Intolerable Adverse Effects Research Articles

Biological and Pharmacogenomics Bases of Gastrointestinal and Some Long-term Selective Serotonin Reuptake Inhibitors-induced Adverse Effects

Background: Patients being treated with SSRIs who experience intolerable Adverse Effects (AEs) have a penchant for discontinuing treatment, inevitably jeopardizing any probability for treatment response. Aim: This study aims to identify the Single Nucleotide Polymorphisms (SNPs) that are associated with certain AEs of SSRI treatment in Major Depression Disorder (MDD). Results: Patients with the short (SS) genotype (44 base pair deletion) and those with the long along with guanine substitution (LgLg - 44 base pair insertion with rs25531- guanine substitution variant) of the serotonin transporter gene (STG) have substantially been reported with a higher incidence of AEs to SSRI. While variants of glutamate receptor ionotropic genes have been found to be linked with different domains of sexual dysfunction, polymorphisms of 5-HT2A gene - rs6311 (G > A), the long allele (L) of STG, rs6295 (C > G) polymorphism of HTR1A and polymorphism rs1160351 (A > C) of MAM domain-containing glycosyl-phosphatidyl inositol anchor 2 (MDGA2) gene have also been found to be associated with sexual dysfunction. The rs4680 (G>A; Val > Met) polymorphism of catechol-O-methyltransferase (COMT), AA genotype of rs18532 polymorphism of tryptophan hydroxylase, the rs6318 (C > G) polymorphism of the serotonin receptor 2C (HTR2C), and S allele of STG were found to be associated with weight gain following SSRI treatment. The sanctity of these results is limited by the inability of some researchers to replicate these association findings. Conclusion: This review highlights a number of polymorphisms associated with some of the key AEs encountered in SSRI treatments. Standardized study designs in pharmacogenomic evaluations hold great promise for replication of association findings.

The Use of Lasers and Light Devices in Acne Management: An Update

Acne vulgaris is a disease of the pilosebaceous unit and the most common inflammatory dermatosis worldwide. It is also associated with significant economic burden. Limitations of conventional topical and systemic treatments include long treatment course, intolerable adverse effects, antibiotic resistance, and patient compliance. Therefore, laser and light-based interventions present as alternative options over the past decade and have been used in combination with conventional pharmacological therapies and other physical modalities. An updated overview on the use of lasers and light-based devices in acne management is presented to help clinicians understand the safety and efficacy of these treatment options. The effectiveness of neodymium:yttrium aluminum garnet (Nd:YAG) for treating acne is supported by more high-level studies compared with other laser devices. There is limited evidence to support the use of CO2 lasers, potassium titanyl phosphate lasers, and 1565-nm non-ablative fractional lasers for treating acne. Among light devices, photodynamic therapy is the most studied, showing higher efficacies than some of the conventional topical and oral acne therapies. Intense-pulsed light and blue light therapies also show favorable outcomes. A limitation is that most studies are non-randomized and lack a control group, and report on a variety of device settings, treatment regimens, and outcome measures, making it challenging to summarize and generalize findings. Although the use of laser and light devices to treat acne is promising, further work with randomized controlled study designs and larger sample sizes will provide improved guidance on the application of these modalities.

Safety of PSMA-Targeted Molecular Radioligand Therapy with 177Lu-PSMA-617: Results from the Prospective Multicenter Phase 2 Trial RESIST-PC (NCT03042312).

The purpose of this analysis was to report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion:177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

Abstract CT206: A phase I open-label, dose escalation and expansion trial to investigate the safety, pharmacokinetics and pharmacodynamics of CB307, a trispecific Humabody T-cell enhancer, in patients with PSMA+ advanced and/or metastatic solid tumors (POTENTIA)

