Tisotumab vedotin is a first-in-human antibody–drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We ...aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor.
InnovaTV 201 is a phase 1–2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0–1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing.
Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 69% of 147 patients), fatigue (82 56%), nausea (77 52%), alopecia (64 44%), conjunctivitis (63 43%), decreased appetite (53 36%), constipation (52 35%), diarrhoea (44 30%), vomiting (42 29%), peripheral neuropathy (33 22%), dry eye (32 22%), and abdominal pain (30 20%). The most common adverse events of grade 3 or worse were fatigue (14 10% of 147 patients), anaemia (eight 5%), abdominal pain (six 4%), hypokalaemia (six 4%), conjunctivitis (five 3%), hyponatraemia (five 3%), and vomiting (five 3%). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2–22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment.
Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours.
Genmab A/S.
To investigate the safety and activity of cetuximab in the pre-operative treatment of squamous cell carcinoma of the head and neck (SCCHN).
Cetuximab was administered for 2 weeks before surgery to 33 ...treatment-naïve patients selected for primary surgical treatment. Tumour biopsies, 2-fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (18FDG-PET) and imaging were carried out at baseline and before surgery. The primary aim of the study was safety and the secondary aims included metabolical, radiological and pathological tumour response. Five untreated patients were included as controls.
Cetuximab given 24 h before surgery was safe. Ninety percent of patients had 18FDG-PET partial response (EORTC guideline) in the cetuximab group versus 0% in the control group. Delta maximal standardized uptake values (ΔSUVmax) were correlated with tumour cellularity on the surgical specimens (P < 0.0001). For patients with ΔSUVmax less than -25% or less than -50%, Ki67 was significantly decreased by cetuximab (P = 0.01 and 0.003). Cetuximab induced down-regulation of pEGFR (P = 0.0004) and pERK (P = 0.003).
Short-course pre-operative administration of cetuximab is safe and shows a high rate of 18FDG-PET response. 18FDG-PET response was correlated with residual tumour cellularity suggesting that 18FDG-PET deserves further investigation as a potential early marker of cetuximab activity in SCCHN.
•This EHNS-ESMO-ESTRO Clinical Practice Guideline provides key recommendations for managing SCCHN.•It covers clinical and pathological diagnosis, staging and risk assessment, treatment and ...follow-up.•Opportunities for personalised medicine in SCCHN are also discussed.•All recommendations were compiled by a multidisciplinary group of experts from different institutions and countries.•Recommendations are based on available clinical evidence and the collective expert opinion of the authors.
Preclinical studies have shown that PTEN loss enhances sensitivity to mammalian target of Rapamycin (mTOR) inhibitors because of facilitated PI3K (phosphatidylinositol-3 kinase)/Akt activation and ...consecutive stimulation of the mTOR pathway. In patients with advanced transitional cell carcinoma (TCC) treated with the mTOR inhibitor everolimus, PTEN loss was, however, associated with resistance to treatment.
Transitional cell carcinoma specimens, human bladder cancer cells and derived mouse xenografts were used to evaluate how the PTEN status influences the activity of mTOR inhibitors.
Transitional cell carcinoma patients with a shorter progression-free survival under everolimus exhibited PTEN deficiency and increased Akt activation. Moreover, PTEN-deficient bladder cancer cells were less sensitive to rapamycin than cells expressing wild-type PTEN, and rapamycin strikingly induced Akt activation in the absence of functional PTEN. Inhibition of Akt activation by the PI3K inhibitor wortmannin interrupted this rapamycin-induced feedback loop, thereby enhancing the antiproliferative effects of the mTOR inhibitor both in vitro and in vivo.
Facilitation of Akt activation upon PTEN loss can have a more prominent role in driving the feedback loop in response to mTOR inhibition than in promoting the mTOR pathway. These data support the use of both PI3K and mTOR inhibitors to treat urothelial carcinoma, in particular in the absence of functional PTEN.
Abstract Background Most patients with metastatic breast cancer (MBC) progress after chemotherapy. Cabazitaxel (XRP6258) is a new taxoid that is active in chemotherapy-resistant tumour cell lines. ...The objectives of this phase I/II study were to assess the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and activity of cabazitaxel plus capecitabine in patients with MBC who had been previously treated with taxanes and anthracyclines. Patients and methods In part I, we used a 3 + 3 dose–escalation scheme to assess the MTD of intravenous cabazitaxel (day 1) with oral capecitabine twice daily (days 1–14) every 3 weeks. In part II, we evaluated the objective response rate (ORR) at the MTD. Results Thirty-three patients were enrolled and treated (15 in part I; 18 in part II). Cabazitaxel 20 mg/m2 plus capecitabine 1000 mg/m2 was the MTD. Pharmacokinetic analysis showed no apparent drug–drug interaction. In all patients, the main grade 3–4 toxicities were asthenia ( n = 5), hand–foot syndrome ( n = 5), neutropenia ( n = 21), neutropenic infection ( n = 1), and neutropenic colitis ( n = 1). One patient had febrile neutropenia. Antitumour activity was observed at all dose-levels with two complete responses, five partial responses (PRs), and 20 disease stabilisations (seven unconfirmed PR). At the MTD, 21 patients were evaluable for efficacy. The ORR was 23.8% (95% CI: 8.2–47.2%). The median response duration was 3.1 months (95% CI: 2.1–8.4 months), with four of five lasting for more than 3 months. Median time to progression was 4.9 months. Conclusions Cabazitaxel combined with capecitabine is active, has a safety profile consistent with a taxane plus capecitabine combination and warrants further investigation in patients with MBC.
