• Immunotherapy
• Kidney Neoplasms
• Clinical Trials as Topic

Managing tumors where there is substantial heterogeneity, multiple treatment options, and a paucity of biomarkers, such as clear cell renal cell carcinoma (ccRCC) is a challenge. Several regimens are approved by the US Food and Drug Administration (FDA) for advanced RCC treatment. Targeted therapies encompass inhibitors of mechanistic target of rapamycin complex 1, and angiogenesis inhibitors, largely tyrosine kinase inhibitors (TKIs). Antiangiogenic therapies primarily target VEGF-driven blood vessel development by inhibiting VEGF receptor 2 on endothelial cells within the tumor microenvironment. Immunotherapies include older cytokines (interleukin-2 (IL-2) and interferon-α) and new immune checkpoint inhibitors (immunotherapy (IO)) targeting programmed death-ligand 1 (PD-(L)1) and cytotoxic T-lymphocytes-associated protein 4 (CTLA-4).

Serving as a benchmark, the combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-programmed cell death protein-1 (PD-1)) (ipi/nivo) was approved by the FDA in 2018 for front-line treatment of patients with advanced RCC with intermediate/poor risk disease based on International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) factors. Based on six adverse risk factors (Karnofsky performance status <80%, need for systemic therapy <1 year from diagnosis, anemia, neutrophilia, thrombocytosis, and hypercalcemia) IMDC divides patients into three categories, favorable (0 factors), intermediate (1-2), and poor (≥3).1 Eighty per cent of patients in the registration trial (CheckMate214) were in an intermediate or poor risk category and were the focus of prespecified coprimary endpoints (objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)). All three endpoints showed statistically significant improvement of ipi/nivo over the TKI sunitinib.2 3 The OS HR was 0.63 (99.8% CI, 0.44 to 0.89; p<0.001) and results remained largely unchanged with 5-year follow-up analyses (HR, 0.66; 95% CI, 0.55 to 0.80).3

In contrast, ipi/nivo was not superior to sunitinib in patients with favorable risk disease (HR 0.93; 95% CI, 0.62 to 1.40) (Albiges et al, 2020). This appears to be driven largely by the increased activity of sunitinib against ccRCC in favorable risk patients. Similar activity of ipi/nivo across risk groups is shown by landmark PFS rates at 18, 30, 42 and 60 months for intermediate/poor versus favorable risk patients of 42% versus 45%; 35% versus 33%; 33% versus 27% and 31% versus 26%, respectively.3 4 Conversely, sunitinib preferential activity against tumors in favorable risk patients is shown by greater landmark PFS rates relative to the intermediate/poor risk patients, although the difference narrows over time. This preferential activity against tumors in favorable risk disease patients may result from the increased frequency of angiogenic tumors in this population.5 Notably, equivalent OS rates between ipi/nivo and sunitinib and greater response durability (56% vs 25%) at 5 years in favorable risk patients, suggests that ipi/nivo may be an appealing choice for this patient population, especially if biomarkers could be developed to identify the immune-responsive subset.4 One promising clinical biomarker is sarcomatoid histology, where ipi/nivo produced a 60% overall response rate and 23% complete response rate in a hypothesis-generating subset analysis (n=74) of CheckMate214.6

Independent of IMDC category, nearly 90% of patients who were free of progression at 3 years on ipi/nivo, remained progression-free at 5 years.3 This plateau effect was maintained despite discontinuation of therapy in the majority of patients who had a response.7 In melanoma, the term ‘functional cure’ has been coined to refer to patients responding to therapy who remain off treatment for >2 years without progression.8 While this criterion has yet to be applied to advanced RCC, some patients with RCC treated with ipi/nivo would qualify as functionally cured.

The optimal administration of ipilimumab in the ipi/nivo regimen has not been precisely defined. Separate data sets of nivolumab monotherapy in front-line RCC demonstrate clinical activity, although response rates, median PFS and primary progressive disease rate are generally inferior than in CheckMate214 (Atkins et al).9 Strategies to add ipilimumab at disease progression (or at some point in patients lacking a response) have led to few complete responses and low salvage rates. Nevertheless, given the substantially lower toxicity of nivo monotherapy compared with ipi/nivo, nivo versus ipi/nivo in front-line, advanced RCC is being evaluated in CheckMate 8Y8 trial (NCT03873402).

