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1.
Recent Results Cancer Res ; 214: 1-70, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473848

RESUMO

Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Recent achievements include conjugating antibodies with toxic payloads resulting in superior efficacy and/or reduced toxicity, development of molecular imaging techniques targeting specific antigens for use as predictive and prognostic biomarkers, the development of novel bi- and tri-specific antibodies to enhance therapeutic benefit and abrogate resistance and the success of immunotherapy agents. In this chapter, we review an overview of antibody structure and function relevant to cancer therapy and provide an overview of pivotal clinical trials which have led to regulatory approval of monoclonal antibodies in cancer treatment. We further discuss resistance mechanisms and the unique side effects of each class of antibody and provide an overview of emerging therapeutic agents.


Assuntos
Anticorpos Monoclonais/farmacologia , Imunoterapia , Neoplasias/terapia , Ensaios Clínicos como Assunto , Humanos
2.
J Clin Neurosci ; 68: 45-50, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31371189

RESUMO

There is limited information on the patterns of care and outcomes of high grade gliomas (HGGs) in young adults, in particular, the impact it has on a person's employment. We retrospectively identified young adult patients (age ≤ 40 years old) with newly diagnosed high grade gliomas treated between January 2013 and June 2018 across four major neuro-oncology centres in Australia. Patient demographics, tumour characteristics and treatment parameters were collected and outcomes determined. A total of 113 patients were identified with a median follow up of 27.0 months (range 1.0-70.2 months). The median age was 31 years, majority were male (65%) and employed (71.6%). IDH mutations were detected in 66 (62%) cases. The median progression-free survival (PFS) was 38.0 months (95% CI 23.3-52.7 months) and median overall survival (OS) was not reached. Patients with IDH wild type anaplastic astrocytoma and glioblastoma had a significantly shorter median PFS (19.3 months vs. NR, p = 0.001) and median OS (43.5 months vs NR, p = 0.007) than those with IDH mutated grade III anaplastic astrocytoma and oligodendroglioma. There was no significant difference in median OS or PFS between patients who underwent gross or subtotal tumour resection. Significantly, after diagnosis only 36 (32%) patients reported being employed. Young patients with IDH wild type astrocytomas and glioblastoma had better outcomes than reported historical controls. Most patients did not continue in employment post diagnosis.

3.
Clin Cancer Res ; 25(16): 4924-4932, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30952639

RESUMO

PURPOSE: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). PATIENTS AND METHODS: This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity. RESULTS: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, C max was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. CONCLUSIONS: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.

4.
Target Oncol ; 14(1): 39-41, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30843167
5.
Clin Cancer Res ; 25(11): 3259-3265, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30796037

RESUMO

PURPOSE: Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing EGFR amplification by multiple assays. Specifically, we evaluated correlation among fluorescence in situ hybridization (FISH), a standard assay for detecting EGFR amplification, with other methods.Experimental Design: Formalin-fixed, paraffin-embedded tumor samples were used for all assays. EGFR amplification was detected using FISH (N = 206) and whole-exome sequencing (WES, N = 74). EGFR mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, N = 206) and transcriptome profiling (RNAseq, N = 64). EGFR protein expression was determined by immunohistochemistry (IHC, N = 34). Significant correlations among various methods were determined using Cohen's kappa (κ = 0.61-0.80 defines substantial agreement) or R 2 statistics. RESULTS: EGFR mRNA expression levels by RNA sequencing (RNAseq) and RT-PCR were highly correlated with EGFR amplification assessed by FISH (κ = 0.702). High concordance was also observed when comparing FISH to WES (κ = 0.739). RNA expression was superior to protein expression in delineating EGFR amplification. CONCLUSIONS: Methods for assessing EGFR mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for EGFR amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapeutic approaches.

