The anti-angiogenic agent nintedanib has been shown to prolong overall and progression-free survival in patients with advanced non-small-cell lung cancer (NSCLC) who progress after first-line ...platinum-based chemotherapy and second-line immunotherapy. Here, we explored the molecular basis and the clinical benefit of incorporating the STAT3 inhibitor silibinin-a flavonolignan extracted from milk thistle-into nintedanib-based schedules in advanced NSCLC. First, we assessed the nature of the tumoricidal interaction between nintedanib and silibinin and the underlying relevance of STAT3 activation in a panel of human NSCLC cell lines. NSCLC cells with poorer cytotoxic responses to nintedanib exhibited a persistent, nintedanib-unresponsive activated STAT3 state, and deactivation by co-treatment with silibinin promoted synergistic cytotoxicity. Second, we tested whether silibinin could impact the lysosomal sequestration of nintedanib, a lung cancer cell-intrinsic mechanism of nintedanib resistance. Silibinin partially, but significantly, reduced the massive lysosomal entrapment of nintedanib occurring in nintedanib-refractory NSCLC cells, augmenting the ability of nintedanib to reach its intracellular targets. Third, we conducted a retrospective, observational multicenter study to determine the efficacy of incorporating an oral nutraceutical product containing silibinin in patients with NSCLC receiving a nintedanib/docetaxel combination in second- and further-line settings (
= 59). Overall response rate, defined as the combined rates of complete and partial responses, was significantly higher in the study cohort receiving silibinin supplementation (55%) than in the control cohort (22%,
= 0.011). Silibinin therapy was associated with a significantly longer time to treatment failure in multivariate analysis (hazard ratio 0.43,
= 0.013), despite the lack of overall survival benefit (hazard ratio 0.63,
= 0.190). Molecular mechanisms dictating the cancer cell-intrinsic responsiveness to nintedanib, such as STAT3 activation and lysosomal trapping, are amenable to pharmacological intervention with silibinin. A prospective, powered clinical trial is warranted to confirm the clinical relevance of these findings in patients with advanced NSCLC.
•New drug schemes are needed for unresectable stage III NSCLC.•Metronomic chemotherapy based on oral vinorelbine and cisplatin exhibits low toxicity.•ctDNA analysis can identify the subgroup of ...patients who might benefit from this treatment.
Little progress has been achieved in non-small cell lung cancer (NSCLC) patients with unresectable stage III disease and new drug schemes are warranted.
In this open-label, single-arm, phase II trial 65 treatment-naïve stage III NSCLC deemed surgically unresectable by a multidisciplinary team were treated with 2 cycles of induction cisplatin at 80 mg/m2 every 21 days plus metronomic oral vinorelbine at 50 mg/day every Monday, Wednesday and Friday. During the concomitant treatment with thoracic radiotherapy cisplatin was administered in the same manner but oral vinorelbine was reduced to 30 mg/day. The objective was to administer a total radiotherapy dose of 66 Gy in 33 daily fractions of 2 Gy. The primary endpoint was progression-free survival (PFS). Correlation between circulating tumor DNA (ctDNA) levels and survival was also evaluated.
Fifty-five (78.5 %) patients completed treatment. Overall response rate, by RECIST criteria, was 66.2 %. Four (6.2 %) patients had complete response, 39 (60.0 %) partial response and 12 (18.5 %) stable disease. Seven patients (10.8 %) had progressive disease during the induction period. Median follow-up was 29.1 months (m), median PFS was 11.5 m (95 %CI: 9.6–15.4). PFS at 12 m in the intention-to-treat (ITT) population was 47.8 % (95 %CI: 35.1–59.4 %) and median OS was 35.6 m (95 %CI: 24.4–46.8). Grade ≥3 treatment-related adverse events occurred in 14 (21.5 %) patients during induction and in 13 (24.5 %) patients during concomitant treatment with esophagitis occurring in 3% and pneumonitis in 1.5 % of the patients. Patients with undetectable ctDNA after 3 m follow-up had median PFS and OS of 18.1 m (95 %CI: 8.8-NR) and not reached (NR) (95 %CI: 11.3-NR), respectively, compared with 8.0 m (95 %CI: 2.7-NR) and 24.7 m (95 %CI: 5.7-NR) for patients who remained ctDNA positive at that time point.
Metronomic oral vinorelbine and cisplatin obtains similar efficacy results with significantly lower toxicity than the same chemotherapy at standard doses. ctDNA can identify populations with particularly good prognosis.
Summary
Introduction
TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has ...been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients.
Methods
Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m
2
) or S-1 (30 mg/m
2
). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety.
