Harnessing the power of combination therapy: reflecting on the final survival data from the CLEAR study with lenvatinib plus pembrolizumab

The continued progress in our understanding of systemic targeted and immunotherapy (IO) has led to meaningful improvements in survival for patients with advanced renal cell carcinoma (aRCC). Initial work made clear the benefit of vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitor (TKI) or IO monotherapy over historical cytokine treatments. More recently, pivotal trials have laid the foundation for combination therapy with IO/TKI or IO/IO treatments to be the preferred first-line choices for most patients with aRCC (Table 1) (6,7). To this end, the CLEAR study demonstrated a significantly higher objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) with lenvatinib plus pembrolizumab compared to sunitinib alone in patients with untreated aRCC (5). These findings are incorporated into the recent American Society of Clinical Oncology guidelines for patients with metastatic RCC (mRCC) (6).

Here, Motzer et al. presented a detailed analysis of tumor response in patients who received treatment with lenvatinib plus pembrolizumab (L + P) as part of the CLEAR study at a median follow-up of ~4 years (8). In the original trial report at a median follow-up of 26.6 months, OS was significantly longer with L + P compared to sunitinib [hazard ratio (HR) 0.66, 95% confidence interval (CI): 0.49–0.88; P=0.005]. Additionally, PFS was significantly longer in the L + P group (median PFS 23.9 vs. 9.2 months, P<0.001) (5). In the final prespecified OS analysis at 49.8 months, the benefit of L + P over sunitinib was maintained (HR 0.79, 95% CI: 0.63–0.99; P=0.04) (9).

In the L + P cohort (n=355), 253 patients had a measurable response by RECIST criteria, of which 65 (18%) were a complete response (CR). This is slightly higher, though overall in line with prior first-line IO-based combination trials including CheckMate 214 (ipilimumab plus nivolumab), KEYNOTE-426 (axitinib plus pembrolizumab), and CheckMate 9ER (nivolumab plus cabozantinib), where the CR was 12%, 10%, and 13%, respectively (10-12). Notably, 85% (n=55) of these patients had a duration of response of >18 months, which the authors display in Fig. 1B. OS rates were 97% at 36 months for those with a CR and 86% for those with a near-CR, with the median OS not reached in these patients. Taken together, the authors highlight a durable response with this therapeutic combination. Even in the 129 patients with a partial response, median OS was 46.3 months. A previously published landmark analysis of this cohort showed that 44 patients had a CR or near-CR at just 6 months, compared to just 16 who received sunitinib, suggesting that response can be rapid as well (13). Overall, these results are consistent with various prior reports demonstrating the utility of early tumor shrinkage extent as an important prognostic biomarker after immune-checkpoint inhibitor treatment (14).

Cross-trial comparisons of outcomes among the various studies of combination treatments for aRCC are difficult due to the heterogeneity of trial methods and patient populations. For example, in the CLEAR trial, 9.3% of patients had IMDC poor-risk disease, in contrast to 18.9% in the CheckMate 9ER trial and 17% in CheckMate 214 (1,3). Along this line, the CLEAR study and KEYNOTE-426 included 31% and 31.9% of patients with favorable-risk disease, respectively, compared to 22.9% in Checkmate 9ER and 19.3% in Javelin Renal 101. Additionally, in all combination therapy trials for aRCC, sunitinib monotherapy is the control arm, which is no longer a first-line treatment in most patients, and no direct comparisons between combination regimens have been done to date (15). Careful subgroup analyses of individual trials are often employed to identify potential treatment pathways for patients with aRCC. To this end, the manuscript authors note that 57% of patients who had a CR and 58% with a near-CR had International Metastatic RCC Database Consortium (IMDC) intermediate risk disease. Compared to patients with favorable IMDC risk where 38% and 34% and a CR or near-CR, respectively, it is encouraging to see that patients with some adverse disease characteristics may have viable therapeutic options. However, caution when analyzing subgroups is always warranted, as such comparisons are often underpowered given the smaller sample size of these cohorts relative to the overall trial population (16).

