Chris Karapetis

Phase III Randomized, Placebo-Controlled Study of Cetuximab Plus Brivanib Alaninate Versus Cetuximab Plus Placebo in Patients With Metastatic, Chemotherapy-Refractory, Wild-Type K-RAS Colorectal Carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 Trial

PURPOSE The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity. PATIENTS AND METHODS Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m(2) intravenous loading dose followed by weekly maintenance of 250 mg/m(2) plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS). RESULTS A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively. CONCLUSION Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.

Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma with severe renal impairment or on haemodialysis.

Study Type – Therapy (case series)

South Australian clinical registry for metastatic colorectal cancer.

Introduction:  The aims of the South Australian Clinical Registry for Metastatic Colorectal Cancer are to record case outcomes according to site of recurrence and mode of clinical practice and to utilize the accumulated information for quality assurance activities.

A novel use of temozolomide in a patient with malignant prolactinoma.

We report a 64-year-old male who presented to our department in 2007 with bitemporal hemianopia secondary to a large recurrent pituitary prolactinoma in the sellar region and metastatic deposits elsewhere in his neuraxis. He underwent a transphenoidal excision of the large pituitary adenoma which was uncomplicated, although he did suffer from diabetes insipidus post-operatively. He had initially been diagnosed with prolactinoma some years before and had undergone multiple craniotomies to debulk recurrent metastatic lesions. As the patient had already undergone radiotherapy in the past, a novel approach to adjuvant therapy was necessary and he was started on a course of oral chemotherapy, temozolomide, with good results.

Gemcitabine and carboplatin in carcinoma of unknown primary site: a phase 2 Adelaide Cancer Trials and Education Collaborative study

Cancer of unknown primary site (CUP) represents up to 5% of all cancer diagnoses and is associated with poor survival. We have performed a prospective multicentre phase 2 trial to evaluate efficacy and toxicity of the combination of gemcitabine (G) and carboplatin (C) for patients with CUP. Patients with histologically confirmed metastatic carcinoma in which the primary site of cancer was not evident after prospectively designated investigation and who had ECOG performance status 0–2 were treated with G 1000 mg m−2 intravenously (i.v.) days 1 and 8, and C AUC 5 i.v. on day 8 every 3 weeks to a maximum of nine cycles. The primary end points were response rate, and toxicity, with secondary end points of progression-free survival and overall survival. Fifty-one (23 male, 27 female) patients were enrolled (one patient ineligible), with a median age of 69 years (range 41–83 years). Fifty patients were evaluable for toxicity and 46 patients were evaluable for efficacy. The overall response rate to the GC regimen was 30.5%. With a median follow-up of 24 months, the median progression-free survival was 18 weeks (4.2 months) and the median overall survival was 34 weeks (7.8 months). The frequency of grade 3 or 4 toxicity was low. Nausea/vomiting was the most common side effect, but was usually only mild in severity. Uncomplicated neutropenia (14%), thrombocytopenia (10%) and anaemia (8%) were the most common causes of grade 3–4 toxicity. The regimen was very well tolerated, particularly in the elderly. The GC regimen is an active regimen in CUP with excellent tolerability and should be considered particularly for elderly patients with CUP.

Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers

Immune checkpoint inhibitors (ICI) are an important development in the treatment of advanced cancer. A substantial proportion of patients treated with ICI do not respond, and additionally patients discontinue treatment due to adverse effects. While many novel biological markers related to the specific mechanisms of ICI actions have been investigated, there has also been considerable research to identify routinely available blood and clinical markers that may predict response to ICI therapy. If validated, these markers have the advantage of being easily integrated into clinical use for nominal expense. Several markers have shown promise, including baseline and post-treatment changes in leucocyte counts, lactate dehydrogenase and C-reactive protein. While promising, the results between studies have been inconsistent due to small sample sizes, follow-up time and variability in the assessed markers. To date, research on routinely available blood and clinical markers has focussed primarily on ICI use in melanoma, the use of ipilimumab and on univariate associations, but preliminary evidence is emerging for other cancer types, other ICIs and for combining markers in multivariable clinical prediction models.

A phase Ib/II study of second-line therapy with panitumumab, irinotecan, and everolimus (PIE) in metastatic colorectal cancer with KRAS wild type (WT).

