Lung cancer is the leading cause of cancer death in both men and women in the United States.1 It is estimated that in 2009, 219,440 men and women were diagnosed with lung cancer and 159,390 men and women died from the disease.2 From 1975 to 2001, non–small-cell lung cancer (NSCLC) 5-year survival rates have increased from 11.9% to 15.6%. These statistics are independent of sex, race, age, and stage at diagnosis, and make acutely evident that there have been few advances in the treatment of NSCLC. This lack of progress may be a result of not analyzing the patient population thoroughly. It is only in the past 5 years that researchers have put more emphasis on analyzing patient- and disease-related factors, including race, age, sex, histology, and genomic testing results. Recent trial results are leading us to a new horizon of patient-centered cancer care, which includes genomic testing, histology- focused treatment plans, and the concept of maintenance drugs.
Chemotherapy doublet du jour
Published in 2002, the Eastern Cooperative Oncology Group (ECOG) 1594 study compared platinum-based doublets in the treatment of advanced NSCLC.3 The four doublets in the trial included cisplatin/paclitaxel, cisplatin/ gemcitabine, cisplatin/docetaxel, and carboplatin/paclitaxel. No differences in overall survival (OS) between the four doublets were found. Although these findings increased options in terms of selecting chemotherapy based on side effect profile, they offer only modest hope for better outcomes.
In 2004, several studies looked at the efficacy of platinum-based doublets in the setting of adjuvant use. The International Adjuvant Lung Trial (IALT) compared platinum-based doublets (cisplatin plus etoposide, vinorelbine, vinblastine, or vindesine) versus observation in postoperative stage I to IIIA patients.4 The result was a 5% improvement in disease-free survival as well as 5-year OS with adjuvant chemo - therapy. That same year, JBR.10 compared cisplatin/vinorelbine versus observation in patients with stage I to II NSCLC and confirmed that adjuvant cisplatin-based chemotherapy provides benefit.5 The results were grossly positive with a difference of 15% in 5-year survival between the two arms (69% cisplatin/ vinorelbine arm vs 54% observation arm). As with palliative regimens, these results offer convincing evidence for meaningful survival with platinumbased doublets in the adjuvant setting, but improving survival hinges on the hope of finding new drugs and better understanding the utility of the drugs currently available.
Focusing on details
With this groundwork laid, we can begin to look at personalizing medicine for patients with NSCLC. In 2008, the JMBD phase 3 randomized study compared gemcitabine/cisplatin with pemetrexed/ cisplatin in the treatment of advanced NSCLC.6 The researchers performed two analyses, one in which they did not look at the histology and one in which histology was included. In the analysis not including histology, the regimens were equivalent, with a median survival of 10.3 months in each arm. In the analysis including histology, a significant difference in OS was found. Patients with squamous cell histology demonstrated a significant improvement in survival with the gemcitabine/ cisplatin compared with cisplatin/ pemetrexed. Conversely, patients with adenocarcinoma and large cell histologies demonstrated a significant improvement in survival with cisplatin/ pemetrexed. One of the targets of pemetrexed is thymidalate synthetase.7 Therefore, the differential benefit of pemetrexed may be due to lower expression of thymidalate synthetase in adenocarcinoma, compared with squamous cell carcinoma.
Recently, three trials opened the door to the idea of maintenance therapy. In 2008, the hypothesis of maintenance pemetrexed after first-line therapy for advanced NSCLC was tested in a double- blind study.8 The study included all histologies of NSCLC. Patients were treated with four cycles of one of six approved platinum-based doublets. They were then randomized to either maintenance pemetrexed plus best support care (BSC) or placebo plus BSC. The primary end point was progression-free survival (PFS), with a secondary end point of OS. The result was a significant increase in both PFS and OS. In July 2009, the US Food and Drug Administration (FDA) approved pemetrexed for maintenance therapy in patients with advanced nonsquamous NSCLC, after receiving four cycles of a platinum-based doublet in the first-line setting.
In 2009, a phase 3 clinical trial by Fidias and colleagues compared immediate versus delayed second-line do cetaxel (75 mg/m2, 21-day cycle) after four cycles of first-line gemcitabine (days 1 and 8)/carboplatin (day 1).9 In the delayed arm, docetaxel was started at the first sign of disease progression. The results showed a significant increase in PFS in the immediate docetaxel arm. However, this increase was not statistically significant, possibly because of the small number of patients in the trial.