6.
Oncologist ; 24(8): 1089-1094, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30710065

RESUMO

BACKGROUND: The objective of this study was to describe the implementation of comprehensive geriatric assessment (CGA) in clinical trials dedicated to older patients before and after the creation of the International Society of Geriatric Oncology in the early 2000s. SUBJECTS, MATERIALS, AND METHODS: All phase I, II, and III trials dedicated to the treatment of cancer among older patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. We considered that a CGA was performed when the authors indicated an intention to do so in the Methods section of the article. We collected each geriatric domain assessed using a validated tool even in the absence of a clear CGA, including nutritional, functional, cognitive, and psychological status, comorbidity, comedication, overmedication, social status and support, and geriatric syndromes. RESULTS: A total of 260 clinical trials dedicated to older patients were identified over the two time periods: 27 phase I, 193 phase II, and 40 phase III trials. CGA was used in 9% and 8% of phase II and III trials, respectively; it was never used in phase I trials. Performance status was reported in 67%, 79%, and 75% of phase I, II, and III trials, respectively. Functional assessment was reported in 4%, 11%, and 13% of phase I, II, and III trials, respectively. Between the two time periods, use of CGA increased from 1% to 11% (p = .0051) and assessment of functional status increased from 3% to 14% (p = .0094). CONCLUSION: The use of CGA in trials dedicated to older patients increased significantly but remained insufficient. IMPLICATIONS FOR PRACTICE: This article identifies the areas in which research efforts should be focused in order to offer physicians well-addressed clinical trials with results that can be extrapolated to daily practice.

7.
Int J Cancer ; 145(3): 639-648, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653255

RESUMO

The advent of immune checkpoint-inhibitors (CPI) has transformed treatment for several cancer types. This review was performed to assess the rate of adverse events (AEs) associated with the use of CPI, alone or in combinations. A review of AEs reporting quality was also performed. All publications of Randomized Clinical Trials (RCTs) assessing CPI published before December 2017 were included. To investigate the quality of AEs reporting, a set of items was defined based on the 2004 CONSORT harms extension statement. Rates of Grade 5, serious, and study-withdrawal related AEs were collected in each treatment category. Specific immune related AEs (irAEs) were also collected when available. Pooled estimates of adverse event rates were calculated by using generalized linear mixed model. A total of 35 RCTs including 16,485 patients were included. The overall quality of AEs reporting was satisfactory, but items pertaining to methods of data collection and analysis were infrequently reported. Grade ≥ 3 AEs were reported for 14% (95% CI 12-16) of patients treated with PD(L)-1 inhibitors, 34% (95% CI 27-42) of patients treated with CTLA-4 inhibitors, 55% (95% CI 51-59) of patients on CPI combinations and 46% (95% CI 40-53) of patients on immunotherapy-chemotherapy combination. The profile of irAEs was different among the treatment categories. The use of CPI, especially in combination, is associated with significant rates of Grade ≥ 3 AEs. Healthcare planning should anticipate the expected high number of patients presenting with irAEs in the future.

8.
J Clin Neurosci ; 56: 127-130, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30318071

RESUMO

Multi-disciplinary team meetings (MDTs) are considered essential to quality cancer care. For some malignancies, MDTs have been associated with improved outcomes, but data regarding the neuro-oncology MDT is limited. We prospectively described the MDT at our institution and evaluated its impact on clinical management. Cases were discussed amongst the treating team and a pre-MDT plan and reason for discussion (RFD) was documented before the MDT. Patient specific clinical data was captured prospectively, with further pathological and radiological information captured during the MDT. Subsequently, the MDT consensus decision was recorded. High impact decisions (HID) were those in which the pre-MDT plan was substantially modified. A HID rate of >10% was considered clinically significant. Adherence to MDT recommendations was recorded. Seventy-nine cases were discussed at the MDT. Fifty-two cases (66%) were male. The median age was 53 (17-84). Thirty-three cases were new diagnoses and the remainder were relapsed/progressive disease. Thirty-nine cases were primary brain tumours, 25 were metastatic tumours and 15 were other. Twenty-eight (35%) had HID. No RFDs were statistically significantly associated with a HID (p = 0.265). Adherence data was collected for 95% (75) of cases. Treatment concordance with the MDT plan occurred in 90% (67) of cases. For cases of non-concordance, six out of eight (75%) were due to patient choice. Overall, a clinically significant proportion of treatment modifications are made at the neuro-oncology MDT. There were no case types which did not benefit from MDT discussion. MDT recommendations were largely adhered to, and in cases of non-concordance, were largely due to patient choice.

