Probability of Continuing Response Metastatic Renal Cancer
INTRODUCTION
Section:
Renal cell carcinoma (RCC) is the most common form of kidney cancer and accounts for close to 74,000 new cases annually in the United States.1 Most patients present with localized disease amendable to surgical treatment with definitive intent. However, approximately one third of patients treated with curative intent will develop metastatic disease recurrence. Likewise, 30% of patients have metastatic disease at their initial presentation.2
Over the last two decades, the management of metastatic renal cell carcinoma (mRCC) has evolved from high-dose interleukin 2 (IL-2) and interferon-α to targeted therapies such as vascular endothelial growth factor receptor (VEGF-R) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and immunotherapy with checkpoint inhibitors. As a result, the median survival has improved from < 1 year in the 1990s to over 4 years in some recent trials.3,4 In this review, we highlight clinically relevant data and provide a practical framework for the management of patients with mRCC.
FIG 1. Practical guide for management of RCC. aCytoreductive nephrectomy candidates have a large renal mass, minimal extra-renal disease, and minimal IMDC risk factors. bCandidates for surveillance have slow-growing disease, 0-1 IMDC risk factors, and ≤ 2 organs involved with metastatic disease. cPatients with contraindications to ICI should be treated with TKI monotherapy. A subspecialist should be consulted to determine risk of ICI therapy. dPending FDA approval. eSpecifically, if the patient did not receive ICI-based therapy in frontline setting. fOther considerations: The patient should receive a TKI different from that used in the frontline setting; patients who did not receive ICI-based combination in frontline setting might be considered for it in refractory setting; bevacizumab/erlotinib should be considered for patients with HLRCC; Everolimus monotherapy is also an option. FDA, US Food and Drug Administration; HLRCC, hereditary leiomyomatosis and renal cell cancer; ICI, immune checkpoint inhibitor; IMDC, International Metastatic RCC Database Consortium; mRCC, metastatic renal cell carcinoma; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor.
MANAGEMENT OF FRONTLINE mRCC
Section:
Risk Stratification
Upon diagnosis of mRCC, patients are risk stratified into favorable, intermediate, and poor risk categories using the Memorial Sloan Kettering Cancer Center or International Metastatic RCC Database Consortium (IMDC) risk models.5,6 These prognostic tools use clinical and laboratory factors and highlight the considerable variability in tumor biology and disease course among patients. Recently, the integration of molecular data with annotated genomic models demonstrated improved stratification of patients across risk groups although they have not yet been routinely integrated into clinical practice.7
Cytoreductive Nephrectomy
Some patients with mRCC are candidates for a cytoreductive nephrectomy (CN) in which removal of the primary tumor is performed in the setting of metastatic disease. Prospective data for CN were first demonstrated in clinical trials of patients with mRCC treated with CN followed by interferon versus interferon alone.8,9 The results indicated that CN followed by systemic therapy can improve time to disease progression and overall survival. However, the applicability of these findings is unclear given that they occurred before the development of IMDC risk criteria, did not describe RCC histologic subtypes, and may be less relevant in an era in which systemic therapies are far more effective in prolonging survival than the cytokine-based treatments available during the time of those clinical trials.10
As newer vascular endothelial growth factor (VEGF)–directed targeted therapies became available, retrospective data emerged that CN may be of clinical value in patients with mRCC treated with these agents.11,12 Subsequent prospective trials were thus conducted to investigate the role of CN in patients with mRCC receiving targeted therapy. In the noninferiority CARMENA trial, 450 patients with newly diagnosed intermediate- or poor-risk mRCC were randomly assigned to receive sunitinib alone versus a CN followed by sunitinib.13 The median overall survival (mOS) was 18.4 months in patients receiving sunitinib alone, which was noninferior to the mOS of 13.9 months for patients who underwent an upfront CN followed by sunitinib (hazard ratio [HR], 0.89; 95% CI, 0.71 to 1.10; upper boundary of the 95% CI for noninferiority: ≤ 1.20). CN had previously been the standard of care (SOC) for mRCC, but the findings in this study suggested that with the improved efficiency of targeted therapies, CN may not be needed or appropriate for all patients.
