Moving Forward in the Debate – 2022 ESMO Advances in Adjuvant Therapy for Kidney Cancer

preface

In recent years, postoperative adjuvant therapy for high-risk kidney cancer has been a hot topic

This year's ESMO conference has announced the preliminary results of three large-scale Phase III clinical studies of postoperative adjuvant immunotherapy for kidney cancer, including the CheckMate 914 study of navuriumab + ipimumab (NIVO+IPI) double-free adjuvant therapy, the IMmotion010 study of adjuvant therapy of attilizumab, and the PROSPER study of the perioperative treatment of navurizumab, which are undoubtedly the biggest focus in the field of kidney cancer at this ESMO conference

Expert profile

Professor Fan Xinrong

• Deputy Chief Physician of the Department of Urology, Peking Union Medical College Hospital

• He is a member of the International Exchange Committee of the Urology Branch of the Chinese Medical Association

• Member of the Expert Committee on Urothelial Cancer of the Chinese Society of Clinical Oncology

• Member of the Urinary Oncology Group of the Oncology Branch of the Beijing Medical Association

• Academic Advisor to Uptodate

• Member of the expert group of the county project on the standardized diagnosis and treatment of urological system tumors of the National Health and Health Commission

• He has published more than 20 papers at home and abroad

• Participated in the compilation of the "Guidelines for the Diagnosis and Treatment of Urological Diseases" of the Chinese Medical Association, and was responsible for the compilation of the "Guidelines for the Diagnosis and Treatment of Bladder Cancer" - "Chemotherapy and Radiotherapy"

• Participated in the compilation and review of Campbell Urology of the Chinese Medical Association

• Participated in the compilation of the "Clinical Diagnosis and Treatment Guidelines • Urology Fascicle" of the Chinese Medical Association

LBA4

Localized renal cell carcinoma (RCC) with high risk of recurrence after nephrectomy with nivolumab + ipimumab (NIVO+IPI) versus placebo (PBO) for nephrectomy: results of the CheckMate 914 trial

CheckMate 914 is a randomized, double-blind, placebo-controlled phase III trial designed to evaluate the efficacy and safety

A total of 816 patients (NIVO+IPI group [n=405] and PBO group [n=411]) were included in this study, and the baseline of patients is shown in the figure

The primary endpoint was not met in this study, and the median DFS in the NIVO+IPI group was 50.

In terms of safety, the incidence of any grade of adverse events (AEs) was 89% and 57%, respectively, in the double-exempt treatment group and 57% in the placebo group, and 28% and 2% in AE associated with ≥ grade 3 treatment, respectively, and 29% and 1%

LBA66

Phase III IMmotion010 study: efficacy and safety of attilizumab versus placebo (PBO) as adjuvant therapy in patients with high risk of recurrence after renal cell carcinoma (RCC).

IMmotion010 is a randomized, double-blind, placebo-controlled phase III trial designed to assess the efficacy and safety
of atezolizumab versus placebo in patients with high-risk RCC after nephrectomy.

The primary endpoint was disease-free survival (INV-DFS)
assessed by the investigators.

A total of 778 patients were enrolled in this study, and the baseline of patients is shown in the figure
below.

As of May 3, 2022, the median follow-up was 44.
7 months
.

The median INV-DFS was 57.
2 months (95% CI: 44.
6, NE) and 49.
5 months (47.
4, NE) (HR: 0.
93; 95% CI: 0.
75, 1.
15; P=0.
495)
in the atezo and placebo groups, respectively.

The results of the DFS subgroup analysis did not show significant differences
between the two groups.

In 5% of patients with PDL1 expression ≥%, DFS showed a trend of benefit in the atezo group, but it did not reach statistical significance, and further exploration and analysis
was needed.

In terms of secondary endpoints, survival data are still immature, with median total survival (OS) not reached
between the two groups.

Security analysis shows that the security results are consistent
with previous studies.

The incidence of grade 3/4 adverse events (AEs) was 27.
2% and 21.
1%, respectively, in the atezo and placebo groups, and 11.
5% and 2.
6%
between AE-induced treatment interruptions.

Study conclusions: In the ITT population, the use of atezo for adjuvant therapy after nephrectomy in patients with RCC with high recurrence risk did not improve clinical outcomes compared with pbo, but had a controlled safety profile
.

LBA67

PROSPER study: Phase III randomized study of patients with renal cell carcinoma (RCC) who underwent nephrectomy in the perioperative period with navulisomab (nivo).

The PROSPER study is a randomized, nonblind, phase III study initiated by the National Cancer Institute to evaluate the efficacy and safety
of the use of nivolumab (nivo) in the perioperative period compared with standard treatment for surgery alone.

Oligometastatic patients assessed as "no evidence of disease" within 12 weeks postoperative are allowed to enroll
.

Patients in the trial group received 1 cycle of nivo neoadjuvant therapy (480 mg, IV, q4 weeks) before surgery, and continued to receive 9 cycles of adjuvant therapy
after surgery.

The control group operated only and did not use placebo
.

The primary endpoint was relapse-free survival (RFS)
in all patients.

Secondary study endpoints included RFS, overall survival (OS), and quality of life assessment
in patients with renal clear cell carcinoma.

Between February 2017 and June 2021, 819 patients were randomly assigned to the perioperative nivo group (n=404) or the surgery alone group (n=415).


The patient's enrollment and postoperative characteristics are shown in the figure below
.

The median follow-up was 16 months, and the results of the interim analysis showed no significant difference in the primary endpoint RFS between the two groups (HR: 0.
97; 95% CI: [0.
74–1.
28]; P 1-sided=0.
43), neither set of median RFS was reached
.