9.
Neuro Oncol ; 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29982805

RESUMO

Background: Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods: M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results: There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions: Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

10.
Intern Med J ; 48(10): 1206-1214, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29923272

RESUMO

BACKGROUND/AIM: This study was conducted retrospectively to evaluate rates of thrombocytopenia and their clinical impact during chemo-radiotherapy for glioblastomas and to elucidate associated clinical factors. METHODS: A total of 64 patients who received temozolomide chemotherapy at our institution was included; 35 patients received full-dose chemo-radiotherapy as per the STUPP protocol (Group A), and 9 patients received abbreviated radiotherapy with concurrent chemotherapy (Group B). Twenty patients received temozolomide alone with an intended 12 cycles of therapy for first relapse at least 6 months after completion of adjuvant chemotherapy (Group C). RESULTS: In Group A, 27 of 35 (77%) patients completed the chemo-radiotherapy phase; 14% had grade 3-4 thrombocytopenia leading to discontinuation. Of 27 patients, 16 (59%) completed adjuvant chemotherapy. There were no grade 3-4 thrombocytopenias, but 4% discontinued due to grade 2 thrombocytopenias. In Group B, four of nine (45%) patients completed the chemo-radiotherapy phase; 11% had grade 3-4 thrombocytopenias and discontinued treatment. Three of four (75%) patients completed adjuvant chemotherapy. Of these, 75% had grade 3-4 thrombocytopenias, but none discontinued. Finally, in Group C, 8 of 20 (40%) patients completed, with 10% discontinuing due to thrombocytopenias and the rest due to disease progression. In exploratory analyses, being female increased the risk of myelosuppresion, and there was a trend noticed in patients having a higher body surface area. CONCLUSION: Our toxicity data were within range of the literature. We identified the group of patients that have increased thrombocytopenia risk. Larger pooled retrospective series and prospective studies are required.

11.
Curr Opin Pharmacol ; 41: 114-121, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29883853

RESUMO

Since Nobel laureate Paul Ehrlich proposed the concept of magic bullet in 1906, Köhler and Milstein discovered Hybridoma technology in 1975, and Greg Winter pioneered the technique to humanize monoclonal antibodies in 1988, monoclonal antibodies have been successfully developed to treat medical illnesses. Monoclonal antibodies are effective treatments for inhibition of alloimmune reactivity, haematological malignancies, solid organ malignancies, viral illnesses and are also used as antiplatelet therapy. Their successful use in cancer and autoimmune diseases in humans have made them one of the fastest growing classes of new drugs approved for these indications in last few decades. This review focuses on the role of monoclonal antibodies as an immunomodulatory therapy against cancer and autoimmune diseases, the strategies used to enhance efficacy, and how resistance mechanisms are being addressed to improve therapeutic outcomes for patients.

12.
Head Neck ; 40(9): 2029-2042, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29667262

RESUMO

BACKGROUND: Newly diagnosed patients with head and neck cancer may be at risk for impaired neurocognitive function (NCF) due to disease, treatment, and lifestyle factors. METHODS: Eighty pretreatment patients with head and neck cancer and 40 control patients without cancer completed assessment of NCF and self-reported cognition, fatigue, and mood. Blood samples to evaluate organ reserves, hormones, and cytokines were collected. RESULTS: Patients experienced worse symptoms of cognitive dysfunction, fatigue, and anxiety than controls. In contrast, NCF was equivalent for patients and controls. Using published norms as comparison, groups had similar high rates of impairment in performance (9/80 patients and 3/40 controls scored in the abnormal range). CONCLUSION: Pretreatment patients with head and neck cancer reported cognitive disturbance. The frequency of impaired performance, albeit high, was consistent with the literature demonstrating false-positive "abnormal" neuropsychological test performance is not uncommon. Inclusion of a noncancer patient control cohort is essential because using solely normative data as a comparison may foster erroneous interpretation.