Similarly, the SURTIME trial investigated the role of CN followed by sunitinib versus a deferred approach in which patients received three cycles of sunitinib followed by a CN. Because of poor accrual, the primary end point was changed to the 28-week progression-free rate, which was not improved in patients who underwent deferred CN (43% v 42%; P = .61). The OS was improved in the deferred CN group intent-to-treat (ITT) analysis (32.4 v 15.0 months; HR, 0.57; 95% CI, 0.34 to 0.95; P = .03), but not in the per-protocol population (P = .23).14 Thus, the CARMENA and SURTIME trials inform that although a subset of patients should be treated with an upfront CN, it is not the SOC for all patients with mRCC.
In summary, patient selection is critical and CN should be reserved in the upfront setting for those with more favorable features such as minimal extra-renal disease and few IMDC risk factors and can be considered in the deferred setting for patients who have exceptional systemic disease responses following systemic therapy.10 Ongoing trials are investigating the role and timing of CN in patients receiving immunotherapy as well.15,16
Active Surveillance
Before initiation of systemic therapy, patients should be considered for active surveillance (AS). Given the toxicity and generally noncurative nature of systemic therapy, asymptomatic patients whose disease is expected to follow a more indolent course could benefit from initial AS. A prospective phase II trial was conducted in which 52 treatment-naive, asymptomatic patients with mRCC were enrolled in an AS protocol.17 The decision to end surveillance and begin systemic treatment was left to physician and patient discretion and not mandated by objective criteria.
For all patients, the median time to progression was 9.4 months and the median time on AS was 14.9 months. Only 23 of the 43 patients who developed disease progression (PD) on trial received immediate systemic therapy. Of the 20 patients with PD who continued surveillance, the median duration of additional surveillance was 15.8 months. The estimated mOS for all patients was 44.5 months (95% CI, 37.6 to not reached [NR]).
Favorable and unfavorable cohorts were identified to risk-stratify patients and highlight patients more likely to benefit from AS. Patients in the favorable group (0-1 IMDC risk factors and metastases in ≤ 2 organ systems) had a median surveillance time of 22.2 months compared with 8.4 months in patients in the unfavorable group (≥ 2 IMDC risk factors and ≥ 3 metastatic organ systems involved). These data provide a framework for selection of patients who may be appropriate for AS and able to defer initiation of systemic therapy. More recently, the prospective observational MaRCC study also identified a cohort that underwent AS and found this approach to be overall safe and an appropriate alternative to immediate initiation of systemic therapy in carefully selected patients.18
First-Line Treatment
Once a patient is considered for CN and evaluated for appropriateness of AS, the next step in management is the selection of frontline systemic therapy (Fig 1 ). Until 2018, the SOC for the frontline treatment of mRCC was high-dose interleukin-2 or targeted therapies such as mTOR inhibitors and VEGF-R tyrosine kinase inhibitors (TKIs). However, since the approval of ipilimumab and nivolumab in 2018, the foundation of therapy for treatment-naïve mRCC has shifted to include an immune checkpoint inhibitor (ICI) backbone. For almost all patients, barring contraindications, an ICI-based combination regimen will be SOC and the discussion herein will focus on these agents.
CheckMate 214 was an international phase III study investigating the combination of nivolumab (antiprogrammed death-1) and ipilimumab (anti–cytotoxic T-lymphocyte–associated protein-4) versus sunitinib in patients with treatment-naïve mRCC.19 The coprimary end points were objective response rate (ORR), progression-free survival (PFS), and OS in the 847 randomly assigned IMDC intermediate- and poor-risk patients. In the initial analysis of the IMDC intermediate- and poor-risk patients, the ORR (42% v 27%; P < .001) and mOS (NR v 26.0 months; HR, 0.63; P < .001) favored patients treated with ipilimumab/nivolumab. Although the median progression-free survival (mPFS) favored ipilimumab/nivolumab (11.6 v 8.4 months), it did not meet prespecified statistical threshold. Rates of complete response (CR) were also higher in patients treated with ipilimumab/nivolumab (9% v 1%). Importantly, 35% of patients treated with this combination required high-dose steroids (≥ 40 mg of prednisone once per day). On the basis of superior efficacy, the US Food and Drug Administration (FDA) approved the use of ipilimumab/nivolumab for intermediate- and poor-risk mRCC on April 16, 2018.
