•Widespread use of targeted-therapies to RET fusion + NSCLCs has not been successful.•Studies of multi-kinase inhibitors showed modest benefits and poor tolerability.•Homology between ALK and RET ...provides rationale to evaluate alectinib efficacy.•We present clinical benefit in 2/4 patients with RET fusion + NSCLCs under alectinib.•There might be benefit treating this subset of NSCLCs with alectinib.
to report outcomes of four cases of chemo-refractory RET-rearranged non-small cell lung carcinomas (NSCLCs) treated with alectinib in a single center.
we retrospectively assessed and reported the activity and tolerability of alectinib 600 mg twice daily in advanced and chemo-refractory RET-rearranged NSCLC patients treated in a Brazilian institution. Identification of RET rearrangements was performed using the FoundationOne® next-generation sequencing (NGS) platform.
The four patients herein reported were white, female and non-smokers, ranging between 59–66 years of age. All patients had been previously treated with chemotherapy and were TKI naïve; three of them presented disease progression to nivolumab as well. Molecular tumor profiling showed a KIF5B-RET fusion in three patients and a CCDC6-RET in the fourth. One patient exhibited disease progression and clinical deterioration two months after treatment initiation. Disease control was documented in two patients with PFS ranging from 4 to 5 months (one partial metabolic response and one stable disease). In one of the cases, which developed oligoprogression on alectinib, radiation therapy plus post-progression alectinib were able to provide additional disease control for 9 more months. No grade 3/4 adverse events, dose reductions or discontinuation due to toxicity were documented.
Although this is a small single center evaluation, alectinib was well tolerated and demonstrated clinical activity against advanced RET-rearranged NSCLCs, suggesting its potential role in this specific subset of malignancies. Clinical trials addressing its efficacy and the optimal dosing schedule in the present context are underway, and results are eagerly awaited.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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10044
Background: Cutaneous squamous cell carcinoma (cSCC) is among the most frequent malignancies worldwide, and an increasing incidence has been documented over the past decades. For ...those not amenable to treatment with curative intent, immune checkpoint blockade (ICP) with anti-PD-1 monoclonal antibodies emerged as a novel therapeutic option, supported by evidences of high mutational burden and expression of PD-L1. In this single-arm study, we sought in investigate the activity of NIVO in pts with advanced cSCC (AcSCC). Methods: We conducted a Simon two-stage, open-label, phase II study to evaluate the safety/efficacy of NIVO for up to 24 systemic-treatment-naïve pts with metastatic and/or locaally advanced cSCC. NIVO at 3mg/kg was administered intravenously every 2 weeks (w) until disease progression, unacceptable toxicity or 12 months of treatment. The primary endpoint was the best objective response rate (bORR) at 24w as per RECIST criteria. Tumor measurements were performed every 12w. Secondary endpoints included safety/tolerability, progression-free survival (PFS) and overall survival (OS). Results: Between October 2018 and October 2019, 24 pts with AcSCC were enrolled, with a median age of 74 years (range 48-93) and a male/female ratio of 1.4:1. Most frequent primary sites were head/neck (42%), trunk (29%) and extremities (25%); identified risk factors included chronic sun exposure or burn scars in 66 % and 12.5 %, respectively. Upon enrolment, the proportions of patients with locally advanced, locoregional (regional lymph node involvement) and metastatic disease were 16.6%, 66.6% and 16.6%, respectively. At data cut off (median number of doses of NIVO: 15), 15 pts (62.5%) remain on treatment and 6 pts have progressed and/or died. Three pts completed 12 months of treatment and entered surveillance. Among 22 pts evaluable for response (n = 2 have not reached 12w of treatment), the bORR was 54.5% (12/22), and disease control (stable disease or objective response) was achieved in 77% (17/22). Median duration of response, PFS and OS have not been reached. Grade ≥3 treatment-related adverse events occurred in 21% of the pts, and 1 patient discontinued NIVO due to toxicities. Conclusions: NIVO resulted in robust antitumor activity and good tolerability in systemic treatment-naïve pts with AcSCC. There were no new safety signals, despite the inclusion of individuals at advanced ages. These data provide further evidence to support the use of ICP as the standard treatment option for pts with AcSCC. Clinical trial information: NCT03834233.
