers.2 The majority of patients with NSCLC present with advanced stage disease – stage IV in particular, and half of the patients treated initially for potentially curable early stage disease will recur with metastatic disease.16 This is true even in developed countries. Patients with stage IV disease are never curable, and chemotherapy, targeted therapy, and radiation can extend survival and palliate symptoms. For patients with resectable disease, adjuvant chemotherapy (vinorebine/cisplatin) may improve the absolute 5-year survival rates from about 43 to 55% and 25 to 40% in Stage II and III NSCLC, respectively.3-7 Other adjuvant regimens may include etoposide/cisplatin, docetaxel/cisplatin, gemcitabine/cisplatin, pemetrexed/cisplatin. In those unable to tolerate cisplatin one may consider paclitaxel/carboplatin5,8,9 Neoadjuvant and/or concurrent chemotherapy with radiotherapy have been shown to reduce the relative risk of death by 13% for unresectable stage III NSCLC, increasing median overall survival (OS) to 16 months-29 months when compared with radiotherapy alone.9-13 Comparative studies have confirmed the superiority of concurrent chemo-radiotherapy over sequential therapy by improving absolute 5 years OS rate from 10.5% to 15%.14,15 For this indication, the optimal cisplatin or carboplatin combination remains to be confirmed. Until a decade ago, systemic chemotherapy was the only treatment available for advanced stage NSCLC. Studies have shown that doublets of chemotherapy extend life modestly for this group of patients, with survivals going from 6 months to 10-12 months. For NSCLC without targetable driver oncogenes, or where molecular diagnostics are not available, or targeted therapies are not available, platinum-based chemotherapy is the standard first line treatment. Pemetrexed/platinum improves median OS by 2 months for patients with non-squamous NSCLC when compared to gemcitabine/cisplatin but not against taxanes/platinum, and is extraordinarily more expensive.25 Commonly used platinum-based doublet include gemcitabine, paclitaxel, docetaxel, vinorelbine or etoposide.26-31 Addition of bevacizumab, an anti-angiogenic drug, may improve PFS and OS in selective patients, particularly when added to carboplatin/paclitaxel but no biomarker is available at this juncture and it is associated with significant toxicity, and occasionally fatal hemoptysis.32,33 Maintenance with pemetrexed, either as a continuation or as a switch maintenance, may increase median OS by 3 months in patients with non-squamous NSCLC if tumor regression or stable disease is achieved after first line therapy.34,35 The majority of patients with stage IV NSCLC will inevitably progress after first-line or maintenance treatment. For elderly or frail patients, single-agent vinorelbine, or low-dose weekly carboplatin and paclitaxel are viable options, though in general doublets as listed are preferred.



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For patients without a driver oncogene, second line single agent chemotherapy may extend the overall survival by a very small amount of time.38-40

Where molecular diagnostics and targeted therapies are available, patient tumors should be subject to molecular analysis, in particular epidermal growth factor receptor (EGFR) gene mutation status and (ALK) gene rearrangement. In the 10-15% of NSCLC with EGFR activating mutations (defined as in-frame deletions in exon 19 and L858R substitution in exon 21), EGFR tyrosine kinase inhibitors (TKI) attain tumor response rate of 70-80% and progression free survival (PFS) of 10 to 14 months.17-23 In addition to improved efficacy EGFR is also superior to chemotherapy in toxicity profile and quality of life (QOL).17-23 For patients with ALK gene rearrangements, first line crizotinib also attain tumor response rate of 71% and PFS of 11.9 months.24 Patients with driver oncogenes who failed to receive a targeted therapy previously may be treated with EGFR TKI or crizotinib as salvage therapy.36,37 When compared with chemotherapy, there are improvements in quality of life and progression-free survival, but no significant improvements in overall survival among patients on crizotinib.59,60

When molecular diagnostics are not available, one could choose initial therapy based on clinical and epidemiologic information. For instance, in an Asian woman, never-smoker, initial treatment with erlotinib or a similar agent can be justified in the absence of mutation testing. On the other hand, a Caucasian heavy smoker with a squamous cell carcinoma, chemotherapy is clearly indicated as first-line therapy. Based on data available by December 2014, reviewers have decided to exclude pemetrexed, afatinib, and crizotinib from the recommendations. Further details on specific inclusion and exclusion criteria are included in the section “Review of Benefits and Harms.”