13.
Oncologist ; 23(9): 1063-1075, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29703764

RESUMO

Primary and metastatic tumors of the central nervous system present a difficult clinical challenge, and they are a common cause of disease progression and death. For most patients, treatment consists primarily of surgery and/or radiotherapy. In recent years, systemic therapies have become available or are under investigation for patients whose tumors are driven by specific genetic alterations, and some of these targeted treatments have been associated with dramatic improvements in extracranial and intracranial disease control and survival. However, the success of other systemic therapies has been hindered by inadequate penetration of the drug into the brain parenchyma. Advances in molecular characterization of oncogenic drivers have led to the identification of new gene fusions driving oncogenesis in some of the most common sources of intracranial tumors. Systemic therapies targeting many of these alterations have been approved recently or are in clinical development, and the ability to penetrate the blood-brain barrier is now widely recognized as an important property of such drugs. We review this rapidly advancing field with a focus on recently uncovered gene fusions and brain-penetrant systemic therapies targeting them. IMPLICATIONS FOR PRACTICE: Driver gene fusions involving receptor tyrosine kinases have been identified across a wide range of tumor types, including primary central nervous system (CNS) tumors and extracranial solid tumors that are associated with high rates of metastasis to the CNS (e.g., lung, breast, melanoma). This review discusses the systemic therapies that target emerging gene fusions, with a focus on brain-penetrant agents that will target the intracranial disease and, where present, also extracranial disease.

14.
AAPS J ; 20(2): 43, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29520671

RESUMO

The selection of therapeutic dose for the most effective treatment of tumours is an intricate interplay of factors. Molecular imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT) can address questions central to this selection: Does the drug reach its target? Does the drug engage with the target of interest? Is the drug dose sufficient to elicit the desired pharmacological effect? Does the dose saturate available target sites? Combining functional PET and SPECT imaging with anatomical imaging technologies such as magnetic resonance imaging (MRI) or computed tomography (CT) allows drug occupancy at the target to be related directly to anatomical or physiological changes in a tissue resulting from therapy. In vivo competition studies, using a tracer amount of radioligand that binds to the tumour receptor with high specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Including imaging studies in early drug development can aid with dose selection and suggest improvements for patient stratification to obtain higher effective utility from a drug after approval. In this review, the potential value of including translational receptor occupancy studies and molecular imaging strategies early on in drug development is addressed.

15.
Mol Cancer Ther ; 17(4): 795-805, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29483208

RESUMO

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression. In addition, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR-targeting ADC comprised of an affinity-matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and antitumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR-amplified GBM patient derived xenograft (PDX) model and is highly effective alone and in combination with standard-of-care temozolomide in an EGFRvIII-positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase I clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR. Mol Cancer Ther; 17(4); 795-805. ©2018 AACR.

