Editor’s Note
The 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GU) was held from January 25th to 27th in San Francisco, showcasing the most innovative scientific advancements in the field and discussing future treatment directions for genitourinary cancers. Among them, several groundbreaking studies in the field of kidney cancer were presented, and "Oncology Frontier" invited Professor Xinan Sheng and Professor Xieqiao Yan from Peking University Cancer Hospital to interpret these studies for readers.LBA358
CheckMate 914 – Nivolumab for Adjuvant Therapy
CheckMate 914 is a randomized, double-blind, multicenter, phase III, 2-stage study aimed at evaluating the efficacy of nivolumab/ipilimumab (NIVO+IPI) compared to placebo (Part A) or nivolumab monotherapy compared to placebo (Part B) as adjuvant therapy for intermediate- to high-risk kidney cancer. The results of the 37.0-month median follow-up from Part A in 2023 showed that NIVO+IPI adjuvant therapy did not increase disease-free survival (DFS) compared to placebo. The preliminary results of Part B were reported at this ASCO GU meeting.
Patients with pathologic stage T2a (grade 3/4) N0M0, T2b~T4N0M0, or any TN1M0 were enrolled. The primary endpoint was independent central review (BICR)-assessed DFS. Secondary endpoints included overall survival (OS) and safety. A total of 619 patients were randomized to receive nivolumab monotherapy (n=411) or placebo (n=208). With a median follow-up of 27.0 months, there was no significant difference in DFS between nivolumab monotherapy and placebo (HR, 0.87; 95% CI, 0.62~1.21; P=0.3962). Median DFS was not reached; the 12-month and 18-month DFS rates were 83.3% vs. 78.2% and 78.4% vs. 75.4%, respectively.
Regarding safety, any-grade treatment-related adverse events (AEs) occurred in 72.5% and 51.7% of patients, and grade 3-4 treatment-related AEs occurred in 8.8% and 1.9%, respectively. Treatment discontinuation due to any-grade treatment-related AEs was observed in 9.6% and 1.0% of patients in the nivolumab monotherapy and placebo groups, respectively.
The CheckMate 914 study’s Part A, evaluating dual immunotherapy for adjuvant therapy in intermediate- to high-risk kidney cancer, did not yield positive results, partially due to adverse reactions associated with dual immunotherapy, particularly grade 3-4 adverse reactions that impacted the final treatment outcomes, resulting in the failure to achieve the primary endpoint of disease-free survival (DFS), which has been widely recognized internationally. It is regrettable that single-agent nivolumab adjuvant therapy failed to replicate the results of the KEYNOTE-564 study, failing to improve patients’ recurrence-free survival. The reasons are multifaceted. There were certain differences in the two cohorts, and subgroup analyses showed that high-risk populations in both cohorts could benefit from adjuvant PD-1 monotherapy. The benefit of the KEYNOTE-564 study may have been enhanced by the proportion of extremely high-risk patients in its cohort, who had undergone metastatic lesion resection, sarcomatoid differentiation, or were PD-L1 positive, thus deriving more benefits from postoperative immune adjuvant therapy.
LBA359
KEYNOTE-564 – Pembrolizumab for Adjuvant Therapy
The KEYNOTE-564 study is a randomized, double-blind, multicenter, phase III trial aimed at evaluating the efficacy of pembrolizumab for adjuvant therapy in intermediate- to high-risk kidney cancer. Patients enrolled in the study had pathologic staging of T2 (grade 4, or with sarcomatoid differentiation) N0M0, T2b~T4N0M0, or any TN1M0, or distant metastases with no residual lesions (M1 NED). Previous results have shown that pembrolizumab significantly improves disease-free survival (DFS) compared to placebo.
This conference reported the results of the third prespecified interim analysis, with a median follow-up time of 57.2 months as of September 15, 2023. In the pembrolizumab group, 55 OS events were observed, compared to 86 OS events in the placebo group. Pembrolizumab demonstrated a statistically significant improvement in overall survival (OS) compared to placebo (median OS not reached, HR 0.62, 95% CI 0.44−0.87; P=0.0024). The estimated 2-year OS rates for the two groups were 91.2% and 86.0%, respectively. Subgroup analyses showed significant benefits in the M1 no evidence of disease (NED) (HR 0.51, 95% CI 0.15−1.75) and CPS≥1 (HR 0.62, 95% CI 0.42−0.91) subgroups. The sarcomatoid feature subgroup had an HR of 0.69 (95% CI 0.28−1.70), while the subgroup without sarcomatoid features had an HR of 0.57 (95% CI 0.39−0.84). Pembrolizumab demonstrated consistent DFS benefits compared to placebo in line with previous interim analyses (HR 0.72; 95% CI 0.59−0.87).