Abstract T cell redirecting therapy, including bispecific antibodies, is a proven anti-cancer treatment modality. Humabodies* are fully human VH antibody components that can be connected by a short peptide linker to make multi-specific molecules. Preclinical studies show that humabodies are distributed to tumors effectively and penetrate the tumor microenvironment efficiently compared with conventional monoclonal antibodies. CB307 is a tri-specific humabody targeting PSMA, CD137 and human serum albumin (HSA) where simultaneous binding to CD137 and PSMA elicits T-cell activation via CD137 agonism only in PSMA-expressing tumors. Binding to HSA ensures half-life extension and efficient systemic delivery of CB307 to the tumor. CD137 agonists promote T cell survival, proliferation and memory-like T cell formation, and are generally considered to be better tolerated than, for example, CD3 targeting agents regarding cytokine release syndrome. The objectives of the POTENTIA study are to determine the maximum tolerated dose (MTD) and pharmacokinetics of CB307 and to assess preliminary anti-tumor activity in PSMA+ solid tumor patients. Methods: The phase 1 study consists of dose escalation (part 1) and cohort expansion (part 2) components. The dose escalation uses an accelerated titration design (ATD) and a modified continual reassessment method (mCRM) to determine the MTD and the recommended phase 2 dose (RP2D). This adaptive design allows rapid dose escalation and helps to minimise the number of patients at suboptimal doses and to determine the MTD and RP2D accurately. Cohort expansion uses the same eligibility criteria, however, at least 3 patients with castration-resistant prostate cancer harbouring either BRCA1, BRCA2, ATM and/or CDK12 mutation(s) will be enrolled. A total of 50 patients overall with prospectively demonstrated PSMA tumor expression determined by immunohistochemistry will be enrolled to receive CB307 administered by weekly IV. PSMA-PET will also be taken at baseline for the assessment of systemic PSMA status. Key inclusion criteria are: histologically confirmed advanced or metastatic solid tumors; not amenable to standard-of-care therapy; RECIST measurable disease or increasing serum PSA at baseline for bone metastasis-only prostate cancer. Patients with brain metastases, patients who have discontinued previous immunotherapy due to intolerable immune-related adverse events and patients with acute infections or autoimmune diseases are excluded from the study. * “Humabodies” is a registered trademark of Crescendo Biologics Ltd. Citation Format: Kenji Hashimoto, Andrew J. Pierce, Albert Chau, Phillip Bartlett, Peter Lloyd, Mark Maginn, Matthias Machacek, Jannik Vollmer, Sultanah Rajbally, Julia Tilson, Phil Bland-Ward. A phase I open-label, dose escalation and expansion trial to investigate the safety, pharmacokinetics and pharmacodynamics of CB307, a trispecific Humabody T-cell enhancer, in patients with PSMA+ advanced and/or metastatic solid tumors (POTENTIA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT206.

Patient Perspectives and Experiences of Preventive Treatments and Self-Injectable Devices for Migraine: A Focus Group Study.

BackgroundAlthough several self-injectable preventive treatments for migraine have become available, they are not yet widely used. Thus, understanding patients’ perceptions towards them is limited.ObjectiveThis study aimed to inform the design of a preference-elicitation instrument, which is being developed to quantify preventive treatment preferences of people with migraine.MethodsWe conducted a qualitative study involving nine in-person focus groups (three per country) in the United States, the United Kingdom, and Germany. Participants were adults (n = 47) with episodic or chronic migraine who were currently using or had used a prescription preventive treatment for migraine within the previous 5 years. During the focus groups, participants described their experiences of migraine and preventive treatments; handled and simulated self-injection using five different unbranded, fired demonstration auto-injectors and prefilled syringes; and ranked different aspects of preventive treatments by importance. Focus groups were analyzed with a focus on themes that would be feasible or meaningful to include in a subsequent preference-elicitation instrument.ResultsReducing the frequency and severity of migraine attacks was consistently ranked as the most important aspect of preventive treatment. Participants expressed dissatisfaction with available daily oral preventive treatments for migraine they had previously used because they were ineffective or caused intolerable adverse events. Many participants were willing to self-inject a treatment that was effective and tolerable. When presented with devices for self-injecting a preventive treatment for migraine, participants generally preferred autoinjectors over prefilled syringes. Participants especially valued safety features such as the unlocking step and automated needle insertion, and audible and visual dose confirmation increased confidence in autoinjector use. Autoinjector needle protection mechanisms were also appreciated, especially by participants averse to needles, as the needles are not visible.ConclusionsThis study highlights the fact that many people with migraine still lack access to a preventive treatment that is effective and tolerable. In addition to efficacy and safety considerations, treatment decisions may be guided by the mode of administration. In the case of self-injectable preventive treatments, key device characteristics affecting these decisions may be ease of use, comfort, and confidence in self-injection. Insights gained from this study were used to help develop a preliminary set of attributes and levels for a preference-elicitation instrument.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40271-021-00525-z.