16.
Neuro Oncol ; 20(6): 838-847, 2018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29077941

RESUMO

Background: We recently reported an acceptable safety and pharmacokinetic profile of depatuxizumab mafodotin (depatux-m), formerly called ABT-414, plus radiation and temozolomide in newly diagnosed glioblastoma (arm A). The purpose of this study was to evaluate the safety and pharmacokinetics of depatux-m, either in combination with temozolomide in newly diagnosed or recurrent glioblastoma (arm B) or as monotherapy in recurrent glioblastoma (arm C). Methods: In this multicenter phase I dose escalation study, patients received depatux-m (0.5-1.5 mg/kg in arm B, 1.25 mg/kg in arm C) every 2 weeks by intravenous infusion. Maximum tolerated dose (MTD), recommended phase II dose (RP2D), and preliminary efficacy were also determined. Results: Thirty-eight patients were enrolled as of March 1, 2016. The most frequent toxicities were ocular, occurring in 35/38 (92%) patients. Keratitis was the most common grade 3 adverse event observed in 6/38 (16%) patients; thrombocytopenia was the most common grade 4 event seen in 5/38 (13%) patients. The MTD was set at 1.5 mg/kg in arm B and was not reached in arm C. RP2D was declared as 1.25 mg/kg for both arms. Depatux-m demonstrated a linear pharmacokinetic profile. In recurrent glioblastoma patients, the progression-free survival (PFS) rate at 6 months was 30.8% and the median overall survival was 10.7 months. Best Response Assessment in Neuro-Oncology responses were 1 complete and 2 partial responses. Conclusion: Depatux-m alone or in combination with temozolomide demonstrated an acceptable safety and pharmacokinetic profile in glioblastoma. Further studies are currently under way to evaluate its efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

17.
Artigo em Inglês | MEDLINE | ID: mdl-29167901

RESUMO

Importance: Neurocognitive deficits (NCD) have been observed in noncentral nervous system cancers, yet short- and long-term neurocognitive data on patients treated for head and neck cancer (HNC) are lacking. Objective: To assess objective neurocognitive function before and after definitive radiation therapy for HNC. Design, Setting, and Participants: In a prospective, longitudinal study, neurocognitive function and self-reported symptoms were assessed in 80 patients with histologically proven HNC requiring definitive chemoradiotherapy or radiotherapy and in 40 healthy controls 4 times (baseline, 6, 12, and 24 months after baseline) prior to commencing treatment at Princess Margaret Cancer Centre, Toronto, Canada. Main Outcomes and Measures: Neurocognitive test scores were converted to age-corrected z scores (mean, 0; standard deviation, 1) and reported as mean scores, standardized regression-based scores, and frequencies of impairments in intellectual capacity, concentration, memory, executive function, processing speed, and motor dexterity. Multivariable analysis was used to identify factors associated with NCD 2 years after treatment. Results: Eighty patients and 40 healthy controls enrolled. Analyses revealed significant differences between patient and control mean performance in some domains, with patient deficits increasing over time: intellectual capacity (Cohen d, effect sizes [95% CIs] of -0.46 [-0.64 to 0.30], -0.51 [-0.72 to -0.30], and -0.70 [-0.92 to -0.49] for time points 6, 12, and 24 months, respectively); concentration/short-term attention span (-0.19 [-0.37 to 0.00], -0.38 [-0.55 to -0.21], -0.54 [-0.71 to -0.37]); verbal memory (-0.16 [-0.33 to 0.02], -0.38 [-0.64 to -0.12], -0.53 [-0.74 to -0.32]); executive function (-0.14 [-0.27 to 0.00], -0.34 [-0.52 to -0.16], -0.43 [-0.64 to -0.22]), and global cognitive function composite (-0.38 [-0.55 to -0.22], -0.75 [-0.92 to -0.58], -1.06 [-1.26 to -0.86]). There was an increased rate of impaired global neurocognitive functioning among patients (38%) at 24 months compared with controls (0%). Neurocognitive deficits were not associated with baseline cytokines. Conclusions and Relevance: Head and neck cancer survivors have neurocognitive sequelae up to 2 years after definitive chemoradiotherapy or radiation treatment. Patients and health care teams should know about such potential risks. Further research is warranted in search of strategies to avoid, reduce, and compensate for declines.