The same hypothesis was tested with erlotinib in the SATURN study.10 After four cycles of chemotherapy, patients were randomized to either immediate erlotinib or observation. Patients in the erlotinib arm showed a clinically meaningful improvement in both PFS and OS. On the basis of this trial, erlotinib was approved by the FDA as maintenance therapy for NSCLC in April 2010.11
In 2005, the ECOG 4599 trial introduced the use of bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, in conjunction with the standard doublet of paclitaxel/ carboplatin.12 The trial compared six cycles of paclitaxel/carboplatin with bevacizumab (15 mg/kg) followed by maintenance bevacizumab until progressive disease versus six cycles of paclitaxel/ carboplatin alone. Results showed a statistically significant improvement in OS with the paclitaxel/carboplatin with bevacizumab arm. The overall response rate was 35%, compared with 15% with paclitaxel/ carboplatin alone. Patients with squamous histology, history of hemoptysis, un treated brain metastasis, uncontrolled hypertension, who were taking anti coagulants, or had had a recent cerebrovascular accident were excluded because of the increased risk of bleeding.13 Because of the study’s design, in which bevacizumab was used as maintenance until progressive disease, we continue to use it as maintenance therapy in this setting. To date, there have been no studies comparing bevacizumab maintenance with placebo.
In 2005, the BR.21 trial showed that erlotinib, a small molecule designed to target the human epidermal growth factor receptor (EGFR)/HER1 pathway by inhibiting the tyrosine kinase activity of HER1, was better than BSC as a second- or third-line therapy for patients with NSCLC.14 Patients were allowed to have received one or two previous lines of therapy. The doubleblind study demonstrated a statistically significant improvement in both OS and PFS.
In 2008, the preliminary results of the Iressa Pan-Asia Study (IPASS) were reported.15 Gefitinib, a tyrosine kinase inhibitor (TKI), was compared with paclitaxel/carboplatin as a firstline therapy. The primary end point was PFS, with a secondary end point of OS. EGFR mutation status was also analyzed. The results showed that patients who were EGFR-mutation positive had a significant increase in OS with gefitinib, compared with standard chemotherapy. Con versely, patients who were EGFR- mutation negative had an increased response to standard chemotherapy in comparison with gefitinib.
Genomic testing: markers of chemotherapy response
As previously discussed, thymidalate synthetase expression in adenocarcinoma potentially affects the utility of pemetrexed. Another potential marker of chemotherapy response is the excision repair cross-complementation group 1 (ERCC1) protein. In 2006, the IALT Bio Investigators performed a subgroup analysis of the IALT trial, looking at expression of the ERCC1 protein and the outcomes of receiving adjuvant cisplatin- based chemotherapy.16 The investigators used immunohistochemical (IHC) analysis to determine the expression of the ERCC1 protein in operative specimens of NSCLC. The IALT trial compared the effect of adjuvant cisplatin- based chemotherapy on survival, which was now being compared with ERCC1 expression. The investigators looked for a validated clinical or biologic predictor of the benefit of chemotherapy. Among 761 tumor specimens, ERCC1 expression was positive in 335 (44%) and negative in 426 (56%). The results indicated that a benefit from cisplatinbased adjuvant chemotherapy was associated with the absence of ERCC1. Adjuvant chemotherapy significantly prolonged survival in patients who were ERCC1-negative. Conversely, patients with ERCC1-positive tumors who received adjuvant chemotherapy did not have prolonged survival. Among the patients who did not receive adjuvant chemotherapy, those with ERCC1-positive tumors survived longer than those with ERCC1-negative tumors. These findings indicate that people with ERCC1-negative tumors benefit from adjuvant chemotherapy, whereas patients with ERCC1-positive tumors do not. Further, these results suggest that the development of genomic profiles, including ERCC1, may help us better select which patients will benefit from adjuvant chemotherapy.
