: Gene fusions are strong driver alterations in various cancers, increasingly diagnosed with multiple testing techniques.
fusions can be found in 1-2% of non-small cell lung cancer (NSCLC) and ...several tyrosine kinase inhibitors (TKIs) have been tested in this oncogene-driven disease.
fusions are characteristic of a few rare types of cancer, also infrequently seen in some common cancers including NSCLC. Entrectinib is a newer ROS1 and NTRK inhibitor developed across different tumor types harboring rearrangements in these genes. Entrectinib was granted FDA accelerated approval in August 2019 for the treatment of ROS1+ NSCLC and NTRK-driven solid tumors.
: This review covers the mechanism of action, safety, and efficacy of entrectinib in patients with metastatic NSCLC.
: Entrectinib is an orally bioavailable TKI of TrkA, TrkB, TrkC, and ROS1, with the ability to cross the blood-brain barrier. Entrectinib was effective and well-tolerated in patients harboring
- or
-rearranged NSCLC treated within phase I and II studies. Entrectinib appears to be the most appropriate treatment choice for TKIs-
patients, especially in those presenting brain metastasis. Conversely, in case of systemic progression with the evidence of acquired resistance mutations in ROS1 or Trk proteins, a sequential therapy with entrectinib could not be successful.
Micro-Abstract Treatment of metastatic colorectal cancer includes resection of liver metastases, however, no biomarkers drive selection of patients. We performed a meta-analysis including 1833 ...patients treated with complete liver resection, showing that Kirsten rat sarcoma viral oncogene homolog and b-viral oncogene homolog B1 mutations are negatively associated with survival. This supports integration of mutational status into a combined score to better identify candidates for resection of colorectal cancer liver metastases.
Ankylosing spondylitis (AS) is an inflammatory disease that involves above all the spine and the pelvis. In the spine, the inflammatory processes cause the formation of syndesmophytes between the ...vertebral bodies and the ossification of ligaments, with bony overgrowth. In this setting, dysphagia is a rare but severe complication and only a few cases have been reported in the literature.
We describe the case of a 50-year-old man suffering from AS, with a 6-month history of severe dysphagia caused by bone compression of the esophagus at the C3-5 level. Because the patient underwent a 10-kg weight loss 2 months after clinical onset, a gastrostomy tube placement was needed. Complete surgical excision of the bone overgrowth via an anterior cervical approach was performed, but despite continuous intensive swallowing rehabilitation therapy, the patient failed to improve in the first following months. Surprisingly, the patient started to improve 18 months after the operation, with a complete recovery from dysphagia 24 months after.
Among the 5 reports (including the present case) available in the current literature with a clear dysphagia recovery follow-up, the present case (the second one harboring gastrostomy) is associated with the slowest complete recovery published so far. This unusually late recovery suggests a possible role not only of the mechanical decompression of the esophagus but also of the degeneration/regeneration ratio of the myenteric plexus, along with local neurotransmitters sensitivity changes, to better understand the dysphagia recovery time course of this unique patient.
The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At ...present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.
BackgroundHER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial ...with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting.MethodsHERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed RAS/BRAF wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1).ResultsThirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue.ConclusionsHERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource.Trial registration number2012-002128-33 and NCT03225937.
ERBB2 amplification occurs in 5% of RAS wild-type metastatic colorectal cancer (mCRC) and it has been shown to be a target for treatment with 2 HER2-directed combinations of trastuzumab and lapatinib ...or trastuzumab and pertuzumab. We present long-term clinical results of trastuzumab and lapatinib (HERACLES-A trial) at 6.7 years (82 months) follow-up and focus on central nervous system (CNS) recurrences.
Patients had histologically confirmed KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive mCRC. HER2 positivity was assessed by immunohistochemistry and in situ hybridization HERACLES diagnostic criteria. Patients were treated with intravenous trastuzumab 4 mg/kg loading dose, then 2 mg/kg once per week, and oral lapatinib 1000 mg per day until disease progression or toxicity. Patients who presented with symptoms or signs of CNS disease received brain computed tomography scan or magnetic resonance imaging.
A total of 35 patients received trastuzumab and lapatinib and 32 were evaluable for response. One patient (3%) achieved complete response (CR), 8 (25%) partial response, and 13 (41%) stable disease. Therefore, response rate was 28%. Median progression-free survival was 4.7 months (95% confidence interval CI 3.7–6.1). Median overall survival was 10.0 months (95% CI 7.9–15.8). One patient achieved sustained CR still maintained at 7 years of follow-up. Progression in the central nervous system (CNS) occurred in 6 (19%) of 32 patients.
Long-term (6.7 years) follow-up analysis of HERACLES-A supports using of trastuzumab and lapatinib as treatment reference for KRAS wild-type, chemorefractory HER2-positive mCRC. In this subset of patients, prolongation of survival is accompanied by CNS recurrences that will require diagnostic and therapeutic attention in future studies.
Clinicaltrials. Gov identifier: NCT 03225937.
ERBB2 amplification is a therapeutic target in 5% of patients with RAS wild-type metastatic colorectal cancer. At 6.7 years of follow-up, therapy with trastuzumab and lapatinib combination resulted in 28% objective response rate with 1 patient still in complete response, median 4.7 months progression-free survival, and 10.0 months overall survival. Progression in the central nervous system occurred in 19% of patients.
Carcinomas of unknown primary (CUP) account for 3-5% of all malignancy and, despite a reduction in incidence, the overall survival has not improved over the last decade. Chemotherapy regimens have ...not provided encouraging results. New diagnostic technologies, such as next generation sequencing (NGS), could represent a chance to identify potentially targetable genomic alterations in order to personalize treatment of CUP and provide insights into tumor biology.