Public Health Relevance Non-small cell cancer accounts for 85% to 90% of all lung cancers (1). According to GLOBOCAN, lung cancer has been the most common cancer globally for several decades (2). GLOBOCAN estimated worldwide incidence of lung cancer in 2012 to be 1,824,701 (12.9% of all cancers) with an ASR of 23.1 per 100,000. Incidence in more developed regions was 758,214 (ASR of 30.8 per 100,000) and 1,066,487 (ASR of 20.0 per 100,000). 58% of the 1.8 million new cases in 2012 occurred in less developed regions. The highest ASR incidence rates in 2012 were found to be Central and Eastern Europe (53.5 per 100,000) and in Eastern Asia (50.4 per 100,000). The ASR incidence rates for men were found to be 25% higher than for women, with ASR incidence rates of 205 and 165 per 100,000 respectively. GLOBOCAN estimated global mortality rate in 2012 to be 1,589,925 with an ASR of 19.7 per 100,000. More developed regions had a mortality rate of 626,570 (ASR of 24.2 per 100,000) and less developed regions had a mortality rate of 963,355 (ASR of 18.0 per 100,000).



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Requirements for diagnosis, treatment, and monitoring Diagnostics: Histopathological diagnosis from surgical sample, core or fine needle biopsies or cytology cell blocks from pleural effusion is essential. It is important to note that one must obtain adequate tissue to perform needed testing as outlined here.

Immunohistochemistry (IHC) help to subtype NSCLC: squamous cells generally being TTF-1 negative, p63 and p40 positive; adenocarcinomas generally being TTF-1 positive and p40 and p63 negative.41,42 Molecular testing is crucial for first line treatment with molecular targeted therapy. This includes EGFR gene mutation analysis by Sanger sequencing or Amplification Refractory Mutation System and ALK gene rearrangement by break-apart fluorescent-in-situ hybridisation (FISH) or IHC.43 Laboratories should utilize a validated mutation platform and participate in an external quality assurance program.

Testing: A minimum of a contrast-enhanced computed tomography (CT) scan of the chest and upper abdomen, blood counts and chemistries to renal and hepatic function is required. CT scan or MRI of brain or bone scan should be offered to patient with clinical symptoms suggestive of brain or bone metastasis.

Administration and Care of Patients: Intravenous (IV) infusion capacity and regular access to acute clinical care is essential. Medications can be delivered in out-patient facilities. Anti-emetics should accompany administration of all chemotherapy. IV hydration should be administered before cisplatin. Vitamin B12 and folic acid supplementation reduces the adverse effects of pemetrexed. Clinical staff should be competent in identifying and managing soft tissue extravasation reactions from vinca alkaloids, and severe allergic reactions during taxanes or carboplatin administration with readily accessible medications.

CT scan is required to assess response to treatment. Access to laboratory facilities is essential to monitor adverse effects of treatment. Clinicians should be proficient in recognizing and addressing potential side effects of chemotherapy, and broad spectrum antibiotics and transfusion facilities available to manage life-threatening events such as bone marrow suppression and neutropenic fever. Social well-being is inevitably affected by diagnosis and treatment of NSCLC, and financial burden is particularly pronounced for patients with metastatic NSCLC as numerous medications are still on patent. Psychological and social support professionals are best integrated into multidisciplinary teams to care for patients with NSCLC

Overview of Regimens The following tables include basic information on administration and dosing for a non-exhaustive list of treatment options. The sources and clinical indication for each regimen are specified in the title. The maximum duration or number of cycles of treatment is stated after the dosages. Ancillary medications for management of side effects are excluded.