TPS162 Background: Activation of the EGFR results in cell proliferation and survival via the RAS/RAF/MAPK, and PI3K/PTEN/AKT signalling pathways. Mutations in the KRAS gene result in a constitutively active protein that is independent of the EGFR and therefore is not inhibited by anti-EGFR monoclonal antibodies. However, recent retrospective studies have shown that aberrations in other down stream signalling molecules also confer resistance to EGFR antagonists, including mutations in BRAF and PI3K, and loss of the PTEN tumour suppressor molecule. The mammalian target of rapamycin (mTOR) is a key downstream regulatory protein that is activated via the PI3K-AKT pathway, and regulates cell growth, proliferation, and survival. Inhibition of mTOR in addition to blockade of the EGFR may cause a more profound anti-tumour effect by overcoming upstream mechanisms of resistance. In EGFR-resistant colon cancer cell lines, in vitro and in vivo studies of the combination of everolimus and an EGFR inhibitor resulted in reduced tumour growth and resensitised resistant cancer cells to EGFR inhibition (Bianco. B J Cancer 2008:923-930). METHODS This is a phase Ib/II, open label, non-randomised study. Eligibility criteria include age ≥ 18 years, metastatic colorectal cancer that is KRAS wild type, following failure of first-line oxaliplatin and fluoropyrimidine combination chemotherapy, with adequate bone marrow reserve and organ function. Patients receive IV irinotecan and panitumumab every 2 weeks, with everolimus administered orally thoughout the 14 day cycle. The starting dose is irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate days. Dose finding will use a standard 3+3 design with the MTD being defined as the dose with DLTs in 1/6 or fewer patients. Following determination of the MTD, the phase II component of the study will begin for which the primary endpoint is response rate. A total of 50 patients will be recruited. Correlation of response rate with BRAF mutation, expression of PTEN, ERK, AKT, mTOR, and pS6K will be performed.

Very high GFR in cancer patients undergoing chemotherapy: prevalence, carboplatin dosing patterns and chemotherapy toxicity

Aim:  Carboplatin dosing depends on accurate glomerular filtration rate (GFR) estimation. There is a lack of clinical agreement about carboplatin dosing when the GFR measurement is very high (>110 mL/min).

Colorectal cancer treatment and survival over three decades at four major public hospitals in South Australia: trends by age and in the elderly.

Data from registries at four major public hospitals in South Australia indicate increased 5-year disease-specific survivals for colorectal cancer from 48% to 63% between 1980-1986 and 2005-2010. For 80+ year olds, the increase was smaller, from 47% to 52%. Risk of case fatality halved overall, adjusting for age, gender, stage, differentiation and sub-site. Patients aged 80+ years had a lower risk reduction of about a third (hazards ratio: 0.69; 95% confidence limits, 0.52-0.92). Percentages having surgery and other specified treatments were lower for 80+ year olds than younger cases, although increases in treatment intensity occurred in this age range during 1980-2010, as seen in younger ages, in accordance with guidelines. The study illustrates the important feedback clinical registries can provide to clinicians on care patterns and outcomes in their hospital settings. Feedback can be the subject of local deliberations on how to achieve the best outcomes, including in the elderly by considering the best trade-offs between optimal cancer care and accommodations for co-morbidity and frailty. Clinical registry data can be used in comparative effectiveness research in local settings where there are sufficient case numbers.

721PA MULTI-CENTRE, PHASE II, OPEN-LABEL, SINGLE ARM STUDY OF PANITUMUMAB, CISPLATIN AND GEMCITABINE IN BILIARY TRACT CANCER: PRIMARY RESULTS OF THE AGITG TACTIC STUDY

ABSTRACT Aim: Curative surgery is possible in less than a third of patients with biliary tract carcinoma (BTC). Most patients die of progressive cancer. This trial was designed to combine an optimal schedule of gemcitabine and cisplatin with the EGFR antibody panitumumab in patients with BTC. The primary objective was to determine the clinical benefit of this combination in KRAS wild-type (WT) BTC. Methods: Patients with KRAS WT locally advanced or metastatic BTC received gemcitabine1000mg/m2, cisplatin 25mg/m2 IV on days 1 and 8 of a 21 day cycle, with panitumumab 9mg/kg IV on day 1. KRAS status was determined by high resolution melt analysis PCR and confirmed with direct sequencing. The primary endpoint was objective clinical benefit at 12 weeks. The regimen was considered to be of interest if at least a 70% clinical benefit rate was achieved. Secondary endpoints included RR by RECIST v1.1; Time to treatment failure; Tolerability and safety; PFS; OS; Duration of response; CA19.9 response; QoL. Results: 80 patients were screened, 68 were WT KRAS (85%). Of these, 48 were enrolled between 2012 and 2013, across 14 Australian centres. Baseline demographics were well balanced with mean age 62yrs (range 40-82yrs). WHO PS 0 to 1. Most common grade III/IV adverse events were neutropenia (33.3%), infection (22.9%), thrombocytopenia (20%) and anaemia (16%). In addition, acneiform rash (12.5%), hypomagnesaemia (10.4%), fatigue (10.4%), vomiting (8.3%) and diarrhoea (6.3%) were also reported. The objective clinical benefit rate at 12 weeks was 84.1% (95% CI 69.5 – 92.1%); 18 SD (40%), 16 PR (36%) and 1 CR (2%). At this early assessment the actuarial rate of progression free survival is 8.4 months (95% CI 5.6 – 16.6%). Among 45 assessable patients, 20 (44%) were responders according to RECIST criteria (95% CI 31 – 59%). Data relating to the Secondary Endpoints will be presented at the meeting. Conclusions: The data presented confirms that the primary endpoint of the study was met. The combination of gemcitabine, cisplatin and panitumumab is a tolerable regimen with proven activity in our patient population. Further investigation of EGFR blockade in BTC is warranted. Disclosure: All authors have declared no conflicts of interest.