Novel Therapies Shaking Up the Renal Cell Carcinoma Landscape

Robert A. Figlin, MD

When to Initiate Targeted Therapy

Although therapeutic options for renal cell carcinoma (RCC) have expanded dramatically during the past decade, oncologists are faced with considerable complexity in selecting the right course of treatment for the individual patient, according to experts who participated in a recent OncLive Peer Exchange® roundtable. Indeed, decisions as to which drugs to administer first to an individual patient and, if necessary, the sequence of drugs or combinations for recurrent disease remain both controversial and challenging, the researchers said during a wide-ranging panel discussion entitled “Treating Advanced Renal Cell Carcinoma.”Panel members were in agreement that it is not necessary to start therapy right away for many patients with metastatic disease. Sandy Srinivas, MD, explained that she waits to make sure that there is growing disease before commencing therapy. In contrast, she offers therapy immediately to symptomatic patients with bulky disease.

Elaborating on this approach, Nizar M. Tannir, MD, FACP, pointed out that a patient presenting with advanced, primary in situ disease requires a different approach than a patient who had nephrectomy with a curative intent a few years earlier and now has recurrent disease. Since advanced disease suggests an aggressive cancer, patients in this category should receive therapy, said Tannir. In addition, surgery plays an important role in the decision-making process, in that there are patients with low-volume disease in a single organ who can be managed with surgery and not immediately started on systemic therapies, which are both costly and toxic.

Selecting an initial therapy is challenging, as there are no validated, established factors that predict with certainty that one agent is superior to any other in this context, noted Martin H. Voss, MD. He has not yet found tissue-based predictive factors to help him decide among FDA-approved options.

Choosing a Frontline TKI Pazopanib Versus Sunitinib

With each individual patient, his decision is based primarily on the person’s performance status and comorbidities. Thus, the patient who is very compromised at baseline is unlikely to be a good candidate for aggressive treatment, for example, with high-dose interleukin-2 (IL-2). Citing additional examples, Voss said a patient with significant cardiac disease would not be the best candidate for a VEGF tyrosine kinase inhibitor (TKI) and a patient with poorly controlled diabetes might not be the most appropriate candidate for an mTOR inhibitor.Both pazopanib (Votrient) and sunitinib (Sutent) are first-line treatment options for patients with advanced RCC. In choosing between the two drugs, the findings of the COMPARZ phase III trial¹ are helpful, said Tannir. In this large randomized trial involving 1110 patients, pazopanib was noninferior to sunitinib regarding progression-free survival (PFS).

Dosing Strategies

Further, pazopanib was found to be superior to sunitinib in 11 out of 14 health-related quality-of-life domains and demonstrated superiority in relation to such adverse events as fatigue, stomatitis, and hand—foot skin reaction. In the subsequent phase II, double blind PISCES trial,² patients picked pazopanib as the preferred agent by a 70% to 22% margin, mostly due to the perception that it caused less fatigue and offers a better overall quality of lide. Looking at these two trials in aggregate, pazopanib is certainly the preferred agent, said Tannir, adding the caveat that sunitinib was administered at a schedule that is now questioned.A criticism of the COMPARZ trial has been that some of the quality-of-life endpoints and the adverse event assessments were conducted precisely when sunitinib toxicity peaks at the 4-week mark, Voss pointed out. He and many other oncologists no longer make use of the schedule that the FDA approved years ago, which calls for 4 weeks on treatment followed by 2 weeks off.

Instead, Voss favors a 2-week on, 1-week off schedule. He said several retrospective studies have shown that the modified sunitinib schedule appears to yield essentially equivalent efficacy accompanied by moderated toxicities. Voss continues to use sunitinib with a considerable number of patients, and he points out there are more data with sunitinib than with any other TKI for patients with nonclear-cell RCC. These data show that sunitinib can be a very active agent for these patients; thus, for untreated patients with nonclear-cell RCC, sunitinib is his agent of choice outside of clinical trials. In contrast, for patients with clear-cell RCC in the frontline setting, he prefers pazopanib.

Defining Progression and Switching Therapies

One of the more challenging matters for oncologists who treat patients with RCC is deciding when to switch therapies based upon progression, said Robert A. Figlin, MD. He noted that the RECIST definition of disease progression used in clinical trials may differ from what clinicians follow in daily practice. “RECIST criteria are helpful but certainly are not consistent with what’s happening clinically with the patient because oftentimes that’s radiographic progression without any change in their clinical situation,” said Figlin.

