Metastatic renal cell carcinoma disease response in the era of immune checkpoint inhibitor-based combinations

The treatment of metastatic renal cell carcinoma (mRCC) has progressively changed over the past few decades, leading to better survival outcomes and disease responses. Previously, cytokines like interleukin-2 and interferon-alpha were the mainstay of mRCC treatment, with objective response rates (ORRs) reaching a maximum of 18.6% and a median overall survival (OS) of 17 months (1,2). This was followed by the introduction of tyrosine kinase inhibitors (TKIs) such as sunitinib, which led to an improved ORR of 31% and a longer median OS of 26 months (3,4). Within the last decade, the standard of care for mRCC treatment has shifted to include immunotherapy-based combinations. Phase 3 trials such as CheckMate 214 (nivolumab plus ipilimumab), KEYNOTE-426 (pembrolizumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), and CLEAR (pembrolizumab plus lenvatinib) have all shown significant improvements in ORR and OS compared to sunitinib alone as a first-line treatment (5).

Many patients with mRCC are finally experiencing durable responses to therapy with current immune therapy combinations such as ipilimumab/nivolumab. For example, the combination of ipilimumab with nivolumab led to an ORR of 39% and a median OS of 52.7 months at an 8-year follow-up (6). This is also true with TKI combinations, such as pembrolizumab combined with axitinib, which achieved an ORR of 60.6% and a 60-month OS rate of 41.9% (7). This represents a dramatic improvement in OS compared to the cytokine era.

This analysis of CLEAR by Motzer et al. sought to evaluate OS stratified by ORR (8). Depth of response as measured by Response Evaluation Criteria in Solid Tumors (RECIST) might be a useful tool in predicting long-term response to immune therapy. Patients were classified into three groups based on disease response: complete response (CR), near-complete response (near-CR), and other partial response (oPR), defined by RECIST version 1.1 (RECIST v1.1). Near-CR was defined as a partial response (PR) with maximum tumor shrinkage ≥75% from baseline and oPR as having a PR that was less than near-CR. Investigators found that the median duration of response (DOR) was higher in the CR group [43.7 months, 95% confidence interval (CI): 39.2–not estimable (NE)] and near-CR groups (30.5 months, 95% CI: 22.4–NE) compared to patients in the oPR group (17.2 months, 95% CI: 12.5–21.4). Prolongation of OS was also observed for these more favorable responses. Indeed, in this analysis, the authors note that nearly 100% of patients with either a CR or near-CR were alive at 2 years. This is a remarkable achievement when compared to prior survival estimates before combination therapies were approved. It is also notable that these favorable responses are frequently observed. Patients with either a CR or near-CR constituted approximately one-third of all patients treated with lenvatinib/pembrolizumab. Identifying these patients early in the treatment process will help with prognostication and patient counseling.

The distribution of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores was generally similar across the ORR cohorts. For instance, the proportion of patients with favorable risk disease is 38%, 34%, and 24% for patients with CR, near-CR and other PR respectively. This suggests that the IMDC risk score is prognostic but not predictive for achieving a durable response. Long-term results of each combination study also support this finding (6,9-11). IMDC is not a predictive tool. All patients have a chance for a durable response through combination treatment regardless of IMDC prognostic risk score.

This report by Motzer et al. is a long-term follow-up study with a median duration of follow-up of greater than 36 months. The hypothesis—depth of response correlates with duration of response—is supported by this data. It is particularly notable that the near-CR group had a relatively similar outcome to the CR group, median DOR of 30.5 months and 43.7 months respectively. Similar correlations have been documented in phase 3 trials of other immune checkpoint inhibitor (ICI)-based first-line regimens in mRCC. In CheckMate 214, investigators found that DOR was positively associated with OS in patients with >75% tumor reduction compared to patients with ≤25% tumor reduction [hazard ratio (HR) 0.08, 95% CI: 0.03–0.17] (12). Interestingly, patients with >50 to 75% tumor reduction had comparable OS to patients with >75% reduction. Similarly, in this report of the CLEAR study by Motzer et al., durable responses were seen not only in patients with CR but also near-CR. This suggests that the utilization of CR alone may be restrictive in disease prognostication. In the CLEAR study, there were 65 patients with a CR (18% of the lenvatinib/pembrolizumab study population) and 59 with near-CRs (17% of the study population). In our quest to search for signals of activity in early-phase clinical trials, it appears that emphasizing CR outcomes is inadequate and misses almost half of the patients with durable responses. CR seems an insufficient early signal for OS as it underrepresents the true proportion of patients who achieve a durable response.

So, how can we further advance the field and help more patients achieve a durable response to immune therapy? Increasing adherence of optimal therapy is one important step. The adoption of guideline-recommended regimens in current real-world practice remains suboptimal. A recent study by our group found that 26% of patients received TKI monotherapy as first-line treatment for mRCC (13).

A potential second approach is to use response-adapted therapy. Currently, the optimal duration of ICI-based combination therapy remains undefined. As treatment is often continued until disease progression or unacceptable toxicity, patients with complete or partial responses may have lengthy treatment durations. For example, in the CLEAR trial, the median duration of treatment was 36.5 months for patients with CR, though notably, no patients remained on pembrolizumab at the data cutoff. Moreover, in one meta-analysis that included 1,833 patients with mRCC treated with ICI, treatment-free survival at 6 and 12 months was 35% and 20%, respectively, with the best outcomes seen in those receiving dual ICI therapy (14). This analysis supports the potential for treatment discontinuation, the need to identify patients who can safely discontinue therapy, and individualized treatment approaches to avoid unnecessary prolongation of ICI therapy, limiting immune-related adverse events. The PDIGREE trial (NCT03793166) uses a response-adapted approach to guide treatment duration in metastatic clear cell RCC. All patients receive 12 weeks of ipilimumab plus nivolumab. Based on response, those with complete response get a fixed 1-year course of nivolumab, those with progression switch to cabozantinib, and those with stable or partial responses receive nivolumab plus cabozantinib or nivolumab alone. This trial will help in personalizing therapy intensity and treatment duration. The primary outcome is 3-year OS. This trial has completed accrual so results are anticipated relatively soon.

