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 trials^1,2,6. 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 approved^2,6. 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 efficacy^8,9,10,11. 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.