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Regimens with pemetrexed have been omitted because they do not result in substantially longer survival, and though they have a good toxicity profile, pemetrexed is very costly, and therefore the benefit/cost ratio causes us not to recommend that it be added to the EML. Regimens including bevacizumab have not been included. The benefit from bevacizumab is marginal, with only a small number of patients potentially benefitting from it and the associated cost and toxicity is significant. Therefore we are not recommending bevacizumab for addition to the EML list. Standard Regimens – By Stage of Disease

Adjuvant chemotherapy for Stage II and III NSCLC 4

Vinorelbine Intravenous infusion 25-30 mg/m2 days 1 + 8 Cisplatin Intravenous infusion 75-100 mg/m2 day 1 every 21 days, for 4 cycles. Etoposide Intravenous infusion 50 mg/m2 days 1-5 Cisplatin Intravenous infusion 50 mg/m2 days 1, 8 Every 21 days, for 4 cycles Gemcitabine Intravenous infusion 1250 mg/m2 days 1,8 Cisplatin Intravenous infusion 75 mg/m2 days 1 Every 21 days for 4 cycles

Paclitaxel Intravenous Infusion 200 mg/m2 day1 Carboplatin Intravenous Infusion AUC 6 day 1 Option for patients unable to tolerate cisplatin/vinorelbine

Concurrent chemotherapy/RT regimen for Stage III unresectable NSCLC 10, 44

If performance status good, age < 70 and adequate renal function Etoposide Intravenous infusion 50 mg/m2 days 1-5, 29-33 Cisplatin Intravenous infusion 50 mg/m2 days 1, 8, 29, 36 Concurrent with thoracic RT. Paclitaxel Intravenous infusion 45-50 mg/m2 weekly Carboplatin Intravenous infusion AUC 2 weekly Concurrent with thoracic RT,



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Followed by: Paclitaxel Intravenous Infusion 200 mg/m2 day1 Carboplatin Intravenous Infusion AUC 6 day 1

given for 2 cycles, starting 2-4 weeks after completion of radiation therapy

If age > 70, or fair performance status, or CrCl 50-60 Cisplatin Intravenous infusion 40 mg/m2

On the first day of each treatment week of thoracic RT.

Standard first-line chemotherapy for metastatic NSCLC 30, 31

Note: For patients with no detectable targeted mutation, or for those where

mutation analysis could not be done (see discussion about populations of patients with increased likelihood of having a targetable mutation

Note: All regimens listed below have similar outcomes in relation to NSCLC

survival. Toxicities vary among regimens but are not greatly different overall. Regimen choice can be based on drug availability and cost.

Paclitaxel Intravenous infusion 90 mg/m2 days 1, 8, 15 Carboplatin* Intravenous infusion AUC 6 day 1 every 21 days, for 4 to 6 cycles. Or Paclitaxel Intravenous Infusion 200 mg/m2 day1 Carboplatin Intravenous Infusion AUC 6 day 1 Every 21 days for 4-6 cycles Or Gemcitabine Intravenous infusion 1000 mg/m2 days 1, 8, 15 Cisplatin* Intravenous infusion 75 mg/m2 day 1 every 28 days, for 4 to 6 cycles. Or Gemcitabine Intravenous infusion 1000 mg/m2 days 1,8 Cisplatin Intravenous infusion 75 mg/m2 days 1 Every 21 days for 4-6 cycles



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Or Gemcitabine Intravenous infusion 1000 mg/m2 days 1,8 Carboplatin Intravenous infusion AUC 5 days 1 Every 21 days for 4-6 cycles

*NB. Cisplatin improves survival only in patients without prior platinum exposure in the first-line setting.45 Standard Regimens – Tyrosine Kinase Inhibitors

Note: For patients who have an identified targetable mutation conveying potential tumor sensitivity to the agent listed below

TKI for metastatic NSCLC with activating EGFR mutations 17-23 Erlotinib Oral 150 mg/day OR

Gefitinib Oral 250 mg/day

Review of Benefits and Harms Benefits NSCLC is generally regarded as a disease of the elderly, but a third of patients are diagnosed before the age of 65 years.16 Surgery and adjuvant chemotherapy are important contributors to cure for early stage disease. Combined modality treatment preserve a chance of long term survival for patient with unresectable stage III disease.

