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Harshman Addresses Potentially Practice-Changing Adjuvant Therapy Trials in RCC

Caroline Seymour
Published: Monday, May 14, 2018

Lauren C. Harshman, MD
Lauren C. Harshman, MD
Although the S-TRAC trial showed a disease-free survival (DFS) benefit at more than 1 year with adjuvant sunitinib (Sutent), Lauren C. Harshman, MD, says that patients with high-risk clear cell renal cell carcinoma (RCC) could still develop recurrence. Therefore, studies of adjuvant immunotherapy offer an exciting alternative.

Some of these adjuvant studies involve atezolizumab (Tecentriq), pembrolizumab (Keytruda), and combination therapy with nivolumab (Opdivo) and ipilimumab (Yervoy).

The results of the ASSURE and S-TRAC trials left unanswered questions regarding the superiority of sunitinib in patients with RCC. ASSURE randomized 1943 patients to 54 weeks of sunitinib daily for 4 weeks of each 6-week cycle, or sorafenib (Nexavar) twice daily each cycle, or placebo. The results showed no comparable benefit in DFS.1

The S-TRAC study also examined adjuvant sunitinib, but the results reflected a 6.8-year median duration of DFS compared with 5.6 years in the placebo group (HR, 0.76; 95% CI, 0.59-0.98; P = .03).2 In November 2017, the FDA approced sunitinib for this indication based on these data.

The PROTECT trial sought to clarify the role of tyrosine kinase inhibitors (TKIs) in practice, but its endpoint was adjusted due to liver toxicity. Harshman shares that, in PROTECT, patients who received 800 mg of pazopanib (Votrient) versus 600 mg saw a benefit in DFS.

“[However], neither group showed a benefit in overall survival (OS),” she explained. “This may counter the use of adjuvant TKIs. If you give adjuvant TKIs, you may be giving patients a year of decreased quality of life from toxicities that otherwise may have never recurred.”

Moreover, it was recently announced that the phase III ATLAS trial showed that adjuvant axitinib (Inlyta) did not extend DFS versus placebo for patients at high risk of recurrent RCC after nephrectomy.

In an interview during the 2018 OncLive® State of the Science Summit™ on Genitourinary Cancers, Harshman, assistant professor of medicine, Harvard Medical School, senior physician, Dana-Farber Cancer Institute, weighed the advantages and disadvantages of emerging adjuvant therapies, and she discussed ongoing clinical trials examining the incorporation of immune therapies into practice.

OncLive: What are the latest adjuvant treatments in high-risk RCC?

Harshman: In terms of nonmetastatic RCC, we are in the early stages of developing something better than nephrectomy alone. The standard of care today remains surgical removal of the primary tumor. A large number of patients, especially those with higher-stage disease—T3, T4, or clinical node-positive disease—have a very high risk of recurrence. There have been 40 years of investigation with various drugs in the metastatic setting that were effective or minimally effective. We have since moved them forward, and the 1 positive trial—S-TRAC, with sunitinib—was countered by the negative ASSURE trial.

At least 3 other targeted therapy studies will mature in the coming 1 to 2 years, but the real excitement stems from the new checkpoint inhibitors. We are now testing them earlier, in combination with surgery.

While we await the results of the other targeted therapy trials, we have shared decision-making with the patients who have high-risk clear cell RCC. That aligns with the criteria from S-TRAC about whether they want to consider adjuvant sunitinib for 1 year. However, we should really be focusing on how to best move the immunotherapy agents, the checkpoint inhibitors, to earlier settings. There are a variety of ways to do that, one of which is determining the most feasible standard of pure adjuvant therapy.

The PROSPER study is looking at a novel way, or adjuvant therapy “with a twist,” of giving a couple of doses of PD-1 priming blockade to rev up the immune system. When you have a significant amount of androgen in place, you can build a T-cell effector army to then take out the tumor. This is followed by 9 months of adjuvant nivolumab to sustain the immune system and work against micrometastatic disease, which is the real killer.

Can you discuss results of the ASSURE and S-TRAC trials?

The controversy stems from the fact that we have 2 big trials with the same drug and disparate results. The ASSURE trial was a large study that randomized more than 1900 patients to sunitinib with placebo, sorafenib with placebo, or placebo with placebo. Patients had lowerstage disease or non–clear cell RCC. The S-TRAC trial focused on a very high-risk subset of patients with clear cell RCC. The ASSURE trial didn’t show a benefit in DFS or OS compared with placebo, whereas the S-TRAC trial showed a DFS benefit at more than 1 year with adjuvant sunitinib compared with placebo.

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