Additional front-line therapy for advanced ccRCC revolves around combinations of TKIs with PD-(L)1-targeting IOs. Multiple regimens exist including axitinib/pembrolizumab (Rini et al), axitinib/avelumab (Motzer et al), cabozantinib/nivolumab (Choueiri et al) and lenvatinib/pembrolizumab (Motzer et al).10–13 These regimens are characterized by unprecedented response rates (up to 70%) and remarkable median PFS rates of up to 2 years. As a reference, the response rate and PFS for the control arms, which all involved sunitinib monotherapy, were in the 40% and 8–11 month range, respectively. These combinations have achieved FDA approval for patients with advanced RCC regardless of IMDC status. Thus, IO/TKI combinations have become a very common front-line therapy for RCC.

However, the curative potential of IO/TKI combinations has not been defined. Extended follow-up of the axitinib/pembrolizumab (axi/pembro) trial shows a PFS rate of 29% at 36 months, and it is yet unclear whether there will be a plateau in the Kaplan-Meier curve even with continued TKI administration.14 While such a plateau has been observed with ipi/nivo (~30% at 5 years in the intention-to-treat population), it is less clear for single-agent anti-PD-1 therapy (and does not exist for TKI monotherapy) (Atkins et al, 2022;9 McDermott et al, 202115). The most mature data available for single-agent anti-PD1 therapy are from the registration trial of nivolumab, where the PFS rate was 5% at 5 years, but nivolumab was given to patients whose disease had progressed after a TKI and higher plateaus and more durable responses may be observed with front-line anti-PD-1 therapy.9 15 16 Thus, longer follow-up is needed to determine the curative potential of IO/TKI regimens, and it remains to be determined if a significant treatment-free interval can be achieved as with ipi/nivo. Notably, pembrolizumab was discontinued at 2 years in the IO combination studies and preliminary data do not suggest an adverse disease effect.14 However, axitinib was continued in most patients and whether it can be discontinued remains to be determined. Additional studies to limit TKI exposure in IO/TKI combinations are ongoing, and such strategies are needed for all combinations.

In evaluating the contribution of the different components in IO/TKI combinations, the most robust IO monotherapy data is for front-line pembrolizumab (KEYNOTE 427), which demonstrated an ORR of 36%, PFS of 9.7 months and median duration of response of 18.2 months.15 These measures are numerically worse than the axi/pembro combination, but no randomized data are available comparing axi/pembro versus either single agent, or the single agents given in sequence. Notably, the primary progression rate for axitinib alone is 10%,17 which is comparable to axi/pembro (11%).10 This suggests that pembrolizumab (which by itself is associated with a primary progression rate of 30%) does not reduce primary progression further.15