Combination chemotherapy as described above modestly improves overall survival from approximately 6 months without chemotherapy to 10-12 months with chemotherapy. Studies also demonstrate an improved quality of life during extended survival.

Molecular targeted therapy for a biomarker selected population with metastatic NSCLC allow long duration of disease control with minimal toxicity for a subset of patients, extending median overall survival beyond 2 to 3 years.37,46 Gefitinib and erlotinib have been shown to be effective in many patients with mutations in the EGFR kinase region and are recommended for these patients as first line therapy. UICC reviewers seriously considered inclusion of afatinib, however this TKI has less data to support its use and potentially increased toxicity (when compared to erlotinib and gefitinib), so we are not recommending inclusion of afatinib at this point. Crizotinib has activity in patients who cancers demonstrate an ALK mutation, extending, progression-free survival and improving quality of life.59,60 Again, although the UICC reviewers were engaged in considering crizotinib, there is not yet clear evidence that first line treatment extends overall survival so we are not recommending inclusion of crizotinib at this time. Pemetrexed was also excluded on the basis of marginal improvement (2 months) in overall



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survival when compared to certain regimens (gemcitabine/cisplatin) but not others (taxanes/platinum), and the high cost.

Given the global burden of NSCLC, treatments of proven survival benefit and manageable toxicities should be made an available option to patients.

Harms and Toxicity Considerations Due to the multitude of couplet options available for treatment of NSCLC, chemotherapeutic-specific harms and toxicities for this briefing are described below by drug or drug class rather than by regimen. Platinum agents including cisplatin and carboplatin cause myelosuppression with dose-limiting thrombocytopenia, and also can cause ototoxicity and asthenia. Nausea and vomiting occur in almost all patients treated with cisplatin and carboplatin and is often severe, necessitating the use of anti-emetic medications. Renal toxicity caused by cisplatin can be significant and may result in electrolyte abnormalities. Intravenous hydration both before and after administering cisplatin is necessary to reduce the incidence of renal toxicity.[48] Notably, carboplatin has decreased incidences of nephrotoxicity, ototoxicity and nausea and vomiting in this patient population, but higher incidences of severe thrombocytopenia.[49] Paclitaxel- Paclitaxel is associated with high incidences of neutropenia, which is frequently severe (grade 3-4). [50] Paclitaxel can cause hypersensitivity reactions in up to 30% of patients and requires premedication to reduce this risk. Most infusion reactions are mild and easily managed.[51] Paclitaxel causes universal alopecia and many patients experience peripheral neuropathy, both of which are reversible. Paclitaxel is associated with high incidences of neutropenia, which is frequently severe (grade 3-4). Gemcitabine frequently causes myelosuppression with dose-limiting thrombocytopenia and leukopenia with associated risk of infection. Gemcitabine is also associated with increased hepatic transaminases which may lead to more severe hepatotoxicity in up to 10% of patients. Many patients experience edema and dyspnea. [52] Vinorelbine often causes severe neutropenia and granulocytopenia, which increases patients’ risk of infection. Like other vinca alkaloids, vinorelbine also frequently causes constipation. Vinorelbine is a strong vesicant, care must be taken to avoid extravasation and associated tissue damage. [53] Etoposide The most frequent dose-limiting toxicity for etoposide is myelosuppression, primarily leukopenia which can be grade 3-4 in >10% of patients. A small percentage (up to 2%) of patients receiving intravenous etoposide experience hypersensitivity reactions, which may include angioedema, bronchospasm, and/or chest discomfort. Etoposide also causes reversible alopecia in up to 60% of patients. [54] The use of etoposide has been associated with a small but increased risk of secondary cancers.