As the first ICI-based combination in mRCC, ipilimumab/nivolumab has the longest follow-up to date. In a 4-year minimum follow-up of the CheckMate 214 trial, the efficacy and durability of this combination remained well-established.3 The 4-year PFS probability continues to favor ipilimumab/nivolumab in the ITT population (31.0% v 17.3%) and in the intermediate- and poor-risk patients (32.7% v 12.3%). Likewise, the mOS was improved with ipilimumab/nivolumab in the ITT (NR v 38.4 months; HR, 0.69; 95% CI, 0.59 to 0.81) and the intermediate- and poor-risk patient population (48.1 v 26.6; HR, 0.65; 95% CI, 0.54 to 0.78).
In addition to the combination of two ICI agents, recent clinical investigations have largely focused on the combination of ICIs and VEGF-directed agents. The combination of axitinib/pembrolizumab was paired against sunitinib in the phase III KEYNOTE-426 clinical trial for treatment-naïve, advanced RCC.20 The primary end point was OS and PFS in the ITT. With 861 patients randomly assigned and a median follow-up of 12.8 months, the mOS (HR, 0.53; 95% CI, 0.38 to 0.74; P < .001), PFS (15.1 v 11.1 months; P < .001), ORR (59.3% v 35.7%; P < .001), and CR rate (5.8% v 1.9%) all favored the combination of axitinib/pembrolizumab. On April 19, 2019, the FDA approved this combination for use in all IMDC risk treatment-naïve mRCC.
In a recent extended update with a median duration of follow-up of 42.8 months, the durability of efficacy of axitinib/pembrolizumab was noted.21 Axitinib/pembrolizumab was favored over sunitinib across the study's primary end points of median improved mOS (45.7 v 40.1 months; HR, 0.73; P < .001) and mPFS (15.7 v 11.1 months; HR, 0.68; P < .0001) as well as multiple others such as ORR (60.4% v 39.6%), CR rate (10.0% v 3.5%), and median duration of response (23.6 v 15.3 months). The durability of response further cements this regimen as a standard in frontline mRCC treatment.
The JAVELIN Renal 101 trial was another phase III trial comparing the combination of axitinib/avelumab versus sunitinib in treatment-naïve patients with mRCC.22 The study randomly assigned 886 patients with primary end points of PFS and OS in the programmed death ligand-1 (PD-L1)–positive patients. A total of 560 (63.2%) patients were PD-L1–positive, and in this population, the mPFS was superior in patients treated with axitinib/avelumab (13.8 v 7.2 months; HR, 0.61; 95% CI, 0.47 to 0.79; P < .001) as was the ORR (55.2% v 25.5%). In an analysis of all patients in the trial, the mPFS also favored axitinib/avelumab (13.8 v 8.4 months; P < .001). On the basis of achieving the coprimary end point of PFS in PD-L1–positive patients, the FDA approved the use of axitinib/avelumab in frontline mRCC on May 14, 2019. However, given a lack of demonstrated OS benefit in the context of other combinations that have demonstrated an OS benefit (ie, ipilimumab/nivolumab and axitinib/pembrolizumab), this combination is perhaps less attractive.
The combination of cabozantinib/nivolumab compared with sunitinib was studied in the phase III CheckMate 9ER trial.23 A total of 651 patients were randomly assigned to receive cabozantinib/nivolumab (n = 323) or sunitinib (n = 328), with a primary end point of PFS and secondary end points of OS and ORR. With a median follow-up of 18.1 months, the primary end point of superior PFS for cabozantinib/nivolumab versus sunitinib was met (16.6 v 8.3 months; HR, 0.51; 95% CI, 0.41 to 0.64; P < .001). Similarly, the secondary end points of ORR (55.7% v 27.1%) and OS (HR, 0.60; 98.89% CI, 0.40 to 0.89; P = .001) also favored the combination of cabozantinib/nivolumab. On the basis of these efficacy end points, on January 22, 2021, the FDA approved this combination for use in the treatment on treatment-naïve mRCC. The role of cabozantinib/nivolumab/ipilimumab versus ipilimumab/nivolumab is under investigation in the COSMIC 313 trial.24
Most recently, the results from the phase III CLEAR study (lenvatinib/pembrolizumab v lenvatinib/everolimus v sunitinib; primary end point of PFS) were published.24 Relevant to this discussion, patients receiving lenvatinib/pembrolizumab (355 patients) had a median PFS of 23.9 months compared with 9.2 months (HR, 0.39; 95% CI, 0.32 to 0.49; P < .001) in patients receiving sunitinib (357 patients). Similarly, the median OS was superior in patients receiving lenvatinib and pembrolizumab (HR, 0.66; 95% CI, 0.49 to 0.88; P = .005). ORR (71% v 36.1%) and CR rate (16.1% v 4.2%) also favored lenvatinib/pembrolizumab. The high response rate, PFS, and CR rate distinguish this trial from previous ICI/TKI trials. This regimen is currently under review at the FDA with decision expected in late 2021.
