Harshman Addresses Potentially Practice-Changing Adjuvant Therapy Trials in RCC

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.

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

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.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.

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

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.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.

Many things have been touted as to why that might be. It may be that we should target the population for which the targeted therapy was built—in this case, the highest-risk patients who have clear cell RCC. It may be the dosing differences. ASSURE started at lower doses about halfway through, whereas S-TRAC was very rigid about starting at the full dose and only going down 1 dose level. However, some subset analyses by the ASSURE investigators revealed no difference in the high-risk clear cell RCC group or those who received the highest doses.

We thought the PROTECT trial would be the tiebreaker. Interestingly, the PROTECT trial had elements that supported both approaches. Overall, the study was negative; it did not meet its primary endpoint because it was amended to look at DFS in the 600-mg subset. The dose of pazopanib was decreased to account for liver toxicity. The subset of patients who received the full dose of 800 mg did see a benefit in DFS.

Can you detail some of the immunotherapy trials in RCC?

That may be a case to support the use of adjuvant TKI therapy, assuming patient tolerability and that it’s given at full dose. It is a very patient- and provider-specific issue.There are at least 5 large-scale perioperative studies that are testing different checkpoint inhibitors. The IMmotion010 trial is looking at atezolizumab versus placebo in patients with highrisk clear cell or metastatic RCC that can be fully resected. The KEYNOTE-427 trial is looking at pembrolizumab in a very similar clear cell or sarcomatoid RCC population. In both studies, patients are to receive 1 year of adjuvant therapy compared with placebo.

What are the implications of a neoadjuvant and adjuvant approach in these patients?

There’s also CheckMate-914, the first combination trial, which is looking at 6 months of adjuvant nivolumab/ipilimumab in patients with high-risk clear cell resected RCC compared with placebo. The PROSPER study is the only phase III study that has a neoadjuvant component. In that study, we are giving 2 doses of neoadjuvant nivolumab to prime the immune system—so that the antigen is in place—to build that T-cell army into the effector CD8 T-cell population against the tumor. The theory is that this will remove the large tumor burden and 9 months of adjuvant nivolumab will continue to engage the immune system. That is compared with the standard of care: surgery followed by observation. This is also the only study that is not placebo-controlled, which matters to many patients. There’s also the RAMPART trial in Europe, which is looking at a combination therapy as well.A neoadjuvant and adjuvant approach is not standard practice, so we are disrupting practice by doing this. As kidney cancer doctors, we should learn from our bladder cancer work, which shows that there is a benefit of neoadjuvant cisplatin-based chemotherapy. We should also learn from our colleagues in breast cancer and head and neck cancer who have shown a benefit in getting rid of micrometastatic disease and controlling the primary tumor before local therapy.

Did the CheckMate-214 data prompt even more excitement with regard to immunotherapy? The CheckMate-214 data on combination ipilimumab and nivolumab in treatment-naïve patients in the metastatic setting support the use of this combination in the adjuvant setting. It’s rare that we ever eliminate cancer with 1 drug, so combinations make sense. However, combinations show increased toxicity. Sixty percent of patients enrolled in CheckMate-214 needed steroids to counteract the immune-related adverse events. We’ll have to see how that translates to the nonmetastatic setting.

References

1. 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.
2. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246-2254. doi: 10.1056/NEJMoa1611406.