External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer.

BACKGROUND: Data for selpercatinib [a selective REarranged during Transfection (RET) inhibitor] from a single-arm trial (LIBRETTO-001, NCT03157128) in RET-fusion-positive advanced/metastatic non-small-cell lung cancer (NSCLC) were used in combination with external data sources to estimate comparative efficacy [objective response rate (ORR), progression-free survival, and overall survival (OS)] in first- and second-line treatment settings. METHODS: Patient-level data were obtained from a de-identified real-world database. Patients diagnosed with advanced/metastatic NSCLC with no prior exposure to a RET inhibitor and one or more prior line of therapy were eligible. Additionally, individual patient-level data (IPD) were obtained from the pemetrexed + platinum arm of KEYNOTE-189 (NCT03950674, first line) and the docetaxel arm of REVEL (NCT01168973, post-progression). Patients were matched using entropy balancing, doubly robust method, and propensity score approaches. For patients with unknown/negative RET status, adjustment was made using a model fitted to IPD from a real-world database. RESULTS: In first-line unadjusted analyses of the real-world control, ORR was 87.2% for LIBRETTO-001 versus 66.7% for those with RET-positive NSCLC (P = 0.06). After adjustment for unknown RET status and other patient characteristics, selpercatinib remained significantly superior versus the real-world control for all outcomes (all P < 0.001 except unadjusted RET-fusion-positive cohort). Similarly, outcomes were significantly improved versus clinical trial controls (all P < 0.05). CONCLUSIONS: Findings suggest improvement in outcomes associated with selpercatinib treatment versus the multiple external control cohorts, but should be interpreted with caution. Data were limited by the rarity of RET, lack of mature OS data, and uncertainty from assumptions to create control arms from external data.

Correlation between treatment effects on response rate and progression-free survival and overall survival in trials of targeted therapies in molecularly enriched populations.

BACKGROUND: The number of randomized trials of agents targeting oncogene-addicted tumors has surged in the past 10 years. Using a meta-analysis, we explored whether improvements in objective response rate (ORR) in comparative trials using targeted agents could serve as a potential surrogate endpoint for improvements in progression-free survival (PFS) or overall survival (OS) in populations with oncogene-addicted cancer. PATIENTS AND METHODS: Using commercial text mining software I2E, we searched ClinicalTrials.gov and MEDLINE databases for randomized, phase III trials based on prospectively defined criteria, including (i) use of agents targeting EGFR activating mutations, ALK rearrangements, BRAF V600E or V600K mutations, and BCR-ABL fusion protein; (ii) molecularly enriched trial population or subpopulation; (iii) control arm only randomized to chemo/cytotoxic therapy. Correlative analyses were performed using ORR, OS, and PFS data from trials that met these criteria. RESULTS: A total of 62 trials were identified; 15 met all of the prespecified criteria. The ORR effect size (both the difference in ORR between arms and the log odds ratio) and log PFS hazard ratio were strongly correlated: -0.78 (P = 0.0007) for the ORR difference model; -0.74 (P = 0.0017) for the log odds ratio model. ORR effect size was positively correlated with the log OS hazard ratio, but more weakly: -0.67 (P = 0.013) for the ORR difference model and -0.58 (P = 0.036) for the log odds ratio model. Analysis of the treatment effects between OS and PFS found no correlation. CONCLUSIONS: These analyses identified a strong correlation between treatment effects on ORR and PFS in randomized clinical trials investigating agents targeting oncogene-driven cancers. A weaker correlation was observed between ORR and OS. These meta-analysis results support the use of a high ORR forming the basis of an initial regulatory approval in biomarker-driven studies.

Amisulpride prevents nausea and vomiting associated with highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled, dose-ranging trial.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) remain significant clinical problems, especially in the delayed phase (24-120 h after chemotherapy). Amisulpride is a dopamine D2/D3-receptor antagonist previously shown to be an effective intravenous antiemetic. We conducted a randomised, double-blind study to characterise the dose response of oral amisulpride in delayed phase CINV. METHODS: Chemotherapy-naïve patients receiving cisplatin ≥ 70 mg/m2 or an anthracycline-cyclophosphamide regimen for breast cancer received, on day 1, 20 mg amisulpride and 8-16 mg ondansetron intravenously followed, once daily on days 2-4, by 10, 20 or 40 mg oral amisulpride or placebo. A control group receiving standard three-drug prophylaxis was enrolled for assay sensitivity purposes. The primary endpoint was complete response (CR), defined as no emesis or rescue medication use, in the delayed phase. RESULTS: Three hundred eighteen subjects were evaluable per protocol. CR rate (24-120 h) was 20% with placebo and 46% with 10 mg amisulpride (p = 0.006 after multiplicity adjustment); in the three-drug control group, it was 59%. Emesis, nausea and 0-120-h CR rate were significantly improved with 10 mg amisulpride compared to placebo. Higher doses of amisulpride were not more effective than 10 mg. In patients with acute phase CR, delayed phase CR rate was 44% for placebo, 75% for 10 mg amisulpride (p = 0.022) and 70% for the 3-drug control. No significant differences were seen between groups in safety parameters. CONCLUSIONS: Amisulpride 10 mg orally is safe and superior to placebo at preventing delayed CINV caused by highly emetogenic chemotherapy. TRIAL REGISTRATION: NCT01857232.