Treatment Considerations in Frontline mRCC
With multiple approved regimens for frontline mRCC, the decision of a treatment plan requires consideration of a variety of factors. The focus of this discussion is on choosing ICI/ICI (ipilimumab/nivolumab) versus one of the ICI/TKI regimens. The ICI/TKI combinations are generally similar (with the exception of no established OS benefit documented for axitinib/avelumab) and are thus generally all acceptable, although lenvatinib/pembrolizumab appears to have the strongest early efficacy signals (Table 1). However, lenvatinib/pembrolizumab does not yet have the extended follow-up data available for some of the other regimens.
 | TABLE 1. Practice-Changing Phase III Trials in Treatment-Naïve mRCC |
A number of important features stand out with ipilimumab/nivolumab. It has the longest follow-up data at over 4 years and has demonstrated exceptional durability over that period with close to one third of patients remaining progression free and a median survival not reached with this follow-up.3 Similarly, with a minimum of 4-year follow-up, 65% of patients have an ongoing response to treatment with a CR rate of 10.7% in the ITT population. Another benefit to this combination is after four doses of combined ipilimumab/nivolumab, patients are maintained on nivolumab monotherapy and do not require daily pills or the chronic toxicity associated with TKIs.
However, the durable responses and long-term follow-up of ipilimumab/nivolumab must be balanced against the fact that this combination has a lower ORR and shorter PFS than patients treated with the ICI/TKI combinations. As is noted in the section of treatment-refractory RCC, the best chance of durable and sustained disease control is with the frontline ICI-based combination. Using ipilimumab/nivolumab as the frontline treatment strategy results in higher numbers of patients who are refractory to their frontline treatment and then limited by the treatment-refractory options. Similarly, ipilimumab/nivolumab results in the lower 12- and 18-month OS percentage and a higher number of patients requiring corticosteroids for treatment-related adverse events (AEs). Finally, although many responses are durable in favorable-risk patients, the ORR in this population is significantly lower for ipilimumab/nivolumab versus sunitinib.
The advantage of using ICI/TKI as the treatment choice for frontline mRCC is the superiority over sunitinib in ORR, PFS, and OS across regimens (except for still immature OS data in axitinib/avelumab) and IMDC risk groups. As such, patients are likely to achieve a response—or at least disease control—to their frontline therapy. This is especially important for patients who have a high disease burden or are symptomatic from their metastatic lesions and need immediate clinical benefit from systemic treatment.
The primary disadvantage of the use of ICI/TKI instead of ipilimumab/nivolumab is the chronic toxicity of daily TKI use, which is continued indefinitely until unacceptable toxicity or disease progression. This is in stark contrast to the ICI/ICI combination, which is a single intravenous infusion once a month (after the four ipilimumab/nivolumab doses are completed). This likely contributes to the differences in quality of life (QOL) in the clinical trials. Although the QOL data for ipilimumab/nivolumab showed improvement over sunitinib, QOL data are mixed for ICI/TKI regimes, which do not necessary demonstrate consistent QOL benefits over the sunitinib comparator arm.23,25-27 Ultimately, a physician and patient must review the above considerations in addition to cost implications, patient reliability or desirability of taking daily pills, toxicity profiles, etc to decide on ICI/ICI versus ICI/TKI for the frontline management of mRCC.
It is also important to note that although a small subset of patients (specifically those with IMDC-favorable risk disease) may benefit from single-agent TKI therapy, the overall consensus of experts is to treat with ICI-based combination therapy in this setting.28 Likewise, although clinical trial data show activity for ICI monotherapy in the frontline setting, the SOC remains combination therapy.28
Treatment After Adjuvant Therapy
An emerging consideration in the frontline management of mRCC is the treatment of patients who received adjuvant therapy postnephrectomy for localized RCC and subsequently develop disease recurrence. Currently, the only approved adjuvant therapy is the use of sunitinib for 1 year on the basis of a disease-free survival (DFS) benefit versus placebo (6.8 v 5.6 years; HR, 0.76; 95% CI, 0.59 to 0.98; P = .03) in the S-TRAC trial.29 More recently, however, the KEYNOTE-564 trial comparing 1 year of adjuvant pembrolizumab versus placebo in patients with high-risk RCC was presented. The primary end point of DFS was reached (HR, 0.68, 95% CI, 0.53 to 0.87; P = .0010) with an interim, but immature, OS trend favoring patients treated with pembrolizumab.30 Additional data, such as absolute DFS benefit and mature OS data, are critical to determining the extent of the benefit of pembrolizumab in this setting.
