Dr. Kan Gong
Department of Urology, Peking University First Hospital
The 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GU 2023) kicked off on February 16th in San Francisco, USA. In the field of kidney cancer diagnosis, a novel molecular imaging agent, 89Zr-DFO-girentuximab, has been shown to accurately diagnose clear cell renal cell carcinoma (ccRCC). In the first-line treatment area, the CheckMate 9ER study reported extended follow-up data, while the COSMIC-313 study presented data on IMDC subgroup patients.
Additionally, research explored the improvement of complete response rates in first-line immunotherapy patients through local treatments and the benefits of reducing the number and duration of immunotherapy treatments for untreated survival. In the area of second-line treatment, CaboPoint reported positive anti-tumor activity of cabozantinib for immunotherapy-resistant patients.
ccRCC Diagnosis
Currently, traditional diagnostic methods for renal masses still have limitations. Techniques such as CT and MRI have shortcomings in distinguishing benign or malignant lesions, and biopsies are not only invasive but also prone to misdiagnosis. CAIX is a transmembrane protein induced by hypoxia and expressed on the cell surface. It is upregulated in up to 90% of clear cell renal cell carcinoma (ccRCC) cases associated with low oxygen or VHL mutations. 89Zr-DFO-girentuximab (TLX250-CDx) is an antibody-conjugated drug, with girentuximab specifically targeting CAIX and 89Zr serving as a radiolabeled payload, both coupled through DFO. The Phase III ZIRCON study aims to evaluate the efficacy of this novel molecular imaging agent for diagnosing ccRCC.
The study included 300 patients with an average age of 62 years ±12 years, of whom 71% were male. Of the 288 patients with available central pathology surgical specimens, 193 cases (67%) were diagnosed as clear cell renal cell carcinoma (ccRCC), and 179 cases (62%) were classified as cT1a stage. The primary analysis included 284 evaluable patients, and the results demonstrated that the diagnostic sensitivity of 89Zr-DFO-girentuximab was 85.5% (95% CI: 79.8%~90%), with a specificity of 87% (78.8%~92.3%), meeting the predefined significance thresholds (the lower 95% CI limits for sensitivity and specificity were both >70% and >68%, respectively). The positive and negative predictive values were 93% and 75%, respectively, with an overall accuracy of 86%.
For the cT1a subgroup of patients, which was considered a key secondary endpoint, the diagnostic sensitivity was 85.5% (77%~91.2%), specificity was 89.5% (78.6%~95.2%), and the positive predictive value (PPV) and negative predictive value (NPV) were 93.4% and 78%, respectively. The overall accuracy for this subgroup was 87%.
Regarding safety, adverse events related to 89Zr-DFO-girentuximab were very rare, with only 18 cases (6%) experiencing TEAEs (Treatment-Emergent Adverse Events) of grade 3 or higher.
This study indicates that the radiolabeled compound 89Zr-DFO-girentuximab achieves a diagnostic accuracy of over 85% for ccRCC and even reaches 87% accuracy for the traditionally challenging diagnosis of small-volume (cT1a) tumors. Furthermore, the imaging agent demonstrates good tolerability. Currently, imaging technologies targeting PSMA have been widely used in the diagnosis and treatment of prostate cancer. 89Zr-DFO-girentuximab may become the first molecular imaging technology available for diagnosing kidney cancer, ushering in a new era of precision diagnosis and treatment for renal cancer.
First-Line Treatment
Previously reported data from the CheckMate 9ER study with a median follow-up of 32.9 months suggested that for advanced renal cell carcinoma (aRCC) patients, the efficacy of nivolumab in combination with cabozantinib (N+C) as first-line treatment was superior to sunitinib (S). This conference reports the results of the study with a median follow-up of 44 months, including survival rates, response rates, and safety.
Among 323 patients receiving N+C treatment and 328 patients receiving S treatment, the results at the median follow-up of 44.0 months showed that N+C maintained its advantage in terms of progression-free survival (PFS) and overall survival (OS) compared to S. The median PFS was 16.6 months for N+C and 8.4 months for S (HR 0.58; 95% CI: 0.48~0.71, P<0.0001), and the median OS was 49.5 months for N+C and 35.5 months for S (HR 0.70; 95% CI: 0.56~0.87, P=0.0014). Subgroup analysis within the IMDC classification indicated that mainly intermediate to high-risk patients benefited, with a more significant benefit observed in the high-risk group (PFS and OS HR of 0.38 and 0.46, respectively). Low-risk patients showed only a trend toward PFS benefit (HR 0.75) with no OS benefit (HR 1.07). N+C had a higher objective response rate (ORR) (56% vs. 28%), with 12% and 5% of patients achieving complete response (CR), respectively. The median duration of response was 23.1 months for N+C and 15.2 months for S. The incidence of any-grade treatment-related adverse events (TRAE) was 97% for N+C and 93% for S (≥3-grade TRAE, 67% for N+C and 55% for S). TRAE led to discontinuation of cabozantinib in 10%, nivolumab in 10%, both in 7%, and sunitinib in 11% of patients. These extended follow-up data confirm the sustained survival and response benefits of N+C, supporting it as a first-line treatment option for aRCC patients.
