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Vascular endothelial growth factor (VEGF)-targeted therapy and mammalian target of rapamycin-targeted therapy clearly have demonstrated their value in the treatment of metastatic clear cell renal cell carcinoma as single agents. Conversely, sorafenib also has demonstrated its benefit as a single agent, albeit compared with placebo in cytokine-refractory patients.1 A series of investigations has sought to assemble evidence regarding the possible value of a sorafenib/interferon combination, whereas the field is deconstructing the bevacizumab/interferon combination to distill the benefit of bevacizumab. Simply put, it is clear that these 2 agents can be combined safely with interferon, but should the combination be investigated further?

Before the report by Jonasch and colleagues in the current issue of Cancer,2 the only evidence generated in support of the sorafenib/interferon combination came from 2 single-arm phase 2 trials.3, 4 In those trials, more “conventional” doses of interferon were administered 3 times weekly. At the dose and schedule used in those 2 trials, the true mechanism of action of interferon remained unclear. However, there is a body of literature supporting the immunologic consequences of interferon given in that way. Jonasch and colleagues chose an alternative dose and schedule of interferon, purportedly to maximize the antivascular effects of interferon that have been described in preclinical models.2 Whether this is more rational or less rational than combining sorafenib with more conventional interferon regimens is difficult to say, but it is clear that it is a different strategy and, thus, one that cannot easily be compared. Therefore, the “negative” results from the study by Jonasch et al do not necessarily provide insight into the potential value of sorafenib with conventional-dose/schedule interferon.

The strength of the study by Jonasch et al is the use of randomization in comparing single-agent sorafenib with combined sorafenib/interferon. The authors rightly conclude that their sample size was adequate to rule out a “paradigm-shifting” effect of combining the agents. However, the authors conclude that “further study of the combination of sorafenib plus interferon is not warranted.” Although this statement can be defended to some degree for the combination of sorafenib with low-dose, twice daily interferon, it cannot be extrapolated to the regimen of higher dose interferon 3 times weekly combined with sorafenib. We still have the results from 2 uncontrolled trials suggesting that the response rate may be significantly higher than that observed with either agent alone in previously conducted trials. Should randomized trials be done to sort out the value of sorafenib with conventional doses of interferon? Only bevacizumab has demonstrated efficacy in combination with interferon in definitive phase 3 trials. The addition of temsirolimus to interferon offered no benefit compared with interferon alone and clearly contributed to excess toxicity.5 The evidence from the 2 phase 3 trials that compared the combination of bevacizumab and interferon with interferon alone clearly placed the bevacizumab/interferon regimen among the effective therapies recently tested in this disease.6, 7 However, little evidence informs the interaction between the 2 drugs, and the field continues to ponder whether single-agent bevacizumab might confer similar benefits to the bevacizumab/interferon combination. Lacking comparative data between single-agent bevacizumab and interferon or a comparison of bevacizumab with a bevacizumab/interferon regimen, it is not possible to tease out single-agent bevacizumab as a standard therapy for renal cell carcinoma.

The mechanistic basis for combining sorafenib or bevacizumab with interferon must be considered distinct from the combinations of the newer “targeted” therapies (eg, bevacizumab or sorafenib with temsirolimus). If low-dose interferon administered frequently is an antiangiogenic therapy, then it appears to be quite a weak one compared with the newer agents.8 Considered that way, interferon would be chosen last among the available therapies in an attempt to assemble more effective antiangiogenic therapy. Compelling experimental evidence supports an immunosuppressive effect of VEGF in the tumor microenvironment.9 Thus, inhibiting VEGF signaling seems to be a rational approach to augment the immunologic effects of interferon to make it a better immunotherapy. Along this line of reasoning, it is logical to want to take advantage of the immunologic effects of interferon, because it is a far more accessible therapy to patients than, for example, high-dose interleukin-2. Bevacizumab clearly can be combined with interferon to achieve an effective and reasonably safe regimen, but sorafenib cannot be considered as a simple substitution. Caution is warranted in light of the experience with combining sunitinib with interferon.10 Sunitinib with interferon, even at substantially reduced doses, cannot be combined safely, and this probably is not simply a consequence of the VEGF signaling effects of the drug. Likewise, sorafenib may have too broad a spectrum of targets to be combined cleanly with an immunotherapy. To this point, there are data indicating that there is an immunosuppressive effect of sorafenib on lymphocytes ex vivo.11 This should give clinicians pause when considering the first principles in combining sorafenib with interferon.