18.
Cancer Chemother Pharmacol ; 80(6): 1209-1217, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29075855

RESUMO

PURPOSE: Patients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~ 50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody-drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monotherapy at the recommended Phase 2 dose (RPTD) in patients with EGFR-amplified, rGBM. METHODS: M12-356 (NCT01800695) is an open-label study with three escalation and expansion cohorts. Sixty-six patients with EGFR-amplified, rGBM were treated with depatux-m monotherapy at 1.25 mg/kg intravenously every 2 weeks. Adults with measurable rGBM, who were bevacizumab-naïve, with EGFR amplification were eligible. RESULTS: Among 66 patients, median age was 58 years (range 35-80). All patients were previously treated with radiotherapy/temozolomide. The most common adverse events (AEs) were eye related (91%), including blurred vision (65%), dry eye (29%), keratitis, and photophobia (27% each). Grade 3/4 AEs occurred in 42% of all patients, and ocular Grade 3/4 AEs occurred in 33% of patients overall. One patient (2%) had a Grade 4 ocular AE. Ocular AEs were manageable and usually resolved once treatment with depatux-m ceased. The objective response rate was 6.8%, the 6-month progression-free survival rate was 28.8%, and the 6-month overall survival rate was 72.5%. CONCLUSION: Depatux-m monotherapy displayed frequent but mostly Grade 1/2 ocular toxicities. A PFS6 of 28.8% was observed in this rGBM population, warranting further study.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Glioblastoma/tratamento farmacológico , Imunoconjugados/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade
19.
Nat Rev Clin Oncol ; 14(11): 695-707, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28675164

RESUMO

Glioblastomas are high-grade brain tumours with a poor prognosis and, currently, few available therapeutic options. This lack of effective treatments has been linked to diverse factors, including target selection, tumour heterogeneity and poor penetrance of therapeutic agents through the blood-brain barrier and into tumours. Therapies using monoclonal antibodies, alone or linked to cytotoxic payloads, have proved beneficial for patients with different solid tumours; these approaches are currently being explored in patients with glioblastoma. In this Review, we summarise clinical data regarding antibody-drug conjugates (ADCs) against a variety of targets in glioblastoma, and compare the efficacy and toxicity of targeting EGFR with ADCs versus naked antibodies in order to illustrate key aspects of the use of ADCs in this malignancy. Finally, we discuss the complex challenges related to the biology and mutational changes of glioblastoma that can affect the use of ADC-based therapies in patients with this disease, and highlight potential strategies to improve efficacy.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Imunoconjugados/uso terapêutico , Barreira Hematoencefálica , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Ensaios Clínicos como Assunto , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Imunoconjugados/farmacologia , Mutação
20.
Cancer Treat Rev ; 59: 1-21, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28715775

RESUMO

The development of HER2-directed monoclonal antibodies and tyrosine kinase inhibitors have provided benefits to cancer patients, as well as produced many insights into the biology of the ErbB receptor family. Current therapies based on ErbB family members have resulted in improved overall survival with associated improvements in quality of life for the cancer patients that respond to treatment. Compared to monotherapy using either two antibodies to block the HER2 receptor blockade or combinatorial approaches with HER2 antibodies and standard therapies has provided additional benefits. Despite the therapeutic success of existing HER2 therapies, personalising treatment and overcoming resistance to these therapies remains a significant challenge. The heterogeneous intra-tumoural HER2 expression and lack of fully predictive and prognostic biomarkers remain significant barriers to improving the use of HER2 antibodies. Imaging modalities using radiolabelled pertuzumab and trastuzumab allow quantitative assessment of intra-tumoural HER2 expression, HER2 antibody saturation and the success of different drug delivery systems to be assessed. Molecular imaging with HER2 antibodies has the potential to be a non-invasive, predictive and prognostic technique capable of influencing therapeutic decisions, predicting response and failure of treatments as well as providing insights into receptor recycling and signalling. Similarly, conjugating HER2 antibodies with novel toxic payloads or combining HER2 antibodies with cellular immunotherapy provide exciting new opportunities for the management of tumours overexpressing HER2. Future research will lead to higher therapeutic responses, lower toxicities and providing insight into the mechanisms of resistance to HER2-targeted treatments.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Terapia de Alvo Molecular/métodos , Receptor ErbB-2/genética , Adulto , Idoso , Neoplasias da Mama/mortalidade , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Receptor ErbB-2/efeitos dos fármacos , Análise de Sobrevida , Trastuzumab/administração & dosagem , Resultado do Tratamento
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