What is the optimal second-line therapy in patients with stage IV inoperable NSCLC?

From Cancer Guidelines Wiki

Introduction

The majority of patients treated with NSCLC have stage IV disease, with common sites of metastases including lymph nodes, the pleura, liver, adrenal glands, bone and brain. Consequently, systemic therapy has been the mainstay of treatment attempting to control overall disease. A historical summary of the evolution of systemic drug treatment for stage IV NSCLC can be found here. The focus of the following question is based on the evidence in support of the old and new practice paradigms for stage IV NSCLC. Empirical therapy refers to therapy given to all fit patients deemed suitable without any particular restrictions.

Monotherapy in unselected patients

Several randomised controlled trials (RCTs) have been reported examining the role of second line systemic therapy in unselected patients. The first studies examined docetaxel, establishing it as a standard of care in suitably fit patients. Subsequent studies examined different schedules of docetaxel, or examined the efficacy of new agents using it as the reference standard.

In 2000, two key RCTs were reported evaluating the efficacy of single agent docetaxel in previously treated NSCLC. Shepherd et al evaluated the efficacy of docetaxel versus best supportive care in 104 patients previously treated with platinum-based chemotherapy.[1] Compared with best supportive care, docetaxel 75 mg/m2 Q three-weekly, improved one-year survival (37% versus 11%; P = 0 .003).[1] Fossella et al randomised 373 previously treated patients with advanced NSCLC to two dose regimens of docetaxel compared with control arm of vinorelbine or ifosfamide.[2] one-year survival was significantly greater with docetaxel 75 mg/m2 than with the control treatment (32% versus 19%; P = 0.025,). Based on these two studies, docetaxel became the standard of care as second-line treatment of advanced NSCLC. Further supporting the clinical value of docetaxel was the results of the QOL analysis in the Shepherd study, which indicated less deterioration in QOL for docetaxel treated patients compared with best supportive care.[3]

Bria et al, compared the efficacy of weekly docetaxel with the reference standard of three-weekly, by evaluating data from 1018 patients from six RCTs. No significant differences in OS or RR in favour of the weekly schedule were found, however weekly docetaxel was associated with fewer grade ¾ neutropaenic events.[4]

Hanna et al, then compared single agent pemetrexed to three-weekly docetaxel as second line monotherapy of advanced NSCLC.[5] This study of 571 patients, randomised to three-weekly pemetrexed or docetaxel, showed equivalent efficacy outcomes (PFS, one-year survival) but significantly fewer side effects in favour of pemetrexed.[5] Consequently, pemetrexed was soon registered as an alternative second-line agent in NSCLC. Scagliotti et al in a post hoc analysis of data from two RCTS of pemetrexed, subsequently showed that pemetrexed increased OS in patients with non-SCC histology (p = 0.047), whereas OS was decreased with pemetrexed in SCC histology (p = 0.018).[6] A subsequent systematic review has confirmed this treatment-by-histology interaction effect with pemetrexed treatment showing greatest benefit in non-SCC histology.[7]

Two studies evaluated the effectiveness of the single agent first generation EGFR TKIs gefitinib or erlotinib compared with placebo in previously treated patients with NSCLC.[8][9] Thatcher et al, reported the effect of gefitinib as second or third-line therapy in 1692 patients with NSCLC refractory to or intolerant of previous treatment (ISEL study). Median survival was not significantly different between gefitinib and placebo treated patients in the overall population or the pre-specified adenocarcinoma subgroup.[8] However, in pre-planned subgroup analyses, OS was longer with gefitinib in never-smokers (n = 375, OS HR 0.67 (95% CI 0.49-0.92), p = 0.012) and patients of Asian origin (n = 342, OS HR 0.66 (95% CI 0.48-0.91)).[8] This sub-group effect most likely can be attributed to the greater incidence of activating EGFR gene mutations in this population.