In clinical studies related to tumor adjuvant therapy, the focus is primarily on disease-free survival. After improvement in disease-free survival, attention turns to whether there is a benefit in overall survival. The long-term follow-up results of KEYNOTE-564 presented at this conference showed statistically significant differences in both disease-free survival and overall survival with pembrolizumab, marking the first instance where checkpoint inhibitors have been shown to increase both disease-free survival and overall survival in kidney cancer. This further validates the value of pembrolizumab for adjuvant therapy and continues to support its use in postoperative adjuvant therapy for intermediate- to high-risk kidney cancer.
Similarly, adjuvant therapy faces the issue of patient selection. Whether T2-stage patients benefit remains a nuanced conclusion. Overall, the results from the entire KEYNOTE-564 study population are positive after patient inclusion. However, subgroup analysis indicates that the degree of benefit is much lower in the low-risk and intermediate-risk groups than in the high-risk and very high-risk groups. Therefore, more data accumulation is still needed for these patients. For subsequent clinical practice, precise selection of the treatment population should focus on patients at high or very high risk, who are likely to derive greater benefit from adjuvant therapy. Additionally, the impact of immune-related adverse events, especially grade 3-4 adverse events, on patient quality of life and survival time should not be overlooked. Therefore, appropriate patient selection and avoidance of severe adverse events remain the goals of adjuvant therapy.
CheckMate 67T Study
The CheckMate 67T study is a multicenter, randomized, open-label, phase III trial aimed at evaluating the non-inferiority of subcutaneous administration of nivolumab (NIVO SC) compared to intravenous administration of nivolumab (NIVO IV) in terms of pharmacokinetics (PK) and objective response rate (ORR) in patients with locally advanced or metastatic clear cell renal cell carcinoma who have previously received first- or second-line therapy. Patients were randomized 1:1 to receive either NIVO SC 1200 mg plus recombinant human hyaluronidase PH20 every 4 weeks or NIVO IV 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity, withdrawal of consent, completion of 2 years of treatment, or death.
The results showed that subcutaneous administration of nivolumab was faster (4.7 vs 30.9 minutes) compared to intravenous injection. Compared to intravenous injection, the subcutaneous injection group had almost double the 28-day average blood drug concentration and minimum concentration (joint primary endpoints). Other secondary study objectives included additional PK exposure measurements, safety, efficacy, and immunogenicity. Subcutaneous and intravenous administration showed comparability, with objective response rates and progression-free survival times of 24.2% vs. 18.2% and 7.2 vs. 5.7 months, respectively. In terms of safety, there were no significant differences between subcutaneous and intravenous administration, and the incidence of hypersensitivity reactions seemed to be lower (1.2% vs. 3.7%), which may be another advantage of subcutaneous injection. The rate of local reactions was slightly higher (8.1% vs. 2.0%), but all were mild and transient.
So far, our focus has been on developing various new drugs for the treatment of advanced kidney cancer as much as possible, but there seems to be less research effort invested in optimizing treatment. Currently, most anti-cancer drugs are still administered intravenously, which has the advantage of rapid absorption and immediate management of any allergic reactions. On the other hand, subcutaneous injection is convenient, quick, reduces constraints on the healthcare system, saves time for both patients and healthcare providers, especially during outbreaks of various epidemics (such as the novel coronavirus, influenza, and epidemic periods of chlamydia infection), and can reduce patients’ contact time at medical centers. Based on this, any attempt to shorten infusion time is absolutely worthwhile.
The principle of subcutaneous injection of nivolumab in the CheckMate 67T study is based on its pharmacokinetic characteristics. The dose range of nivolumab is 0.3-10 mg/kg body weight, and there was no difference in safety and efficacy in phase II studies. It is very reasonable to use the average serum concentration and steady-state minimum serum concentration at 28 days as study endpoints. The subcutaneous injection group added recombinant hyaluronidase to facilitate rapid absorption, providing higher drug exposure.
It is worth noting that the subcutaneous injection group had a threefold higher rate of anti-drug antibodies (22% vs. 7%), which may lead to faster development of resistance to nivolumab, but this remains unknown. FDA approval for nivolumab indications was based on overall survival benefits. However, the median follow-up time of this study was only about 8 months, so the overall survival efficacy of the subcutaneous injection route cannot be commented on at present. In the combination regimen of ipilimumab/nivolumab, the first four induction doses can be administered intravenously, followed by switching to subcutaneous maintenance therapy with nivolumab, which may also be a good choice. Whether subcutaneous injection of nivolumab can be safely combined with cabozantinib, and whether it will alter pharmacokinetics, remains to be observed.
In summary, subcutaneous injection of nivolumab is comparable to intravenous injection and can be promoted as a more convenient and tolerable treatment option.
Abstract 361
Quality of Life Data from the LITESPARK-005 Study
LITESPARK-005 is a multicenter, randomized, open-label, phase III study aimed at evaluating the safety and efficacy of bevacizumab versus everolimus in the second-line treatment of advanced clear cell renal cell carcinoma. The primary endpoint of PFS benefit (HR 0.75, 95% CI 0.63-0.90, P=0.01) and key secondary endpoint of ORR benefit (21.9% vs. 3.5%) were reported at the 2023 ESMO Congress. In December 2023, the FDA approved bevacizumab for second-line treatment of advanced clear cell renal cell carcinoma. This conference reported the quality of life data of bevacizumab compared to everolimus in the population of advanced renal cell carcinoma patients.
