Investigators Seek to Boost Surgical Cures in RCC With Immune Priming

Mohamad Allaf, MD

In the phase III PROSPER trial (NCT03055013), investigators will attempt a novel approach in localized renal cell carcinoma (RCC): priming the immune system prior to nephrectomy with neoadjuvant nivolumab (Opdivo) and continuing with adjuvant blockade. The study will be the first to combine neoadjuvant and adjuvant immunotherapy with standard of care (SOC) nephrectomy.

The experimental regimen will be compared with nephrectomy alone in 805 patients with T2NX RCC or TanyNpositive RCC for which radical or partial nephrectomy is planned (Figure).

Although previous trials have explored the efficacy of conventional tyrosine kinase inhibitors and adjuvant methods in this setting, results did not demonstrate an advantage over surgery alone for this patient population. Moreover, SOC nephrectomy is often noncurative. Disease eventually recurs in many patients with localized RCC who undergo partial or radical nephrectomy.

“There’s been an interest in trials for patients with high-risk localized [RCC] to decrease the recurrence rate that we see with surgery alone, and those trials have been negative to date, so we haven’t really moved the needle in many, many years on these patients who are seemingly cured by surgery, only to recur later,” said Mohamad Allaf, MD, co-principal investigator of the PROSPER trial and vice chairman of the Department of Urology at The Johns Hopkins Hospital in Baltimore, Maryland.

“When we diagnose high-risk localized kidney cancer and we remove it surgically and believe we’ve cured the patient, in reality, it turns out that a significant proportion of these patients—more than 30%—will have a recurrence,” he added.

The lack of a standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone in nonmetastatic RCC represents another unmet need in this patient population.¹ Although a variety of drugs are FDA approved for use in the metastatic setting, sunitinib (Sutent) showed a statistically significant benefit in the adjuvant setting when contrasted with placebo. This finding emerged from the phase III S-TRAC trial (NCT00375674), in which sunitinib improved disease-free survival (DFS) versus placebo in (6.8 vs 5.6 years).² However, conflicting results on DFS (5.8 years for sunitinib vs 6.6 years for placebo) came from the phase III ASSURE study (NCT00326898).³ S-TRAC nevertheless secured sunitinib an indication for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy.⁴

PROSPER investigators hope to not only augment surgery cure rates but also address the need for a viable adjuvant therapy, which is reflected in the trial’s novel design. Investigators believe that neoadjuvant nivolumab can help the immune system better recognize and attack the cancer prior to nephrectomy and removal of the bulk of the cancer. “There are trials currently doing immunotherapy after the tumor is removed and only after the tumor is removed, and in that setting there are fewer cancer cells around to interact with the immune system,” Allaf said. “Treating patients with nivolumab peri- and postoperatively has the potential to maximize the effect of the immunotherapy at the point of care and subsequently reduce recurrence rates.”

Nivolumab in Metastatic RCC

Neoadjuvant anti—PD-1 priming of the immune system with nivolumab is attractive to PROSPER investigators for 2 key reasons: the agent’s mechanism of action and nivolumab’s demonstrated efficacy in the metastatic setting. As an anti–PD-1 monoclonal antibody, nivolumab possesses immune checkpoint inhibitory properties that augment the immune system’s ability to stymie the growth and diffusion of tumor cells.

Figure. PROSPER Trial Explores Neoadjuvant and Adjuvant Immune Therapy With Nephrectomy

The treatment of metastatic RCC has changed significantly over the past decade, with several targeted therapies of the antiangiogenic class and the mTOR inhibitor class becoming treatment options for those with metastatic disease. Meanwhile, the introduction of immune checkpoint inhibitors (ICIs) also bolstered treatment for metastatic RCC. Besides nivolumab, approved PD-1/PD-L1 agents for RCC include pembrolizumab (Keytruda) and avelumab (Bavencio). In addition, CTLA-4 blocker ipilimumab (Yervoy) in combination with nivolumab is approved for treatment of advanced RCC. Notably, nivolumab was the first ICI to demonstrate significant efficacy in metastatic RCC.³ It did so in the phase III CheckMate 025 trial (NCT01668784), in which patients with advanced or metastatic clear-cell RCC who had completed at least 1 prior line of systemic therapy were randomized to receive either nivolumab or everolimus. Nivolumab’s objective response rate (ORR) rivaled that of everolimus: Nivolumab effected an ORR of 25% versus 5% with everolimus (P <.001).⁵ Nivolumab also led to better median OS—25.0 months compared with 19.6 months with everolimus.