Despite such improvements in outcomes with combination treatments for favorable and intermediate risk RCC, poor-risk disease and aggressive pathologic and radiographic features still confer a distinctly inferior prognosis (17). Here, Motzer and colleagues show that just 7 patients (5.6%) of the complete or near-complete responders and only 16 (12%) of the partial responders (<75% tumor reduction) had IMDC poor-risk disease, shown in Tab. 1 and Fig. 1A. Importantly, based on data provided in Tab. 1, authors show that 57.3% of patients with a CR or near-CR had ≥2 metastatic organ sites involved, showing these durable responses can still be achieved in higher volume disease with this drug combination.

Ongoing work across this space continues to identify novel combination therapies for patients. In addition to IO/TKI treatment, clinical trials investigating IO/IO therapies have shown similarly encouraging results for intermediate and poor-risk disease, though its role in favorable-risk patients requires further clarification. In CheckMate 214, the secondary endpoints were ORR, PFS, and OS in the intent-to-treat population, which included favorable-risk patients (1). Median OS was not reached in either the treatment or control arm and thus the IO/IO combination of nivolumab and ipilimumab was not approved for patients with favorable risk disease. However, recent reporting of long-term follow-up data for CheckMate 214 may change this (18). Nivolumab plus ipilimumab was shown to provide an OS benefit and prolonged response compared to sunitinib in favorable-risk aRCC. Median OS was 77.9 months with nivolumab/ipilimumab vs. 66.7 months with sunitinib (HR, 0.82), with higher OS rates at 72 months (52.3% vs. 46.4%) and 90 months (42.8% vs. 34.4%). However, median PFS was shorter with nivolumab/ipilimumab (12.4 vs. 28.9 months; HR, 1.76), though the CR rate was higher (13% vs. 6%). Median duration of response was longer with nivolumab/ipilimumab (61.5 vs. 33.2 months; HR, 0.70), and more patients maintained responses at 72 months (37% vs. 14%) and 90 months (37% vs. 14%), suggesting a durable benefit despite shorter PFS in this population. This discrepancy between PFS and OS, as well as response duration, is interesting and may be related to a pseudo-progression effect sometimes seen after IO therapy. Additionally, it is possible that tumor biology allows for a more rapid onset of response to sunitinib compared to more delayed kinetics with IO therapy in this population. These findings highlight that PFS may not fully capture the long-term durable benefits of immune checkpoint blockade in certain cohorts.

As these IO-based combination treatments have become the preferred first-line choice in aRCC treatment, it is vital that both providers and patients are aware of potential treatment-related adverse events (TRAEs) and how they can be managed or mitigated (19). Certainly, the choice of which therapy a patient receives is likely to be dictated in part by these TRAEs. Among first-line aRCC combination therapies, lenvatinib plus pembrolizumab exhibited the highest rate of Grade 3–5 TRAE at 82.4%, followed by pembrolizumab plus axitinib at 62.9% (2,5). In the CLEAR trial, 69% of patients required dose reductions of lenvatinib due to adverse effects. Common toxicities included fatigue (63.1%), diarrhea (61.9%), musculoskeletal pain (58.0%), hypothyroidism (56.8%), hypertension (56.3%), stomatitis (43.2%), decreased appetite (40.6%), rash (37.2%), nausea (35.8%), dysphonia (29.8%). Discontinuation due to adverse events and fatal adverse events was also most common across the trials with lenvatinib plus pembrolizumab (37.2%). Of note, the authors here report that 10 patients had a CR and 18 had a near-CR despite treatment discontinuation due to an adverse event. Interestingly, although there have been concerns about increased immune-related toxicity with IO/IO combinations, nivolumab plus ipilimumab had the lowest TRAE rates (46%), suggesting that dual IO is not necessarily associated with higher toxicity compared to IO/TKI combinations (1). However, IO-specific TRAEs do differ from those of TKIs, and thus a more granular comparison of IO/IO to IO/TKI trials may be warranted to better understand the overall safety of these therapeutic combinations.