Genomic testing: markers of TKI response
As discussed, the IPASS trial revealed the relationship between EGFRmutation status and response to TKI therapy.14 Another potential novel molecular marker, a fusion of echinoderm microtubule-associated proteinlike 4 (EML4) and the anaplastic lymphoma kinase (ALK), has recently been identified in a small subset of NSCLC.17
Shaw and colleagues examined the clinical characteristics, as well as treatment outcomes, of NSCLC patients with and without the EML4-ALK oncogene. EML4-ALK was identified using fluorescent in situ hybridization for ALK rearrangements and was confirmed by IHC for ALK expression. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. Of the 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild-type (WT/ WT) for both ALK and EGFR. Compared with the EGFR-mutant and WT/WT cohorts, patients with EML4-ALK– mutant tumors were significantly younger and more likely to be men. Patients with EML4-ALK–positive tumors, like patients who have EGFR mutations, also were more likely to be never/light smokers compared with the WT/WT cohort. Eighteen of 19 EML4- ALK–positive tumors were adenocarcinomas, predominantly the signet-ringcell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR TKIs. Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in OS. These findings provide information about the clinical characteristics of NSCLC patients who harbor this fusion, as well as the lack of benefit from EGFR TKIs in this population.
Currently, Pfizer has a phase 3 clinical trial investigating an oral c-Met and ALK inhibitor, PF-02341066, versus standard-of-care chemotherapy in patients with advanced NSCLC carrying the EML4-ALK oncogene who have progressed on one prior treatment with a platinum-based chemotherapy.18 The primary end point is PFS, and secondary outcomes include OS, objective re sponse rate, duration of response, disease-control rate, and patient-reported outcomes. Patients will be randomized to receive PF-02341066 (250 mg orally twice daily), pemetrexed (500 mg/m2 on day 1 of each 21-day cycle), or docetaxel (75 mg/m2 on day 1 of each 21-day cycle).
The past 5 years have brought us to an era with choices and possibilities in treating lung cancer—an era of personalizing NSCLC treatment. These new advances give us hope for improving outcomes and survival; hope that we can pass on to our patients.
1. American Cancer Society. Cancer Facts and Figures 2009. Atlanta, GA: American Cancer Society; 2009.
2. Ries LAG, Eisner MP, Kosary CL, et al, eds. SEER Cancer Statistics Review, 1975-2001. National Cancer Institute. http://seer.cancer.gov/csr/1975_2001. Accessed January 21, 2010. 3. Schiller JH, Harrington D, Belani CP, et al; for the Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-98.
4. Le Chevalier T; for the IALT Investigators. Results of the randomized international adjuvant lung cancer trial (IALT): cisplatin-based chemotherapy (CT) vs no CT in 1867 patients (pts) with resected non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2003; 22:Abstract 6.
5. Winton TL, Livingston R, Johnson D, et al. A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell lung cancer (NSCLC) Intergroup JBR.10. J Clin Oncol. 2004;22(14S):Abstract 7018.
6. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advancedstage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551.
7. Scagliotti G, Monica V, Ceppi P, et al. Baseline thymidylate synthase expression according to histological subtypes of non-small cell lung cancer. J Clin Oncol. 2009;27(15S):Abstract 7521.
8. Ciuleanu TE, Brodowicz T, Belani CP, et al. Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: as phase III study. J Clin Oncol. 2008;26(May 20 suppl):Abstract 8011.
9. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:591-598.
10. Cappuzzo F, Ciuleanu T, Stelmakh L, et al; for the SATURN Investigators; Istituto Clinico Humanitas IRCCS. SATURN: a double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol. 2009;27(15S):Abstract 8001.
11. Erlotinib approved as maintenance therapy for non-small cell lung cancer. NCI Cancer Bulletin. April 20, 2010.
12. Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial—E4599. J Clin Oncol. 2005;23(16S pt 1):Abstract LBA4.
13. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevaciz - umab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184-2191.
14. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; for the National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-132.
15. The IPASS study. www.iressa.com/ipass-study/. Accessed February 5, 2010.
16. Olaussen KA, Dunant A, Fouret P, et al; for the IALT Bio Investigators. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006; 355:983-991.
17. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4- ALK. J Clin Oncol. 2009;27:4247-4253.
18. Pfizer presents data with novel investigational agents in select patient groups with non-small cell lung cancer [press release]. May 30, 20009. www.pfizer.com/news/press_releases/pfizer_press_releases.jsp?rssUrl=http://mediaroom.pfizer.com/ portal/site/pfizer/index.jsp?ndmViewId=news_view&ndmConfigId=1016273&newsId=20090530005019&newsLang=en. Accessed January 29, 2010.