Evaluating the likelihood to be helped or harmed after treatment with viloxazine extended-release in children and adolescents with attention-deficit/hyperactivity disorder.

AimsWhen clinicians evaluate potential medications for their patients, they must weigh the probability of a treatment's benefits against the possible risks. To this end, the present analyses evaluate the novel nonstimulant viloxazine extended‐release (viloxazine ER) using measures of effect size to describe the potential benefits of its treatment in children and adolescents with attention‐deficit/hyperactivity disorder (ADHD) as well as the risk of discontinuation because of intolerable adverse events.MethodsThese post hoc analyses use pooled data from four pivotal Phase 3 trials in paediatric patients treated with viloxazine ER. The Likelihood to be Helped or Harmed (LHH) effect size measure was calculated to describe the probability of patients benefiting from treatment vs discontinuing. The Number Needed to Treat (NNT) was calculated from frequently used thresholds of response. The Number Needed to Harm (NNH) was calculated using discontinuations because of adverse events.ResultsLHH values for viloxazine ER ranged from 5 to 13, suggesting that subjects were 5‐13 times more likely to benefit from, rather than discontinue, viloxazine ER treatment. Specifically, NNT values for viloxazine ER treatment ranged from 6 to 7. NNH values for viloxazine ER treatment ranged from 31 to 74. By convention, single‐digit NNTs (<10) suggest the intervention is potentially useful, while NNH values ≥10 for adverse events suggest it is potentially safe or tolerable.ConclusionsThese results indicate that patients with ADHD are likely to benefit from treatment with viloxazine ER, and are unlikely to discontinue, as viloxazine ER treatment was associated with favourable LHH, NNT, and NNH values. Clinicaltrials.gov: NCT03247530, NCT03247543, NCT03247517, NCT03247556.

Planned drug holiday in a cohort study exploring the effect of lenvatinib on differentiated thyroid cancer.

6070 Background: Lenvatinib is now available for unresectable radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). However, toxicities are considerable and require frequent dose interruption and modification. Recently, planned drug holidays, which are dose interruptions in accordance with the timing of severe or intolerable adverse events, have been proposed to avoid severe adverse events due to lenvatinib (Tahara M.ESMO Open 2018). Our retrospective study demonstrated that progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who used planned drug holidays than those who did not (Matsuyama C et.al, 2020 Annual Meeting of the Japan Association of Endocrine Surgeons). Methods: In this prospective observational study, patients with curatively unresectable and progressive RAI-refractory DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities were permitted. Primary endpoint was OS, and secondary endpoints were time to treatment failure (TTF), time to failure of strategy (TFS), PFS with clinical progressive disease, response rate, quality of life, safety, and patient reports. This study was registered with UMIN Clinical Trials Registry (UMIN000022243). Results: 262 patients were accrued. Of 255 evaluable, 153 were female; median age was 70 (range 27.0-88.0); histology was papillary thyroid carcinoma/follicular thyroid carcinoma/poorly DTC in 204/45/4; previous therapy was surgery/RAI/molecular targeted drug in 246/164/14; reason for initiation of lenvatinib was disease progression/unsuitable for RAI in 241/4. 1-year OS was 85.6% (95%CI: 80.6-89.4%); 1-year TTF rate was 74.9% (95%CI: 69.1-79.8%); 1-year TFS rate was 80.8% (95%CI: 75.4-85.2%); and 1-year PFS rate was 84.4% (95%CI: 79.3-88.4%). Overall response by RECIST was 3 (1.2%) in CR and 151 (61.9%) in PR. Most common grade 3 or 4 toxicities were hypertension (61.4%), hand foot syndrome (10.2%), fatigue (9.1%), anorexia (8.3%) and diarrhea (4.7%). Grade 5 toxicities occurred in 4 patients (fistula, hypoxia, respiratory failure, trachea stenosis). Of 253 patients evaluable for efficacy, 73 used planned drug holidays. TTF, TFS and PFS were significantly longer in patients who used planned drug holiday than those who did not (Table). Conclusions: Planned drug holiday for lenvatinib demonstrated significantly better clinical outcomes, including TTF, TFS and PFS, than daily oral administration. These data further support use of a planned drug holiday in RAI-refractory DTC patients receiving lenvatinib. Clinical trial information: 000022243. [Table: see text]