Cisplatin in the modern era: The backbone of first-line chemotherapy for non-small cell lung cancer.

The treatment of advanced non-small cell lung cancer (NSCLC) may be changing, but the cisplatin-based doublet remains the foundation of treatment for the majority of patients with advanced NSCLC. In this respect, changes in practice to various aspects of cisplatin use, such as administration schedules and the choice of methods and frequency of monitoring for toxicities, have contributed to an incremental improvement in patient management and experience. Chemoresistance, however, limits the clinical utility of this drug in patients with advanced NSCLC. Better understanding of the molecular mechanisms of cisplatin resistance, identification of predictive markers and the development of newer, more effective and less toxic platinum agents is required. In addition to maximising potential benefits from advances in molecular biology and associated therapeutics, modification of existing cisplatin-based treatments can still lead to improvements in patient outcomes and experiences.

Feasibility of home delivery of pemetrexed in patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES: To evaluate the feasibility and adherence to home delivery (HD) of pemetrexed maintenance treatment in patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC). MATERIALS AND METHODS: Exploratory, prospective, single-arm, Phase II study in advanced nsqNSCLC patients, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1 that did not progress after 4 first-line induction cycles of a platinum doublet. The first cycle of pemetrexed (500mg/m(2)) was hospital administered, further cycles were HD until progressive disease or discontinuation. Feasibility was assessed by the adherence rate to HD (probability of reversion to hospital administration or treatment discontinuation due to HD) as primary endpoint, and by health-related quality-of-life (HRQoL: EQ-5D, lung cancer symptom scale [LCSS]), satisfaction with HD, overall survival (OS), and safety. RESULTS: 52 patients (UK & Sweden) received a median of 4 (range 1-19) pemetrexed maintenance cycles. Adherence rate up to Cycle 6 was 98.0% (95% confidence interval [CI]: 86.4%, 99.7%). All but 2 patients remained on HD. 1 patient discontinued after Cycle 1 (patient decision), and 1 after Cycle 6 (non-compliance with oral dexamethasone). 87% (33/38) of the patients preferred home to hospital treatment and in 90% (28/31) of cases, physicians were satisfied with distant management of patients. During HD Cycles 2-4 mean change from baseline ranged from 3.0 to 7.7 for EQ-5D visual analog scale. The 6-month OS rate was 73% (95% CI: 58%, 83%). 1 patient had an HD-related adverse event (device-related infection, Grade 2) and 1 patient died after Cycle 1, before HD, due to a possibly drug-related atypical pneumonia. CONCLUSION: HD of pemetrexed maintenance treatment in patients with advanced nsqNSCLC was feasible, safe, and preferred by patients, while maintaining HRQoL. Physicians were satisfied with distant patient management.

The effect of resistance inspiratory muscle training in the management of breathlessness in patients with thoracic malignancies: a feasibility randomised trial.

OBJECTIVES: Breathlessness in patients with lung cancer is a common and distressing symptom affecting 50-70 % of patients, rising to some 90 % for those with advanced lung cancer. The aim of the current study was to assess how feasible inspiratory muscle training (IMT) is in the lung cancer population and explore changes in outcome variables. MATERIALS AND METHODS: A pilot feasibility randomised trial was conducted in patients with clinically stable lung cancer. The experimental group received training using a pressure threshold device. Patients were instructed to carry out five IMT sessions weekly for 12 weeks for a total of 30 mins/day. Patients in the control group received standard care. Outcome measures were completed at baseline and monthly for 3 months, and included: physiological parameters (FEV1, FVC); perceived severity of breathlessness using six 10-point NRS; modified Borg Scale; quality of life using the short form Chronic Respiratory Disease Questionnaire; Hospital Anxiety and Depression Scale, and safety. RESULTS: Forty-six patients (M = 37, F = 9) at a mean age of 69.5 years old and a mean of 16 months post-diagnosis who were not currently receiving chemotherapy and/or radiotherapy were recruited. Seventy-percent had NSCLC and advanced disease. Statistical (area under the curve-AUC) and clinically important differences were seen with regard to distress from breathlessness (p = 0.03), ability to cope with breathlessness (p = 0.01), satisfaction with breathlessness management (p = 0.001), fatigue (p = 0.005), emotional function (p = 0.011), breathlessness mastery (p = 0.015) and depression (p = 0.028). The m-Borg difference between the two groups at 3 months was 0.80, which is borderline clinically significant. Changes were more evident in the 3-month assessment where the effect of the intervention came to its peak. CONCLUSION: This trial shows the IMT is feasible and potentially effective in patients with lung cancer. These findings warrant a fully powered larger randomised controlled trial.

Effect of temozolomide on central nervous system relapse in patients with advanced melanoma.

