IASLC 2011 Report – Maintenance therapy in the management of non-small cell lung cancer

by Dr Sunil Upadhyay – A platinum doublet remains the current gold standard in the management of EGFR mutation negative, advanced non-small cell lung cancers. Pemetrexed is the favourite agent for non-squamous histology whilst gemcitabine, vinorelbine or paclitaxel are commonly added to a platinum compound for treatment of patients with squamous cell histology.

Most of the trial data has supported the use of 4-6 cycles of the platinum doublets. Unfortunately, despite good initial response, almost all patients relapse sooner or later. Early second-line therapy is definitely better than delayed or no treatment¹ However, it is estimated that 30-40% of the advanced non-small cell lung cancer patients never get second-line systemic treatment. This may be because many clinicians are not very good at identifying the most suitable time to commence the second-line systemic therapy, concerns about quality of life or patient’s choice. It is accepted that early second-line treatment is not without toxicity but careful drug selection and optimum supportive care can overcome most of the disadvantages associated with this approach. Encouraged by the improvement in the outcome, maintenance therapy using single agents has been investigated in various settings to prolong the tumour response or stabilise disease with a goal of improving PFS and OS. The intriguing question is which type of maintenance to use – continue with an existing agent, switch to a different cytotoxic agent or switch to a TKI?

 

Extended chemotherapy approaches (modified ESMO2011)

 

Initially at ASCO 2011 and subsequently at WCLC 2011 in Amsterdam, the results of a phase III study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced non-squamous, non-small cell carcinoma was presented (PARAMOUNT TRIAL).² The data presented showed significant improvement in PFS in patients treated with pemetrexed continuation maintenance therapy compared to the placebo group (HR = 0.62).

The highly significant PFS supported the view that pemetrexed was well tolerated and continuation maintenance is an effective treatment for patients with advanced non-squamous cell lung cancer following pemetrexed plus cisplatin induction therapy.

The use of pemetrexed was well established as first-line treatment in the management of non-squamous, advanced lung cancer patients mainly following the publication of the so called Scagliotti trial.³ Similarly, switch maintenance has been found to improve PFS and OS in several trials using various agents.⁴ The PARAMOUNT data provides evidence in favour of continuation maintenance with pemetrexed. However, 30% of the randomised patients did not get any benefit from maintenance pemetrexed though few patients got a relatively large benefit with almost doubling of the PFS rate at 6 months. The EGFR mutation status was unknown and EGFR mutation positive patients should be preferably treated with a TKI agent.  The forest plot from this trial favoured maintenance for patients with PS 0, never smokers, females and advanced age. It is important to note that continuation maintenance is beneficial only in patients who show initial sensitivity to the agent, objective benefit, acceptable side effects and the quality of life has to be maintained.

The results of the TS study looking at thymidylate synthase up-regulation should throw further light on the role of this enzyme in the maintenance setting. Similarly, the presence or absence of TTF-1 may also have some role to play. Clearly, these data provide further evidence to support the benefits of maintenance therapy leading to increased PFS and OS. Unfortunately, we do not have direct comparisons of different maintenance approaches and agents. We do not know how to select patients who are most likely to benefit with a minimum price to pay. It remains unclear whether maintenance is really better than appropriate and timely second-line treatment at the time of progression. Finally, the overall survival benefits remain unknown, hence, based on the currently available evidence, maintenance therapy has to be offered only within a trial setting.

 

References:

1. Fidias PM, Dakhill SR, Lyss AP, Loesch DM, Waterhouse DM et al. JCO 2009; 27: 591-598
2. Paz-Ares LG et al. ASCO 2011; Abstract CRA7510
3. Scagliotti GV, Prikh P, von Pawel J, Biesman B, Vansteenkiste J et al. JCO 2008; 26: 3542-3551
4. Cappuzzo F, Ciuleanu T, Stelmakh L, Cienas S, Szczésna A et al. Lancet Oncology 2010; 11: 521-529