Retrospective pilot study of regorafenib combined with ICIs in the third-line treatment of advanced colorectal cancer.

e15582 Background: An increasing number of patients with advanced colorectal cancer tend to receive third-line treatment. Although there are several treatment options, concerns about efficacy and adverse events still remained. Regorafenib seems to enhance the effect of immune checkpoint inhibitors (ICIs) by modulate tumor microenvironment. In the absence of stage III clinical trial data, the real-world study might show certain clinical value. Methods: From Aug 2019 to June 2020, 23 advanced MSS colorectal cancer patients underwent third-line treatment of regorafenib combined with ICI. All patients received regorafenib 80 mg QD for 21 days, as a 28-day cycle, combined with ICIs until disease progression or intolerable adverse events. We retrospectively collected the overall response data, survival data and adverse events data from these patients. Results: The characteristics of all 23 patients is shown in the table. All patients had received at least 2 lines of prior systemic chemotherapy, the median time from diagnosis to third-line treatment was 31 months. The overall response rate was 26% (6/23), including one complete response. Almost all the responders were male (5/6) and with pulmonary metastasis (5/6). The disease control rate was 60% (14/23). The progression free survival ranges from 0.69 month to 19.3 months (median 4.8 months), with 6 patients continued response and constantly treatment. Duration of response range from 6.4 months to 19.4 months. Serious adverse events were hepatitis occurred in two patients and lead to the termination of subsequent anticancer therapy, which was considered to be related to immunotherapy. Conclusions: Regorafenib combined with ICIs might favor a certain group of advanced colorectal cancer patients, with a acceptable response rate and comparatively long duration of response. Interestingly, this retrospective pilot study was in consistence with that of REGONIVO trials to some extent for that the male patients with pulmonary metastasis appeared to response better. Key words: colorectal cancer; regorafenib; immune check point inhibitors Clinical characteristics of 23 patients.[Table: see text]

Update results from ALTER-C-001: Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC-A single-arm, multicenter, phase Ⅱ clinical trial.

e15550 Background: The combination of anti-VEGF or anti-EGFR targeted drugs with chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC), and the followed maintenance treatment is an optional approach to balance the efficacy and toxicity. However, studies regarding the maintenance strategies based on antiangiogenic TKIs are limited currently. Anlotinib, a novel oral multi-target TKI which can inhibit both tumor angiogenesis and tumor cell proliferation simultaneously, substantially prolonged the PFS with manageable toxicity for refractory mCRC in the phase III ALTER0703 clinical trial. Here we report an update on the effectiveness and safety of anlotinib plus XELOX as first-line treatment followed by anlotinib monotherapy for mCRC. Methods: In this open label, single-arm, multicenter phase II clinical trial, 53 mCRC patients without prior systemic treated, aged 18-75 and an ECOG performance status of 0 or 1 were planned to recruit. Eligible patients received capecitabine (1000 mg/m2, po, d1-14, q3w) and oxaliplatin (130 mg/m2, iv, d1, q3w) plus anlotinib (10mg, po, d1̃14, q3w) treatment for 6 cycles. After 6 cycles of inducing therapy, patients would receive anlotinib (12mg, po, d1̃14, q3w) as maintenance therapy until disease progression or intolerable adverse events (AEs). The primary endpoint was PFS; Secondary endpoints included ORR, DCR, DOR and safety. Results: By the data analysis cutoff date of January 22, 2021, a total of 18 patients were enrolled, of which 12 patients were available for efficacy assessment. In best overall response assessment, there were 50.0% PR (6/12), 33.3% SD (4/12) and 16.7% PD (2/12). The ORR was 50.0% (95% CI, 21.1-78.9%) and DCR was 83.3% (95% CI, 51.5-97.9%). The longest duration of treatment was 8.8 months and the response was still ongoing. The median PFS was not reached. The most common treatment related adverse events (TRAEs) of any grade (≥20%) were leukopenia, hypertension, neutropenia, diarrhea, fatigue, hypertriglyceridemia. Grade 3/4 TRAEs included hypertension (22.2%), hypertriglyceridemia (11.1%), lipase elevated (11.1%) and neutropenia (5.6%). No grade 5 AEs occurred. Conclusions: The update results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy showed promising anti-tumor activity and manageable safety for patients with mCRC. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: ChiCTR1900028417.

