Determining a Role for Neoadjuvant/Adjuvant Therapy in RCC

David M. Nanus, MD

Surgical resection, including cytoreductive nephrectomy, remains an effective option for many patients with metastatic renal cell carcinoma (RCC), with results of randomized trials showing a survival benefit with the addition of nephrectomy. However, many patients will have a recurrence. Much research has been done to define the role of neoadjuvant and adjuvant therapies in these patients, but the standard of care has not significantly changed.

ROLE OF NEOADJUVANT THERAPY

“The [benefit] of giving therapy, like a tyrosine kinase inhibitor for instance, would be to start systemic therapy right away, have the tumor shrink, and the nephrectomy will be easier,” said David M. Nanus, MD, during his presentation at the New York GUTM: 10th Annual Interdisciplinary Prostate Cancer Congress and Other Genitourinary Malignancies meeting.

Nanus explained that rapid initiation of systemic therapy prior to surgery could decrease cancer-related mortality and eliminate these risks in patients who would not benefit from nephrectomy. However, commented Nanus, the Mark W. Pasmantier Professor of Hematology and Oncology in Medicine, Weill Cornell Medicine, “it may add to the morbidity or mortality of surgery if you give the drug; you may ‘decondition’ the patient and [then] they can’t get systemic therapy. And it hasn’t been proven that it improves survival, so why should we do it?”

Previously, there were several prospective clinical trials in the neoadjuvant setting prior to cytoreductive nephrectomy, but such investigations have become less frequent due to the recent push to develop immunotherapies. One such study was a phase II trial of pazopanib (Votrient) in patients with localized RCC to optimize the preservation of the renal parenchyma.¹Of 13 patients originally unable to undergo a partial nephrectomy, 6 underwent surgery. There was also a significant decrease in the size of the tumors in the patients. "I think that keeping a patient from going on dialysis by shrinking the tumor preoperatively is something that should be done," Nanus commented.

In another phase II study assessing pazopanib therapy prior to nephrectomy in patients with metastatic clear cell RCC (ccRCC), investigators discovered that a nephrectomy could be performed safely after upfront treatment with pazopanib and was associated with good outcomes in patients with intermediate-risk disease.²A significant reduction in the primary tumor was observed, with a median reduction of 14.4% (range, 1.4%-21.1%). “Progression-free survival in this study was about 7 months, so it’s not very clear that giving preoperative [pazopanib] in the metastatic setting made a big difference,” Nanus said. “I think giving cytoreductive neoadjuvant therapy should be restricted to select patients.”

ROLE OF ADJUVANT THERAPY

Nanus explained that patients tend to relapse at high rates, with a tendency toward mortality for those who progress to metastatic disease. Patients in these populations could benefit from an adjuvant treatment if one is proven effective. However, investigations into adjuvant treatments have been a mixed bag, at best, with several trials leading to negative results.

The phase III ARISER trial assessed adjuvant girentuximab (Rencarex), an antibody to the RCC-associated G250 antigen that is especially overexpressed in ccRCC, in patients with nonmetastatic RCC. The investigators determined that girentuximab had no clinical benefit as an adjuvant treatment for patients with high-risk ccRCC based on a median disease-free survival (DFS) of 71.4 months for the girentuximab arm (n = 433); DFS was not reached in the placebo arm (n = 431). Overall survival (OS) was not reached for either arm.³

The phase III ASSURE trial, compared adjuvant sorafenib (Nexavar) or sunitinib (Sutent) with placebo for patients with unfavorable RCC. There was no difference observed in 5-year DFS or OS between the 3 arms.4 A preplanned ccRCC subset analysis also revealed that there was no significant difference among the 3 arms.

Recently updated data from the ccRCC subset of this trial on patients whose RCC was removed by surgery show that there was no improvement in DFS and OS.5 In the secondary analysis, the 5-year DFS rates were 47.7%, 49.9%, and 50.0% for sunitinib, sorafenib, and placebo, respectively. Additionally, dose intensity did not affect outcomes.

From the phase III S-TRAC study, which compared the efficacy and safety of sunitinib versus placebo for patients at a high risk for recurrent RCC, early data show that DFS was longer in the sunitinib group than in the placebo group (6.8 vs 5.6 years), although at the cost of a higher rate of adverse events.⁶However, the results were only just statistically significant (HR, 0.76; 95% CI, 0.59-0.98; P = .03).

LOOKING TO THE FUTURE

There are many challenges in assessing treatments in the neoadjuvant and adjuvant settings for patients with RCC, Nanus pointed out DFS may not reflect OS, the 5-year follow-up period may not be long enough, dose reductions and discontinuations make it tricky to compare trials, and there are varying eligibility factors and treatment durations.

Conversely, there are a lot of opportunities in these settings. There is a clinical need to improve survival in these patients. “This is a patient population that we’ve really let down; a lot of these patients go through surgery and then they relapse,” Nanus said.

With large datasets incoming, there will be an opportunity to develop prognostic and molecular models to determine which patients are at the highest risk for recurrence and who would benefit from certain therapies.

References:

1. Rini BI, Plimack ER, Takagi T, et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J Urol. 2015;194(2):297-303. doi: 10.1016/j.juro.2015.03.096.
2. Powles T, Sarwar N, Stockdale A, et al. Safety and e cacy of pazopanib therapy prior to planned ne- phrectomy in metastatic clear cell renal cancer. JAMA Oncol. 2016;2(10):1303-1309. doi: 10.1001/jama- oncol.2016.1197.
3. Chamie K, Donin NM, Klöpfer P, et al. Adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: the ARISER randomized clinical trial [published online October 27, 2016]. JAMA Oncol. 2016. doi: 10.1001/jamaoncol.2016.4419.
4. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016;387(10032):2008-2016. doi: 10.1016/S0140-6736(16)00559-6.
5. Haas NB, Manola J, Dutcher JP, et al. Adjuvant treatment for high-risk clear cell renal cancer: updated results of a high-risk subset of the ASSURE randomized trial [published online March 9, 2017]. JAMA Oncol. 2017. doi:10.1001/jamaoncol.2017.0076.
6. Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcino- ma after nephrectomy. N Engl J Med. 2016;375(23):2246-2254. doi: 10.1056/NEJMoa1611406.