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Pemetrexed may cause anemia, neutropenia and leukopenia ands should be given with folic acid and vitamin B-12 to reduce the incidence of hematologic toxicity. The most common dose limiting toxicity is fatigue which is serious in up to 1/3 of patients. [55] This information has been kept in for comprehensiveness, however this drug is not being recommended for addition to the Essential Medicines List. EGFR tyrosine kinase inhibitors (TKIs) are well tolerated in many patients. Agents have similar toxicity profiles that vary in incidence depending on drug. Diarrhea is common, occurring in greater than 60% of patients treated with the EGFR TKIs listed here. Rarely, more severe gastrointestinal toxicity including perforation can occur most specifically with erlotinib. All agents are associated with EGFR TKI-characteristic dermatologic toxicity and rash, but incidence is highest (up to 90%) in patients treated with afatinib. These agents also may cause hepatic toxicity and increased hepatic transaminases. Though incidence is small, hepatic failure and hepatorenal syndrome have been reported in patients treated with erlotinib.[56,57,58] Information regarding these TKIs have been kept in for comprehensiveness, however they are not being recommended for addition to the Essential Medicines List. Systematic Reviews These systematic reviews and meta-analyses summarize the literature supporting the use of chemotherapy in the treatment of Stage II - IV NSCLC and the use of TKI in metastatic NSCLC.

• Pignon, J.P., et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J. Clin. Oncol. 26 (21), 3552-3559 (2003).

• Arriagada, R., et al. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med. 350, 351-360 (2004).

• NSCLC Meta-Analyses Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 311, 899 (1995).

• Bayman, N.A., et al. Management of unresectable Stage III non-small-cell lung cancer with combined-modality therapy: a review of current literature and recommendations for treatment. Clin Lung Cancer. 9, 92-101 (2008).

• Pritchard R.S., Anthony, S.P. Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer. A meta-analysis. Ann Intern Med. 125(9), 723-9 (1996).

• Auperin, A., et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small cell lung cancer. J Clin Oncol. 28, 2181-2190 (2010).

• Lee, C.K., et al. Impact of eGFR inhibitor in Non–Small Cell Lung Cancer on Progression-Free and Overall Survival: A Meta-Analysis. J Natl Cancer Inst. 105(9), 595-605 (2013).



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• NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomised controlled trials. J Clin Oncol. 26, 4617-4625 (2008).

Expanding on the Systematic Reviews and Meta-analyses

General benefit of chemotherapy

NSCLC Meta-Analyses Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 311, 899 (1995).

Objective: To evaluate the effect of cytotoxic chemotherapy on survival in patients with non-small cell lung cancer. Design: Meta-analysis using updated data on individual patients from all available randomised trials, both published and unpublished. Subjects: 9387 patients (7151 deaths) from 52 randomised clinical trials. Main Outcome Measure: Survival. Results: The results for modern regimens containing cisplatin favoured chemotherapy in all comparisons and reached conventional levels of significance when used with radical radiotherapy and with supportive care. Trials comparing surgery with surgery plus chemotherapy gave a hazard ratio of 0.87 (13% reduction in the risk of death, equivalent to an absolute benefit of 5% at five years). Trials comparing radical radiotherapy with radical radiotherapy plus chemotherapy gave a hazard ratio of 0.87 (13% reduction in the risk of death; absolute benefit of 4% at two years), and trials comparing supportive care with supportive care plus chemotherapy 0.73 (27% reduction in the risk of death; 10% improvement in survival at one year). The essential drugs needed to achieve these effects were not identified. No difference in the size of effect was seen in any subgroup of patients. In all but the radical radiotherapy setting, older trials using long term alkylating agents tended to show a detrimental effect of chemotherapy. This effect reached conventional significance in the adjuvant surgical comparison. Conclusion: At the outset of this meta-analysis there was considerable pessimism about the role of chemotherapy in non-small cell lung cancer. These results offer hope of progress and suggest that chemotherapy may have a role in treating this disease.

EGFR Inhibitors

Lee, C.K., et al. Impact of eGFR inhibitor in Non–Small Cell Lung Cancer on Progression-Free and Overall Survival: A Meta-Analysis. J Natl Cancer Inst. 105(9), 595-605 (2013).