Temozolomide has shown efficacy in the treatment of metastatic melanoma similar to that of dacarbazine (DTIC), the standard chemotherapy, but with the added benefit of penetration into the central nervous system (CNS). Isolated CNS relapse is increasingly a problem for patients who respond to biochemotherapy. By replacing DTIC with temozolomide in treatment regimens, the incidence of CNS relapse might be reduced. This hypothesis is difficult to test in a prospective randomized controlled trial because of the large number of patients that would be required. We have examined this question in a retrospective case control study, observing the rates of CNS relapse in advanced metastatic melanoma patients responding to DTIC- or temozolomide-based chemotherapy in three institutions. Twenty-one DTIC and 20 temozolomide responders were identified, and have been followed up for a median of 19.0 months (range 6.0-74.3 months). CNS relapse occurred in nine DTIC- and two temozolomide-treated patients, a statistically significant difference in favour of the new agent (P = 0.03). These results support the investigation of temozolomide as a replacement for DTIC in systemic treatment regimens for melanoma.

Cord blood G(0) CD34+ cells have a thousand-fold higher capacity for generating progenitors in vitro than G(1) CD34+ cells.

We examined the functional differences between G(0) and G(1) cord blood CD34+ cells for up to 24 weeks in serum-free suspension culture, containing Flt-3 ligand, thrombopoietin and stem cell factor. By week 24, there is more than a 1,000-fold difference in granulocyte, macrophage-colony-forming cells (GM-CFC) cumulative production between the two populations, with cultures initiated from G(0) demonstrating an amplification of 1.1 x 10(5)-1.8 x 10(6) of GM-CFC compared to 45-2.7 x 10(3) for the G(1) cells. Cells from the initial G(0) population are able to produce about 250-fold higher numbers of BFU-E than those from G(1) which translates to 3 x 10(3)-1.1 x 10(5)-fold expansion and 25-390-fold expansion for G(0) and G(1), respectively. This amplification of the progenitor cells is reflected in finding that a greater proportion of the progeny of the G(0) population are CD34+, resulting in a 600-fold expansion of CD34+ cells at week 8. As in other in vitro systems, total cell expansion is less discriminatory of stem cell behavior than progenitor cells, and there is no significant difference in total cell numbers between G(0) and G(1) cultures with a mean fold expansion of 2 x 10(7) at 24 weeks.

Randomized phase II study of cyclophosphamide, doxorubicin, and vincristine compared with single-agent carboplatin in patients with poor prognosis small cell lung carcinoma.

BACKGROUND: Information on the effect of chemotherapy in a group of patients with poor prognosis, poor performance status small cell lung carcinoma (SCLC) is scarce. A randomized study comparing single-agent carboplatin with combination chemotherapy in this largely unreported population of SCLC patients was undertaken. METHODS: One hundred nineteen patients were allocated to four cycles of either cyclophosphamide, doxorubicin, and vincristine (CAV) or single-agent carboplatin. Patients had either a Karnofsky performance score < or = 50 and/or a prognostic score indicative of a 1-year survival rate < or = 15%. RESULTS: Grade 3-4 neutropenia and intravenous antibiotic use were significantly more common with the CAV regimen (P < 0.005). Conversely, Grade 3-4 thrombocytopenia was more common (P < 0.0009) and platelet transfusion was more frequent (P < 0.05) with carboplatin therapy. Nonhematologic toxicity was similar in both treatment arms, except for alopecia with CAV therapy (P < 0.0007). Symptom relief occurred in 48% and 41% of patients in the CAV and carboplatin treatment arms, respectively. Dyspnea was improved in 66% and 41% of patients and cough was improved in 21% and 7% of patients in the CAV and carboplatin treatment arms, respectively. CAV therapy produced a higher response rate than carboplatin (38% vs. 25%), but this was not statistically significant (P = 0.15). The median overall survival for patients in the CAV and carboplatin treatment arms was 17 weeks and 15.9 weeks, respectively, with 1-year survival rates of 12% and 6%. CONCLUSIONS: Single-agent carboplatin is a feasible treatment in patients with poor prognosis SCLC and produces response rates, relief of tumor-related symptoms, and survival similar to what is seen in patients who receive CAV chemotherapy. The lower risk of life-threatening sepsis and less need for hospitalization or intravenous antibiotic courses is advantageous in this susceptible patient population.

Thromboembolism related to a Port-a-Cath device in a patient with cystic fibrosis.

The case is described of a potentially life threatening complication relating to the use of a totally implantable venous access device (Port-a-Cath) in a 28 year old patient with cystic fibrosis. The device was inserted in 1990 and used repeatedly for antibiotic therapy without any complications. In 1995, during assessment for double lung transplantation, a 3 cm thrombus was found at the tip of the catheter in the right atrium. Embolisation of the thrombus to the pulmonary arteries occurred after the infusion of recombinant tissue plasminogen activator (rt-PA). Thrombus formation may be associated with totally implantable venous access devices and thromboembolism may occur following the use of thrombolytic agents in the treatment of such thrombosis.