An exploratory clinical study of gefitinib combined with anlotinib in the first-line treatment of stage ⅢB-Ⅳ EGFR gene mutant non-small cell lung cancer patients with slow progress.

e21089 Background: Anlotinib is a new type of small molecule anti-angiogenic drug that can inhibit the activity of a variety of tyrosine kinase receptors. Based on the initial efficacy of the combination of anti-angiogenic drugs and EGFR-TKIs and a clearer definition of people who are sensitive to EGFR-TKIs treatment, this study explores the slow progress of first-line use of gefitinib in patients with non-small cell lung cancer slowly progress, the efficacy and safety of combined Anlotinib. Methods: Fifteen patients with first-line non-small cell lung cancer who received gefitinib treatment and slowly progressed after enrolled in Xuchang Central Hospital, 15 received anlotinib(12mg/d from day 1 to day 14 in a 21-day cycle) combined with gefitinib（250mg /d） treatment until the disease progressed or died or was intolerable Adverse events. The primary endpoint was the progression-free survival(PFS), and the secondary endpoints were objective response rate (ORR), disease control rate( DCR) and safety. Results: As of January 4, 2021, a total of 15 patients have been enrolled and 14 patients can be evaluated. 0CR, 5PR, 8SD, 1PD. The median progression-free survival was 13.3 months (95% Cl, 3.71-4.89), and the most common adverse reactions were Grade 1, including hypertension (42.86%) and fatigue (21.42%). No higher-grade adverse reactions. Conclusions: Gefitinib combined with Anlotinib Hydrochloride Capsules is safe, effective and well tolerated when the first-line treatment of EGFR gene mutant non-small cell lung cancer patients progresses slowly.

A retrospective study of anlotinib in patients with cervical cancer after chemoradiotherapy.

e17509 Background: Anlotinib is a novel small molecule antiangiogenic drug, which can inhibit multiple tyrosine kinase receptor activity. Its antitumor activity has been proved in various cancers, including gynecological tumors. This retrospective study explored the efficacy and safety of anlotinib monotherapy or anlotinib combined chemotherapy in cervical cancer patients who have disease progressed or metastasis after chemoradiotherapy. Methods: 28 patients with cervical cancer admitted to the Second Affiliated Hospital of Zhengzhou University were enrolled. These patients who had received radiotherapy and at least one line chemotherapy had tumor progression or metastasis. 13 patients received anlotinib monotherapy (12mg/d from day 1 to day 14 in a 21-day cycle) and 15 patients received chemotherapy combined with the anlotinib. Treatment was continued until disease progression or death or intolerable adverse events. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS) and safety. Results: As of Dec 31 2020, no one was lost follow up. 2 patients were still under treatment, and 26 patients were evaluable. 1 CR, 6 PR, 13 SD, 6 PD, yielding the ORR of 26.92%, and the DCR of 76.92%. The median PFS for receiving anlotinib monotherapy was 4.57 (95% CI, 3.85-5.29) months, and 8.47 (95% CI, 5.09-11.85) months for combination group. The most common adverse events (AEs)were grade 1, including hypertension (46.43%), anemia (42.85%) and fatigue (39.29%). Grade 3 AEs were hypertension(10.71%) and anemia(7.14%). No higher grade AEs occurred. Conclusions: Anlotinib is safe and effective for patients with advanced cervical cancer after chemoradiotherapy, and it is well tolerated.