Shepherd et al, randomised 731 patients, previously treated for advanced NSCLC, to receive erlotinib 150 mg daily or placebo as second or third-line treatment (BR21 study). A RR of 8.9 % was observed with erlotinib, which was shown to prolong OS (median 6.7 months (erlotinib) versus 4.7 months (placebo); HR 0.70, p <0.001).[9] More patients receiving erlotinib had improvements in cough, pain, dyspnoea and in the overall physical function domain of QOL.[9]

Kim et al randomised 1433 patients previously treated for advanced NSCLC to receive gefitinib 250 mg daily or three-weekly docetaxel chemotherapy (INTEREST study).[10] The primary objective was to compare OS and to assess non-inferiority of gefitinib in the overall population and superiority in patients with high EGFR gene copy number.[10] Non- inferiority of gefitinib compared with docetaxel was confirmed for OS (HR 1.02, 95% CI 0.905 – 1.15). Superiority of gefitinib in patients with high EGFR gene copy number was not proven. Skin rash and diarrhea were more common with gefitinib, whilst neutropaenia, asthenia and alopecia were more common with docetaxel.[10]

Ciuleanu et al, randomised patients that progressed after first line platinum doublet chemotherapy to recive either erlotinib 150 mg daily or chemotherapy (pemetrexed or docetaxel by investigator choice). This study (TITAN) was originally designed to test for superiority of erlotinib versus chemotherapy, in patients progressing after the induction chemotherapy phase of the switch maintenance erlotinib study by Capuzzo et al.[11][12] However, when the Capuzzo study closed, so to did recruitment to the TITAN study. Nonetheless, for the 424 patients randomised, median overall survival was 5.3 months (95% CI 4.0–6.0) with erlotinib and 5.5 months (4.4–7.1) with chemotherapy (HR 0.96, 95% CI 0.78–1.19; log-rank p=0.73). The adverse-event profile of each group was in line with previous studies, with more skin rash and diarrhea with erlotinib, and alopecia associated with chemotherapy (mainly due to docetaxel).[12]

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Combination therapy in unselected patients

Di Maio et al, examined whether doublet chemotherapy is more effective than single agent chemotherapy as second-line treatment of advanced NSCLC in 847 patients from six RCTS from 1999 – 2005.[13] Single agents evaluated include docetaxel (three studies), irinotecan, cisplatin, or pemetrexed. Response rate was greater for doublet therapy (15 % versus 7.3 %, p = 0.0004), as was PFS (HR 0.79, 95% CI 0.68 – 0.91).[13] However, there was no significant difference in OS between single agent and doublet chemotherapy and there were significantly more grade ¾ haematologic and non-haematologic toxicities with doublet chemotherapy.[13]

Qi et al, examined whether doublet pemetrexed based therapy is more effective than single agent pemetrexed as second-line treatment of advanced NSCLC in 1,186 patients from five RCTS from 1999 – 2005.[14] Only one of these studies was a phase III RCT, that of the dual targeted TKI vandetanib (anti-VEGF and anti EGFR).[15] Here doublet therapy was associated with a greater RR, but did not improve PFS ).[15] The other four phase II RCTS evaluated the addition of carboplatin, and the new agents enzastorurin, matuzumab and bortezomib to pemetrexed.[14] Overall, there was improvement in RR and PFS with doublet therapy but not survival.[14] Furthermore, there was more grade ¾ neutropaenia and thrombocytopaenia with the doublet therapy.[14]

Herbst et al, also evaluated the efficacy of vandetanib. In their double blind RCT, the effect of Vandetanib plus docetaxel was compared with docetaxel as second-line treatment for patients with advanced NSCLC, on PFS in 1391 patients.[16] Vandetanib plus docetaxel was shown to be an active regimen with significant improvement in PFS versus placebo plus docetaxel (HR 0.79, 97.58% CI 0.70–0.90; p<0.0001).[16], however, the size of the effect on median PFS was small (4.0 months (vandetanib) versus 3.2 months (placebo), and therefore of questionable clinical significance, and survival benefit not shown.[16]

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Evidence summary and recommendations

Evidence summary Level References
In previously treated patients with advanced NSCLC, single agent docetaxel 75 mg/m2 improves survival compared with best supportive care or vinorelbine and ifosfamide.

Last reviewed December 2015

II [1], [2]
In previously treated patients with advanced NSCLC, single agent pemetrexed has similar efficacy but fewer side effects than three-weekly docetaxel.

Last reviewed December 2015

II [5]
In previously treated patients with advanced NSCLC, compared with docetaxel, pemetrexed appears to have greater efficacy in non-squamous cell carcinoma histology, and inferior efficacy in squamous cell carcinoma.

