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33rd Congress of the European Society for Medical Oncology

Stockholm, Sweden / September 12-16, 2008

Renal cell carcinoma (RCC) and gastrointestinal stromal tumours (GIST), which are often first detected at advanced stages, have long had a dismal prognosis even if treated aggressively. Until the introduction of targeted therapies, the average median survival for metastatic RCC was seven months; for advanced GIST, average survival had ranged between nine and 20 months. Tyrosine kinase inhibitors (TKIs) active in these diseases have increased survival times radically. Since their introduction, sunitinib in RCC and imatinib in GIST have become standards of care. The efficacy of these therapies in each cancer demonstrates the substantial anti-tumour activity achieved by inhibiting molecular pathways of tumour growth.

“Targeted therapy has revolutionized outcomes for patients with metastatic RCC and advanced GIST,” observed Dr. Cora Sternberg, La Sapienza University, Rome, Italy, and Tufts University School of Medicine, Boston, Massachusetts. “The introduction of TKIs has changed the approach to treatment by demonstrating large survival benefits over previous standards.”

The previous standard in metastatic RCC, which has never shown an acceptable rate of response to cytotoxic agents, was the cytokine interferon-alfa (IFN-a) administered in relatively high doses. The TKI sunitinib replaced IFN-a as the reference standard when a phase III trial associated it with a large improvement in progression-free survival (PFS) (Motzer et al. N Engl J Med 2007;356:115-24). Longer follow-up more recently confirmed an advantage for overall survival (OS). In data first presented at the American Society of Clinical Oncology (ASCO) and now updated at ESMO, the OS advantage for sunitinib was demonstrated despite such confounders as crossovers and the use of adjuvant strategies employed after the study was completed.

“When unadjusted, the survival advantage of sunitinib was marginal [26.4 months vs. 21.8 months; P=0.051] but in those who received study treatment only, the median survival was doubled on sunitinib [28.1 months vs. 14.1 months; P=0.003],” reported Dr. Sylvie Négrier, Cytokine and Cancer Research Unit, Léon-Bérard Comprehensive Cancer Centre, Lyon, France. “Even when adjusted according to strata, the survival advantage for sunitinib was significant (P=0.0491) despite the fact that nearly 60% of patients received post-study treatment including crossover from IFN-a to sunitinib in 33% of the IFN-a group” (Figure 1).

Figure 1. Kaplan-Meier estimates of OS for patients who did not receive any post-study treatment

The registration trial randomized 750 patients to receive sunitinib or IFN-a. Entry criteria included metastatic RCC, ECOG performance status (PS) of 0 or 1 and no prior systemic treatment. The TKI was administered in a dose of 50 mg orally once-daily in a series of six-week cycles that called for four weeks of treatment followed by two weeks off therapy. IFN-a was administered subcutaneously in a dose of 9 MU three times per week. Based on evidence of sunitinib activity, the protocol was amended early in the trial to permit patients randomized to IFN-a to cross over to sunitinib upon documented disease progression.

The primary end point of the trial was PFS. At that time median OS had not been reached for either arm. Again, like the subsequent survival in patients who only took study treatment, the PFS was doubled (11 months vs. 5 months, P<0.0001) for sunitinib relative to IFN-a. This was consistent with the significantly higher objective response rate (31% vs. 6%; P<0.001) and a reduced likelihood of progressive disease (21% vs. 45%). Objective outcomes and progressive disease were documented by an independent central review.

The enhanced activity seen with sunitinib was achieved with greater tolerability. For example, grade 3 or 4 adverse events (AEs) were identified in 12% of those randomized to IFN-a vs. 7% (P<0.05) treated with sunitinib. Although there were higher rates of grade 3 vomiting (4% vs. 1%), hypertension (8% vs. 1%) and hand-foot syndrome (5% vs. 0%) on sunitinib than IFN-a (P<0.05 for each AE), grade 3 or 4 fatigue (12% vs. 7%) and several grade 3 laboratory abnormalities such as lymphopenia (22% vs. 11%) were more common on IFN-a. The greater tolerability of sunitinib was reflected in an improved quality of life (QoL) measured with either the Functional Assessment of Cancer Therapy – General (FACT-G) or the FACT –Kidney Symptom Index (FKSI) questionnaires (P<0.001 favouring sunitinib over IFN-a for both validated QoL measures).