Nominally, the 60–70% response rate observed with IO/TKI combinations is similar to the sum of response rates expected for the single agents in untreated patients. If this were the case, benefit would be additive rather than synergistic. Modeling studies suggest that oncology drug combinations are generally effective because each drug in the combination benefits at least partially independent groups of patients.18 There is also evidence that some tumors respond preferentially to IOs whereas others to TKIs. One such example are tumors metastasizing to the pancreas (and perhaps more broadly to glandular organs), which tend to be angiogenic, exhibit frequent mutations in PBRM1, and preferentially respond to TKIs.19 Conversely, sarcomatoid tumors are notoriously resistant to TKIs and particularly responsive to IOs.6 20 This is also consistent with the paucity of blood vessels and lower frequency of PBRM1 mutations in sarcomatoid tumors.5 Supposing that some tumors exclusively respond to only one of the drugs in the combination, some patients are likely overtreated and unnecessarily exposed to toxicities. Practically, this means that patients cope with the chronic toxicities from TKIs (fatigue, diarrhea, loss of appetite, hypertension, etc) and are exposed to the risks of IOs (immune-related adverse events; irAEs). At the same time some patients may be undertreated with the effective agent in order to prevent excessive toxicity of the combination (eg, cabozantinib (cabo)/nivo where the dose of cabo is 40 mg/day compared with 60 mg/day when administered as a single agent). Importantly, adequate drug exposure is likely to be important for optimal efficacy. Thus, continuation of an adequate but tolerable TKI dose and rechallenge with anti-PD-1 monotherapy after resolved toxicity from ipi/nivo are important efficacy considerations that must be balanced against toxicity. There is also the added financial toxicity to the patient, healthcare system and society. This could potentially be ameliorated by the administration of the drugs in sequence. While combination therapy is likely to be superior to the administration of the drugs in sequence, as evidenced by the OS benefit seen relative to sunitinib in several trials (where the majority of patients discontinuing sunitinib received IO), this has not yet been established for IO/TKIs in comparison to ipi/nivo followed by a TKI. While strategies for selecting patients for monotherapy are being evaluated, in the absence of drug-specific contraindications, patients should receive an IO-based doublet in the frontline, either IO/IO or IO/TKI, given the overall survival and other clinical advantages compared with sunitinib monotherapy.

There are settings where IO/TKI combinations are especially advantageous including life-threatening, symptomatic and/or bulky disease or more broadly in patients where progression on first-line therapy may preclude further treatment or have symptomatic consequences (table 1). IO/TKI combinations are also preferable for patients with severe autoimmune conditions or concerns about their ability to cope with serious irAEs. In contrast, ipi/nivo may be preferred in patients with cardiovascular disease and poorly controlled hypertension or in patients with advanced kidney disease and proteinuria, which are both aggravated by antiangiogenic drugs. Patients needing surgical interventions or with chronic wounds would also preferentially benefit from ipi/nivo, which unlike TKIs, does not affect wound healing. Finally, while ipi/nivo carries more initial toxicity, maintenance nivo monotherapy is generally more tolerable than TKIs (alone or in combination with an anti-PD(L)1 drugs). Overall, it seems fitting for patients to weigh in on their preference about chronic side effects of TKIs in IO/TKI combinations or the risk of early irAEs for ipi/nivo.

The above considerations also apply to patients with non-clear cell histologic subtypes of advanced RCC, although data regarding the application of systemic therapy to these patients is largely derived from single-arm studies owing to their lower frequency.15 In general, papillary and unclassified RCC tend to be more responsive to IO-based regimens than chromophobe or other non-clear cell variants, but each is less responsive than ccRCC. Sarcomatoid changes within non-clear cell histologies likely render them more IO-responsive as noted for ipi/nivo above.

Following the historic oncology paradigm that combining multiple drugs with non-overlapping mechanisms of action increases cure rates, multiple trials are currently evaluating triple combinations and it is incumbent for oncologists to devise strategies to ensure that such combinations have significant advantages. Initial data from COSMIC-313 provides the first insight into this strategy.21 Untreated patients with advanced RCC and IMDC intermediate/poor risk were randomized to ipi/nivo plus placebo or ipi/nivo plus cabozantinib. A PFS advantage was seen for the triplet combination in the initial 550 patients randomized, but no OS benefit was reported. In addition, the response rates to the triplet (ORR 43% and CR 3%) were not meaningfully different than ipi/nivo alone. While additional follow-up is needed, the limited added benefit may have resulted from suboptimal drug administration due to excess toxicity from the addition of cabo to ipi/nivo. Seventy-three per cent of patients experienced a grade 3+ treatment-related adverse event and high-dose corticosteroids were administered to 58% of patients. In this regard, the median daily dose of cabo administered to patients receiving the triplet was less than in the cabo/nivo doublet in CheckMate 9ER (23 vs 36 mg). Similarly, 15% fewer patients received all four doses of ipilimumab than on the ipi/nivo control arm. Appropriate patient selection as well as strategies for ensuring adequate drug delivery (eg, staggered administration or earlier treatment discontinuation) should be considered as multidrug development proceeds in RCC.