Importantly, patients treated with nivolumab reported fewer adverse events (AEs) than those treated with everolimus. CheckMate 025 study investigators said that grade 3/4 treatment-related AEs occurred in 19% of patients in the nivolumab cohort versus 37% of patients treated with everolimus. The favorable toxicity profile for nivolumab was another factor in the PROSPER investigators’ decision to use the PD-1 inhibitor over another agent.

“Certainly, a CTLA-4 drug could be used, but they’re fairly toxic, and we’re using this [neoadjuvant and adjuvant] strategy in patients who are potentially cured by surgery alone. A portion of our patients will be cured by nephrectomy alone,” Allaf said. For that reason, investigators don’t want to give them something with a high-toxicity profile.

A Favorable Neoadjuvant

Nivolumab demonstrated a manageable safety profile in the CheckMate 025 trial and in a phase II study (NCT02575222) of neoadjuvant nivolumab in patients with nonmetastatic high-risk stage II-IV clear cell RCC. The latter trial, conducted at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, in Baltimore, Maryland accrued 16 patients who received a total of 3 doses of nivolumab over a 6-week period. Patients experienced minor autoimmune AEs such as dermatitis, flaring of arthritis, and thyroiditis. Investigators did not observe any high-grade AEs, and Allaf expects this trend to continue in the larger PROSPER trial, in which patients will be treated with just 1 dose of neoadjuvant nivolumab.

The phase II trial supplied PROSPER investigators with important insight—specifically, that presurgical nivolumab did not hinder nephrectomy. “It did not cause any [AEs] that would delay surgery or make surgery more difficult,” Allaf said. “None of the surgical complications were attributable to nivolumab.”

Further, although the 6-week nivolumab dosing period that preceded nephrectomy constituted a delay in SOC operative treatment, it did not result in metastatic risk. “We did not see that the delay in treatment resulted in the growth of the tumor or any other significant change,” Allaf said.

He noted that the dosing period in the phase II study was more intensive and longer than that planned for PROSPER. Patients randomized to receive neoadjuvant and adjuvant nivolumab in PROSPER will be treated with the agent every 14 days for 2 cycles and undergo partial or radical nephrectomy 7 to 28 days later. The primary objective is recurrence-free survival (RFS). Secondary objectives include OS, RFS among patients with clear cell cancer, and incidence of toxicity.

Challenging Tradition

PROSPER investigators face a specific challenge pertaining to the standard workflow in the treatment of localized RCC and to the trial’s structure. Patients with localized kidney tumors frequently present not to medical oncologists but, instead, to urologists such as Allaf. Although urologists typically see the patient to discuss options, ultimately, the common treatment recommendation is to move swiftly to surgery, according to Allaf. Investigators are aware that the perioperative nivolumab dosing period and concerns about cancer progression could dissuade eligible patients from participating in PROSPER.

“Most patients and physicians are going to be nervous and are going to want to remove the kidney sooner rather than later,” Allaf said. “Now we have a very good trial with good scientific rationale.” This should change the way that patients and physicians think about this disease, he added.

Although patient and physician anxiety represents an obstacle for PROSPER investigators, Allaf remains hopeful that it will be just a temporary impediment. To date, the study has accrued about 200 patients with localized RCC, according to Allaf.

“We’d love to have urologists and patients engaged and understand that the delay is not significant: The tumor has been there for a long time and is not going anywhere in the short term. Participating in the study is value added for the patient [and the] urologist and for society as a whole,” Allaf said.

References

1. Harshman LC, Puligandla M, Haas NB, et al. PROSPER: a phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients with localized renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN 8143). Presented at: 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 14-16, 2019; San Francisco, CA. Abstract TPS684. ascopubs.org/doi/abs/10.1200/JCO.2019.37.7_suppl.TPS684.
2. Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375:2246-2254. doi: 10.1056/nejmoa1611406.
3. Bakouny Z, McGregor BA, Choueiri TK. Investigators seek expanded use of checkpoint inhibitors in RCC. OncLive® website. onclive.com/publications/Oncology-live/2018/vol-19-no-23/ investigators-seek-expanded-use-of-checkpoint-inhibitors- in-rcc. Published December 5, 2018. Accessed June 19, 2019.
4. Sunitinib (Sutent) [highlights of prescribing information]. New York, NY: Pfizer Inc.;2019. www.accessdata.fda.gov/drugsatfda_docs/ label/2019/021938s036lbl.pdf. Accessed July 1, 2019.
5. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi: 10.1056/ NEJMoa1510665.