Tannir agreed the RCC field needs better methods to assess benefit or response to therapy. He said that when patients are enrolled in clinical trials, physicians are required to follow RECIST version 1.1 response criteria that define progression as a new lesion or an increase of more than 20% in the sum of the longest diameters of the selected target lesions.³

Sandy Srinivas, MD

The provisions of such trials state that the patient’s therapy must be changed or the patient must be removed from the protocol once progression, as defined, appears. If he is treating a patient off protocol, however, Tannir will not alter therapy if that patient is clinically benefiting from the treatment and has slight growth, even if that growth is 21% or 25%, but there are no new lesions, no cancer symptoms, and the treatment is well tolerated.

In contrast, symptomatic progression or clinical progression, regardless of whether or not radiographic changes are present, would prompt Tannir to change therapies. Similarly, he would alter the therapy of a patient who did not have 20% growth but is experiencing pain due to a metastasis or night sweats, fever, or chills—that is, constitutional symptoms.

Adding Nivolumab to the Mix

Further, he commented that a new way of defining progression is needed in order to incorporate immune checkpoint agents, where pseudoprogression has complicated analysis of response.In November 2015, nivolumab (Opdivo) became the first checkpoint blockade immunotherapy agent approved in RCC; it is indicated for patients with advanced disease who have received prior antiangiogenic therapy.

In the pivotal CheckMate 025 study, the PD-1 inhibitor demonstrated median overall survival (OS) of 25 months compared with 19.6 months for everolimus (Afinitor), the mTOR inhibitor that has been the standard of care in this setting (HR, 0.73; P = .002).⁴ The phase III trial enrolled 821 patients who had been previously treated with one or two VEGF-directed therapies. The only other FDA-approved therapy for RCC that has registered an OS improvement is temsirolimus (Torisel), the agency said in announcing the new indication for nivolumab.⁵ In addition, nivolumab demonstrated a more favorable toxicity profile and significantly better quality-of-life measures than everolimus.

Nevertheless, approximately 20% of patients treated with nivolumab during the trial had grade 3 or 4 treatment-emergent events. Voss said these toxicities, if recognized early and treated well, are very manageable.

Nizar M. Tannir, MD, FACP

However, since the toxicities associated with nivolumab are mostly mediated by the immune system, they are largely different from those associated with molecularly targeted agents. And, because they are different, the danger exists that they might be misinterpreted and mismanaged, Voss said.

Moreover, nivolumab elicited a response in 20% to 25% of patients in the CheckMate 025 trial and did not confer an advantage over everolimus in terms of PFS.

In light of these statistics, Srinivas said she speaks carefully with patients before prescribing the drug, explaining that she does not know if it’s going to be very effective for them, but that if it is, they are likely to have a response for a prolonged period of time.

Novel Regimens in Development

Further, she is careful not to take patients off the drug prematurely, and noted that many patients should be permitted to continue treatment beyond progression. She also pointed out that in her experience immune-related side effects can happen any time—side effects such as cough and shortness of breath can emerge even after a patient has been using the drug for 2 years, she noted.Two new agents advancing rapidly in clinical development for RCC are the receptor tyrosine kinase (RTK) inhibitors lenvatinib (Lenvima) and cabozantinib (Cometriq). Both drugs have received breakthrough therapy status in RCC— cabozantinib as a second-line agent for advanced disease and lenvatinib in patients previously treated with a VEGF-targeting therapy.

Martin H. Voss, MD

Lenvatinib, which targets fibroblast growth factor as well as the VEGF pathway, generated a median PFS of 14.6 months when combined with everolimus compared with 7.4 months for single- agent lenvatinib and 5.5 months for everolimus monotherapy in a three-arm trial among patients with recurrent disease.⁶ Srinivas said the PFS for the combination was “astonishing” but noted that there are many unanswered questions about how this regimen would be employed in practice.

Cabozantinib also inhibits the activity of multiple tyrosine kinases in addition to VEGF, notably MET and AXL, which Voss said are pathways that are relevant in progressive disease. In the METEOR trial, patients treated with cabozantinib achieved a median PFS of 7.4 months, far longer than the 3.8-mnth PFS experienced by patients who received everolimus (HR, 0.58; P <.001).⁷

Voss said an FDA approval of the drug would bring to 10 the number of therapies approved for the disease. “It is going to be challenging not only for people in the community who may see a handful of patients with RCC per year but even for us in academic circles,” said Voss, noting that questions that will arise over sequencing. “I think it will be interesting.”

References

1. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722-731.
2. Escudier B, Porta C, Bono P, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014;32(14):1412-1418.
3. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
4. Motzer R, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.
5. FDA approves Opdivo to treat advanced form of kidney cancer [press release]. US Food and Drug Administration. November 23, 2015. http://goo.gl/NNdQQE.
6. Motzer R, Hutson T, Glen H, et al. Randomized phase 2 three-arm trial of lenvatinib (LEN), everolimus (EVE), and LNE+EVE in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2015;33 (suppl; abstr 4506).
7. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823.