The COSMIC-313 study, which was reported at last year’s ESMO conference, demonstrated that a first-line triple therapy regimen using cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) significantly improved progression-free survival (PFS) in IMDC intermediate/high-risk aRCC patients compared to N+I. The ASCO-GU conference this year further presented data on patients from different IMDC subgroups.
In the PITT population, 75% of patients were classified as IMDC intermediate risk, and 25% were considered high risk. Among intermediate/high-risk patients, there were significant baseline differences between the N+I+C and N+I groups: KPS≥90 (67% vs. 47%), prior nephrectomy (71% vs. 44%), and BIRC ≥2 target/non-target lesions (68% vs. 83%). Baseline characteristics were balanced between the two groups for intermediate-risk patients, but there were differences in high-risk patients (e.g., KPS≥90: 42% vs. 52%; prior nephrectomy: 37% vs. 50%).
In intermediate-risk patients, C+N+I improved PFS (HR 0.63, 95% CI 0.47~0.85), and the numerical values for ORR (objective response rate) and DCR (disease control rate) were higher. For high-risk patients, there were no significant differences in PFS and ORR, but C+N+I had a higher DCR. In both risk groups, C+N+I had a lower proportion of patients with best response being progressive disease (PD) compared to P+N+I. None of the treatment groups achieved a prolonged duration of response. In the C+N+I group and P+N+I group, the incidence of grade 3/4 treatment-related adverse events (TRAEs) in the intermediate-risk population was 74% and 42%, respectively, and in the high-risk population, it was 67% and 38%, respectively. In the intermediate-risk group, the discontinuation rates due to TRAEs were 14% and 5% for the two groups, while in the high-risk group, they were 5% and 4%, respectively. The results of the COSMIC-313 study suggest that, compared to N+I, C+N+I as first-line treatment for IMDC intermediate/high-risk aRCC can improve PFS, with the subgroup analysis indicating that the benefit is primarily observed in intermediate-risk patients.
New Treatment Paradigms in First-Line Therapy
Immunotherapy has become the standard of care for first-line treatment in advanced RCC. In addition to studies like CheckMate 9ER and COSMIC-313, which explore combination immunotherapy regimens with two or three drugs, this year’s ASCO-GU also reported on other novel treatment approaches, including local therapy for residual lesions in patients after first-line treatment and treatment strategies that limit the number and duration of immunotherapy drugs.
A retrospective study conducted by Moinard-Butot included 80 mRCC patients with a median age of 68 (ranging from 41 to 89) years, of whom 75% were male, and 36 patients (45%) had previously undergone kidney surgery. IMDC risk stratification included 12 patients (15%) in the low-risk group, 50 patients (63%) in the intermediate-risk group, and 18 patients (22%) in the high-risk group. First-line treatment regimens included 47 patients (59%) receiving IO+IO therapy, 24 patients (30%) receiving IO+TKI therapy, and 9 patients (11%) receiving another IO-based treatment.
In the analysis of the effectiveness of systemic treatment alone in these 80 patients, the results were as follows: 9 patients (11%) achieved complete response (CR), 35 patients (44%) achieved partial response (PR), 23 patients (29%) had stable disease (SD), and 13 patients (16%) had progressive disease (PD). Among the 35 patients who achieved PR, 10 patients reached CR by ablating or surgically removing residual lesions, increasing the overall CR rate to 24% (19/80). Among the 19 CR patients, 5 had sarcomatoid tissue components, and the median age was 60 years. The median duration of IO exposure before local treatment was 13 months. Residual lesion removal sites included the kidney (N=6), lymph nodes (N=4), lung metastases (N=2), and liver metastasis (N=1). This study suggests that after first-line IO treatment for mRCC, the removal of residual lesions can increase the CR rate (from 11% to 24%), making this treatment approach an option for specific patient populations.
