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".

There have been nine studies conducted formally addressing the question of maintenance therapy in advanced NSCLC, eight of which were evaluated in a systematic review by Zhang et al, with the most recent RCT of maintenance pemetrexed after induction pemetrexed/platinum therapy reported in 2011 but not yet published.[1][2] Zhang et al undertook a systematic review of eight trials (3, 736 patients) investigating maintenance therapy with either a continuous or a switch strategy for patients with non-progressing NSCLC compared with placebo or observation with overall survival (OS) as the primary outcome.[1] Another study not included in the meta-analysis by Zhang evaluated the role of maintenance carboxyaminotriazole (CAI) in patients with advanced NSCLC with non-progression after initial chemotherapy. CAI was a novel but unproven therapy, demonstrated to modulate tumour cell motility, adhesion and angiogenesis. Unfortunately no benefit was observed compared to placebo.[3]

Three studies were identified evaluating continuation maintenance with gemcitabine whilst the switch maintenance studies included in this meta-analysis evaluated either docetaxel, pemetrexed, erlotinib, erlotinib and bevacizumab, or gefitinib.[1] Zhang et al found that the concept of switch maintenance therapy substantially improved OS compared with placebo or observation (hazard ratio [HR], 0.85; 95% CI, 0.79-0.92; P , .001). However, gemcitabine as continuous maintenance therapy, did not statistically improve survival (HR, 0.88; 95% CI, 0.74-1.04; P = 0.124).[1] Subgroup analyses showed benefits of switch maintenance therapy with both cytotoxic agents (docetaxel/pemetrexed studies combined) (HR, 0.80; 95% CI, 0.69-0.93; P 5 .003) and EGFR TKI-targeted agents (gefitinib/erlotinib studies combined) (HR, 0.87; 95% CI, 0.80-0.95; P 5 .001).[1] Clinically and statistically significant improvement in PFS was found with both maintenance strategies (switch maintenance therapy HR, 0.67; 95% CI, 0.57-0.78; continuous maintenance therapy HR, 0.53; 95% CI, 0.43-0.65; interaction P = 0.128).[1]

The meta-analysis by Zhang et al thus confirmed in principle that there is benefit from the concept of maintenance therapy in NSCLC, with OS benefit observed in switch maintenance approach and PFS benefit from both switch and continuous maintenance approaches. Of the studies included in the meta-analysis by Zhang et al, the three positive published studies are of switch maintenance using docetaxel, pemetrexed or erlotinib.[4][5][6] These are discussed in more detail below to determine the benefits and harms of each approach for the purposes of providing a more specific practice guideline.

The first study by Fidias et al, compared immediate with delayed docetaxel after first-line therapy with gemcitabine and carboplatin in 309 patients with advanced NSCLC.[4] 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)).[4] 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.[4]

The second study by Ciuleanu et al, randomised 663 patients who had not progressed after four cycles of first-line platinum-based chemotherapy to pemetrexed or placebo.[5] 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.[5] 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).[5] 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).[5] Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (mainly fatigue and neutropaenia).[5]

The final study, by Capuzzo et al, randomised 884 patients who had not progressed after four cycles of first-line platinum-based chemotherapy were randomised to erlotinib 150 mg daily or placebo. The co-primary endpoints were PFS in all patients irrespective of EGFR status, and PFS in patients whose tumours had EGFR protein over-expression, as determined by IHC.[6] Median PFS was signifi cantly longer with erlotinib than with placebo: 12.3 weeks (erlotinib) versus 11.1 weeks (placebo) group (HR 0.71, 95% CI 0.62–0.82; p<0.0001). PFS was also significantly longer in patients who were EGFR IHC positive and treated with erlotinib (n=307) compared with EGFR-positive patients given placebo (n=311; median PFS 12.3 weeks (erlotinib) versus 11.1 weeks (placebo); HR 0.69, 0.58–0.82; p<0.0001).[6] A pre-planned analysis of PFS in patients with EGFR-activating mutations confirmed a substantial benefit (HR 0.10, 95% CI 0.04 – 0.25; p<0.0001; ) but also benefit, albeit more modest, in patients with wild-type EGFR (HR 0・78, 95% CI 0.63–0.96; p=0.0185).[6] Overall survival was significantly prolonged with erlotinib versus placebo in the intention-to-treat population (median 12.0 versus 11.0 months; HR 0.81, 95% CI 0.70–0.95; p=0.0088).[6] The commonest grade 3 or higher toxicities associated with erlotinib were rash (9%) and diarrhea (2%).[6]

Taken collectively and allowing for differences in study design, all three studies indicated benefit in unselected patients from this “switch maintenance” approach of immediate alternative treatment with single agent docetaxel, pemetrexed or erlotinib, by significantly delaying progression free survival (PFS), and in the cases of erlotinib and pemetrexed in non-SCC histology, also improving OS. In each study, the treatment switch was evaluated only in patients with stable disease or response after four cycles of standard first-line chemotherapy. In the case of pemetrexed, the benefit appears to be in the non-SCC histology sub-group. In the case of patients with known EGFR-gene activating mutations, switch maintenance erlotinib provides substantial benefit.

Evidence summary and recommendations

Evidence summary Level References
In patients with stable or responsive advanced NSCLC after initial platinum doublet chemotherapy, the principle of switch maintenance therapy to either chemotherapy or anti-EGFR TKI improves overall survival.

Last reviewed December 2015

I [1]
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 December 2015

I [1]
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 December 2015

II [4]
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 December 2015

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 December 2015

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 erlotinib or docetaxel, whilst in patients with non-squamous cell carcinoma histology, pemetrexed or erlotinib.

Options most proven for prolongation of survival include erlotinib or pemetrexed. In the case of patients with known EGFR-gene activating mutations treated initially with chemotherapy, switch maintenance erlotinib is recommended.
Last reviewed December 2015

A


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References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 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.
  2. Paz-Ares LG, Gomez-Roca C, Delord JP, Cervantes A, Markman B, Corral J, et al. Phase I pharmacokinetic and pharmacodynamic dose-escalation study of RG7160 (GA201), the first glycoengineered monoclonal antibody against the epidermal growth factor receptor, in patients with advanced solid tumors. J Clin Oncol 2011 Oct 1;29(28):3783-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21900113.
  3. Johnson EA, Marks RS, Mandrekar SJ, Hillman SL, Hauge MD, Bauman MD, et al. Phase III randomized, double-blind study of maintenance CAI or placebo in patients with advanced non-small cell lung cancer (NSCLC) after completion of initial therapy (NCCTG 97-24-51). Lung Cancer 2008 May;60(2):200-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18045731.
  4. 4.0 4.1 4.2 4.3 4.4 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.
  5. 5.0 5.1 5.2 5.3 5.4 5.5 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.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 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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