A potential third approach is with debulking treatment. For instance, in patients with mRCC receiving nivolumab, radiotherapy with ablative intent has been observed to be associated with superior progression-free survival (PFS) and OS compared to radiotherapy with palliative intent (15). Moreover, in a single-arm multi-institutional phase 1/2 trial, the combination of stereotactic radiotherapy with pembrolizumab in patients with oligometastatic RCC who progressed on two or fewer lines of systemic therapy led to a significant local disease control with 2-year PFS of 45% and disease control rate of 92% (16). Additionally, reducing tumor burden with cytoreductive nephrectomy (CN) may improve outcomes. It is noteworthy that in the CLEAR trial, 94% of patients with CR had a history of prior nephrectomy compared to 86% in patients with near-CR and 64% in patients with oPR. This trend towards higher rates of prior nephrectomy in patients with better response suggests possible efficacy for CN in the era of ICI-based combinations.

Historically, CN was shown to have survival benefits in cytokine-based therapies, however, its role in the current treatment landscape of mRCC is less clear. For example, the phase 3 CARMENA trial showed no significant difference in OS or PFS in patients receiving sunitinib with upfront CN versus sunitinib alone (17). However, some data suggest that it might have a more significant role in patients treated with immune therapy. A post hoc analysis of the JAVELIN renal 101 trial compared clinical outcomes stratified by CN (18). Progression or death in patients receiving avelumab plus axitinib who received prior CN was compared to those who did not undergo CN. Investigators found that while the adjusted hazard ratio (aHR) of progression was not significantly different between groups, the aHR of death favored patients who received prior CN (aHR 0.59, 95% CI: 0.38–0.93). Similarly, a pooled analysis from 5 trials that investigated ICI-TKI combinations, including data from 981 patients with de novo mRCC, evaluated the impact of CN before ICI and antiangiogenic therapy (19). They found that CN was associated with significantly better outcomes, with a median PFS of 15 vs. 11 months, a median OS of 46 vs. 28 months, and an ORR of 60% vs. 46%. Prospective studies investigating the role of CN with ICI-based combination therapy are ongoing. For example, in the PROBE phase 3 clinical trial (NCT04510597), treatment-naïve patients with clinical benefit on ICI-based therapy will be randomized to undergo CN with continued systemic treatment or to receive systemic treatment alone. This approach is also being explored with radiation therapy in the SAMURAI clinical trial (NCT05327686).

The CLEAR study employed RECIST v1.1 criteria to characterize treatment response. In these criteria, CR is defined as the disappearance of all lesions and pathologic lymph nodes (20). PR is defined as a ≥30% decrease in the sum of the longest diameters of target lesions (SLDs) with no new lesions or progression of non-target lesions. In 2009, RECIST criteria were updated to RECIST v1.1. These updated criteria were largely validated with cytotoxic chemotherapies and preceded the approval of immunotherapy for the treatment of mRCC. Thus, it may not capture atypical response patterns seen in ICI-based treatments. For instance, pseudoprogression can be seen in patients treated with ICI-based regimens. Additionally, RECIST v1.1 does not incorporate functional imaging techniques, such as fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) [nor the upcoming carbonic anhydrase (CA)-IX-PET/CT imaging].

Multiple efforts are underway to develop criteria to better characterize treatment response to ICI-based regimens. Among these new criteria are the immune-related response criteria (irRC), immune-related RECIST (irRECIST), and immune RECIST (iRECIST) (21). These criteria incorporate key changes to better reflect treatment response to immunotherapies. For instance, in irRECIST, new lesions are added to the overall tumor burden instead of automatically signifying disease progression. Additionally, iRECIST requires confirmation of disease progression with a scan at least 4 weeks later to distinguish disease progression from pseudoprogression (22). RECIST was compared to iRECIST in a phase 2 trial that included patients with locally advanced melanoma receiving pembrolizumab (23). They found that iRECIST was more appropriately able to detect pseudoprogression. Additionally, patients with pseudoprogression had longer OS than patients with true progression, suggesting that RECIST v1.1 may underestimate ICI-based treatment efficacy. In mRCC, iRECIST was also observed to better characterize atypical responses to ICI-based therapy (24). It is intriguing to consider if alternative imaging assessment tools might better capture patients with deep responses compared to RECIST criteria and might be a better assessment for early phase clinical trials, which rely heavily on ORR as a measurement of clinical activity.

In conclusion, this investigation by Motzer et al. showed that strong, durable response rates were observed in patients treated with pembrolizumab with lenvatinib across IMDC risk criteria. A higher proportion of prior nephrectomy was seen in patients with CR and near-CR, suggesting a possible role for CN in conjunction with ICI-based treatments. Moreover, an association between depth of response and DOR was also observed and may guide clinicians in prognostication and patient counseling. Although RECIST v1.1 remains the most commonly applied response criteria in clinical practice, new criteria that account for atypical response patterns that might be seen with ICIs may better characterize the efficacy of ICI-based therapies in future studies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-93/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-93/coif). B.L.M. reports paid consultant/advisor to Abbvie, Pfizer, AVEO oncology, Janssen, Astellas, Bristol-Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology and Peloton Therapeutics; Huntsman Cancer Institute has received research funding from Exelixis (Inst), Bavarian-Nordic (Inst), Clovis (Inst), Genentech (Inst) and Bristol-Myers Squibb (Inst) on his behalf. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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