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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 15th European Cancer Conference and 34th ESMO Multidisciplinary Congress

Berlin, Germany / September 20-24, 2009

According to the 2009 Canadian Kidney Cancer Forum Consensus Update (Can Urol Assoc J June 2009;3(3):200-4), the first option for patients with advanced or metastatic renal cell carcinoma (mRCC) is to enrol them in well-designed clinical trials. Observation can be considered for patients with slow-growing disease. The Canadian consensus guidelines indicate temsirolimus as an option for patients with adverse risk factors. The mTOR inhibitor showed improved progression-free and overall survival over interferon monotherapy and over combination interferon/temsirolimus, as demonstrated in a phase III trial of poor-risk patients (Hudes et al. N Engl J Med 2007;356:2271-81). The Canadian guidelines also indicated sorafenib and everolimus as other appropriate choices. As discussed here at the ECCO-ESMO congress, physicians treating patients with mRCC must keep in mind three principles of treatment optimization: correct dosing, pro-active side-effect (SE) management and duration of therapy. As confirmed by the Canadian Kidney Cancer Forum’s recommendation based on phase III data (Motzer RJ, Basch E. Lancet 2007;370:2071-3), the tyrosine kinase inhibitor (TKI) sunitinib is recommended as first-line therapy for patients with advanced or mRCC with clear-cell pathology. Currently, standard dosing of sunitinib, as confirmed in clinical trials, is 50 mg/day every day for four weeks, followed by two weeks off, in a six-week cycle.

Investigators have shown that the probability of treatment response to sunitinib increases in proportion with the area under the curve (AUC). Indeed, based on a meta-analysis of clinical trial experience, investigators found that time to tumour progression (TTP) was longer among patients with higher median AUCs of the TKI compared to those with lower median AUCs, noted Prof. Martin Gore, Chair, Royal Marsden Hospital NHS Trust, London, UK. “And in fact, the benefit for higher AUCs over lower AUCs was seen for overall survival as well,” he remarked.

These data suggest that physicians need to expose patients to as much drug as they can tolerate well for optimal efficacy. At this point in time, the goal of therapy is to maintain patients on sunitinib 50 mg/day, given on the “4/2” schedule, Prof. Gore indicated.

Strategies for Controlling Side Effects

Another important contributor to optimization of treatment response is pro-active management of SEs. “Even before initiating treatment with sunitinib, it’s important to assess the risk:benefit ratio of treatment in each patient and stabilize or reduce comorbidities,” Prof. Gore told delegates.

Physicians should ensure the most prevalent and acute SEs—hypertension, hand-foot syndrome, diarrhea—are controlled. For instance, in hypertensive patients, blood pressure should be monitored on a regular basis and not allowed to exceed 150/90 mm Hg. Often within the first six weeks of treatment, hand-foot syndrome might arise and calls for better hand and foot protection and proper moisturizing with lanolin or urea-based products to minimize TKI toxic effects. “Diarrhea can also be problematic,” he explained. Gastrointestinal side effects may be managed by avoidance of dietary triggers, diet modification (small meals and more frequently) and the use of antidiarrheals.

Hypothyroidism, hypophosphatemia and anemia all contribute to fatigue and can be treated. For a minority of patients, the dose may need to be reduced or temporarily stopped to allow symptoms to resolve. Energy-saving strategies should also be recommended for patients experiencing fatigue but it is often difficult to avoid dose reduction in the presence of significant fatigue, as speakers here acknowledged.

Myelosuppression can occur with TKI therapy as well, Prof. Gore noted, but hematological toxicities are not usually severe enough to warrant treatment interruption. Cardiac toxicity has also been reported with TKI therapy, and especially with longer-term use, physicians should monitor left ventricular function.

Investigating Continuous Dosing

As Prof. Gore indicated, duration of therapy is also important for optimization of treatment response. In the final analysis of the pivotal sunitinib trial, response to treatment increased from 31% to 39% as treatment was extended from six to 11 months. “These data suggest that length of treatment is important,” he remarked.

Maintenance of standard-dose sunitinib is a key strategy in the optimization of treatment benefit but other approaches are being explored in an effort to improve patient outcomes. In a recent trial, Escudier et al. (J Clin Oncol 2009; 27:4068-75) reported that sunitinib 37.5 mg/day given on a continuous, once-daily schedule demonstrated a manageable safety profile and significant antitumour activity as a second-line treatment in mRCC. This schedule could provide flexibility in the dosing regimen and may be a reasonable alternative for patients who experience significant SEs during the two-week “off” interval, as speakers suggested.

In another phase II trial reported here, Barrios et al. presented final results of an open-label, multicentre trial of continuous, once-daily sunitinib 37.5 mg given as first-line treatment for mRCC. Patients in the study had received no prior systemic therapy for RCC.

Of 116 patients evaluable for tumour response, 41 achieved a confirmed partial response for an objective response rate of 35.3%. Median duration of response was 10.4 months, while disease stabilized in 43% of the cohort. Combined, the clinical benefit rate (complete response, partial response and stable disease) was 78%, as the authors reported, while median progression free survival was nine months.

Grade 3 and 4 SEs did occur most frequently with this regimen, particularly hand-foot syndrome (13%), neutropenia (11%) and diarrhea (9%). One patient also experienced grade 3 congestive heart failure. Investigators concluded that continuous daily dosing of sunitinib demonstrated a manageable safety profile as first-line mRCC therapy, making it a feasible alternative dosing regimen.

Results from the on-going EFFECT (Efficacy and Safety of Sunitinib Malate Schedule 4/2 vs. Sunitinib Malate Continuous Dosing as First-line Therapy for Metastatic Renal Cell Cancer) trial are expected next year and should shed additional light on optimal dosing schedules. Approximately 300 patients are randomized to either standard-dose sunitinib, given on the “4/2” schedule, or continuous daily dosing at 37.5 mg.

Future Directions

An ambitious investigative program is underway exploring the use of sunitinib in combination with a variety of other proven agents in advanced breast cancer. As pointed out by Dr. Martine Piccart-Gebhart, Professor of Oncology, Université Libre de Bruxelles, Belgium, anti-angiogenesis has been shown to be an active therapeutic strategy in breast cancer. Initial case reports in which sunitinib was given in combination with docetaxel suggest that the combination can achieve long periods of disease control in advanced breast cancer and that it has an acceptable toxicity profile. This combination is currently being explored in a more formal study of metastatic breast cancer in which sunitinib plus docetaxel will be compared with docetaxel alone.

Meanwhile, results from three randomized trials in metastatic breast cancer suggest that the addition of bevacizumab to standard control arms increased progression-free survival from 0.8 to 5.6 months across the three studies but that there was no overall survival advantage from additional bevacizumab.

Summary

In daily clinical practice, patients are often more challenging to manage than those who are selected for randomized clinical trials and the benefit of treatment as demonstrated in those trials may not be fully appreciated in real-world setting. In order to extend potential benefits to patients, physicians must heed lessons learned from clinical trials, including the need to use standard-dose TKI therapy, given for an appropriate interval and without interruption or dose reduction wherever possible. Other innovative scheduling regimens with TKI therapy may yet emerge as may other indications for combination therapy in the setting of advanced breast cancer. The multi-target TKI sunitinib with anti-angiogenic activity has become the reference standard of care in the first-line treatment of mRCC, doubling progression-free survival compared with interferon-alpha and extending median overall survival to more than two years.