Results
In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio HR 1.16, 95% confidence interval CI 0.71–1.88;
P
= 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80–2.14;
P
= 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group.
Conclusions
Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS.
Clinical Trial Registration No.
NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.
Objectives
The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in ...advanced non‐small cell lung cancer (NSCLC) patients treated with first‐ or second‐generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival.
Methods
Stage IV NSCLC patients with locally confirmed EGFR‐TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to receive first‐ or second‐generation EGFR‐TKI as first‐line therapy were included. Plasma samples were obtained at baseline and every 4 weeks during treatment until a progression‐free survival (PFS) event or until study completion (72‐week follow‐up). The mutant allele fraction (MAF) was determined for each identified mutation using BEAMing.
Results
A total of 68 of the 110 (61.8%) patients experienced a PFS event. Twenty‐six patients (23.6%) presented with an emergent p.T790M mutation in plasma at some point during follow‐up, preceding radiologic progression with a median of 76 (interquartile ratio: 54–111) days. Disease progression correlated with the appearance of p.T790M in plasma with a hazard ratio (HR) of 1.94 (95% confidence interval CI, 1.48–2.54; p < 0.001). The HR for progression in patients showing increasing plasma sensitizing mutation levels (positive MAF slope) versus patients showing either decreasing or unchanged plasma mutation levels (negative or null MAF slopes) was 3.85 (95% CI, 2.01–7.36; p < 0.001).
Conclusion
Detection and quantification of EGFR mutations in circulating tumor DNA using the highly sensitive BEAMing method should greatly assist in optimizing treatment decisions for advanced NSCLC patients.
The manuscript is a multicenter, prospective study conducted in the real‐world setting. The study reveals that the detection and quantification (MAF slope) of EGFR mutations in ctDNA using the highly sensitive BEAMing method may assist in optimizing treatment decisions for advanced NSCLC patients.
Our understanding of the spatial and temporal dynamics of soil CO2 pulses after rainfall events is still limited and thus, our capacity to predict the consequences of future changes in precipitation ...patterns for dryland soils. In this study we examined the response of soil CO2 pulses to rainfall size and pre-rain soil moisture conditions in a semiarid grassland. In a first experiment, we manipulated the amount of rainfall in a factorial combination that included three levels of rainfall size (1, 5 and 15mm), three soil covers: vegetated areas (VEG), biological soil crusts (BSC) and bare soil (BS) and two nearby sites: a natural grassland and a degraded grassland. We measured soil CO2 efflux over 24h to capture rainfall pulses. In a second experiment conducted at the natural grassland, we measured soil CO2 efflux after manipulating soil moisture to its full range in the area by wetting the soil to: 0–10%, 10–15%, 20–25%, 30–35% water content levels. All soil covers responded to the rainfall treatments within minutes, reaching up to 120 times baseline values and shortly returning to background rates. Rainfall size had a larger impact on the response than pre-rain soil moisture conditions. Whereas in most cases rainfall amount increased soil CO2 pulses, initial moisture conditions did not affect total carbon losses despite much larger CO2 peaks in very dry soils. Interestingly, even extremely low rainfall events (1mm) caused significant carbon losses. The amount of carbon lost after rainfall events ranged from 0.45 in bare soils to 1.18gCm−2day−1 in vegetated areas. Overall, rainfall had a larger impact in vegetated areas at the degraded site implying that larger carbon losses can be expected as a result of land degradation. Sudden changes in soil moisture caused by rainfall predicted 65% of total carbon losses in BS, 70% in BSC and 80% in VEG at both sites. However, the slope was significantly lower in bare soils suggesting substrate limitation. Since most of the carbon resides belowground in these grasslands, carbon losses as a result of larger rainfall events and longer dry periods in this area could have important consequences for soil carbon stocks.
•Soil CO2 pulses can be predicted from changes in soil moisture upon rewetting.•Rainfall size had a larger impact on CO2 pulses than pre-rain moisture conditions.•Difference between soil covers could be explained by differences in soil carbon.•Land degradation will lead to depletion of belowground carbon stocks.•Rainfall events of just 1mm cause significant soil C losses.
Background
Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (
EGFR
) mutant non-small cell lung cancer (NSCLC). We evaluated the ...outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring
EGFR
mutations.
Methods
We retrospectively analyzed 19 patients with advanced
EGFR
-mutant NSCLC who had progressed to
EGFR
tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan–Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS).
Results
Median age was 58.9 years (range 42.8–81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0–1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common
EGFR
mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the
EGFR
T790M
. 94.8% of the patients had received 2–3 previous treatment lines.
Docetaxel was administered at 75 mg/m
2
/3 weeks to 16 patients, at 60 mg/m
2
to 2 patients and at 45 mg/m
2
to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h.
