Impact of prior ALK-tyrosine kinase inhibitor on pemetrexed-based chemotherapy in patients with advanced ALK positive non-small cell lung cancer.
Authors: Yabe Michitoshi , Kenmotsu Hirotsugu , Kodama Hiroaki , Nishioka Naoya , Miyawaki Eriko , Miyawaki Taichi , Mamesaya Nobuaki , Kobayashi Haruki , Omori Shota , Wakuda Kazushige , Ono Akira , Naito Tateaki , Murakami Haruyasu , Takahashi Toshiaki 
Published: June 2021

e21113 Background: In phase Ⅲ trial comparing crizotinib with chemotherapy in patients with ALK-positive non-small-cell lung cancer (NSCLC) patients, it suggests that pemetrexed is highly effective against ALK-positive NSCLC. However, it is unclear that pemetrexed-based chemotherapy is effective in patients previously treated with ALK-tyrosine kinase inhibitor (ALK-TKI) as well as ALK-TKI naïve patients. Therefore, we investigated the impact of prior ALK-TKI therapy on pemetrexed-based chemotherapy. Methods: We retrospectively reviewed 28 ALK positive NSCLC patients who had received pemetrexed-based chemotherapy at Shizuoka Cancer Center, Japan, from January 2011 to October 2020. The efficacies of pemetrexed-based chemotherapy after or before ALK-TKI was evaluated. Results: Eight patients (29 %) were treated with pemetrexed-based chemotherapy before ALK-TKI (ALK-TKI treated group), and 20 (71%) with this regimen after the failure of ALK-TKI (ALK-TKI naïve group). Patients characteristics (ALK-TKI naïve/ALK-TKI treated) were as follows: median age (range) 66 (27-72)/57 (35-73); male 100/45%; PS0-1 100/85%; adenocarcinoma 100/90%; stageⅣ 88/90%; with CNS metastasis 12/40%. The pemetrexed-based chemotherapy was administered in 5 (18%) patients as the 1st line, 11 (39%) as 2nd line, and 12 (43%) as 3rd or latter line. Twenty-five patients received the combination of platinum with pemetrexed and 3 done pemetrexed monotherapy. Regarding previous ALK-TKI, 17 patients received only alectinib and 8 patients did both alectinib and crizotinib. Progression-free survival (PFS) in ALK-TKI treated group was shorter than in ALK-TKI naïve group (median PFS 3.8 months vs 12.4 months Hazard ratio = 0.41; 95%CI 0.16-1.01 by wald test, p = 0.047 by log-rank test). In overall survivals (OS) from first line treatment between two groups, and ALK-TKI treated group tended to be shorter than ALK-TKI naïve group (median OS 29.5 months vs. 48.8 months; Hazard ratio 0.47, 95%CI 0.13-1.7, p = 0.248). OS from pemetrexed-based chemotherapy of ALK-TKI treated group was also significantly shorter than ALK-naïve group (median OS 10.1 months vs. not reached; Hazard ratio 0.20, 95%CI 0.05-0.75, p = 0.01). Overall response rate (ORR) of pemetrexed-based chemotherapy was lower in ALK-TKI treated group than ALK-TKI naïve group (35% vs 50%) and ORR of ALK-TKI was 85% vs 63%. There was no difference in PFS of pemetrexed-based chemotherapy regardless of efficacy of prior ALK-TKI (PFS ≥24 months vs < 24 months; median PFS 4.5 months vs 7.2 months, Hazard ratio 0.99, 95%CI 0.42-2.31, p = 0.99). Conclusions: Pemetrexed-based chemotherapy might be less effective in ALK-positive NSCLC patients previously treated with ALK-TKI. This retrospective study results suggested that ALK-TKI sequence can be a better treatment option in ALK-positive NSCLC patients.