Subgroup analysis showed that only the pTx or pT1 stage subgroup had significant
benefit from receiving nivo perioperative treatment.

OS was still immature as of data analysis, but there was no statistical difference between the two groups (HR: 1.
48; 95% CI: [0.
89–2.
48]; P 1-sided=0.
93）
。
The study was terminated
early due to a lack of efficacy.

In terms of safety, the incidence of treatment-related adverse events was 93% and 59% between the trial group and the control group, respectively, ≥the incidence of grade 3 adverse events was 33% and 13%, respectively, and the incidence of interruption of treatment due to adverse events was 14%
in the experimental group.

Conclusions: This study is the first phase III study of neoadjuvant immunotherapy for RCC, and the application of navulumab in the perioperative period did not improve RFS in patients with high risk of recurrence, and the safety was consistent
with previous studies of navullizumab.

Comments

Surgery has always been the standard treatment for locally advanced kidney cancer, but patients with high-risk renal cell carcinoma still face a high risk of recurrence after surgery, so in the clinic, we urgently need to find effective drug treatment options as an organic supplement to surgery, reduce the risk of disease recurrence, and prolong survival
.

In the era of cytokine and targeted drug therapy, only phase III clinical studies of sunitinib for postoperative adjuvant therapy for high-risk kidney cancer have benefited from RFS, but due to the lack of benefit from patient quality of life and long-term survival, they have not been widely recognized by experts at home and abroad, while other phase III studies of anti-vascular TKI for postoperative adjuvant therapy for kidney cancer have been folded in the OS benefit and have not achieved substantial breakthroughs
.

The layout of immunotherapy in the field of advanced kidney cancer has been making great progress, and several phase III studies are being carried out
.

The mid-term analysis of the 2021 KEYNOTE564 study showed significant benefits for DFS in the Pabolizumab group, which successfully fired the first shot for the application of immunotherapy in the adjuvant treatment stage of kidney cancer, which is of landmark significance
.

Its recently published 30-month follow-up results show that DFS still benefits significantly
.

In November 2021, the FDA approved pabolizumab for postoperative adjuvant therapy
in patients with medium to high risk M1 NED renal cell carcinoma (RCC).

However, the results of the phase III study of three adjuvant immunotherapy for kidney cancer announced at this year's ESMO conference were not satisfactory, failing to repeat the positive results
of KEYNOTE564.

Regarding the differences in the findings, the congress suggested several possible points in the discussion of these three studies:

1. Differences in efficacy of PD1/PD-L1 inhibitors in the treatment of kidney cancer: In the IMmotion010 study, the treatment agent was selected as PD-L1 inhibitor altilizumab, while two phase III studies (IMmotion151, JAVELIN Renal101) using a combination regimen of PD-L1 inhibitors in the first-line treatment of advanced renal cancer failed to benefit from OS, while studies using PD1 inhibitors were highly successful.
   Does this suggest that PD-L1 inhibitors are slightly less effective than PD1 inhibitors in kidney cancer treatment, leading to the IMmotion010 study failing to achieve DFS benefits?

2. Inclusion of patients with M1 ND: From the study enrollees, the CheckMate 914 study did not enroll M1 NED patients as the other three studies, and from the results of the KEYNOTE564 study, this subgroup had a more significant
   benefit from DFS than M0 patients.
   
   

3. Double exemption treatment toxicity may affect patient compliance and thus affect efficacy: CheckMate 914 study using a double exemption treatment regimen will undoubtedly increase toxicity to some extent, and only 57% of patients in the trial group completed the complete treatment cycle, which is also worth pondering
   .
   
   

4. Study design differences: For the PROSPER study, the use of imaging staging of disease may result in the inclusion
   of more low-risk patients.
   
   Moreover, the study is open-label, and patients have a clear understanding of the treatment plan they are receiving, and there will be some bias
   .
   
   According to the study, patients in the neoadjuvant treatment group who did not undergo surgery later in the course were automatically judged to have a recurrence
   of the disease at D0.
   
   Not all patients in the study group underwent surgery, and some patients undergoing surgery were delayed by surgical complications or did not receive adjuvant treatment with navullizumab
   .
   

All of these factors can have an impact
on DFS results.

The publication of these three LBAs has made the benefits of adjuvant immunotherapy for kidney cancer a mystery, and the contradictory data suggest that there are still many unknowns in this field, which are worthy of further analysis and exploration
.

KEYNOTE564 study clearly states that postoperative adjuvant immunotherapy can significantly reduce the risk of disease recurrence, but the current OS data is still immature, from the current trend, the survival benefit improvement is not obvious, considering that the reason may be that after the resection of the lesion, it can greatly alleviate the disease load and bring certain survival benefits, so whether it is necessary to wait for the OS results to decide the diagnosis and treatment plan is also a hot topic
of debate at this conference.

From my personal point of view, the choice of adjuvant therapy needs to be considered and trade-offs from multiple dimensions such as patient benefits, safety issues, and cost issues to provide patients with reliable drug treatment options
.

In addition, how to effectively screen out the advantageous population suitable for receiving adjuvant therapy is also a hot topic
of future research.

Specific pathology type screening, effective biomarker prediction, and more accurate high-risk stratification may help us refine our dominant
populations.

I believe that with the generation of more research evidence and the accumulation of clinical practice, we will certainly be able to explore more scientific adjuvant treatment options to bring more benefits
to patients.

Reviewer: Uni

Typography: Uni

Execution: Small Garden