If potentially curative (IO containing) strategies for a particular patient have been exhausted, the goals of care should shift to control the disease while minimizing the impact on quality of life. An important unanswered question currently being explored in randomized trials is whether an IO-containing regimen has advantages over TKI monotherapy after progression on IO. Although single-arm data exist for lenvatinib/pembrolizumab in this setting, no randomized data yet exist and thus following IO-containing regimens, most patients with ccRCC are treated with single-agent TKIs.

Given the variable exposure across patients for a given dose of a TKI, dose titration can be explored in an attempt to maximize the benefit/risk ratio. In patients with progression on a IO/TKI combinations involving TKI doses below conventional single-agent doses, one approach is to continue the TKI and increase the dose as has been previously investigated with TKI monotherapy.22 To maintain quality of life, disease control rather than maximizing response becomes the goal in these patients without remaining potential curative treatment options. Both dose and schedule can be tailored to reduce side effects. If a patient has a response, but tolerability is poor, the dose can be reduced and/or periodic breaks may be introduced to keep the disease from progressing while maintaining quality of life. At progression, the intensity of the regimen (drug dose and/or schedule) may be increased, if tolerable, to extend the duration of the particular agent given the limited number of therapies available. Fine titration of axitinib in 1 mg intervals enables optimization of benefit/risk ratios.23 24 Similar approaches, although less well-established, can be applied to other TKIs.

While in disuse, high-dose IL-2 is associated with complete and durable responses in ~5% of patients, who would qualify as functional cures.25 Notably, high-dose IL-2 may have activity after immune checkpoint inhibitor therapy.26 IL-2 may also have potential in combination with anti-PD-1 therapy.27 While it requires inpatient administration and it is associated with acute (though reversible) toxicities, several aspects of IL-2 administration serve as a model for future immunotherapy development—a short treatment interval, durable disease control and potential for cure.

Belzutifan, a recently FDA-approved HIF-2 inhibitor for patients with familial kidney cancer (von Hippel-Lindau syndrome),28 may also have a role in advanced ccRCC, where it is being evaluated in several phase 3 trials. Belzutifan suppresses VEGF signaling, but it does so primarily in the tumor, where VEGF production is coupled to HIF-2 overexpression.29 This likely accounts for its limited cardiovascular toxicity compared with TKIs. In addition, unlike TKIs which are non-specific, HIF-2 inhibitors are highly specific.29–31 Since HIF-2 plays a limited role in physiological processes (largely restricted to erythropoiesis and ventilation), HIF-2 inhibitors are particularly well tolerated.32 33 The most common toxicity of belzutifan is anemia due to the on-target inhibition of erythropoietin gene transcription resulting in reduced erythropoietin production. Notably, as with TKIs, resistance to HIF-2 inhibitors eventually develops.29 34

With a plethora of therapies available, there is a pressing need for predictive biomarkers. IMDC risk factors have been advocated as selection criteria for ipi/nivo, but as alluded to above, do not meaningfully select patients who will or will not benefit from a given therapy. This is likely because different biologies are enriched within each IMDC risk category,5 which is consistent with the finding that some tumors induce systemic inflammation.35 IMDC factors were developed in the era of TKIs and may be particularly suitable in identifying patients less likely to respond to TKI therapy, for example, those with inflamed tumors. This is consistent with the notion that IMDC risk factors, specifically thrombocytosis and anemia, have been linked to tumor inflammation and inflamed tumors are enriched for BAP1 mutations and tend to be less angiogenic.35 Ultimately, there is a need to move to biology-based decision-making which will require prospective validation in clinical trials. However, at present, no clinically useful biomarkers for advanced RCC, including PD-L1 expression, exist. Nevertheless, PD-L1 has been shown to be predictive in other tumor types, and it is possible that its limited value in RCC arises from expression heterogeneity and approaches using imaging are being explored to overcome this obstacle (NCT04006522). Finally, ongoing trials are exploring RNA-based gene expression and other biomarkers to increase the benefit/risk ratio in selected patient populations (eg, NCT05361720).