Osimertinib versus afatinib in patients with T790M-positive, non-small-cell lung cancer and multiple central nervous system metastases after failure of initial EGFR-TKI treatment

BackgroundThe purpose of this study was to compare the efficacy of osimertinib (OSI) versus afatinib (AFA) in patients with T790M-positive, non-small-cell lung cancer (NSCLC) and multiple central nervous system (CNS) metastases after failure of initial epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment.MethodsConsecutive patients with T790M-positive NSCLC and multiple CNS metastases after failure of initial EGFR-TKI treatment were retrospectively identified from our medical institution during 2016–2018 and underwent either oral 80 daily OSI or oral 40 daily AFA every 3 weeks for up to 6 cycles, until disease progression, intolerable adverse events (AEs), or death. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS).ResultsThe cohort consisted of 124 patients (OSI: n = 60, mean age = 64.24 years [SD: 12.33]; AFA: n = 64, mean age = 64.13 years [SD: 13.72]). After a median follow-up of 24 months (range, 3 to 28), a significant improvement in OS was detected (hazard ratio [HR] 0.59, 95% confidence interval [CI], 0.39–0.91; p = 0.0160; median, 13.7 months [95% CI, 11.1–14.8] for OSI vs 9.6 months [95% CI, 8.4–10.2] for AFA). The median duration of PFS was significantly longer with OSI than with AFA (HR 0.62; 95% CI, 0.41–0.91; p = 0.014; median, 4.5 months [95% CI, 3.5–5.7] vs 3.9 months [95% CI, 3.1–4.8]). The proportion of grade 3 or higher adverse events (AEs) was lower with OSI (22.4%) than with AFA (39.4%).ConclusionsIn patients with T790M-positive NSCLC and multiple CNS metastases after failure of initial EGFR-TKI treatment, OSI may be associated with significantly improved survival benefit compared with AFA, with a controllable tolerability profile.

Delayed hypersensitivity reactions to multiple aromatase inhibitors followed by successful desensitization to letrozole

Aromatase inhibitors (AIs) are a class of medications that can suppress plasma estrogen levels by inhibiting or inactivating aromatase—the enzyme responsible for converting androgens to estrogens.1 They are the preferred adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer.2 Anastrozole, letrozole, and exemestane are the most often used third-generation AIs with similar efficacy and tolerability.1,2 If patients develop intolerable adverse effects with one AI, they can switch to a different one.

Combination of gemcitabine, nab-paclitaxel, and S-1(GAS) as the first-line treatment for patients with locally advanced or advanced pancreatic ductal adenocarcinoma: study protocol for an open-label, single-arm phase I study

BackgroundPancreatic ductal adenocarcinoma (PDAC) is still a highly fatal malignancy among the most common cancers. More powerful treatments are expecting to bring hope for patients. Biweekly gemcitabine/nab-paclitaxel/S-1 (GAS) was proved safe and effective for patients with locally advanced pancreatic cancer in Japan. The objective of this study is to evaluate the feasibility and toxicity of GAS (repeated every 3 weeks) in the treatment of locally advanced or advanced pancreatic cancer and determine the recommended dose of S-1 in this combination.MethodsThis is an open-label, single-arm, and single-center phase I trial. Patients who have been diagnosed with locally advanced or advanced PDAC pathologically without previous systemic treatments will be enrolled and be treated with GAS chemotherapy every 3 weeks (nab-paclitaxel 125 mg/m 2, ivgtt, day1, 8; gemcitabine 1000 mg/m2, day1, 8; different doses of S-1 within a dose escalation scheme) until the presence of disease progression (PD), intolerable adverse events (AEs), or requirement of patients and researchers. The primary endpoints are maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). The secondary endpoints include safety, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).DiscussionThis trial will adjust the administration of GAS to make it more effective for Chinese patients, while exploring the toxicity and feasibility of this adjustment.Trial registrationChiCTR, (ChiCTR1900027833). Registered 30 November 2019.

Locoregional Combined With Systemic Therapies for Advanced Hepatocellular Carcinoma: An Inevitable Trend of Rapid Development.

