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.

Immunotherapy

Following first line therapy and maintenance therapy, patients should be considered for immunotherapy with PD-1 or PD-L1 antibodies. Patients not suitable for immunotherapy or progressing on immunotherapy should be considered for chemotherapy based on the information below.

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]

Older studies in patients not tested for EGFR activating mutations had indicated that EGFR TKIs were potential 2nd line therapies in patients without EGFR mutations. However, in the TAILOR study of 222 patients, erlotinib and docetaxel were compared as 2nd line therapy in patients with wild type EGFR.[8] Overall survival was superior for docetaxel (median OS 8.2 vs 5.4 months, HR 0.73, p=0.05). There were some imbalances between the arms of this study, with more squamous tumours and current or former smokers in the erlotinib arm. However, the results were confirmed by the DELTA study, a Japanese study involving 301 patients.[9] Patients with wild-type EGFR were randomised to docetaxel or erlotinib as 2nd or 3rd line therapy. PFS favoured docetaxel (median 2.9 vs 1.3 months, p=0.01), with no significant difference in overall survival (median 10.1 vs 9.0 months, p=0.91). Note that in this study, docetaxel was administered at a dose of 60mg/m2 every 3 weeks, as this is the standard dose in Japan.


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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.[10] 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).[10] 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.[10]

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.[11] Only one of these studies was a phase III RCT, that of the dual targeted TKI vandetanib (anti-VEGF and anti EGFR).[12] Here doublet therapy was associated with a greater RR, but did not improve PFS ).[12] The other four phase II RCTS evaluated the addition of carboplatin, and the new agents enzastorurin, matuzumab and bortezomib to pemetrexed.[11] Overall, there was improvement in RR and PFS with doublet therapy but not survival.[11] Furthermore, there was more grade ¾ neutropaenia and thrombocytopaenia with the doublet therapy.[11]

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.[13] 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).[13], 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.[13]

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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 September 2017

II [1], [2]
In previously treated patients with advanced NSCLC not suitable for immunotherapy, single agent pemetrexed has similar efficacy but fewer side effects than three-weekly docetaxel.

Last reviewed September 2017

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 September 2017

I [7]
Evidence-based recommendationQuestion mark transparent.png Grade
In unselected patients previously treated for advanced NSCLC not suitable for immunotherapy, 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 September 2017

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 September 2017

I [10], [11]
Evidence-based recommendationQuestion mark transparent.png Grade
Doublet therapy is not recommended as second-line treatment of advanced NSCLC .

Last reviewed September 2017

A


Evidence summary Level References
Erlotinib is inferior to docetaxel as 2nd line therapy in patients without EGFR activating mutations.
Last reviewed September 2017
II [9], [8]
Evidence-based recommendationQuestion mark transparent.png Grade
Erlotinib is not effective in WT EGFR patients.
Last reviewed September 2017
B


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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 Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol 2013 Sep;14(10):981-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23883922.
  9. 9.0 9.1 Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol 2014 Jun 20;32(18):1902-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24841974.
  10. 10.0 10.1 10.2 10.3 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.
  11. 11.0 11.1 11.2 11.3 11.4 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.
  12. 12.0 12.1 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.
  13. 13.0 13.1 13.2 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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