An Update on the Treatment of Papillary Renal Cell Carcinoma

Simple Summary Papillary renal cell carcinoma is the second most common type of kidney cancer, after clear cell kidney cancer. Given that it is relatively rare, studying this disease has been quite a challenge. New treatments and techniques for studying papillary kidney cancer have led to some meaningful improvements in therapy for this disease. In this review article, we summarize some of the historical studies in this space, and look ahead to three upcoming trials in papillary renal cell carcinoma. Abstract Papillary renal cell carcinoma (pRCC) is the second-most common subtype of kidney cancer following clear cell renal cell carcinoma (ccRCC), representing 15% of kidney cancers. Despite advances in therapy, including combination strategies with targeted therapies and immune checkpoint inhibitors, progress has lagged behind that of ccRCC. This is in part due to the heterogenous nature of the various subtypes of pRCC. More recently, investigators have turned efforts towards histology and biology-based trials. In this review, we outline some of the distinct biological characteristics of pRCC and discuss the most impactful clinical trials to date. Finally, we look ahead to several highly anticipated ongoing trials in pRCC.


Introduction
There will be an estimated 79,000 cases of renal cell carcinoma (RCC) in 2022, of which non-clear renal cell carcinoma (nccRCC) will represent approximately 25-30% [1,2]. The most recent global statistics indicate that there were over 400,000 cases of RCC in 2020 [3]. nccRCC is comprised of several subtypes, including papillary (pRCC), chromophobe, collecting duct, renal medullary, translocation, and unclassified. pRCC represents 15% of kidney cancers and the most common type of nccRCC [4].
pRCC is diagnosed most commonly between the ages of 50-70 and occurs more often in men [5]. These tumors are often characterized radiologically by calcification and are frequently multifocal in nature [6,7]. Although retrospective and limited in sample size, Dudani and colleagues' analysis of the International Metastatic RCC Database Consortium (IMDC) suggested that metastatic pRCC is associated with worse survival compared to metastatic clear cell RCC (ccRCC), regardless of the site of metastasis [8]. pRCC has a threefold-higher incidence among Black people than White people [5]. Additionally, Asian Americans have been found to have an increased risk of pRCC based on data from a regional database with nearly 10,000 patients [9].
In metastatic renal cell carcinoma (mRCC), randomized phase III trials have predominantly focused on ccRCC. Consequently, the treatment paradigm of advanced nccRCC has historically been predicated on retrospective data, phase II trials, and subgroup analyses pRCC in the IFN and temsirolimus cohorts, respectively. Median progression-free survival (PFS) for pRCC patients was 1.8 months with IFN versus 3.8 months with temsirolimus (95% CI, 0.28-0.83). Median OS in the pRCC cohort was 5.7 months with IFN, compared to 10.9 months for patients treated with temsirolimus (95% CI, 0.27-0.94). Although limited by the small sample size, these findings suggested the superiority of temsirolimus over IFN in pRCC.
The RAPTOR trial, a single-arm phase II trial of everolimus in previously untreated pRCC (32% with type 1 and 64% with type 2), enrolled a total of 88 patients in its intentionto-treat (ITT) cohort [21]. Results were notable for an OS of 21.4 months (95% CI, 15.4-28.4) despite a very low response rate of 1%. The substantially longer OS with everolimus in the RAPTOR trial, compared to temsirolimus in the ARCC trial, may in part be attributable to the high number of patients (65%) in the RAPTOR trial that exhibited stable disease (SD) as a best response. Furthermore, as noted by the authors, a significant number of patients in RAPTOR continued therapy with everolimus in spite of progressive disease, which likely contributed to the high OS in this study. The results of ARCC and RAPTOR established mTOR inhibition as a frontline strategy in pRCC.
With the introduction of vascular endothelial growth factor (VEGF)-pathway tyrosine kinase inhibitors, two early studies signaled that these agents held promise in the non-clear cell setting. Tissue-based-and mRNA-expression studies indicated that pRCC exhibits substantial expression of VEGF and VEGF receptors [22,23]. Furthermore, MET mutations in type 1 pRCC were shown to lead to VEGF transcription via overaccumulation of hypoxiainducible factor, augmenting the biological rationale of testing these agents in pRCC [24]. A single-arm phase II study of sunitinib in nccRCC included 22 (71%) patients with pRCC, in whom the response rate was 36% [25]. In the overall cohort, median PFS was 6.4 months (95% CI, 4.2-8.6) and median OS was 25.6 months (95% CI, 8.4-42.9). In addition, sunitinib was evaluated in the SUPAP trial, which enrolled 61 pRCC patients (15 patients with type 1 and 46 patients with type 2 pRCC) [26]. In this single-arm phase II trial, median PFS was 6.6 months (95% CI, 2.8-14.8) and 5.5 months (95% CI, 3.8-7.1), and OS was 17.8 months (95% CI, 5.7-26.1) and 12.4 months (95% CI, 8.2-14.3), in type 1 and type 2 pRCC, respectively. These studies both affirmed that VEGF inhibition is an effective therapeutic strategy in pRCC.
Taken together, the ESPN and ASPEN trials largely supported the use of sunitinib in pRCC, although this was limited due to a small sample size. A meta-analysis that included these studies showed that sunitinib demonstrated a superior PFS compared to everolimus in nccRCC (p < 0.00001, HR 0.67 (0.56-0.80)), although there was no difference seen in OS [29]. While the heterogenous populations and the limited sample size makes it difficult to draw strong conclusions, sunitinib appeared to have more activity than everolimus in these trials. These studies paved the way for future studies with this class of therapy in pRCC.
Axitinib, a more specific and potent VEGF inhibitor, was assessed in the AXIPAP trial, a multicenter phase II single-arm study that included 44 patients with pRCC [30]. In this previously untreated cohort, 13 patients had type 1 pRCC, 30 had type 2 pRCC, and 1 had unspecified papillary histology. With a median follow-up of 32 months, the median PFS was 6.6 months in patients with type 1 disease (95% CI, 5.5-9.2) and 6.2 months in type 2 disease (95% CI, 5.4-9.2). The median PFS at 24 weeks, which was the primary endpoint, was 45.2% (95% CI 32.6%-NR) in the overall cohort and 46.2% (95% CI, 23.4-NR) and 42.9% (95% CI, 27.5-NR) in type 1 and type 2 pRCC subgroups, respectively. The ORR was 28.6% (95% CI, 15.7-44.6), and higher response rates of 35.7% were seen in the type 2 subgroup compared to 7.7% in type 1 patients. This suggests more reliance on the VEGF pathway in type 2 pRCC compared to type 1 pRCC.
Given the activity of single-agent targeted therapy in nccRCC, attention then turned toward the efficacy of doublet therapy. Based on the activity of lenvatinib (a multikinase inhibitor with predominant anti-VEGF activity) with everolimus in ccRCC following one line of VEGF-directed therapy, Hutson et al. evaluated the regimen in nccRCC [31,32]. In this phase II single-arm study of previously untreated unresectable advanced or metastatic nccRCC, patients received lenvatinib/everolimus with a primary endpoint of safety and tolerability. Out of 31 patients, 20 (65%) had papillary histology. Median PFS in the pRCC group was 9.2 months (95% CI, 3.5-NE), and median OS was 11.7 months (95% CI, 8.1-NE). Overall, the results of this trial were promising for a combination approach in pRCC.