Background
Inflammation is associated with a worse outcome in cancer and neutrophil:lymphocyte ratio (NLR) is a strong prognostic value. In cancer, nonsteroidal anti-inflammatory drugs (NSAIDs) could ...be of interest. We investigated the prognostic significance of NLR and the impact of intraoperative NSAIDs in cancer surgeries.
Methods
We performed an observational study in early breast, kidney, and lung cancers (357, 227, and 255 patients) with uni- and multivariate analyses (Cox model).
Results
In breast cancer (Centre 1), NLR ≥ 4 is associated with a higher risk of relapse (hazards ratio (HR) = 2.41; 95 % confidence interval (CI) 1.01–5.76;
P
= 0.048). In breast cancer (Centre 2), NLR ≥ 3 is associated with a higher risk of relapse (HR = 4.6; 95 % CI 1.09–19.1;
P
= 0.04) and higher mortality (HR = 4.0; 95 % CI 1.12–14.3;
P
= 0.03). In kidney cancer, NLR ≥ 5 is associated with a higher risk of relapse (HR = 1.63; 95 % CI 1.00–2.66;
P
= 0.05) and higher mortality (HR = 1.67; 95 % CI 1.0–2.81;
P
= 0.05). In lung cancer, NLR ≥ 5 is associated with higher mortality (HR = 1.45; 95 % CI 1.02–2.06;
P
= 0.04). The intraoperative use of NSAIDs in breast cancer patients (Centre 1) is associated with a reduced recurrence rate (HR = 0.17; 95 % CI 0.04–0.43;
P
= 0.0002) and a lower mortality (HR = 0.25; 95 % CI 1.08–0.75;
P
= 0.01). NSAIDs use at the beginning of the surgery is independently associated with a lower metastases risk after lung cancer surgery (HR = 0.16; 95 % CI 0.04–0.63;
P
= 0.009). Ketorolac use is independently associated with longer survival (HR = 0.55; 95 % CI 0.31–0.95;
P
= 0.03).
Conclusions
In these cohorts, these analyses show that NLR is a strong perioperative prognosis factor for breast, lung, and kidney cancers. In this context, intraoperative NSAIDs administration could be associated with a better outcome.
In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell ...carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years.
Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m2/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed.
Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 95% confidence interval (CI) 0.45–1.03, P = 0.061} and younger patients 2.6 versus 1.6 months, HR = 0.79 (0.62–1.01), P = 0.052. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months HR = 0.84 (0.54–1.31) and 6.7 versus 6.2 months HR = 0.98 (0.76–1.28). ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%–77%) and diarrhea (70%–80%) with afatinib, and stomatitis (43%) and fatigue (31%–34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups.
Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients.
NCT01345682 (ClinicalTrials.gov).
Objective
To assess, in a multicentre phase II trial, the safety and efficacy of BEZ235, an oral pan‐class I phosphoinositol‐3‐kinase (PI3K) and mammalian target of rapamycin (mTOR) complex1/2 ...inhibitor, in locally advanced or metastatic transitional cell carcinoma (TCC) after failure of platinum‐based therapy.
Patients and Methods
Patients with locally advanced or metastatic TCC progressing after platinum therapy were prospectively stratified by PI3K/Akt/mTOR pathway alterations, defined as PTEN loss and PIK3CA mutation. All patients received BEZ235 until progressive disease or unacceptable toxicity. The primary endpoint was the progression‐free survival (PFS) rate at 16 weeks. This study was, however, closed prematurely because BEZ235 was withdrawn from further development.
Results
A total of 20 patients (18 without and two with PI3K/Akt/mTOR alterations) were enrolled and received BEZ235. One partial response (5%) and two cases of stable disease (10%) were observed, all in patients without PI3K/mTOR pathway alterations. The PFS rate at 8 and 16 weeks was 15 and 10%, respectively; the median (range) PFS was 62 (38–588) days (95% confidence interval CI 53–110); and the median (range) overall survival was 127 (41–734) days (95% CI 58–309). Among the 90% of patients who experienced drug‐related adverse events of any grade, 50% experienced grade 3–4 adverse events, including stomatitis (15%), fatigue (5%), nausea (5%), diarrhoea (5%), renal failure (5%), cutaneous rash (5%), hepatotoxicity (5%) and hypertension (5%).
Conclusion
BEZ235 showed modest clinical activity and an unfavourable toxicity profile in patients with advanced and pretreated TCC; however, a minority of patients experienced a clinical benefit, suggesting that a complete blockade of the PI3K/mTOR axis could improve outcome in some specific patients. Furthermore, this study showed that molecular stratification of patients for personalized medicine before treatment is feasible.
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