The potential approval of pembrolizumab for adjuvant therapy in localized RCC raises important considerations for patients who ultimately develop mRCC. Key factors will be whether metastatic disease developed while on pembrolizumab or after therapy was discontinued. Similarly, patients who progress within a short time after discontinuing pembrolizumab (eg, < 6 months) are likely to be approached different from those who develop metastatic disease with a longer latency period postpembrolizumab therapy. Pattern of recurrence, such as isolated or oligometastatic disease versus more extensive disease burden, will also be important. Whether an immunotherapy-based combination or targeted therapy should be used as frontline therapy in patients who previously received adjuvant pembrolizumab is uncertain. Data from ongoing clinical trials in the metastatic setting will likely be extrapolated for such patients, and clinical trials for this population are certain to be conducted as well.31
TREATMENT-REFRACTORY mRCC
Section:
Frontline treatment selection in mRCC is critical as it provides the most likely chance at a durable response and potentially a CR. Treatment options in the refractory setting are more limited and generally do not produce long-term responses. Moreover, although in the frontline setting, there is general consensus that an ICI-based regimen is the SOC for most patients, the lack of randomized clinical trial data for treatment-refractory patients results in a more heterogeneous approach to treatment. Options for treatment in patients whose cancer has progressed on frontline ICI-based combinations largely focus on targeted therapies with VEGF-R TKI monotherapy (eg, axitinib, cabozantinib, etc) or the combination of lenvatinib and the mTOR inhibitor, everolimus.
The role of axitinib in ICI-refractory mRCC was demonstrated in a phase II trial in which patients who received previous ICI therapy were treated with axitinib on an individually dosed schema.32 The trial enrolled 40 patients, most of whom (72%) received ≥ 2 previous therapies and had largely (90%) IMDC intermediate and poor risk. Axitinib was clinically active in this population with an ORR of 45% (CR 3%, partial response 43%, and stable disease 45%) and an mPFS of 8.8 months. There were no grade 5 AEs and only one grade 4 AE, and most grade 3 AEs occurred in fewer than 10% of patients. These efficacy and tolerability solidify axitinib as a treatment option for patients who had received previous ICI-based therapy.
Tivozanib is a highly selective VEGF-R TKI that was investigated in the TIVO-3 trial versus sorafenib in patients who had received two or three previous systemic therapies.32 A total of 350 patients were randomly assigned. The primary end point of PFS was superior in patients receiving tivozanib (5.6 v 3.9 months; HR, 0.73; 95% CI, 0.56 to 0.94; P = .016) with an ORR of 18% for tivozanib versus 8% for sorafenib. In 26% of patients who received previous ICI therapy, the median PFS was 7.3 versus 5.1 months favoring tivozanib. There were no grade 4-5 treatment-related AEs in patients treated with tivozanib, and with the exception of hypertension (20%), all grade 3 events only occurred in ≤ 5% of patients, highlighting its exceptional tolerability. On the basis of these data, the FDA (March 10, 2021) approved tivozanib for use in patients with relapsed or refractory mRCC following ≥ 2 previous treatments.
Other treatment options in refractory mRCC include cabozantinib, which was established as a viable treatment option in patients with refractory mRCC in the phase III METEOR trial comparing cabozantinib with everolimus (ORR 17% v 3%; mPFS 7.4 v 3.9).33 Similarly, lenvatinib/everolimus is another option in the refractory setting as demonstrated by its superior efficacy when compared with everolimus in a randomized phase II trial of treatment-refractory mRCC (ORR 43% v 6%; mPFS 14.6 v 5.5 months).34
Given the general lack of durable responses in patients with treatment-refractory mRCC, it is important to consider toxicity when choosing a second-line therapy. In this manner, axitinib and tivozanib may be favored over cabozantinib or lenvatinib/everolimus given lower rates of severe TKI-specific toxicities such as fatigue and diarrhea.32-35 Other important considerations include which TKI was part of the frontline ICI-based combination; half-life of TKIs, which has implications in AE resolution; and specific TKI toxicity profiles.