Despite the application of antiviral drugs and improved surveillance tools, the number of patients diagnosed with hepatocellular carcinoma (HCC) at an advanced stage and with a dismal prognosis is still on the rise. Systemic treatment with multiple multitargeted tyrosine kinase inhibitors (TKIs), such as sorafenib, has been a widely utilized approach for a decade. In addition, the use of a combination of TKIs with other types of compounds, including immune checkpoint inhibitors (ICIs) and antiangiogenic inhibitors, has shown efficacy in treating advanced HCC. However, the presence of intolerable adverse events, low disease response and control rates, and relative short overall survival of such combinatory therapies makes novel or optimized therapies for advance HCC urgently needed. Locoregional therapy (transarterial chemoembolization, and thermal ablation) can destroy primary tumors and decrease tumor burden and is widely used for HCC management. This type of treatment modality can result in local hypoxia and increased vascular permeability, inducing immunogenic effects by releasing tumor antigens from dying cancer cells and producing damage-associated molecular patterns that facilitate antiangiogenic therapy and antitumor immunity. The combination of systemic and locoregional therapies may further produce synergistic effects without overlapping toxicity that can improve prognoses for advanced HCC. In preliminary studies, several combinations of therapeutic modes exhibited promising levels of safety, feasibility, and antitumor effects in a clinical setting and have, thus, garnered much attention. This review aims to provide a comprehensive, up-to-date overview of the underlying mechanisms of combined systemic and locoregional therapies in the treatment of advanced HCC, commenting on both their current status and future direction.

Efficacy of Adding Calcitonin to Methylprednisolone in Erector Spinae Plane Block for Thoracic Cancer Pain Management

ABSTRACT Background: Pain continues to be a very prevalent symptom too often undertreated in cancer patients at all stages of their disease. It is difficult to manage, and patients often show a poor or limited response to analgesic medications or experience intolerable adverse effects. Objective: The aim of the current work was to compare the effect of adding calcitonin to methylprednisolone versus methylprednisolone alone to local anesthetic in erector spinae plane block for patient suffering from thoracic cancer pain. Patients and methods: A double-blind study was conducted from November 2019 until November 2020 at Outpatient Pain Clinic, Oncology Center, Mansoura University (OCMU). This study included thirty patients of both sexes and range of ages (30-70 years), with a history of chronic thoracic cancer pain ≥ 4 on a visual analogue scale (VAS) of 0 – 10 and Chronic pain for at least 3 months prior to study entry. Patients were divided into ywo groups, 15 each, Group (I) (methylprednisolone group) and Group (II) (calcitonin group). Results: Any post block events like nausea, vomiting, respiratory depression (when SpO2 less than 92%) and pneumothorax were recorded. Consumption of analgesics (tramadol 1 – 1.5 mg / kg when needed) during first three months post procedure was measured. Patients of both groups gained benefits from the techniques. The two groups showed decline in the VAS scores and the total tramadol consumption. Calcitonin group has more prolonged duration of pain relief, significant reduction in pain scores, lower tramadol requirements, tolerable side effects. Conclusion: Patients received calcitonin added to methylprednisolone and local anesthetics had significant reduction in pain scores, more prolonged duration of pain relief, less rescue analgesia (tramadol) consumed and was more satisfied with the treatment modality as compared to methylprednisolone and local anesthetics treated patients in 3 months follow up periods.

Tenacissoside G synergistically potentiates inhibitory effects of 5-fluorouracil to human colorectal cancer

BackgroundColorectal cancer (CRC) is one of the most malignant tumors worldwide with poor prognosis and low survival rate. Since the clinical efficacy of the commonly used 5-fluorouracil (5-FU) based chemotherapy in CRC patients is limited because of its intolerable adverse effects, there is an urgent need to explore agents that can enhance the anti-cancer activity of 5-FU, reduce adverse effects and prevent resistance. PurposeThis study aims to investigate Tenacissoside G (TG)’s synergistic potentiation with 5-FU in inhibitory activity to colorectal cancer cells. MethodsThe anti-proliferation effect of TG on 5 colorectal cancer cell lines was assessed by CCK-8 assay. The isobologram analysis and combination index methods were used to detect the synergistic effect of TG and 5-FU by the CompuSyn software using the T.C. Chou Method. The effects of TG/5-FU combination on cell cycle distribution and apoptosis induction were detected by flow cytometry. DNA damage degrees of cells treated with TG, 5-FU and their combination were evaluated by the alkaline comet assay. Protein expression regulated by the TG/5-FU combination was investigated by western blotting. Furthermore, a xenograft mouse model was established to investigate the synergistic anti-tumor effect in vivo. ResultsIn this work, we observed a dose-dependent growth inhibitory activity and cell cycle arrest induction of TG, a monomeric substance originated from Marsdenia tenacissima (Roxb.) Wight et Arn, in colorectal cancer cells. It was found that TG potentiated the anticancer effects of 5-FU with a synergism for the first time. And the co-treatment effects were also validated by in vivo experiments. The underlying mechanisms involved in the synergistic effects were probably included: (1) increased activation of caspase cascade; (2) enhancement of DNA damage degree and (3) induction of p53 phosphorylation at Serine 46. ConclusionTG potentiated 5-FU's inhibitory activity to human colorectal cancer through arresting cell cycle progression and inducing p53-mediated apoptosis, which may present a novel strategy in CRC therapies and contribute to the optimizing clinical application of 5-FU.