MET Inhibitors
In light of the central role of the MET pathway in type 1 pRCC (and to a lesser degree type 2 pRCC), researchers sought to interrogate MET inhibitors in pRCC. Foretinib, one of the first MET inhibitors, was assessed in a phase II trial at two dosage levels with a primary endpoint of ORR [33]. In total, 74 patients were enrolled, with an ORR of 13.5% (95% CI, 6.7-23.5%) and a median PFS of 9.3 months (95% CI, 6.9-12.9). Notably, 5 of 10 patients (50%) with germline MET mutations had a response, compared to 5/57 (9%) patients that did not harbor these mutations, bolstering the utility of targeting this pathway.
SAVOIR was a randomized phase III trial that employed a biomarker-driven approach to MET inhibition in pRCC. Criteria for enrollment included the presence of chromosome 7 gain, amplification of MET, mutation of the MET kinase domain, or alteration of hepatocyte growth factor [34]. With a total accrual of 60 patients, the study was terminated early. However, it should be noted that savolitinib showed a numerically superior response rate to sunitinib, 27% (95% CI, 13.3-45.5) vs. 7% (95% CI, 0.9-24.3), respectively [34].
Several other targeted drugs with anti-MET pathway activity were considered potential candidates in the therapy of pRCC. The PAPMET trial enrolled pRCC patients in one of the four drugs with anti-MET activity: sunitinib, cabozantinib, crizotinib, and savolitinib [35]. In this multicenter study, 147 patients (with ≤1 line of therapy that did not include a VEGF or MET inhibitor) received one of the four aforementioned agents, with a primary endpoint of PFS. Based on prespecified futility analysis, randomization of the crizotinib and savolitinib cohorts stopped at 29 and 28 patients, respectively. Cabozantinib, which is a multikinase inhibitor targeting VEGF, MET, and AXL, demonstrated a superior median PFS of 9.0 months, compared to sunitinib with 5.6 months (95% CI, 0.37-0.97, p = 0.019). Cabozantinib also had a 23% response rate, compared to 4% for sunitinib (p = 0.010). Savolitinib and crizotinib fared worse than sunitinib in terms of PFS. These data firmly established cabozantinib as the preferred frontline therapy for pRCC.