The field continues to regret the fact that a single-agent bevacizumab arm was not included in the bevacizumab phase 3 trials. After the 2 phase 3 trials were launched, it was reported that bevacizumab was associated with a 14% response rate and a median progression-free survival of 8.5 months among 53 treatment-naive patients with clear cell patients who mostly had intermediate-risk disease, suggesting that single-agent bevacizumab may be a sufficiently active therapy to warrant evaluation in randomized trials.12 The window of opportunity is now closed for a comparative study versus interferon. To my knowledge, the only trial that is exploring single-agent bevacizumab further is the Eastern Cooperative Oncology Group phase 2 trial E2804 (or BeST) in which bevacizumab serves a control arm compared with combinations of targeted agents.

The objectives of therapy for metastatic renal cell carcinoma are dichotomous. If the aim is to eradicate metastatic disease with high-dose interleukin-2, then the price of short-term, severe toxicity is paid toward the payoff of a cure. However, if the aim is to maximize the quality and quantity of life with therapies that are given chronically, then minimizing toxicity must be considered equally with the gains made in life expectancy. This balance is on tenuous ground with current efforts to combine the available therapies for renal cell carcinoma. However, this practice rightly is confined to clinical trials in which the possibility of synergistic interaction can be measured. Although promising data have been produced for combinations of bevacizumab with either temsirolimus or sorafenib, the data from single-arm sorafenib/interferon trials do not point so clearly toward a randomized trial.

Jonasch and colleagues conclude that the similar response rates observed between their study arms and the sorafenib/interferon trials that used higher doses of interferon 3 times weekly indicate that interferon has not added to the activity of sorafenib. If such cross-trial comparisons were made so readily, then the renal cell carcinoma field would not have such difficulty in determining which agent represents the standard, first-line therapy for metastatic disease. The study reported by Ryan and colleagues was conducted in the cooperative group setting, a patient population that hardly is comparable to a cohort accrued at a single, large referral center. Furthermore, just over 50% of the population enrolled in the study by Jonasch et al had favorable-risk disease according to the criteria published by Motzer et al.13 This is a significantly higher proportion of such patients than what was accrued to previously reported sorafenib or bevacizumab trials as single agents or in combination with interferon. This may explain the unusually high objective response rate observed in the single-agent sorafenib arm. It is possible that, in a group with such a high response rate, there was less room for improvement than there would be in a group with more refractory disease.

With phase 3 data demonstrating superior outcomes with sunitinib or temsirolimus compared with interferon, the field largely had left single-agent interferon off the standard therapy algorithm.14 With bevacizumab, interferon made a quick comeback. However, even in that instance, it is not known whether the interferon component truly added value. In the temsirolimus phase 3 trial, the temsirolimus/interferon combination arm proved to be toxic and ineffective.5 Single-agent temsirolimus improved survival compared with single-agent interferon, which made interferon seem even more obsolete. The significant constitutional toxicities associated with interferon make it a therapy that oncologists and patients gladly would have left behind. The only current role for interferon in treatment is in combination with bevacizumab. If the ongoing phase 3 trial comparing the combination of bevacizumab and temsirolimus with bevacizumab and interferon demonstrates a significant improvement in progression-free survival for the bevacizumab/temsirolimus arm, then the field likely will move further away from interferon-based combinations.

It is difficult to conduct a trial in the current era in which patients would be assigned randomly to receive interferon. The motivation of patients to put up with the toxicities of interferon probably is less now than it was a decade ago. If the conviction to take interferon at doses that are truly immunomodulatory is lacking, then trials that randomize patients to receive interferon in addition to targeted therapy ultimately will not test the question. Consequently, such trials would be underpowered to detect a difference in outcome, as having a proportion of combination therapy patient abandoning the treatment will dilute any potential treatment effect.

Although a case can be made for the scientific importance of continuing investigations with VEGF-targeted therapy and interferon, the era in which these investigations have high priority appears to be passing. The pace with which novel targeted agents and targeted therapy combinations are being evaluated in renal cell carcinoma clinical trials is quickly moving the field to new questions. The therapeutic potential of VEGF-targeted therapy combined with immunotherapy well may be revisited as immune checkpoint inhibitors, such as cytotoxic T-lymphocyte antigen 4 or programmed death 1 blocking and CD40 and CD137 agonist antibodies, mature in clinical trials. For now, the momentum behind a combination of interferon at any dose and schedule with sorafenib seems insufficient to execute a definitive phase 3 trial.

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The author made no disclosures.

REFERENCES

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  2. CONFLICT OF INTEREST DISCLOSURES
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