Novel therapeutics for the treatment of hypertension and its associated complications: peptide- and nonpeptide-based strategies.

The renin-angiotensin-aldosterone system (RAAS) is responsible for maintaining blood pressure and vascular tone. Modulation of the RAAS, therefore, interferes with essential cellular processes and leads to high blood pressure, oxidative stress, inflammation, fibrosis, and hypertrophy. Consequently, these conditions cause fatal cardiovascular and renal complications. Thus, the primary purpose of hypertension treatment is to diminish or inhibit overactivated RAAS. Currently available RAAS inhibitors have proven effective in reducing blood pressure; however, beyond hypertension, they have failed to treat end-target organ injury. In addition, RAAS inhibitors have some intolerable adverse effects, such as hyperkalemia and hypotension. These gaps in the available treatment for hypertension require further investigation of the development of safe and effective therapies. Current research is focused on the combination of existing and novel treatments that neutralize the angiotensin II type I (AT1) receptor-mediated action of the angiotensin II peptide. Preclinical studies of peptide- and nonpeptide-based therapeutic agents demonstrate their conspicuous impact on the treatment of cardiovascular diseases in animal models. In this review, we will discuss novel therapeutic agents being developed as RAAS inhibitors that show prominent effects in both preclinical and clinical studies. In addition, we will also highlight the need for improvement in the efficacy of existing drugs in the absence of new prominent antihypertensive drugs.

UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI.

Background Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5–7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF-mutated mCRC. Patients and Methods. This retrospective study included 17 patients with BRAF-mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS). Results Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m2 or required deescalation to 150 mg/m2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3–54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status. Conclusions The oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes.

A phase I/II study of REGN5678 (Anti-PSMAxCD28, a costimulatory bispecific antibody) with cemiplimab (anti–PD-1) in patients with metastatic castration-resistant prostate cancer.

TPS174 Background: Bispecific antibodies (bsAbs) are emerging as a protein-based therapeutic strategy for directing T-cell-mediated cytotoxicity in a tumor antigen-specific manner, typically by binding to both tumor antigen and the CD3 receptor on T-cells. REGN5678 is a human IgG4-based, first-in-class costimulatory bsAb designed to target prostate tumors by bridging prostate specific membrane antigen expressing tumor cells with the costimulatory receptor, CD28, on T-cells, and providing amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor through the activation of CD28 signaling. At the tumor site, REGN5678 may synergize with PD-1 inhibitors. In mouse models, REGN5678 in combination with a PD-1 antibody has improved anti-tumor activity compared with either therapy alone (Waite JC et al. Sci Transl Med. 2020:12;549). Methods: This is an open label, Phase I/II, first-in-human study evaluating safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of REGN5678 alone and in combination with cemiplimab in patients with metastatic castration resistant prostate cancer (mCRPC) who progressed after prior therapy (NCT03972657). For inclusion, patients must have received at least two prior lines of systemic therapy (in addition to androgen deprivation therapy) approved for metastatic and/or castration-resistant disease including a second-generation anti-androgen therapy. REGN5678 is administered weekly; cemiplimab (350 mg) is administered once every 3 weeks. During dose escalation, a 3-week safety lead-in of REGN5678 monotherapy will be administered prior to addition of cemiplimab. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate safety, tolerability, and PK of REGN5678 alone and in combination with cemiplimab. Expansion cohort(s) will be enrolled once a maximum-tolerated REGN5678/cemiplimab dose is reached, or if a recommended Phase 2 dose or doses have been determined. During the expansion phase, the primary objective is to assess clinical activity, as measured by objective response rate of REGN5678 in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. At selected sites, prostate-specific membrane antigen PET/CT scans are performed at baseline and select time points on study. This study is currently open to enrollment. Clinical trial information: NCT03972657.