Weighing the Evidence for Immune Therapy and Targeted Therapy in Renal Cancer and Melanoma

Drs. Amin and White have done an outstanding job of condensing a large body of data for two separate malignancies linked by a common thread of immune responsiveness.[1] They have nicely juxtaposed the advantages and disadvantages of immune therapy, specifically high-dose interleukin-2 (HD IL-2), compared with long-term oral vascular endothelial growth factor (VEGF)-targeted therapies. The chief advantage of immune therapy for renal cell cancer (RCC) remains the potential for durable remissions, which has yet to be equaled by targeted therapeutics. While the toxicity is daunting, with specialized, highly trained teams delivering HD IL-2 and utilizing modern supportive measures, including prophylactic antibiotics, safety is acceptable. The authors also highlight emerging immune therapeutics based on inhibition of the cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death protein 1 (PD-1) immune checkpoints, which may ultimately be shown to have improved therapeutic ratios. As a counterpoint, encouraging data describing longer-term and complete responses to targeted therapy in RCC are also emerging. Rini and colleagues published a series describing five patients with nonbulky RCC with pulmonary metastases who were treated with sunitinib (Sutent) and achieved complete responses or near-complete responses.[2] A trial of intermittent dosing for sunitinib responders found that 4 out of 36 (11%) did not have immediate tumor rebound, and one patient was able to stay off sunitinib for 12 months before resuming treatment,[3] suggesting that benefit may extend beyond the treatment time period. Furthermore, newer agents may be associated with better quality of life, as seen in the COMPARZ trial[4]; this will make long-term continuous therapy more acceptable. Nevertheless, at the University of Southern California, we continue to offer HD IL-2 to select individuals with minimal comorbidities, normal organ function, and excellent performance status as an optimal first-line option.

A few points about HD IL-2 warrant additional attention. First, careful selection of patients for HD IL-2 therapy is truly critical. As pointed out by the authors, the renal SELECT trial unfortunately found that the level of tissue expression of carbonic anhydrase 9 was not able to predict response to HD IL-2.[5] However, the response rate of 29% (35/120), with seven complete responses (5.8%), was notably higher than that of previous trials of HD IL-2 in RCC. One hypothesis that has been put forth to explain this outcome is that the clinical inclusion criteria selected for a more responsive population-for instance, perhaps patients had better performance status than in previous studies.

Safety has been a major concern for patients and physicians contemplating a course of HD IL-2. Data from the ongoing national HD IL-2 registry, PROCLAIM, report no deaths on a retrospective analysis of HD IL-2 outcomes from 13 institutions,[6] and Drs. Amin and White report a similarly low mortality rate in their experience. In weighing the risks and benefits of HD IL-2 against those of other available therapies, the potentially fatal toxicities associated with oral targeted agents, especially with VEGF inhibitors, should not be overlooked. In the registration trial for bevacizumab (Avastin), the rate of deaths related to adverse events was 2%, with three deaths convincingly linked to bevacizumab (bleeding and gastrointestinal perforation), as well as a case of myocardial infarction that one could argue fits with a VEGF-targeted therapy toxicity profile.[7] Patients treated with sunitinib and sorafenib (Nexavar) are at risk for nonfatal cardiac events: 5% of patients in the TARGETS trial who were treated with sorafenib reported myocardial infarction, and 1.5% experienced cerebrovascular ischemia[8]; in addition, a pooled analysis of patients treated with either agent showed that 13.5% experienced symptomatic cardiac events, including several that required angiography, surgery, or pacemaker implantation.[9] In the RECORD-1 trial of everolimus (Afinitor) vs placebo, 1 patient out of 272 on the everolimus arm died from candidal sepsis, which was possibly related to immunosuppression caused by the study drug.[10] Toxic deaths from HD IL-2 are much more immediately related to our treatment orders, but the “hidden” toxic deaths related to VEGF-targeted therapy pose a real threat to our patients as well. In addition, durable treatment reponses from HD IL-2 are achieved without maintenance therapy, whereas those from tyrosine kinase inhibitors require prolonged, if not sustained, exposure to the drug.