Abstract
Epidermal Growth Factor Receptor (EGFR) activating mutations predict sensitivity to first- and second-generation anti-EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell ...lung cancer (NSCLC). However, NSCLC invariably develops acquired resistance (AR) to these agents, leading to disease progression. EGFR-T790M secondary mutation is the most frequent AR mechanism in this setting. Patients with EGFR-T790M positive tumors demonstrate impressive response rate to osimertinib, a third-generation EGFR-TKI, but disease progression also occurs. Intratumor heterogeneity and selection of genetic alterations that confer resistance to target therapy have been recognized as crucial in the development of AR to EGFR-TKIs. In the present study, we used liquid biopsies to monitor the appearance and dynamics of genetic alterations known to be associated with EGFR-TKIs AR in circulating tumor DNA (ctDNA) of patients with metastatic NSCLC treated with EGFR-TKIs. A total of 21 patients were recruited for this study, of whom 17 were initially treated with erlotinib, 2 with gefitinib, and 2 with afatinib. Disease progression was observed in 9 patients using erlotinib, 2 patient using gefitinib, and 1 patient using afatinib. The detection of EGFR mutations in these patients was carried out in serial liquid biopsies using droplet digital PCR (ddPCR) at a sensitivity between 0.1-0.5%. Of the 12 patients with disease progression, 7 (58.3%) were positive for the EGFR-T790M mutation in tissue biopsy and for 4 (57.1%) of these patients the EGFR-T790M was also detected by liquid biopsy at disease progression. Of the 7 EGFR-T790M positive patients, 5 received osimertinib, including 2 patients with EGFR-T790M positive liquid biopsy. Patients with EGFR-T790M positive liquid biopsies were followed closely using serial liquid biopsies to monitor the levels of the original EGFR mutation and of the EGFR-T790M resistance mutation. In general, plasma levels of the activating EGFR mutation and of the EGFR-T790M mutation accurately paralleled the clinical and radiologic evolution of the disease. Patients showing sequential increase in both EGFR mutations showed marked disease progression while those with stable levels presented indolent disease. EGFR-T790M plasma levels became undetectable within 1-2 weeks after the start of osimertinib, anticipating radiologic response to the drug. Of note, increases in T790M levels during treatment anticipated AR to osimertinib in one of our patients. This was accompanied by the emergence of a second EGFR resistance mutation (C797S) and a selective amplification of the EGFR-exon19del allele. In conclusion, liquid biopsies for EGFR genotyping can be used as a complementary strategy to tissue biopsies and should be considered the initial approach to identify both EGFR-TKI sensitizing and resistance mutations due to its minimally invasive nature. Also, plasma levels of EGFR mutations accurately paralleled the clinical and radiologic evolution of disease for these patients, allowing early detection of AR to TKIs. Finally, liquid biopsies can also be used to study novel mechanisms of AR to EGFR-TKIs.
Citation Format: Franciele Knebel, Fabiana Bettoni, Andrea Shimada, Manoel Cruz, João Victor Alessi, Marcelo Negrao, David Muniz, Luiz Fernando Reis, Artur Katz, Olavo Feher, Daniel Saragiotto, Anamaria Camargo. Monitoring acquired resistance to EGFR-TKIs and clonal evolution in metastatic NSCLC patients using liquid biopsies abstract. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B168.
Treatment of adult osteosarcoma (AOS) includes perioperative chemotherapy and surgery. Standard chemotherapy consists of cisplatin (CP) and doxorubicin (DOX). Although considered the standard of care ...for pediatric patients, high-dose methotrexate (HDM) remains controversial in adults. We aimed to evaluate the role of HDM in AOS treated with curative intent. This study included patients with AOS who received perioperative chemotherapy with DOX and CP (group 1; N=16) and DOX, CP, and HDM (group 2; N=10). The primary endpoint was grade 3 or superior toxicities. The secondary endpoints included overall survival (OS) and disease-free survival. Despite lower average age (35.0±12.1 vs. 18.9±2.1 years), group 2 presented more grade 3–4 thrombocytopenia (0 vs 50%) and mucositis (0 vs 40%), whereas group 1 presented more grade 3–4 neutropenia (43.75 vs 40%). No grade 3–4 renal toxicities occurred. Two grade 5 toxicities occurred in group 2, both after the first HDM cycle. Disease-free survival (4.38±0.61 vs. 2.3±0.54 years, P=0.228) and OS (4.70±0.56 vs 2.52±0.57 years, P=0.107) were not statistically different, but presented a trend toward better outcomes in group 1. The 4-year OS was 65.6 and 32.8% for groups 1 and 2, respectively. In conclusion, HDM was associated with greater severe and lethal toxicity when added to CP and DOX in AOS. Also, it does not seem to impact on treatment efficacy. These data do not support the use of HDM for the perioperative treatment of AOS.
Background:
The current standard treatment for glioblastoma (GBM) is maximal safe surgical resection followed by radiation and chemotherapy. Unfortunately, the disease will invariably recur even with ...the best treatment. Although the literature suggests some advantages in reoperating patients harboring GBM, controversy remains. Here, we asked whether reoperation is an efficacious treatment strategy for GBM, and under which circumstances, it confers a better prognosis.
Methods:
We retrospectively reviewed 286 consecutive cases of newly diagnosed GBM in a single university hospital from 2008 to 2015. We evaluated clinical and epidemiological parameters possibly influencing overall survival (OS) by multivariate Cox regression analysis. OS was calculated using the Kaplan–Meier method in patients submitted to one or two surgical procedures. Finally, the survival curves were fitted with the Weibull model, and survival rates at 6, 12, and 24 months were estimated.
Results:
The reoperated group survived significantly longer (
n
= 63, OS = 20.0 ± 2.3 vs. 11.4 ± 1.0 months,
P
< 0.0001). Second, the multivariate analysis revealed an association between survival and number of surgeries, initial Karnofsky Performance Status, and age (all
P
< 0.001). Survival estimates according to the Weibull regression model revealed higher survival probabilities for reoperation compared with one operation at 6 months (83.74 ± 3.42 vs. 63.56 ± 3.59, respectively), 12 months (64.00 ± 4.85 vs. 37.53 ± 3.52), and 24 months (32.53 ± 4.78 vs. 12.02 ± 2.36).
Conclusion:
Our data support the indication of reoperation for GBM, especially for younger patients with good functional status. Under these circumstances, survival can be doubled at 12 and 24 months.
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