Although the CheckMate-9ER trial, comparing cabozantinib plus nivolumab to sunitinib in frontline metastatic renal cell carcinoma (mRCC), had recently demonstrated superiority in progression-free survival  (PFS) and overall survival (OS), patients treated with nivolumab and cabozantinib also had statistically significant health-related quality of life (HRQoL) benefits, compared with patients treated with sunitinib. Physician’s Weekly interviews lead study author Dr. David Cella, professor at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA, who presented these results during the 2021 ASCO Genitourinary Cancers Symposium [1]. The topline results of the trial were presented at ESMO 2020 [2] and published a few weeks after Dr Cella’s presentation on the HRQoL data in the New England Journal of Medicine [3].

In a nutshell, the phase 3, open-label CheckMate-9ER trial (NCT03141177) demonstrated the superiority of nivolumab plus cabozantinib to sunitinib in the first line treatment of patients with advanced renal cell carcinoma with respect to both progression-free survival and overall survival and led to its approval.  In CheckMate 9ER, mRCC patients were randomized in a 1:1 fashion to receive nivolumab 240 mg IV Q2W + cabozantinib 40 mg PO QD (n=323) or sunitinib (S) 50 mg PO (4 weeks of 6-week cycles; n=328) in the first-line setting, with randomization stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk score, tumor programmed death ligand 1 expression, and geographic region. Treatment was continued until disease progression or unacceptable toxicity for up to 2 years.

Primary and secondary outcomes were reported previously and published recently [2,3], with the primary aim of progression-free survival being superior for nivolumab plus cabozantinib after a median follow-up of 18.1 months (HR 0.51; P<0.0001). Both key secondary outcome measures overall survival (OS) and objective response rate (ORR) were superior in the nivolumab plus cabozantinib group (HR 0.60; OS, P=0.001; ORR, P<0.0001) [2,3]. The 40% reduction in the risk of death versus. sunitinib, as well as the doubling of median PFS outcomes, was consistent  for patients receiving cabozantinib plus nivolumab across all pre-specified subgroups. The safety and tolerability profiles were expected and considered acceptable.

The current analysis, presented by Prof. Cella, focused on in-depth HRQoL patient-reported outcomes, utilizing 2 instruments: the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) and the 3-level version of the EuroQol-5 Dimensions scale (EQ-5D-3L). Participants in both study arms were invited to complete the questionnaires at baseline (>90% completion rate) and common on-treatment and follow-up visits (≥80% completion rate).

Participants receiving nivolumab plus cabozantinib reported a smaller treatment burden than those receiving sunitinib. Patients in the nivolumab plus cabozantinib treatment arm had both a decreased risk of confirmed deterioration and a delay in deterioration. Patients in the nivolumab plus cabozantinib arm demonstrated significantly better FKSI-19 total score (mean change 2.9; P<0.0001) and subscale scores of disease-related symptoms (DRS; mean change 1.55; P<0.0001), DRS-physical, DRS-emotional, and functional well-being (P<0.05 for all subscores). EQ-5D-3L scores were in favor of nivolumab plus cabozantinib compared with sunitinib for both utility index (mean change 0.05; P=0.0005) and visual analog scale (mean change 3.26; P=0.0011).

Overall, these results demonstrated that patients with untreated advanced or metastatic RCC can benefit from both favorable clinical outcomes and an improved quality of life when treated with nivolumab plus cabozantinib instead of sunitinib.

Physician’s Weekly interviewed the presenting author, Dr David Cella, about the impact of his work.

What were the take-home messages of the health related quality of life data in CheckMate-9ER?

“Let me put this into context. This trail addressed first-line treatment for advanced and metastatic renal cell carcinoma. The interesting thing about this particular study and these particular results is that, whereas historically in oncology. adding a drug to an existing therapy will tent to compound toxicity with consequent  increased burden of side effects. Therefore, historically, we often find a more clinically effective treatment is typically a little harder on patients, due to additive toxicity”.
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“However, In the case of CheckMate-9ER, that is not what we found at all. We actually found that the newer, more effective, combination of nivolumab and cabozantinib was not only clinically superior in terms of progression-free survival and overall survival, but it actually was superior to sunitinib from the patient’s perspective in terms of their symptoms and side effects. This trial represents a win-win situation, basically.”

What were the sorts of tools you used to measure this impact?

“We simply used very basic questionnaires. One is called the Fact Kidney Symptom Index, or FKSI-19, and another is a health preference questionnaire, the EuroQOL 5 item measure of value (EQ-5D) that one places on their overall health. For both the FKSI-19 and with the EQ-5D instrument, we found that the nivolumab-cabozantinib combination was superior with almost 2 years of follow-up data. ”

How would you place this in perspective with other trials?

“Immuno-oncology has really revolutionized cancer care, and in particular renal cancer.

The news has been very good for people with kidney cancer, relative to where things were maybe15-20 years ago. It is very exciting to see that people can not only do better, live longer, but they can also not have as many of the adverse effects. It is not that these treatments are without adverse effects, they do definitely have some, but they are not as harsh as some other treatments, such as traditional chemotherapy regimens. Another unique thing about the treatments these days is that some of the standard measures of disease progression- like watching a tumor getting larger or showing up in a new place- is not always necessarily a reason to stop a therapy. If somebody is doing well, they can often continue on the therapy, and in many cases get continued benefit.”

What are the next steps with regarding to this study? Are there additional subsets that need to be analyzed for health-related quality of life?

“The next step for this particular study is to look at the overall picture, that is, to put it all together. What we did in the ASCO-GU presentation was we looked at the patient perspective and found that the nivolumab-cabozantinib arm was superior to sunitinib over time and also, this combination also delayed the time to worsening of the symptoms. What we have not yet done, but will do in the near future, is to take those data and combine them with the clinical data, to see the overall picture. We wonder if putting all those data into one analysis will show the same kind of benefit, or perhaps even more benefit? Time will tell.”

 

References

  1. Cella D et al. Patient-reported outcomes of patients with advanced renal cell carcinoma (aRCC) treated with first-line nivolumab plus cabozantinib versus sunitinib: The CheckMate 9ER trial. ASCO Genitourinary Cancers Symposium, abstract 285, 11–13 February 2021.
  2. Choueiri TK, et al. N Engl J Med 2021, 4 March; 384:829-841.
  3. Choueiri TK, et al. ESMO Virtual Congress 2020, presentation 6960, 19–21 September.