In the newly reported survival analysis, sunitinib has become the first therapy to provide a median lifespan of more than two years after treatment. This is an important and meaningful milestone, particularly for a therapy with fewer adverse effects than many of the commonly used cytotoxic chemotherapies. In addition to randomization to sunitinib, seven factors were found on multivariate analysis to be predictors of OS, which now exceeds 36 months in a substantial proportion of patients in ongoing follow-up. These were ECOG PS of 0 relative to a PS of 1, a hemoglobin in the normal range, treatment initiated within a year of diagnosis, a corrected calcium, an alkaline phosphatase below the upper limit of normal, a lactate dehydrogenase less than 1.5 times the upper limit of normal, and fewer than two metastatic sites.

The ability to show a survival benefit despite the crossovers consolidated the clinical benefit previously reported for PFS. According to Dr. Négrier, the introduction of sunitinib represents an “improvement in the overall treatment landscape for RCC.” Echoing current treatment guidelines for metastatic RCC, she characterized sunitinib as “a reference standard of care for the first-line treatment of patients with metastatic RCC.”

The same terminology was employed by Dr. Sternberg, who indicated that sunitinib has provided a viable option for inoperable patients with advanced RCC for whom options had been extremely limited. Displaying a treatment algorithm for metastatic RCC, she identified sunitinib as the standard of care in intermediate or favourable risk disease (Table 1). However, she and other experts contended that optimal rates of response and of QoL are achieved with pre-emptive management of AEs.

“Targeted agents such as sunitinib are generally well tolerated, but AEs have the potential to discourage patients and lead to dose reductions. We have data that show that the efficacy of sunitinib relates to exposure. In addition, targeted agents generally act by inhibiting cell growth rather than by killing tumour cells, making it important to sustain adequate drug levels to maintain disease control,” explained Dr. Alain Ravaud, Centre Hospitalier Universitaire (CHU), Bordeaux, France.

Table 1. Treatment alg
renal cell carcinoma

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Several strategies were outlined by Dr. Ravaud for avoiding or minimizing dose-limiting side effects. For example, blood pressure elevations, a side effect common to many targeted agents, can be modified by treating patients with elevated blood pressure prior to therapy and adding antihypertensive drugs as needed to keep patients controlled. Counselling about such side effects as hand-foot syndrome prior to initiating therapy can help manage expectations. Most importantly, Dr. Ravaud advised intensive supportive care during the first two cycles of treatment when the risk of AEs is greatest.

“It is important to remember that general practitioners know very little if anything about the AEs of targeted therapies. Sunitinib is much easier to administer than the cytokines or many of the cytotoxic agents, but it is also important not to forget the risk of side effects,” Dr. Ravaud maintained. The attention to AEs is an important step both to preserving the QoL advantages as well as providing the greatest opportunity for a meaningful extension of survival.

Overcoming Mutational Resistance

Like the improvement in outcome offered by sunitinib in RCC, the impact of TKIs in GIST has been dramatic. With the introduction of imatinib, now well established as the first-line therapy, one-year survival has climbed from 35% to almost 90%. The major limitation of imatinib has been resistance, but subsequent studies with other TKIs, including sunitinib, have demonstrated that tumour control can be regained. Progress in this area has been rapid, including the definition of strategies to test for resistance and implement second-line agents as appropriate. Identifying the mutations and evaluating the activity of newer targeted therapies in the presence of these mutations has provided progress in understanding the molecular biology of the disease.

“Imatinib is the first-line choice against GIST expressing stem-cell factor receptor (KIT) that is either unresectable or metastatic,” reported Dr. Jean-Yves Blay, Léon-Bérard Comprehensive Cancer Centre. “Although raising imatinib doses to 800 mg/day can overcome some types of resistance, such as KIT exon 9 mutations, we now know that other targeted agents are active when imatinib fails.”

Dr. Blay observed, “Sunitinib is the therapy of choice after imatinib failure. The question is whether mutational testing should be standard either before starting therapy or after imatinib fails.” One reason to consider mutational testing is that the majority of patients develop resistance to the standard 400-mg dose of imatinib usually as the result of secondary mutations on the KIT gene. While increasing the dose to 800 mg is often performed empirically to overcome the modest resistance incurred by the exon 9 mutation, mutation testing could accelerate introduction of second-line therapies when the KIT mutations, such as those on exon 13 or 14, are not likely to respond to an increased imatinib dose.

