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  • Even though docetaxel is considered the reference

    2019-08-26

    Even though docetaxel is considered the reference second-line chemotherapy for advanced NSCLC, in the real-life, its toxicity can't be ignored. With the intent of reducing docetaxel toxicity, in the past decades alternative regimens, consisting of lower doses or different administration schedules, have been explored [[16], [17], [18]]. Weekly docetaxel repeatedly demonstrated a better safety profile than the standard three-weekly schedule, with a lower incidence of neutropenia in pre-treated patients [19].
    Materials and methods
    Discussion The SENECA trial was a real-world experience during which investigators had the possibility to optimize the use of nintedanib, after clear efficacy and safety demonstration as second line treatment option in association with docetaxel q3wks for recurrent non-squamous NSCLC in the LUME-Lung1 trial [14]. During the accrual period, no alternative therapeutic option was available to the use of the sole docetaxel for patients with adenocarcinoma already treated with platinum/pemetrexed chemotherapy in the front-line setting. The reports of the extraordinary efficacy of the immune checkpoint inhibitors for recurrent NSCLC were starting to emerge in 2015 from the results of randomized phase III trials comparing these drugs to docetaxel [[6], [7], [8]], but in Italy the first approval and reimbursement for immune checkpoint inhibitors in this Suramin hexasodium salt setting was on April 2017, when 69.8% (148 patients out 212) was already enrolled in SENECA. In this historical context, the present study represented for Italian investigators an intriguing challenge in order to overcome their distrust toward docetaxel, its huge and well known toxicity (especially for the q3wks schedule), and to give patients the possibility to improve survival adding to chemotherapy an anti-angiogenic compound. At the present time, these data seem outclassed from the availability in the clinical practice of many immune checkpoint inhibitors as standard treatment option for recurrent non-squamous NSCLC, but these are not discounted, as the efficacy of the weekly docetaxel schedule plus nintedanib had never been investigated before, and can be now considered as a valid alternative to the other regimens, giving to clinicians a new therapeutic opportunity after the publication of the LUME-Lung1 data. This would be even more interesting for those patients receiving immunotherapy combined with chemotherapy in the first-line setting or subsequently after failure of docetaxel/nintedanib. Angiogenesis and immunosuppression have been recently described as closely related processes, physiologically involved in non-pathological tissue repair. They can also be exploited in cancer, facilitating tumor development and progression [26]. Some angiogenic factors, such as VEGF, may have an immunosuppressive function, and anti-angiogenic drugs targeting VEGF can stimulate an immune response [27]. These preclinical data, even if still partially unclear, are really interesting and give clinicians the possibility to build a new hypothetical therapeutic algorithm which includes both anti angiogenic drugs and immunotherapy, variously combined. Because of the lack of data about optimal therapeutic algorithms for nsNSCLC patients and the evidence of a strong biologic rationale for using antiangiogenic drugs and immunotherapy variously combined, it could be of great interest in the next future to investigate if survival expectancy of SENECA patients could be positively influenced by previous immunotherapy, as well as evaluating the post-progression survival, exploring if third-line immunotherapy may be influenced from prior nintedanib use. In this trial, patients that the investigators thought with the poorest prognosis did not experience the survival advantage expected. Data previously published had described a significantly prolonged survival for patients with recurrent adenocarcinoma who had progressed within 9 months from the start of first-line therapy, treated with nintedanib and docetaxel q3wks, compared to patients of the placebo containing arm, in contrast to what observed for late onset progressors (median OS 9.8 vs 6.3 months; HR 0.62 [95% CI 0.41–0.94], p = 0.0246 for early progressors) [14]. This left us to suppose a similar trend also in the present study, while, on the contrary, an opposite situation has been described, possibly due to independent prognostic factors for patients classified in C2 or R2 cohorts, or more likely due to the non-randomized study design.