This is the first study indicating that a blood-based protein signature (VS) could be considered as a novel and valid method to predict efficacy of pemetrexed/platinum or combined with bevacizumab in the first-line treatment for Chinese advanced lung adenocarcinoma patients.
The concept of combination therapy refers to that using the best combination of existing treatment methods according to the specific conditions of patients, such as body condition, pathological type, invasion range (pathological stage) and development trend, to greatly improve the cure rate, prolong the survival period and improve the quality of life of patients. Surgery, radiotherapy, and systemic therapy are the 3 modalities of combination therapy for cancer patients. Systemic therapy, including chemotherapy, targeted therapy and immunotherapy, is suitable for the treatment of advanced NSCLC patients. Recently, although a significant progress has been made in immunotherapy and targeted therapy, chemotherapy remains the cornerstone for advanced NSCLC patients[13-20]. Pemetrexed is a third generation cytotoxic agent. It can inhibit cell replication and tumor growth by disrupting folate-dependent normal cellular metabolism. Several clinical trials demonstrated that first-line pemetrexed based therapy was associated with significant better survival outcome than other chemotherapy regimens for advanced lung adenocarcinoma patients. Besides, the combination of bevacizumab could further improve survival for these patients. Therefore, pemetrexed/platinum combined with bevacizumab has been the standard first-line chemotherapy regimen for advanced non-squamous NSCLC patients. But some patients still showed poor response to pemetrexed based regimen[21, 22]. Currently, for lacking of clinical evidence, no specific biomarkers have been applied in clinical practice Therefore it is urgently needed to find promising biomarkers to predict efficacy of cytotoxic agents.
In 2007, David Carbone etc initially established a VeriStrat method that can be used to predict the first-line efficacy of EGFR tyrosine kinase inhibitor (TKI) for advanced NSCLC patients who did not receive EGFR mutation test before treatment. In this study, the median survival was 306 days in VS-G group of 69 patients, far more than 107 days in VS-P group of 27 patients[4]. A series of follow up studies demonstrated that VS is predictor of therapeutic benefit from EGFR TKI therapy[23]. In PROSE study, VS method was utilized to predict second-line single-drug chemotherapy for advanced lung cancer (pemetrexet/docetaxel). The results show that among the 129 patients receiving single-drug chemotherapy, OS and PFS were significantly lower in VS-P group than in VS-G group [24]. Another study examined the performance of VeriStrat in three independent clinical trials from 481 patients treated with platinum-based chemotherapy in first line. Patients classified as VS-G had significantly longer PFS and OS than VS-P patients. These results demonstrated that VS is a strong predictive test in NSCLC patients treated with platinum-based regimens in the first line[10]. However, so far there has been no study using this VS method for the prediction of first-line pemetrexed plus platinum-based chemotherapy or combined with bevacizumab for Chinese advanced lung adenocarcinoma patients.
To address these issues, we conducted a retrospective analysis of plasma samples from lung adenocarcinoma patients with stage IIIB or IV, who recieved first-line pemetrexed based chemotherapy. Our study showed that median PFS was unreached in VS good group, significantly superior than that in VS poor group, the PFS of which was 4.2 months. For 35 patients received chemotherapy, an improved PFS was still observed for patients in VS-G vs. VS-P group (median PFS: Unreached vs. 4.0 months) A recent study included 76 non-squamous patients treated with a combination of carboplatin or cisplatin with pemetrexed. Patients classified as VS-G had longer PFS and OS than VS-P: 6.5 vs 1.6 months and 10.8 vs 3.4 months, respectively.[11] The PFS in our study was longer than previously reported data likely because pemetrexed maintainence therapy was administered in our study. PARAMOUNT study demonstrated that continuation maintenance therapy with pemetrexed was an effective and well tolerated treatment option for patients with advanced non-squamous NSCLC with good performance status who did not progress after induction therapy with pemetrexed plus cisplatin[25]. In PARAMOUNT study, the median PFS was 4.1 months for pemetrexed and 2.8 months for placebo[26]. The result in our study was consistent with that in PARAMOUNT study.
In POINTBREAK study, PFS was significantly improved with pemetrexed/carboplatin plus bevacizumab and pemetrexed/bevacizumab maintenance therapy (median PFS, 6.0 v 5.6 months; P = 0.012)[27]. In AVAPEAL study, bevacizumab plus pemetrexed maintenance was also associated with a significant PFS benefit compared with bevacizumab alone (median, 3.7 v 7.4 months; P < 0.001)[28]. Updated survival analysis of the AVAPERL study showed maintenance with bevacizumab-pemetrexed was associated with a nonsignificant increase in OS over bevacizumab alone[29]. A recent study (WJOG 5610L) reported in 2019 American Society of Clinical Oncology annual meeting demonstrated that bevacizumab and pemetrexed maintenance therapy could not prolong OS compared with bevacizumab maintencance therapy alone (median, 23.3 vs 19.6 months; P=0.069). In our study, for 37 patients treated with chemotherapy and bevacizumab, PFS was also significantly longer in the VS-G compared with VS-P group (median PFS: Unreached vs. 4.8 months). Our study indicated that VS is also predictive for chemotherapy and bevacizumab combined therapy. Although this study clearly identified patients who might have worse outcome on pemetrexed based therapy. These data are not compelling enough to deny pemetrexed therapy to VS-P patients. But perhaps in these VS-P patients, alternative treatment approaches could be considered.
Several limitations of our study are worthy of note. First, 72 were eligible for inclusion and analysis,and only a small subset of participants (12/72, 16.7%) tested as VS-P. This limited the power of the analysis we performed. Further, OS data was not available. Because OS is typically not calculated until more than 50% of patients experienced events, and median OS was not reached in either group. But our study still indicates that VS could be considered as a novel and valid method to predict efficacy of pemetrexed based therapy and identify a subset of advanced lung adenocarcinoma patients who have intrinsic resistance to pemetrexed based regimen.