What is the optimal first-line maintenance therapy for treatment of stage IV inoperable NSCLC?

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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.

First-line maintenance therapy

"Maintenance" therapy, described in detail here refers to the concept of continuing drug therapy until progression. Maintenance treatment can be further characterised by continuing part of the initial treatment regimen (usually the new generation regimen whilst stopping the platinum) - this is referred to as "continuation maintenance" or by switching after disease control with an initial combination therapy to another agent - this is referred to as "switch maintenance".

Fidias et al compared immediate with delayed docetaxel after first-line therapy with gemcitabine and carboplatin in 309 patients with advanced NSCLC.[1] Patients were randomised to immediate versus delayed docetaxel if they were stable after four cycles of induction chemotherapy. The primary endpoint of OS was not significantly different (p = 0.085) even though there was a trend in median OS in favour of immediate docetaxel (12.3 months versus 9.7 months (delayed)).[1] However, PFS was significantly longer for immediate docetaxel (5.7 months) than for delayed docetaxel (2.7 months) (P .0001), and QOL results were not statistically different (P= 0.76) between docetaxel groups.[1]

Ciuleanu et al randomised 663 patients who had not progressed after four cycles of first-line platinum-based chemotherapy to pemetrexed or placebo.[2] The primary endpoint of the study was PFS. Pemetrexed was shown to significantly improve PFS (4.3 months [95% CI 4.1–4.7] versus 2.6 months [1.7–2.8]; HR 0.50, 95% CI 0.42–0.61, p<0.0001) and also improve OS (13.4 months [11.9–15.9] versus 10.6 months [8.7–12.0]; HR 0.79, 0.65–0.95, p=0.012) compared with placebo.[2] These benefits were mainly in patients with non- SCC histology (PFS HR 0.44; (95% CI 0.36–0.55); and OS HR 0.70; (95% CI 0.56–0.88). compared with squamous histology (PFS HR 0・69, 95% CI 0.49–0.98); and OS HR 1.07, (95% CI 0.77–1.50).[2] In the non-SCC population, the benefit with pemetrexed was most certain in the adenocarcinoma (PFS HR 0.51 (0.38–0.68); <0.0001, and OS HR 0.73 (0.56–0.96); 0.026) and other NSCLC sub-groups. This observation was confirmed by a significant treatment-by-histology interaction with both PFS (p=0・036) and OS (p=0・033).[2] Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (mainly fatigue and neutropaenia).[2]

In the PARAMOUNT study, 539 patients with advanced non-squamous NSCLC were randomised to “continuation maintenance” with pemetrexed + BSC versus placebo + BSC, following induction with 4 cycles of cisplatin and pemetrexed. Updated results demonstrated that maintenance pemetrexed improved overall surival (OS HR 0.78 (0.64-0.96); p = 0.02, median 13.9 months vs 11.0 months).[3]

The SATURN maintenance erlotinib study showed significantly longer median PFS for erlotinib compared to placebo, including in a subgroup with EGFR activating mutations. However, the subsequent IUNO study of maintenance versus delayed erlotinib in patients without EGFR activating mutations showed no OS or PFS benefit for maintenance erlotinib.[4] This indicates that the likely benefit of maintenance erlotinib is restricted to patients with EGFR activating mutations.

Taken collectively, the studies indicated benefit in unselected patients from the “switch maintenance” approach of immediate alternative treatment with single agent docetaxel by significantly improving PFS. Both “switch” and “continuation” maintenance with pemetrexed improve OS in patients with non-squamous histology. In each study, maintenance was evaluated only in patients with stable disease or response after four cycles of standard first-line chemotherapy.

Evidence summary and recommendations

Evidence summary Level References
In patients with stable or responsive advanced NSCLC after four cycles of initial platinum doublet chemotherapy, both approaches of switch maintenance and continuation maintenance improves progression free survival.

Last reviewed September 2017

I [5]
In patients with stable or responsive advanced NSCLC after four cycles of initial carboplatin/gemcitabine chemotherapy, immediate docetaxel prolongs progression free survival compared with delaying treatment for relapse, without decreasing quality of life.

Last reviewed September 2017

II [1]
In patients with stable or responsive advanced NSCLC after four cycles of initial platinum doublet chemotherapy, in patients with non-SCC histology, “switch maintenance” chemotherapy with pemetrexed improves progression free survival and overall survival.

Last reviewed September 2017

II [6]
In patients with stable or responsive advanced NSCLC after four cycles of initial platinum doublet chemotherapy, “switch maintenance” therapy with erlotinib improves progression free survival and overall survival.

Last reviewed September 2017

II [6]
Evidence-based recommendationQuestion mark transparent.png Grade
In unselected patients with stable or responsive advanced NSCLC after four cycles of initial platinum doublet chemotherapy, “switch maintenance” therapy to an alternative agent is recommended to delay tumour progression.

Options for delaying tumour progression in unselected patients, include docetaxel, whilst in patients with non-squamous cell carcinoma histology, pemetrexed.

Options most proven for prolongation of survival is pemetrexed.
Last reviewed September 2017

A


Evidence summary Level References
Maintenance pemetrexed improves overall survival in advanced non-squamous NSCLC
Last reviewed September 2017
II [3]
Evidence-based recommendationQuestion mark transparent.png Grade
Pemextrexed in stage IV non-squamous NSCLC should be considered for maintenance therapy.
Last reviewed September 2017
B


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References

  1. 1.0 1.1 1.2 1.3 Fidias PM, Dakhil SR, Lyss AP, Loesch DM, Waterhouse DM, Bromund JL, 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 Feb 1;27(4):591-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19075278.
  2. 2.0 2.1 2.2 2.3 2.4 Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009 Oct 24;374(9699):1432-40 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19767093.
  3. 3.0 3.1 Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2013 Aug 10;31(23):2895-902 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23835707.
  4. Cicènas S, Geater SL, Petrov P, Hotko Y, Hooper G, Xia F, et al. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer 2016 Dec;102:30-37 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27987585.
  5. Zhang X, Zang J, Xu J, Bai C, Qin Y, Liu K, et al. Maintenance therapy with continuous or switch strategy in advanced non-small cell lung cancer: a systematic review and meta-analysis. Chest 2011 Jul;140(1):117-26 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21436247.
  6. 6.0 6.1 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.

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Appendices

Further resources

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