Background: The epidermal growth factor receptor (EGFR) signaling pathway is crucial for regulating tumorigenesis and cell survival and may be important in the development and progression of non-small cell lung cancer (NSCLC). We examined the impact of EGFR-tyrosine kinase inhibitors (TKIs) on progression-free survival (PFS) and overall survival (OS) in advanced NSCLC patients with and without EGFR mutations. Methods: Randomized trials that compared EGFR-TKIs monotherapy or combination EGFR-TKIs-chemotherapy with chemotherapy or placebo were included. We used published hazard ratios (HRs), if available,



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or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs for the EGFR mutation-positive (EGFRmut(+)) and EGFR mutation-negative (EGFRmut(-)) subgroups were calculated with the fixed-effects inverse variance weighted method. All statistical tests were two-sided. Results: We included 23 eligible trials (13 front-line, 7 second-line, 3 maintenance; n = 14570). EGFR mutation status was known in 31% of patients. EGFR-TKIs treatment prolonged PFS in EGFRmut(+) patients, and EGFR mutation was predictive of PFS in all settings: The front-line hazard ratio for EGFRmut(+) was 0.43 (95% confidence interval [CI] = 0.38 to 0.49; P < .001), and the front-line hazard ratio for EGFRmut(-) was 1.06 (95% CI = 0.94 to 1.19; P = .35; P interaction < .001). The second-line hazard ratio for EGFRmut(+) was 0.34 (95% CI = 0.20 to 0.60; P < .001), and the second-line hazard ratio for EGFRmut(-) was 1.23 (95% CI = 1.05 to 1.46; P = .01; P interaction < .001). The maintenance hazard ratio for EGFRmut(+) was 0.15 (95% CI = 0.08 to 0.27; P < .001), and the maintenance hazard ratio for EGFRmut(-) was 0.81 (95% CI = 0.68 to 0.97; P = .02; P interaction < .001). EGFR-TKIs treatment had no impact on OS for EGFRmut(+) and EGFRmut(-) patients. Conclusions: EGFR-TKIs therapy statistically significantly delays disease progression in EGFRmut(+) patients but has no demonstrable impact on OS. EGFR mutation is a predictive biomarker of PFS benefit with EGFR-TKIs treatment in all settings. These findings support EGFR mutation assessment before initiation of treatment. EGFR-TKIs should be considered as front-line therapy in EGFRmut(+) advanced NSCLC patients.

Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., ... & Nukiwa, T. (2010). Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. New England Journal of Medicine, 362(25), 2380-2388.

BACKGROUND: Non–small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy. METHODS: We randomly assigned 230 patients with metastatic, non–small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin–paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects. RESULTS: In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P=0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. CONCLUSIONS: First-line gefitinib for patients with advanced non–small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)



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Figure from Maemondo, M et al 2010

Zhou, C., Wu, Y. L., Chen, G., Feng, J., Liu, X. Q., Wang, C., ... & You, C. (2011). Erlotinib versus chemotherapy as first-line treatment for patients with advanced< i> EGFR</i> mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The lancet oncology, 12(8), 735-742.

Background: Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor (TKI) therapy in non-small-cell lung cancer (NSCLC). The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus standard chemotherapy in the first-line treatment of patients with advanced EGFRmutation-positive NSCLC. Methods: We undertook an open-label, randomised, phase 3 trial at 22 centres in China. Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin. Patients were randomly assigned (1:1) with a minimisation procedure and were stratified according to EGFRmutation type, histological subtype (adenocarcinoma vs non-adenocarcinoma), and smoking status. The primary outcome was progression-free survival, analysed in patients with confirmed disease who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT00874419, and has completed enrolment; patients are still in follow-up. Findings: 83 patients were randomly assigned to receive erlotinib and 82 to receive



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gemcitabine plus carboplatin; 82 in the erlotinib group and 72 in the chemotherapy group were included in analysis of the primary endpoint. Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 [95% CI 10.58–16.53] vs 4.6 [4.21–5.42] months; hazard ratio 0.16, 95% CI 0.10–0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib); the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations (three [4%] of 83 patients) and skin rash (two [2%] patients). Chemotherapy was also associated with increased treatment-related serious adverse events (ten [14%] of 72 patients [decreased platelet count, n=8; decreased neutrophil count, n=1; hepatic dysfunction, n=1] vs two [2%] of 83 patients [both hepatic dysfunction]). Interpretation: Compared with standard chemotherapy, erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability. These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC.