Inclusion into the CLEAR trial necessitated histological or cytological confirmation of RCC with a clear-cell component. In the L + P cohort, 7.9% of patients had sarcomatoid features, though no percentage of sarcomatoid component was described. A prior report of the trial subgroup outcomes highlighted a benefit of L + P over sunitinib with respect to OS, PFS, and ORR in patients with a pathologic sarcomatoid component (20). These results are in line with a growing body of evidence that sarcomatoid features are particularly responsive to immune-checkpoint inhibition. An exploratory analysis of the CheckMate 214 trial evaluated the efficacy of nivolumab + ipilimumab compared to sunitinib in aRCC with sarcomatoid differentiation. The findings revealed a higher ORR with nivolumab + ipilimumab (60.8% vs. 23.1%) and a greater CR rate (23% vs. 6.2%). Additionally, median OS was significantly improved with combination therapy (48.6 vs. 14.2 months, HR 0.46), reinforcing ASCO guideline recommendations to administer IO/TKI or IO/IO therapy in the first-line setting for patients with mRCC with sarcomatoid features (21). However, the relatively low overall incidence of sarcomatoid differentiation makes any definitive analysis on this population difficult. Indeed, across various trials of first-line therapies for aRCC, the inclusion of sarcomatoid features accounted for less than 20% of the study cohort, with several trials having the status of sarcomatoid features incomplete for the entire cohort or only identified upon post hoc analysis (22). The present study does not comment on such patients with sarcomatoid differentiation and so the impact of this pathology on response at the final OS analysis is not explicit. Further work could hopefully provide some clarification in order to optimize treatment selection in aRCC with sarcomatoid features (22).

The mechanisms driving the variable responses of combination therapies among the different risk groups and pathologic variants are not yet fully clear. Ongoing work to better classify RCC tumors at the molecular level may shed light on how tumors respond to these different treatments. A recent phase 2 trial randomly assigned 202 patients to treatment with IO monotherapy, IO/IO doublet therapy, or TKI monotherapy according to previously defined biologically distinct clear cell RCC tumor groups based on transcriptomic data (23). Interestingly, the investigators found that this more targeted allocation of treatments based on the molecular subgroups was able to improve response rates compared to historical cohorts. As similar precision-based medicine protocols continue to be explored, further enhancements to current treatment algorithms should be expected. To this end, the COSMIC-313 study was the first phase 3 trial investigating triplet therapy (cabozantinib, nivolumab, and ipilimumab) vs. IO/IO doublet therapy (nivolumab and ipilimumab) in aRCC (24). In the recently presented final analysis, triplet therapy improved PFS compared to doublet, though an OS benefit was not observed (median OS: 41.9 vs. 42.0 months; HR 1.02, 95% CI: 0.85–1.23; P=0.84) in a final analysis recently presented (25). However, an exploratory analysis suggested that the efficacy of this triplet therapy is strengthened in patients with higher amounts of M2-like macrophages, which may be explored as a useful predictive biomarker. While molecular subtyping is not yet routine in real-world clinical practice, ongoing efforts to validate predictive biomarkers may help enable its future integration. Standardization of molecular assays that are both high-throughput and cost-effective will be critical in this regard.

The above manuscript offers a deeper understanding of tumor responses for patients in the experimental cohort of the CLEAR trial. It is evident that combination therapy with L + P in patients with aRCC can confer an expeditious, durable, and safe response. As the therapeutic landscape for aRCC continues to expand, future studies should aim to more precisely define the patient populations that are best suited for each treatment option in order to maximize response and optimize outcomes.

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.

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Funding: This work was supported by a grant from the National Cancer Institute (2P30CA016058).

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