In 2019, more than 73,000 Americans were diagnosed with kidney cancer. Renal cell cancer made up approximately 62,000 of those kidney cancers that were diagnosed. 

In terms of mortality, around 15,000 Americans die of kidney cancer every year.

There is, however, a beacon of hope. 

In the last four years, renal cell cancer patients have had a tremendous improvement in treatment options. 

Along that line, at the European Society of Medical Oncology virtual meeting on September 19–21, 2020, I had a chance to talk to Dr. Toni Choueiri about advances in kidney cancers and clinical trials that are practice-changing for physicians.

The following is an interview between Dr. Chandler Park, President of the Kentucky Society of Clinical Oncology (ASCO); and Dr. Toni Choueiri, Director of the Lank Center for Genitourinary (GU) Oncology at Dana-Farber Cancer Institute/Brigham and Women’s Hospital and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School. He is the co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center and President of the Medical Staff at Dana-Farber. The interview has been edited for length and clarity.

Dr. Chandler Park: Dr. Choueiri, congratulations on your practice-changing paper and outstanding ESMO 2020 Checkmate 9ER Presidential Symposium presentation. 

Dr. Toni Choueiri: Dr. Park, thank you. 

Dr. Park: You have been a key opinion leader in kidney cancers for nearly a decade and have seen major changes in treatment options for patients with renal cell cancers. Can you discuss some of these medical advances for first-line treatment for metastatic renal cell carcinoma (mRCC)?

Dr. Choueiri:

1. We have moved from single agent tyrosine kinase inhibitor (TKI) based treatment based on the pazopanib versus sunitinib trial. 
2. Also, what TKI to use, such as the CABOSUN trial: Cabozantinib Versus Sunitinib as Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial.
3. What TKI to combine with Immuno-oncology (IO) 

1. March 2019. Keynote 426: Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. 
2. May 2019. Javelin Renal 101: Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.
3. September 2020. CheckMate 9ER: Nivolumab plus Cabozantinib versus Sunitinib in first-line treatment for Advanced Renal Cell Carcinoma 

Dr. Park: Based on the July 2020 updated NCCN guidelines for kidney cancer with clear cell renal cell cancer first line (Category 1), the treatment options include TKI plus IO and dual checkpoint inhibitors of nivolumab and ipilimumab based on the CheckMate 214 trial. What factors do you consider for treatment for newly diagnosed metastatic clear cell renal cell cancer?

Dr. Choueiri: Doublets should be the standard of care (SOC) in the vast majority of mRCC. There are still questions for the 20-30% "good-risk" patients, but even in that group, doublets do have an overall response rate (ORR) and progression-free survival (PFS) benefit at least.

Dr. Park: Can you discuss the practice-changing CheckMate 9ER trial that was discussed at the Presidential Symposium at ESMO 2020? The clinical study evaluated patients as initial treatment for metastatic clear cell renal cell cancer.

Dr. Choueiri: This was a randomized phase 3 trial of cabozantinib plus nivolumab versus sunitinib in all international metastatic renal cell carcinoma database consortium (IMDC) risk groups (favorable, intermediate, or poor). The primary endpoint of PFS and secondary endpoints of ORR/OS (overall survival rate) were all met, and quality of life (QOL) in addition was superior to sunitinib. Patients live longer and live better with QOL. This is a win for our patients with mRCC.

Dr. Park: Very impressive data. Progression-free survival was doubled. PFS (16.6 v 8.3 months) OS with the combination was very strong with cabozantinib plus nivolumab. Decreased risk of death by 40%. {OS (HR 0.60 [98.89% CI 0.40e0.89]}.

Nivolumab + cabozantinib (N+C) versus sunitinib (SORR (95% CI) was significantly higher with N+C v S (55.7% [50.1e61.2] v 27.1% [22.4e32.3]; P < 0.0001), and 8.0% v 4.6% of pts achieved complete response. Median duration of response was 20.2 versus 11.5 months. This study also showed improvement in health-related QOL for our patients.

Any thoughts on how you would consider cabozantinib plus nivolumab as a first-line treatment option?

Dr. Choueiri: The field continues to evolve, but cabozantinib plus nivolumab will be a very strong contender as a first-line treatment option. This combo is the only regimen with three efficacy endpoints met (PFS/OS/ORR) plus the tolerability QOL. 

Patients do have options they did not have before. The median survival for stage IV RCC is being pushed further and further until, one day, we have the right drugs, in the right combinations, at the right time to dream about a cure.

Dr. Park: Thank you Dr. Choueiri for the very informative interview.

My personal thoughts — after reviewing all of the current data — on the various treatment options for first-line metastatic clear cell renal cell cancer patients:

1. Cabozantinib and nivolumab will be added to future NCCN Kidney Cancer guidelines for first-line treatment for metastatic clear cell renal cell carcinoma
2. First-line metastatic treatment options are moving toward TKI and IO doublet as the standard of care for a vast majority of metastatic renal cell cancer patients. The upcoming Keynote 581 clinical trial of lenvatinib plus pembrolizumab versus sunitinib for mRCC will likely further tip the balance toward IO plus TKI. 
3. There will still be a role for the dual checkpoint inhibitor of nivolumab and ipilimumab for first-line treatment. It depends on many factors including the IMDC risk group. For patients that need to get a faster response rate, I will go with IO plus TKI. However, nivolumab and ipilimumab has the most mature data of all of the first-line treatment options, patients have the highest complete response (CR), and patients don’t have to take a TKI pill (with associated treatment-associated toxicities) every day.
4. Also, there are select patients with favorable risk oligometastatic mRCC patients; I would consider observation with possible surgery (i.e. one lobe of the lung involved). For patients that have favorable risk and high-volume disease, I will consider TKI plus IO due to the response rate. Single-agent TKI has some activity but very few of these patients get CR.
5. As for cabozantinib and nivolumab versus axitinib and pembrolizumab, this will be a tough choice. This is a chess match. I have to consider not just the initial treatment but subsequent treatments, metastatic bone involvement, patient’s QOL and cancer-associated pain, and side effect profile (cabozantinib and axitinib have similar but some different side effects). Also, the data for Keynote 581 of lenvatinib plus pembrolizumab might make that combination a contender for first-line treatment. Our treatment options are still evolving. Most importantly, we have to consider the sequencing of future lines of treatment and biomarker studies to help guide treatments. 

Image: Marish / shutterstock