Chemotherapy for patients with metastatic disease, without EGFR/ALK mutations

Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomised controlled trials. J Clin Oncol. 26, 4617-4625 (2008).

Background: Since our individual patient data (IPD) meta-analysis (MA) of supportive care and chemotherapy for non-small-cell lung cancer (NSCLC), published in 1995, many trials have been completed. An updated, IPD MA has been carried out to assess newer regimens and determine conclusively the effect of chemotherapy. Methods: Systematic searches for randomized controlled trials (RCTs) were undertaken, followed by central collection, checking, and reanalysis of updated IPD. Results from RCTs were combined to calculate individual and pooled hazard ratios (HRs). Results: Data were obtained from 2,714 patients from 16 RCTs. There were 1,293 deaths among 1,399 patients assigned supportive care and chemotherapy and 1,240 among 1,315 assigned supportive care alone. Results showed a significant benefit of chemotherapy (HR, 0.77; 95% CI, 0.71 to 0.83; P <or= .0001), equivalent to a relative increase in survival of 23% or an absolute improvement in survival of 9% at 12 months, increasing survival from 20% to 29%. There was no clear evidence that this effect was influenced by the drugs used (P = .63) or whether they were used as single agents or in combination (P = .40). Despite changes in patient demographics, the effect of chemotherapy in recent trials did not differ from those included previously (P = .77). There was no clear evidence of a difference or trend in the relative effect of chemotherapy across patient subgroups. Conclusion: This MA of chemotherapy in the supportive care setting demonstrates conclusively that chemotherapy improves overall survival in all patients with advanced NSCLC. Therefore, all patients who are fit enough and wish to receive chemotherapy should do so.



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Costing and Price Considerations The following costing table is for metastatic (stage IV) non-small cell lung cancer.



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Recommendations The reviewers recommend the incorporation of non-small cell lung cancer treatment options into the WHO Model List of Essential Medicines, and recommend specifically that vinorelbine, cisplatin, gemcitabine, erlotinib and gefitinib be added to the core Essential Medicines List.

Additions proposed for Section 8.2 of the EML Cytotoxic chemotherapy Vinorelbine Cisplatin* Gemcitabine TKI agents Erlotinib Gefitinib *Carboplatin is currently in the WHO Essential Medicines List for Adults (2013, 18th Edition). Next to Carboplatin in the list is a symbol that indicates that the listing of the drug indicates “similar clinical performance within a pharmacological class. The listed medicine should be the example of the class for which there is the best evidence for effectiveness and safety. In some cases, this may be the first medicine that is licensed for marketing; in other instances, subsequently licensed compounds may be safer or more effective. Where there is no difference in terms of efficacy and safety data, the listed medicine should be the one that is generally available at the lowest price, based on international drug price information sources. Not all square boxes are applicable to medicine selection for children — see the second EMLc for details. Therapeutic equivalence is only indicated on the basis of reviews of efficacy and safety and when consistent with WHO clinical guidelines. National lists should not use a similar symbol and should be specific in their final selection, which would depend on local availability and price.” The present proposal calls for the explicit addition of Cisplatin to the EML given its distinct use in the treatment of a number of cancers.



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References 1. Soerjomataram, I., et al. Global burden of cancer in 2008: a systematic analysis of disability-

adjusted life-years in 12 world regions. Lancet. 380 (9856), 1840-1850 (2012). 2. Jemal, A., et al. Global cancer statistics. CA Cancer J Clin. 61, 61-90 (2011). 3. Lim, E., et al. Preoperative versus postoperative chemotherapy in patients with resectable

non-small cell lung cancer: systematic review and indirect comparison with meta-analysis of randomised trials. J Thorac Oncol. 4, 1380-1388 (2009).

4. Pignon, J.P., et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J. Clin Oncol 26 (21), 3552-3559 (2003).

5. Arriagada, R., et al. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med. 350, 351-360 (2004).

6. Winton, T., et al. Vinorelbine plus cisplatin vs. observation in resected non-small-lung cancer. N Engl J Med. 352, 2589-2597 (2005)

7. Douillard, J.Y., et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 7, 719-727 (2006).

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