The aforementioned discussion of treatment-refractory mRCC is specific to TKI-based therapy given the unclear role of ICIs in ICI-refractory mRCC. A primary example of this is the data demonstrating that salvage ipilimumab in patients with a suboptimal response to nivolumab monotherapy or in patients who have received previous ICI is associated with a lower ORR and CR rate compared with its use as a combination in the frontline setting.36-39 However, there are strong phase II data for the use of lenvatinib/pembrolizumab in ICI-refractory mRCC.40 Likewise, ongoing randomized phase III trials are investigating the role of ICI/TKI versus TKI monotherapy in ICI-refractory mRCC.40 As such, there may be some benefit to using an ICI in patients who received previous ICI therapy, but the data remain uncertain.
Other strategies under investigation in treatment-refractory mRCC include novel agents such as the hypoxia-inducible factor-2 alpha inhibitor belzutifan, novel cytokine-directed antibodies, and the GAS6/AXL pathway inhibitor.41-43 Until further data are available, the SOC in most patients whose cancer has progressed on ICI-based therapy is treatment with a TKI monotherapy or the combination of lenvatinib/everolimus.
NONCLEAR CELL AND HEREDITARY mRCC
Section:
The treatment of patients with nonclear cell renal cell carcinoma (nccRCC) poses a unique challenge.44 Although 75%-80% of RCC is clear cell renal cell carcinoma (ccRCC), the subtypes of nccRCC comprise an important subset of patients and include papillary, chromophobe, unclassified, and others. Although patients with sarcomatoid features on pathology derive a clear benefit from treatment with ICI-based regimens with ORR and CR rates as high as 60.8% and 18.9%, respectively, these data have been largely identified in ccRCC clinical trials and their extrapolation to nccRCC patients with sarcomatoid features is less certain.45
As there are fewer nccRCC-specific clinical trials, the management of nccRCC often follows that of ccRCC especially given data supporting the use of ICI therapy in this setting.46-49 Regarding metastatic papillary RCC, the PAPMET trial demonstrated that cabozantinib is the preferred TKI likely because of its MET-inhibitory properties.50 Similarly, there are hints of benefit to savolitinib in patients with MET-driven papillary RCC although completing such trials has been challenging.51 ICI-based therapy is also an option in patients with papillary RCC.
Fumarate hydratase (FH)–deficient RCC is a subset of nccRCC that results from somatic or germline mutations in the FH gene. Importantly, patients with germline FH mutations can develop hereditary leiomyomatosis and renal cell cancer (HLRCC), a syndrome characterized by aggressive papillary type 2 RCC as well as cutaneous and uterine leiomyomas.52,53 Clinical trial data for HLRCC have historically been sparse. However, a recent phase II study of bevacizumab and erlotinib in patients with advanced HLRCC demonstrated impressive clinical activity (ORR 64%; mPFS 21.1 months), making it an attractive treatment option for these patients.54
Another hereditary RCC is succinate dehydrogenase–associated RCC. Deficiencies in this enzyme are also associated with pheochromocytomas and paragangliomas in multiple areas including the head and neck, abdomen, and pelvis. Its histology can be composed of clear cell, chromophobe, or papillary RCC.55-57 SDH-associated RCC is a rare hereditary RCC, often occurs in relatively young patients, and has limited data directing therapy. However, there have been reports of response to VEGFR-TKI therapy.58
There are also limited data for the management of metastatic chromophobe RCC. There is biologic rationale for the use of the mTOR inhibitor everolimus in this setting given the genomic profile of chromophobe RCC, which often has mutations that upregulate mTOR pathways.59 Likewise, small clinical trials have demonstrated the efficacy of combined anti-VEGF therapy and everolimus—either bevacizumab/everolimus or lenvatinib/everolimus—for patients with advanced chromophobe RCC.60,61
Unlike other nccRCC subtypes, renal medullary carcinoma (RMC) and collecting duct carcinoma have cytotoxic therapies as the foundation of treatment. RMC largely occurs in patients with sickle hemoglobinopathies and is characterized by undetectable protein expression of tumor suppressor gene SMARCB1 (also known as INI1).62,63 Collecting duct carcinoma is an aggressive cancer arising in the distal collecting tubules that has biologic features and a clinical course more reflective of a urothelial carcinoma than RCC.64,65 Both RMC and collecting duct carcinoma are resistant to VEGF-directed therapy and have improved clinical outcomes with platinum-based chemotherapy.63-68