With a median follow-up of 11.4 months (1–38), the median PFS was 6.1 months 95% confidence interval (CI), 4.9–7.3 and the median OS 10.1 months (95% CI 5.9–14.3). The objective response rate (ORR) was 44.4% (23.7–66.8%) and the disease control rate (DCR) 72.2% (49.4–88.5%). Efficacy tended to be greater in patients with the acquired
T790M
who had received osimertinib, with a median PFS of 6.3 (95% CI 2.1–10.5)
versus
(
vs
.) 4.8 (95% CI 3.5–6.1) and a median OS of 12.3 months (95% CI 8.6–16.0)
vs.
6.7 months (95% CI 3.9–9.4), although this tendency was not statistically significant (
p
= 0.468 and
p
= 0.159, respectively).
Sixteen patients (84.2%) had a total of 34 adverse events (AEs), with a median of two (0–6) AEs per patient. The most frequent AEs were asthenia (20.6%) and diarrhea (20.6%). One treatment-related death due to portal thrombosis was reported.
Conclusions
Our data indicate that the combination of docetaxel and nintedanib can be considered to be an effective treatment for
EGFR
TKI-resistant
EGFR
-mutant NSCLC.
Germline mutations in TP53, a tumor suppressor gene, are involved in the development of Li-Fraumeni syndrome, a rare disorder that predisposes carriers to multiple tumors. TP53 mutations have been ...associated with resistance to treatment and poor prognosis. A young female with the pathogenic germline TP53 mutation c.844C > T (p.R282W) was diagnosed with two metachronous breast tumors, one HER2-negative and the other HER2-positive. She was later diagnosed with synchronous glioblastoma, epidermal growth factor receptor-mutated lung adenocarcinoma, and HER2-negative breast cancer metastases. The patient was treated with local therapies, including brain surgery and radiotherapy, lung surgery, and a bilateral mastectomy, as well as with targeted systemic treatment. She proved to be highly sensitive to systemic therapy, and 13 years after the initial diagnosis of breast cancer and 6 years after the diagnosis of the two new primary tumors and recurrence of a prior cancer, she is alive with an excellent performance status. This surprising positive evolution may well be partly due to the pronged multidisciplinary approach to managing her disease and her extraordinary response to treatment: the lung adenocarcinoma showed excellent response to erlotinib; the breast cancer responded extremely well to eribulin and pegylated liposomal doxorubicin; and the glioblastoma has remained in response to surgery and radiotherapy. Despite harboring a TP53 mutation and having multiple tumors, this patient has shown an unexpectedly favorable evolution. The coordinated participation of a multidisciplinary team and the patient's own extraordinarily high sensitivity to systemic treatment played a major role in this evolution.
•Globally adverse events grade 3/4 per cycle were fewer in the vinorelbine and cisplatin arm than in the etoposide and cisplatin arm.•Median progression free survival was similar in both ...arms.•Preliminary median overall survival was 30 months in the vinorelbine and cisplatin arm and 31.9 months in the etoposide and cisplatin arm.
Concomitant chemo-radiation is the standard treatment for unresectable stage III non-small cell lung cancer (LA-NSCLC). The aim of this study was to assess the safety and efficacy of oral vinorelbine and cisplatin (OVP) compared with etoposide and cisplatin (EP), both in combination with radiotherapy, in this setting.
An open-label, randomized phase II trial was undertaken including 23 hospitals in Spain. Adults with untreated unresectable stage III NSCLC were randomized1:1 to receive: oral vinorelbine (days 1 and 8 with cisplatin on day 1 in 3-week cycles; 2 cycles of induction, 2 cycles in concomitance) or etoposide (days 1–5 and 29–32 with cisplatin on days 1 and 8 in 4-week cycles; 2 cycles in concomitance). Both groups received concomitant radiotherapy 2 Gy/day (66 Gy). The primary endpoint was progression free survival (PFS).
One hundred and forty patients were enrolled. Sixty-nine patients received OVP and 71 received EP. Globally adverse events grade 3/4 per cycle were fewer in the vinorelbine arm (19.4%) than in the etoposide arm (62.6%) (p < 0.001). One patient (1.5%) in the OVP arm and 12 pts (17.6%) in the EP arm presented esophagitis grade 3/4 (p = 0.002). Median PFS was similar in both groups (10.8 95% CI 7.7–13.8 and 9.6 months 95% CI 4.4–14.8; p = 0.457, respectively). Preliminary median overall survival was 30 months in the OVP arm and 31.9 months in the EP arm (p = 0.688).
Our findings show that OVP could be considered a standard combination with similar efficacy and better safety profile for the treatment of LA-NSCLC patients.
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