Currently, there is still controversy regarding the duration of immunotherapy treatment. As seen in the COSMIC-313 study, dual immunotherapy still carries a relatively high risk of adverse effects. Previous studies like CheckMate 067 and 214 were also forced to terminate due to toxicity. Immunotherapy typically offers a longer duration of disease control, and patients can still experience a prolonged treatment-free survival (TFS) after discontinuation.
In an effort to further reduce the adverse effects of immunotherapy, the HCRN GU16 260 cohort A explored a novel treatment approach: initially providing NIVO monotherapy, with patients achieving partial response (PR) or complete response (CR) continuing NIVO treatment. Patients with progressive disease (PD) or stable disease (SD) switched to a sequential treatment of 4 cycles of NIVO+IPI dual immunotherapy followed by maintenance NIVO. Both of these regimens had a duration of approximately 96 weeks, with patients transitioning to TFS after discontinuation and moving to second-line treatment upon disease progression.
The study results showed that the 3-year overall survival (OS) rates for the overall population, low-risk patients, and intermediate/high-risk patients were 68.3%, 96.8%, and 56.6%, respectively. The median OS was 29.9 months, 35.7 months, and 27.4 months, respectively.
Of note, the median treatment-free survival (TFS) for the overall population, low-risk patients, and intermediate/high-risk patients was 9.4 months (with a 3-year TFS rate of 26%), 12.9 months (with a 3-year TFS rate of 36%), and 8.0 months (with a 3-year TFS rate of 22%), respectively. This implies that patients can have nearly one year without receiving treatment while continuing to survive. The reduction in treatment can help lower adverse effects, with only 3% of the overall population, 3% of low-risk patients, and 4% of intermediate/high-risk patients experiencing grade 3 or higher treatment-related adverse events (TRAEs).
Backline Treatment
First-line treatment with immune checkpoint inhibitors (CPI) is the standard of care for advanced RCC. However, there is currently a lack of prospective research on cabozantinib as a backline treatment following first-line CPI therapy. CaboPoint is an ongoing Phase II, multicenter, open-label study that analyzes backline treatment in patients with unresectable, locally advanced, or metastatic clear cell RCC after first-line therapy.
At the time of the interim analysis, 88 patients had completed 3 months of follow-up. Among them, there were 60 patients in cohort A and 28 patients in cohort B (cohort A: progression after treatment with nivolumab + ipilimumab; cohort B: progression after CPI + vascular endothelial growth factor-targeted therapy). The baseline characteristics of the two cohorts were similar. Patients had an ECOG PS of 0 (55.0%/60.7%), and IMDC classified them as intermediate risk (46.3% and 13.0%) or high risk (40.7% and 11.1%). The most common prior treatment regimen in cohort B was a combination of pembrolizumab and axitinib (71.4%), followed by a combination of avelumab and axitinib (28.6%). The study results showed that the overall population, cohort A, and cohort B had objective response rates (ORR) of 29.5%, 31.7%, and 25.0%, respectively.
This interim analysis indicates that in advanced RCC patients who have progressed after first-line combination therapy based on CPIs, cabozantinib treatment shows preliminary efficacy and is independent of the first-line regimen. The CaboPoint trial is currently ongoing, with the final analysis scheduled to be released in September of this year.
Reference
1. Results from phase 3 study of 89Zr-DFO-girentuximab for PET/CT imaging of clear cell renal cell carcinoma (ZIRCON). （Abstract：LBA602）https://meetings.asco.org/abstracts-presentations/216521
2. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial.（Abstract：603）https://meetings.asco.org/abstracts-presentations/216519
3. Outcomes by IMDC risk in the COSMIC-313 phase 3 trial evaluating cabozantinib (C) plus nivolumab (N) and ipilimumab (I) in first-line advanced RCC (aRCC) of IMDC intermediate or poor risk.（Abstract：605）https://meetings.asco.org/abstracts-presentations/216532
4. Effect of treatment of residual disease after immunotherapy-based combinations on complete response rate in metastatic renal cell carcinoma（Abstract：601）https://meetings.asco.org/abstracts-presentations/217346
5. Treatment-free survival (TFS) outcomes from the phase II study of nivolumab and salvage nivolumab + ipilimumab in advanced clear cell renal cell carcinoma (aRCC) (HCRN GU16-260-Cohort A).（Abstract：604）https://meetings.asco.org/abstracts-presentations/216520
6. CaboPoint: Interim results from a phase 2 study of cabozantinib after checkpoint inhibitor (CPI) therapy in patients with advanced renal cell carcinoma (RCC).（Abstract：606）https://meetings.asco.org/abstracts-presentations/216534