“Mutational testing and awareness of patient-related factors may help optimize treatment choices in patients with advanced GIST,” Dr. Blay told delegates. However, he conceded that the quality of laboratory analysis might vary, and that it would be critical to have mutational testing conducted at experienced centres. Mutational testing may also accelerate the introduction of second- or third-line therapies. As a result of the different activity profiles of TKIs, cross-resistance has been modest. While sunitinib is often effective when imatinib fails, other TKIs, such as sorafenib, have demonstrated activity for GIST resistant to both imatinib and sunitinib. Dr. Blay predicted that formal strategies of how to sequence TKIs based on mutational testing are a likely direction of future research.

New Paradigms in GIST Management and Other Tumour Sites

TKIs may also have broader use in GIST. One of the most closely watched areas of development is the potential for TKIs to serve as adjunctive therapies in GIST surgical candidates. Case reports of benefit have now led to a trial in which patients with KIT-positive GIST are being randomized to imatinib or placebo. The ability of adjunctive TKIs to improve outcome is a logical expectation from their activity in advanced disease, but this has not yet been confirmed.

Sunitinib has been associated with an improvement in median OS in a placebo-controlled phase III study that has led to regulatory approval of this TKI for the treatment of imatinib-resistant or imatinib-intolerant GIST. In the trial, the sunitinib dose was 50 mg/day administered in the same six-week cycle that is now standard for the treatment of RCC. Compared to placebo, active treatment boosted the median OS from 35.7 weeks to 73.9 weeks (P<0.001) (Demetri et al. J Clin Oncol 2008;26(suppl): Abstract 10524).

Targeted therapies are increasingly being incorporated into standard protocols for a variety of cancers but are likely to be at an early stage of their potential. Bevacizumab, a monoclonal antibody targeted at the extracellular receptor of vascular endothelial growth factor (VEGF), has been associated with activity in several types of cancer, including breast malignancies, but redundant signalling pathways may limit its anti-tumour effect. TKIs, which act on intracellular signalling, often block more than one signalling pathway and therefore may have broader activities. Experimental studies associate sunitinib with blockade of KIT, VEGF, platelet-derived growth factor (PDGF) and downstream proteins on these signalling pathways. Other TKIs, such as imatinib and sorafenib, have both overlapping and unique actions on intracellular signalling.

“We can expect to see an increasing array of combinations. Already targeted therapies are now routinely combined with cytotoxic agents, but we may also see these agents used more frequently together or in combination with cytokines, such as IFN-a, or immunosuppressive agents, such as everolimus,” stated Dr. Joaquim Bellmunt, University Hospital del Mar, Barcelona, Spain. He also predicted that targeted therapies would be increasingly tested in protocols that sequence single agents to reduce toxicity and increase the duration of response while reducing the risk of resistance.

In RCC and GIST, the differences in the specific mechanisms of the growing array of targeted therapies have the potential to reveal more about how cancers proliferate, including the molecular changes induced by resistance. A number of phase III studies designed to evaluate clinical strategies for resistant disease may also reveal which signalling pathways are active. Citing a number of such trials, Dr. Bellmunt noted that in metastatic RCC, a study is being launched to compare the effects of enzastaurin, a serine/threonine kinase inhibitor, plus sunitinib to sunitinib plus placebo. In phase III trials already underway, axitinib, temsirolimus and sorafenib are being tested in sunitinib-refractory disease.

“In the adjuvant setting [for RCC], three large multicentre trials are ongoing. One is comparing sunitinib vs. placebo, another is comparing sunitinib to sorafenib or placebo, and a third is comparing sorafenib to placebo,” Dr. Bellmunt told delegates. “At the same time, the list of targeted therapies is growing with a number of other agents, such as cediranib and pazopanib, being tested in first- and second-line settings. This gives us hope that the progress already made in RCC will continue,” he remarked.

Summary

The development of targeted therapies is proceeding rapidly, driven at least in part by the substantial survival benefits provided by sunitinib in RCC and imatinib in GIST. While these targeted agents are already an accepted standard in routine patient care, they represent a vanguard for an approach to cancer that will involve controlling specific molecular processes important to tumour growth. It is likely that the full potential of neither sunitinib nor imatinib has been fully realized, particularly as they are combined with other classes of drugs, even as the number of targeted agents continues to expand.