Mixed Trial Results Underscore Challenges of Adjuvant TKI, IO Regimens in RCC

Helen Moon, MD

Despite mixed results with TKI-based approaches in the adjuvant setting for patients with renal cell carcinoma (RCC), further investigation is warranted due to the modest benefit observed with pembrolizumab (Keytruda) and the potential of perioperative immunotherapy strategies, according to Helen Moon, MD.

Although TKIs demonstrated early efficacy in metastatic RCC, their limited benefit in the adjuvant setting, coupled with significant toxicity, has restricted their integration into routine clinical practice, Moon explained. In contrast, immunotherapies like pembrolizumab have shown more favorable outcomes resulting in broader uptake, but their otherwise modest success in the adjuvant space underscores the need for further optimization, she said.

“The jury is still somewhat out [on the role of immuno-oncology (IO) regimens] in the adjuvant space. The results are not so definitive that future trials will cease; in other words, we do not consider this a closed chapter where a question was asked, answered, and resolved,” Moon said in an interview with OncLive® regarding a State of the Science Summit™ on genitourinary cancer. “There remains only one approved agent, and the benefit—although meaningful—is not beyond improvement.”

In the interview, Moon reviewed historical data with TKIs and IO agents in the adjuvant setting, highlighted ongoing challenges in their clinical implementation due to a lack of consistently positive trial results, and discussed the rationale for continued evaluation of perioperative immunotherapy regimens in patients with high-risk or borderline resectable RCC.

Moon is a hematologist and oncologist at the Kaiser Permanente Riverside Medical Center, and principal investigator with the Cancer Clinical Trials Access Program in the Southern California Permanente Medical Group. She is also the regional medical oncology lead for genitourinary cancer and research lead for melanoma.

OncLive: What is the current role of TKIs in the adjuvant management of RCC?

Moon: TKIs, which came to the market in the early 2000s, have had a disappointing track record in the adjuvant setting. They have performed well in metastatic disease, but in the adjuvant setting, there are multiple [phase 3] trials—including ASSURE [NCT00326898], SORCE [NCT00492258], and PROTECT [NCT01235962]—that are essentially negative. Of those, only the [phase 3] S-TRAC [trial (NCT00375674)] is considered positive. That trial did end up leading to FDA approval [of adjuvant sunitinib (Sutent)]. However, the very modest benefit it provided, along with the significant adverse effects of sunitinib, have hindered its widespread adoption among the RCC community. Also, 1 positive trial out [among other negative ones] makes those of us who treat [patients with] RCC question the value of using TKIs in this space.

Have these mixed results limited the adoption of TKIs as adjuvant therapy? What questions remain regarding their overall value in this setting?

One of the conversations that always comes up in discussions is whether the comparator arm [for trials evaluating adjuvant treatment strategies] should be a TKI because of the FDA approval [of sunitinib] or placebo, which is what many of the trials ultimately used. As a community, we have felt comfortable with having a placebo-controlled comparator arm, which in and of itself tells you a bit about how widely TKIs have been adopted.

The 1 positive trial that is often focused on is S-TRAC, [which] showed overlapping overall survival [OS] curves [for sunitinib vs placebo] and a fairly modest hazard ratio [HR] of 0.76 for progression-free survival [(PFS) in favor of sunitinib]. This highlights that, given the toxicity, [TKIs] are probably not being used [as standard adjuvant treatment] for [patients with] RCC in the United States [US].

What trials have provided context on the role of adjuvant IO regimens?

In the adjuvant immunotherapy space, we typically reference 4 trials, but there are some important subtleties. Three of the trials are truly adjuvant, meaning the patient undergoes surgery, is rendered with no evidence of disease, and then initiates systemic treatment with the goal of delaying—or potentially preventing—recurrence. The fourth [phase 3] trial often included in this discussion, PROSPER-RCC [NCT03055013], is not technically a purely adjuvant study. It is a neoadjuvant-adjuvant study with a component of immunotherapy administered before surgery, aiming to prime the immune system in advance of the major physiologic insult of surgery. The rationale is that the immunotherapy may work synergistically with the immune activation induced by the surgical event, rather than relying on the drug effect alone.

Of these 4 trials, we have 1 positive trial and 3 that essentially [failed to meet their primary end points]. However, even the positive trial presents some limitations. That study—[the phase 3] KEYNOTE-564 trial [NCT03142334]—demonstrated robust PFS benefit [with pembrolizumab] and is beginning to show signals of potential OS benefit.

Given the moderate success achieved with adjuvant IO-based regimens thus far, do you think they have a future role in the RCC treatment paradigm?

Because of the familiarity [clinicians have] with pembrolizumab as a systemic treatment in general, and the relative comfort in the US—and perhaps worldwide—among treating clinicians, the adoption of adjuvant pembrolizumab has been much more robust than the adoption of adjuvant sunitinib, even though both have FDA approval in this space.

Two key implications arise from the positive adjuvant pembrolizumab trial. First, the era of using placebo as the comparator in adjuvant trial design is likely over. Investigators will now be expected to acknowledge that there is an approved and actively used agent in this setting: pembrolizumab. Therefore, future trials will need to contend with the improved survival outcomes associated with adjuvant pembrolizumab, rather than relying on observation or placebo. That said, there remains clear room for progress in this space.

How has the development of perioperative IO-based approaches evolved in RCC, and what concerns have arisen regarding the use of immunotherapy in the neoadjuvant setting?

There has long been strong interest [for perioperative immunotherapy regimens] in kidney cancer, which for many years has paralleled melanoma in the development of adjuvant treatment strategies. For those less familiar with the melanoma data, there are now 2 robust studies demonstrating that systemic immunotherapy, when administered earlier, can significantly improve long-term survival outcomes, even for patients with advanced disease. Although kidney cancer differs in several important ways, this parallel has remained conceptually influential.

One longstanding barrier in RCC is that diagnosis is often made radiologically rather than through biopsy, due to concerns about the safety and utility of renal mass biopsy. In many cases, a CT scan or other imaging modality identifies a mass highly consistent with RCC, and treatment proceeds accordingly. In fact, some pathologists and interventional radiologists still maintain that biopsy is not the standard of care in this setting. This creates ethical and practical challenges in trial design, particularly when considering neoadjuvant therapy: is it acceptable to administer combination immunotherapy, or any potentially toxic systemic treatment, based solely on a radiographic diagnosis? This concern contributed to the challenges seen in the PROSPER trial, which used a neoadjuvant approach.

A second key concern [that is] common to all neoadjuvant trials is the risk of disease progression or loss of surgical candidacy during systemic treatment. If the therapy is ineffective, the window for potentially curative surgery could be missed.

How might ongoing or future research with perioperative immunotherapy regimens address these concerns?

Despite these concerns, there are also compelling reasons to continue exploring the neoadjuvant approach in RCC. Drawing from melanoma as a comparator, sequencing immunotherapy earlier in the disease course has translated into significant survival benefits. Early-phase RCC studies have demonstrated that neoadjuvant immunotherapy is generally safe and does not prevent patients from undergoing surgery. Most patients proceed to resection, and only a small minority are rendered unresectable during therapy.

Several ongoing trials are now investigating this strategy more rigorously, including in patients with borderline resectable disease or those with tumor thrombosis where TKI or TKI/IO combinations may convert them into surgical candidates. Collectively, these studies may help determine whether a neoadjuvant/adjuvant ‘sandwich’ approach can meaningfully improve outcomes in resectable RCC and establish a new standard of care.