A host of other hereditary and sporadic nccRCC histologies exist, each worthy of a detailed discussion beyond the scope of this manuscript. The additional subtypes and/or syndromes include, but are not limited to, Birt-Hogg-Dube, tuberous sclerosis complex, von Hippel-Lindau, and microphthalmia-associated transcription factor family translocation renal cell carcinoma.69-72
OTHER CONSIDERATIONS AND UNANSWERED QUESTIONS
Section:
Despite drastic improvements in clinical outcomes as noted above, a variety of important considerations in the treatment of mRCC are required. With the advent of ICI-based combinations, toxicity management is critical. For patients on ipilimumab/nivolumab, the primary concern is related to the management of immune-related adverse events (irAEs), which requires early intervention, multidisciplinary management, and corticosteroids with or without additional immunosuppressive agents. The management of such irAEs is now well-described with multiple cancer society guidelines.73,74
In contrast to patients receiving ICI/ICI therapy, patients on ICI/TKI combinations may have toxicities (eg, diarrhea and transaminitis) that can be immune-mediated or a consequence of TKI therapy, each of which is managed differently. A practical approach to differentiate between such overlapping toxicities is to hold the TKI for a number of days (depending on TKI half-life). If the toxicity improves, then it is likely caused by the TKI; otherwise, it likely requires corticosteroids for an irAE.75 TKIs can usually be resumed following AE improvement with either enhanced supportive care or a dose reduction. ICI-based toxicities require input from subspecialists to determine the safety of ICI resumption and risk of irAE recurrence.
Patients with brain and bone metastases are generally treated with similar treatment paradigms although they often have poorer responses to treatment.76,77 Patients with brain metastases should have brain-directed therapy with modalities such as radiosurgery or other more invasive surgeries when needed. Patients with bone metastases generally only require intervention in the setting of pain or an impending fracture.
Another important consideration in treating patients with mRCC is the duration of therapy. Retrospective and prospective data highlight that subsets of patients treated with ICI-based therapy can derive clinical benefit even after therapy discontinuation.78,79 Some clinical trials such as KEYNOTE-426, which discontinued pembrolizumab after a maximum of 35 cycles of therapy, and CheckMate 214 in which ipilimumab is discontinued after four cycles established a role for early therapy discontinuation.19,80 However, in general, patients are treated until treatment failure or excessive toxicity. Knowledge that some patients—especially those on prolonged courses of treatment—can have durable response off therapy should be taken into consideration when considering therapy reinitiation after toxicity or when a patient requires a treatment-free holiday for other reasons.
Finally, we consider the next few years in RCC research. Although no biomarkers for treatment selection are currently available, various genomic and molecular signatures are being developed to optimize patient selection for specific treatment.81,82 This will likely be incorporated into clinical trials that are designed with biomarker-based treatment selection. Likewise, trials assessing various combinations, therapies with novel mechanisms, and treatment intensification and deintensification are also likely to reshape the future of mRCC management.24,31,41-43,83
In conclusion, the incorporation of ICI-based therapy into the frontline treatment of mRCC has drastically altered the clinical trajectory of patients with mRCC and is thus an SOC for most patients. Beyond the treatment-naïve setting, the role of treatment sequencing is not yet fully optimized and treatment decisions that balance toxicity and efficacy require careful consideration. Future trials of novel agents and biomarker-based therapy and a focus on treatment-free intervals will define mRCC treatment over the next few years.
© 2021 by American Society of Clinical Oncology
See accompanying commentary on page 197
Conception and design: Moshe C. Ornstein
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Clinical Review on the Management of Metastatic Renal Cell Carcinoma
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/op/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Moshe C. Ornstein Consulting or Advisory Role: Pfizer, Eisai, Exelixis, Merck, AVEO, Bristol Myers Squibb Foundation Speakers' Bureau: Exelixis, Bristol Myers Squibb Research Funding: Bristol Myers Squibb, Pfizer Travel, Accommodations, Expenses: Exelixis, Bristol Myers Squibb No other potential conflicts of interest were reported.
REFERENCES
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