Across solid tumor oncology, intriguing new studies are combining immune therapy with chemotherapy and targeted therapies, leveraging the distinctive toxicity profiles of the therapeutic classes that allow them to be combined, and enhancing the innate immune activation that can be induced by cytotoxic therapy. In RCC, combining immune therapy and VEGF-targeted therapy is particularly appealing, since sunitinib, for one, was shown to modulate T-cell responses with increased interferon λ expression and decreased IL-4 expression by T cells after exposure.[11] However, the increased cardiac toxicity that has been noted in patients treated with HD IL-2 after VEGF tyrosine kinase inhibitor pretreatment raises concerns about the tolerability of combinations involving HD IL-2. A retrospective analysis of 23 patients treated with HD IL-2 after failure of VEGF-targeted therapy (15 patients with prior sorafenib/sunitinib, 8 patients with prior bevacizumab [Avastin]) found that 6 patients, all treated with a tyrosine kinase inhibitor, experienced severe cardiac toxicity, including one death.[12] There is a Danish trial testing the addition of bevacizumab to low-dose IL-2 and interferon (NCT01274273), but other combinations of VEGF-targeted therapy plus immunotherapy are predominantly utilizing newer immune therapies, particularly PD-1 and PD ligand inhibitors. Other classes of targeted therapy may be more successfully combined with HD IL-2. For instance, there is an open trial combining HD IL-2 with entinostat, a histone deacetylase inhibitor (NCT01038778), based on synergy seen in an RCC xenograft mouse model.

The landscape for melanoma therapy has undergone dramatic change in the past several years. Inhibition of V600-mutant BRAF provides dramatic tumor responses, but the durability of response and the frequent development of resistance suggest continued opportunity for HD IL-2 use. Several trials testing the sequencing of HD IL-2 and vemurafenib (Zelboraf) (PROCLIVITY trial) and combinations of these two agents are recently open or in late development. Melanoma therapeutics diverge from RCC therapies most acutely in the arena of immunotherapy. The ease of administration of ipilimumab (Yervoy)-ie, in the outpatient setting-compared with the requisite use of a specialized unit for HD IL-2 treatment obscures the fact that 2.1% of the patients receiving ipilimumab in the registration study died as a result of the study drug.[13] While HD IL-2 toxicity occurs predictably during inpatient administration and abates soon after, ipilimumab toxicity can occur 3.6 to 9.2 weeks after administration and can linger for weeks afterwards.[14] Thus, the sequencing of HD IL-2 followed by ipilimumab salvage (as was used in patients in the Hodi trial) allows for the densest schedule for back-to-back immunotherapy. Interestingly, combining these two immunotherapies for simultaneous administration may lead to an increase in the durable complete response rate. Long-term follow-up on such a combination was reported by Prieto and showed a complete response rate of 17% and a 5-year survival rate of 25%, without increased toxicity-thus warranting additional studies.[15]

As Drs. Amin and White point out, all these immunotherapies in melanoma may be superseded by the ability of PD-1 blockade to deliver sustainable durable stability or responses with very few high-grade toxicities. Interestingly, preclinical studies that point to the ability of HD IL-2 to rescue lymphocytes from PD-1–mediated blockade[16] suggest a possible role for HD IL-2 in patients who relapse or who fail to respond to anti–PD-1 therapies-which remains the majority of patients in the anti–PD-1 trials.

Finally, the increasing cost of therapy for RCC bears mention. Over $500 million are spent annually in the United States to treat RCC.[17] One cost-effectiveness analysis compared therapy with sunitinib to interferon or HD IL-2, using a Markov model. Sunitinib was associated with a cost of $52,593 per quality-adjusted life-year gained over interferon, and HD IL-2 was found to be the most expensive strategy.[18] Although HD IL-2 failed to prolong overall survival for the total population, a cost-effectiveness strategy would need to take into account the possibility of durable complete remissions for the patients who attain them, resulting in a potential life expectancy improvement of 20 years or more[19]; strategies that enhance the population for durable remissions would be expected to shift the cost-effectiveness data. Similarly, the costs of HD IL-2 are largely driven by the need for intensive care unit monitoring and treatment, and likely vary by center depending on experience and standard protocols for HD IL-2 patients. Cost-effectiveness would be shifted by developing algorithms for treatment delivery with protocols that avoid intensive care for routine supportive interventions such as dopamine infusion.

Ultimately, as agents in both VEGF-targeted and immunotherapy classes with lower toxicity rates are developed, questions of combination and sequence will inspire clinical investigations of strategies that, it is hoped, will maximize both the quantity and quality of life for patients with RCC. Melanoma therapy drug development continues to lead the way with regard to what is therapeutically possible with immunotherapy-and suggests that HD IL-2 continues to be relevant in today’s treatment landscape. Tissue and circulating markers that can predict benefit from HD IL-2 remain a high priority in the short term so that we can get the most “bang for our buck” when selecting therapies for patients.

Financial Disclosure: Dr. Dorff has served as a consultant for Novartis and has been a promotional speaker for Pfizer. Dr. Wong has served on advisory boards for Merck and Genentech.