The LITESPARK-005 study reported baseline to week 17 quality of life assessment scores, with quality of life deterioration defined as a decrease of ≥3 points in FKSI-DRS or ≥10 points in EORTC QLQ-C30. As of June 13, 2023 (the data cutoff date for the second prespecified interim analysis), the median follow-up time was 25.7 months. The median treatment duration was 7.6 months for bevacizumab and 3.9 months for everolimus; 84 (22.6%) patients in the bevacizumab group and 18 (5.0%) patients in the everolimus group were still receiving treatment. Among the 374 subjects in the bevacizumab group and 372 subjects in the everolimus group, 366 and 354 subjects, respectively, were included in the PRO analysis population. Completion rates of FKSI-DRS and QLQ-C30 were >90% at baseline and >55% at week 17 (~4 months). The FKSI-DRS and QLQ-C30 GHS/QoL score TTDs showed significant prolongation in the bevacizumab group compared to the everolimus group, with values of 19.4 vs. 10.2 months and 19.3 vs. 13.9 months, respectively. The LS mean change in FKSI-DRS and QLQ-C30 GHS/QoL scores indicated stability in the bevacizumab group from baseline to week 17 and a trend of deterioration in the everolimus group, with the everolimus group showing a potentially greater trend of deterioration in PF scores compared to the bevacizumab group.
For years, studies on patient symptoms in clinical trials have been lacking.
Data from three randomized trials show a large discrepancy between physician-reported symptoms, even common symptoms and drug toxicities, and patient-reported symptoms—almost exceeding 50%. This is why patient-reported outcomes have become so important. In the initial weeks, a large proportion of patients rapidly deteriorated, with a significant decrease in quality of life. Compared to the everolimus group, approximately 10% more patients in the bevacizumab group completed the questionnaire survey at week 17. In this patient population, it needs to be clarified whether clinical responses are consistent with patient-reported outcomes, meaning whether patients with imaging improvements experience an improvement in quality of life. While the bevacizumab group showed an 18.4% increase in objective response rate compared to everolimus, the proportion of improvement in quality of life increased by 8% (25.4% vs. 17.5%), and the proportion of deterioration in quality of life decreased by 5% (18.0% vs. 24.6%).
It is worth noting that both bevacizumab and everolimus have their toxicities. From the quality of life line chart, we can see that the scores of both groups of patients have decreased compared to baseline levels. There was not a significant difference in symptom scales between the two groups, with the bevacizumab group. Therefore, treatment itself induces toxic reactions. Regardless of which treatment method is used, the quality of life of these patients tends to deteriorate compared to baseline levels. However, on the other hand, in some cases, it is difficult to distinguish drug-related toxicity from symptoms related to tumor progression, and seriously ill patients may not provide quality of life scale scores. The significance of the LITESPARK-005 study lies in the inclusion of patient-reported symptoms. While bevacizumab improved ORR and PFS, it also prolonged the time to deterioration of the disease, and compared to everolimus, bevacizumab did show some moderate benefits in terms of quality of life. When making treatment decisions for patients and designing clinical trials, we need to consider factors such as patient symptoms and quality of life.
Professor Xinan Sheng
Director, Chief Physician, Professor, Doctoral Supervisor
Deputy Director, Department of Genitourinary Oncology, Peking University Cancer Hospital
Director, Chinese Society of Clinical Oncology (CSCO)
Executive Secretary, Kidney Cancer Expert Committee, CSCO
Executive Committee Member, Urothelial Cancer Expert Committee, CSCO
Member, Bladder Cancer Quality Control Expert Committee, National Tumor Quality Control Center
Executive Committee Member, Genitourinary Tumor Professional Committee, Chinese Anti-Cancer Association
Deputy Group Leader, Rare Types of Kidney Cancer Collaboration Group, Genitourinary Tumor Professional Committee, Chinese Anti-Cancer Association
Incoming Chairman, Genitourinary Tumor Subcommittee, Beijing Oncology Prevention and Treatment Research Association
Chairman, Youth Committee, Genitourinary and Reproductive Tumor Subcommittee, Beijing Anti-Cancer Association
Executive Committee Member, Oncology Branch, Beijing Medical Association
Professor Qiao Yanxie
Associate Chief Physician
Department of Genitourinary Oncology, Peking University Cancer Hospital
Member, Rare Types of Kidney Cancer Collaboration Group, Genitourinary Male Reproductive Tumor Professional Committee, Chinese Anti-Cancer Association
Member, Tumor Cardiology Expert Committee, Chinese Society of Clinical Oncology (CSCO)
Member, Youth Committee, Oncology Branch, Beijing Medical Association
Member, Head and Neck Melanoma Professional Committee, Beijing Cancer Prevention and Treatment Association
Member, Head and Neck Tumor MDT Professional Committee, Beijing Cancer Prevention and Treatment Association
