Predictive Biomarkers Needed for Immunotherapy Combo Choice in Frontline RCC

Ulka Vaishampayan, MD, discusses the role of frontline immunotherapy and patient selection in metastatic renal cell carcinoma. 

Ulka Vaishampayan, MD

In just over 1 year, 3 immunotherapy combinations were approved for the frontline treatment of patients with metastatic renal cell carcinoma (mRCC). These advancements, however, have highlighted a need to identify biomarkers that can guide treatment selection for these patients, said Ulka Vaishampayan, MD.

For example, the FDA approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in April 2018 for patients with intermediate- and poor-risk mRCC based on results from the CheckMate-214 trial, which demonstrated a 32% reduction in risk of death with the combination compared with sunitinib (Sutent) for patients with metastatic RCC.1 In those specifically with intermediate- and poor-risk RCC, the risk reduction was 37%.

One year later, the combination of axitinib (Inlyta) and pembrolizumab (Keytruda) was approved by the FDA for patients with advanced RCC, based on findings from the KEYNOTE-426 trial, which showed a 47% reduction in the risk of death versus sunitinib.2

Similarly, the combination of axitinib and avelumab (Bavencio) was approved in May 2019, based on data from the phase III JAVELIN Renal 101 trial, which showed a 31% reduction in the risk of disease progression or death with the combination versus sunitinib.3

These approvals have shifted the treatment paradigm for these patients; however, treatment selection remains a clinical challenge, said Vaishampayan. 

"The question is, still, ‘How do we choose between these regimens?’" explained Vaishampayan. "Right now, we have no validated biomarkers to guide our selection. Knowing whether a patient is likely to respond to an immune-based regimen or an anti-VEGF—based regimen could save a lot of toxicity and time for patients. Not everybody responds to immunotherapy, so a patient may be receiving 1 treatment while they could have benefited from another."

In an interview during the 2019 OncLive State of the Science Summit on Genitourinary Malignancies, Vaishampayan, a professor of oncology at Wayne State University, and chief of the Solid Tumor Program at Barbara Ann Karmanos Cancer Institute, discussed the role of frontline immunotherapy and patient selection in mRCC. 

OncLive:  How is immunotherapy being utilized in this space currently?

Vaishampayan: We have always known that kidney cancer is an immune-sensitive disease. For a long time, immunotherapy with high-dose interleukin-2 (IL-2) and interferon were used. However, those were cytokine therapies. Even though IL-2 made a difference in about 10% of patients treated, the majority of them were unable to receive the therapy because of significant toxicities.

Now, checkpoint inhibitors are applicable to the majority of our patients with mRCC. It has allowed patients to have a chance at long-term complete remission. 

What are some of the key trials that have read out in this paradigm? 

The 3 main trials that have led to FDA approval for frontline mRCC with immune checkpoint—based regimens are CheckMate-214, KEYNOTE-426, and JAVELIN Renal 101. Each had an immunotherapy-based regimen up front. KEYNOTE-426 and JAVELIN Renal 101 had axitinib in combination with pembrolizumab and with avelumab, respectively. CheckMate-214 is an immune-based regimen, it has PD-1 inhibition with nivolumab plus CTLA-4 inhibition with ipilimumab.

What have we learned from these trials?

Combination immunotherapy is superior to single-agent anti-VEGF therapies. Also, we learned that there is a chance of long-term remission—potentially curative effects—that can be seen with these regimens. The response rate has improved dramatically as compared with previous regimens of anti-VEGF therapy alone. 

What are some of the factors you consider when choosing frontline treatment?

At present, we consider clinical biomarkers that include patient performance status, disease course, nephrectomy status, hemoglobin, calcium, lactate dehydrogenase, and white blood cell count. These elements factor into the overall International Metastatic Renal Cell Carcinoma Database Consortium Risk Score.

Going forward, the hope is that there will be a panel of biomarkers—like the angiogenesis panel that has been reported—that will allow us to select patients for a specific therapy based on risk stratification.

How do you currently choose 1 of the 3 combinations for an individual patient?

The nivolumab/ipilimumab combination is only approved for intermediate- and poor-risk patients, so I do not consider that regimen for favorable-risk patients.

Both axitinib/pembrolizumab and axitinib/avelumab are approved across all risk groups in mRCC. The toxicity profiles are something to consider. Avelumab has a lower incidence of significant colitis, while pembrolizumab has increased risk of transaminitis.

Of course, patient convenience and how often patients are willing to come into the clinic is also considered when choosing between the 2 regimens.

Are there other exciting combinations or approaches under investigation?

The biomarker testing is the most interesting thing that is ongoing. We have published research looking at the neutrophil lymphocyte ratio. That has been shown to be potentially a predictive marker for immune therapy response. Of course, it needs to be validated in a much larger patient sample size before we can use it in the prime time setting. 


  1. Motzer RJ, Tannir NM, McDermott DF, Frontera OA, et al; CheckMate-214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.
  2. Rini BI, Plimack ER, Stus V, et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Eng J Med. 2019;380(12):1116-1127. doi: 10.1056/NEJMoa1816714.
  3. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal cell carcinoma. N Engl J Med. 2019;380(12):1103-1115. doi: 10.1056/NEJMoa1816047.