A systematic review of studies of patients with CUP, whose tumor specimen was evaluated through a NGS panel, has been performed on June 10th, 2019 according to PRISMA criteria from PubMed, ASCO meeting library and Clinicaltrial.gov. We have identified potentially targetable alterations for which approved/off-label/in clinical trials drugs are available. Moreover, we have included case reports about CUP patients treated with targeted therapies driven by NGS results in order to explore the clinical role of NGS in this setting.
We have evaluated 15 publications of which eleven studies (9 full-text articles and 2 abstracts) have analyzed the genomic profiling of CUPs through NGS technology, with different platforms and with different patients cohorts, ranging from 16 to 1,806 patients. Among all these studies, 85% of patients demonstrated at least one molecular alteration, the most frequent involving
(41.88%),
(18.81%),
(8.8%), and
(9.3%). A mean of 47.3% of patients harbored a potentially targetable alteration for which approved/off-label/in clinical trials drugs were available. Furthermore, we have identified 4 case reports in order to evaluate the clinical relevance of a specific targeted therapy identified through NGS.
NGS may represent a tool to improve diagnosis and treatment of CUP by identifying therapeutically actionable alterations and providing insights into tumor biology.
Pneumatosis intestinalis (PI) is a rare condition due to the presence of gas within the bowel wall; it is mainly caused by endoscopic procedures, infections and other gastrointestinal diseases. ...Oncological therapies have been reported to be a cause of PI as well, but their role is not clearly defined. This systematic review investigates the concurrency of PI and antitumor therapy in cancer patients, considering both solid tumors and onco-hematological ones. We performed a literature review of PubMed, Embase and the Web of Science up to September 2021 according to the PRISMA guidelines. A total of 62 papers reporting 88 different episodes were included. PI was mainly reported with targeted therapies (sunitinib and bevacizumab above all) within the first 12 weeks of treatment. This adverse event mostly occurred in the metastatic setting, but in 10 cases, it also occurred also in the neoadjuvant and adjuvant setting. PI was mostly localized in the large intestine, being fatal in 11 cases, while in the remaining cases, symptoms were usually mild, or even absent. A significant risk of PI reoccurrence after drug reintroduction was also reported (6/18 patients), with no fatal outcomes. Potential pharmacological mechanisms underlying PI pathogenesis are also discussed. In conclusion, although uncommonly, PI can occur during oncological therapies and may lead to life-threatening complications; therefore, consideration of its occurrence among other adverse events is warranted in the presence of clinical suspicion.
Regorafenib improves progression free survival (PFS) in a subset of metastatic colorectal cancer (mCRC) patients, although no biomarkers of efficacy are available. Circulating methylated DNA (cmDNA) ...assessed by a five-gene panel was previously associated with outcome in chemotherapy treated mCRC patients. We hypothesized that cmDNA could be used to identify cases most likely to benefit from regorafenib (i.e., patients with PFS longer than 4 months).
Plasma samples from mCRC patients were collected prior to (baseline samples
= 60) and/or during regorafenib treatment (
= 62) for the assessment of cmDNA and total amount of cell free DNA (cfDNA).
In almost all patients, treatment with regorafenib increased the total cfDNA, but decreased cmDNA warranting the normalization of cmDNA to the total amount of circulating DNA (i.e., cmDNA/ml). We report that cmDNA/ml dynamics reflects clinical response with an increase in cmDNA/ml associated with higher risk of progression (HR for progression = 1.78 95%CI: 1.01-3.13,
= 0.028). Taken individually, high baseline cmDNA/ml (above median) was associated with worst prognosis (HR for death = 3.471 95%CI: 1.83-6.57,
< 0.0001) and also predicted shorter PFS (<16 weeks with PPV 86%). In addition, high cmDNA/ml values during regorafenib treatment predicted with higher accuracy shorter PFS (<16 weeks with a PPV of 96%), therefore associated with increased risk of progression (HR for progression = 2.985; 95%CI: 1.63-5.46;
< 0.0001).
Our data highlight the predictive and prognostic value of cmDNA/ml in mCRC patients treated with regorafenib.
oxaliplatin with fluoropyrimidine is a "mainstay" regarding the upfront treatment of metastatic colorectal cancer (mCRC). In contrast, the efficacy and safety of oxaliplatin-based regimens in ...late-care settings have been poorly reported.
we identified a real-world mCRC patient cohort who were re-treated with oxaliplatin, and in which clinicopathological features were retrospectively analyzed to identify efficacy-predictive determinants (RETROX-CRC study).
of 2606 patients, 119 fulfilled the eligibility criteria. Oxaliplatin retreatment response rate (RR) and disease control rate (DCR) were 21.6% (CI 14.4-31.0%), and 57.8% (CI 47.7-67.4). A trend towards better RR and DCR was observed among patients who had first oxaliplatin in an adjuvant setting; a poorer outcome was observed if two or more intervening treatments were delivered. Median progression-free survival (PFS) was 5.1 months (95%CI 4.3-6.1), reducing to 4.0 months (95%CI 3.07-5.13) if oxaliplatin was readministered beyond third-line (HR 2.02; 1.25-3.25;
= 0.004). Safety data were retrieved in 65 patients (54.6%); 18.5% (12/65) and 7.7% (5/65) had G3-4 toxicities. Toxicities led to discontinuation in 34/119 (28.6%).
oxaliplatin retreatment produced further RR in around one-fifth of patients and DCR 57.8%. Efficacy decreased in more pre-treated patients and around one-third of patients discontinued treatment due to adverse events. Translational studies improving patient selection are warranted.
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