What is Currently the Best for Adenocarcinoma without Driver Mutation?

Since the discovery of driver mutations or actionable alterations in several genes such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), the management paradigms of non-small cell lung cancer (NSCLC) have changed dramatically1. However, in global guidelines2, platinum-based chemotherapy remains a standard of care for patients who do not harbor driver mutations. Among several regimens of platinum doublet chemotherapy, the pemetrexed/cisplatin combination confers better overall survival compared to gemcitabine/cisplatin in patients with adenocarcinoma histology3. In the PARAMOUNT study, continuation maintenance therapy with pemetrexed is an effective and well-tolerated treatment for patients with advanced non-squamous NSCLC with good performance status who have not progressed after 4 cycles of pemetrexed/cisplatin45. Moreover, pemetrexed became one of the most frequently administered cytotoxic chemotherapeutic agents for treating stage IV non-squamous NSCLC6.

In the article of the last issue of Tuberculosis and Respiratory Diseases (TRD), Paik et al.7 addressed that pemetrexed continuation maintenance treatment is associated with better clinical outcomes in patients with wild-type lung adenocarcinoma, compared to those associated with conventional platinum-based chemotherapy. A total of 114 patients with EGFR-negative adenocarcinoma who were treated with platinum doublet chemotherapy were retrospectively enrolled. They compared the survival rates between patients who received pemetrexed maintenance after induction chemotherapy and those who received at least 4 cycles of platinum doublet chemotherapy without maintenance strategy as a first-line treatment. The median progression-free survival (PFS) was significantly higher in the pemetrexed maintenance group than in the conventional group (5.8 months vs. 2.2 months, respectively; p<0.001). Multivariate analyses showed that pemetrexed maintenance chemotherapy was associated with better PFS (hazard ratio, 0.73; 95% confidence interval, 0.15–0.87).

Despite having some limitations, this study had a similar purpose and results as those of the PARAMOUNT trial, in that the study was conducted to demonstrate the benefit of the pemetrexed maintenance strategy. However, this study did not demonstrate overall survival benefits in the pemetrexed maintenance group (22.3 months vs. 16.1 months, p=0.098). This finding seemed to be the result of a retrospective, small sample-sized design. In particular, patients in the conventional chemotherapy group received 4–6 cycles of platinum doublet chemotherapy. If the number of cycles had been operatively restricted to 4, like in well-designed prospective clinical trials, differences in overall survival could have been identified. However, the strength of this study was the reflection of current real-world clinical practice in Korea.

Paik et al8. conducted their retrospective study because the previously published phase III clinical trials that proved the clinical benefits of the pemetrexed maintenance strategy enrolled patients regardless of the presence of driving mutations. Moreover, the efficacy of pemetrexed-containing chemotherapy according to EGFR mutation status is also controversial8. However, recent guidelines have already included pemetrexed continuation after induction chemotherapy for non-squamous type NSCLC treatment following from the results of large-scaled prospective trials126. Therefore, a different approach seems necessary for personalized therapy.

Several molecular biomarkers have been investigated for the predictive marker for pemetrexed, but none have been approved26. Most retrospective data have suggested that low levels of thymidylate synthase expression may be responsible for better sensitivity to pemetrexed, but there have also been reports with inconsistent results6. In addition, ALK rearrangements are being investigated as a potential predictive biomarker of pemetrexed efficacy891011. Xu et al.9 demonstrated that ALK rearrangements were indeed shown to be associated with low thymidylate synthase messenger RNA expression, and Shaw et al.10 showed that PFS was not statistically different between patients who were ALK-positive and ALK-negative.

Paik et al.7, in the last issue of TRD, showed the PFS benefits of pemetrexed continuation maintenance chemotherapy over those of conventional 4- or 6-cycle chemotherapy in patients with EGFR wild-type lung adenocarcinoma. This result confirmed that of previously published pivotal studies, which included non-selective patients, and we must now focus our efforts to identify predictive biomarkers of pemetrexed efficacy.