Last reviewed December 2015

I [7]
Evidence-based recommendationQuestion mark transparent.png Grade
In unselected patients previously treated for advanced NSCLC, chemotherapy with docetaxel or pemetrexed may be used as second-line therapy. Pemetrexed is preferred in non-squamous cell carcinoma histology, and docetaxel is preferred in squamous cell carcinoma.

Last reviewed December 2015

B


Evidence summary Level References
In unselected previously treated patients with advanced NSCLC single agent erlotinib150 mg per day orally as second-line therapy improves survival compared with placebo.

Last reviewed December 2015

II [9]
In unselected previously treated patients with advanced NSCLC, single agent gefitinib 250 mg per day orally does not improve survival compared with placebo.

Last reviewed December 2015

II [8]
In unselected previously treated patients with advanced NSCLC, gefitinib 250 mg per day orally is equivalent to three-weekly docetaxel chemotherapy.

Last reviewed December 2015

II [10]
In unselected patients with advanced NSCLC, progressing after first-line platinum-based chemotherapy, there is no difference in survival between erlotinib 150 mg daily or chemotherapy (either pemetrexed or docetaxel).

Last reviewed December 2015

II [12]
Evidence-based recommendationQuestion mark transparent.png Grade
In unselected patients previously treated for advanced NSCLC, erlotinib 150 mg per day orally can be used as second-line therapy, instead of chemotherapy.

Last reviewed December 2015

B


Evidence summary Level References
Doublet therapy as second-line treatment of advanced NSCLC increases response rate and progression free survival, but is more toxic and does not improve overall survival compared with single agent chemotherapy.

Last reviewed December 2015

I [13], [14]
Evidence-based recommendationQuestion mark transparent.png Grade
Doublet therapy is not recommended as second-line treatment of advanced NSCLC .

Last reviewed December 2015

A


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References

  1. 1.0 1.1 1.2 Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000 May;18(10):2095-103 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10811675.
  2. 2.0 2.1 Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000 Jun;18(12):2354-62 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10856094.
  3. Dancey J, Shepherd FA, Gralla RJ, Kim YS. Quality of life assessment of second-line docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: results of a prospective, randomized phase III trial. Lung Cancer 2004 Feb;43(2):183-94 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14739039.
  4. Bria E, Cuppone F, Ciccarese M, Nisticò C, Facciolo F, Milella M, et al. Weekly docetaxel as second line chemotherapy for advanced non-small-cell lung cancer: meta-analysis of randomized trials. Cancer Treat Rev 2006 Dec;32(8):583-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16919884.
  5. 5.0 5.1 5.2 Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004 May 1;22(9):1589-97 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15117980.
  6. Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 2009 Mar;14(3):253-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19221167.
  7. 7.0 7.1 Standfield L, Weston AR, Barraclough H, Van Kooten M, Pavlakis N. Histology as a treatment effect modifier in advanced non-small cell lung cancer: a systematic review of the evidence. Respirology 2011 Nov;16(8):1210-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21801275.
  8. 8.0 8.1 8.2 8.3 Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005 Oct;366(9496):1527-37 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16257339.
  9. 9.0 9.1 9.2 9.3 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005 Jul 14;353(2):123-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16014882.
  10. 10.0 10.1 10.2 10.3 Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008 Nov 22;372(9652):1809-18 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19027483.
  11. Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010 Jun;11(6):521-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20493771.
  12. 12.0 12.1 12.2 Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol 2012 Mar;13(3):300-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22277837.
  13. 13.0 13.1 13.2 13.3 Di Maio M, Chiodini P, Georgoulias V, Hatzidaki D, Takeda K, Wachters FM, et al. Meta-analysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2009 Apr 10;27(11):1836-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19273711.
  14. 14.0 14.1 14.2 14.3 14.4 Qi WX, Tang LN, He AN, Shen Z, Yao Y. Effectiveness and safety of pemetrexed-based doublet versus pemetrexed alone as second-line treatment for advanced non-small-cell lung cancer: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2012 Jan 19 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22258853.
  15. 15.0 15.1 de Boer RH, Arrieta Ó, Yang CH, Gottfried M, Chan V, Raats J, et al. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 2011 Mar 10;29(8):1067-74 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21282537.
  16. 16.0 16.1 16.2 Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 2010 Jul;11(7):619-26 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20570559.

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Appendices

Further resources

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