Immunotherapy
The advent of immune checkpoint inhibitors (ICIs)-antibodies that target either programmed cell death-1 (PD-1), its ligand (PD-L1), or the cytotoxic T-lymphocyte-associated antigen (CTLA-4)-transformed the treatment landscape for advanced/metastatic ccRCC [36,37]. Although there are no phase III trials of ICIs in nccRCC to date, several phase II trials have provided valuable information regarding these agents' biologic activity in this setting.
Although pembrolizumab appears to have outperformed nivolumab, it is notable that the former enrolled only untreated patients, whereas the latter included 34% of patients who had received prior therapy. Furthermore, there was a greater preponderance of patients with papillary histology in KEYNOTE-427, which likely contributed to an improved response compared to that of CheckMate-374. Notwithstanding these differences, KEYNOTE-427 and CheckMate-374 established the role of single-agent immunotherapy in nccRCC.
Checkmate-214 was a randomized phase III trial that established the role of doublet immune checkpoint inhibition (CTLA-4 blockade along with PD-1 inhibition) in ccRCC, which had superior efficacy over sunitinib in the intermediate/poor IMDC risk group [36,41]. These findings spurred interest in this combination in nccRCC. CheckMate-920 was a single-arm phase III/IV trial that included 52 patients with previously untreated advanced/metastatic nccRCC [42]. The response rate was 19.6%, with a median PFS and OS of 3.7 months (95% CI, 2.7-4.6) and 21.2 months (95% CI, 16.6-NE), respectively. Patients with pRCC made up 34.6% of the cohort, of whom five patients had a response (1 CR, 4 PR). These findings were further bolstered by several studies recently reporting retrospective and systematic review data, which, once again, showed the potential for response to immune checkpoint inhibition in advanced/metastatic pRCC [43][44][45].

Combination Therapy
While the therapeutic strategy of using single-agent VEGF-TKIs, mTOR inhibition, MET inhibitors, and ICIs each demonstrated some activity in pRCC, these paled in comparison to that of the findings in ccRCC. Interest in the potential synergy of these combinations in pRCC was in part due to the impressive response rates of combination cabozantinib/nivolumab in CheckMate 9ER in ccRCC [46]. A single-arm phase II trial is investigating the combination in patients with advanced nccRCC, allowing a maximum of one line of prior non-ICI therapy [47]. Cohort 1 of the study, with a total of 40 patients, included 32 (80%) patients with pRCC, 6 (15%) patients with unclassified-without-papillary features, and 2 (5%) patients with tRCC, demonstrating an impressive 48% (95% CI, 31.5-63.9) ORR. Similarly, COSMIC-021 evaluated atezolizumab, an anti-PD-L1 monoclonal antibody, plus cabozantinib across 102 patients. Among the 15 patients in this cohort with pRCC, 47% had an objective response (Table 1). In an effort to leverage the MET pathway along with an ICI, CALYPSO was a singlearm phase II study that treated pRCC patients with the combination of durvalumab (a PD-L1 inhibitor) plus savolitinib [51]. Previous lines of therapy were allowed. ORR was 27% among the 42 patients that were enrolled. After a median follow-up of 8.9 months, median PFS was 3.3 months in the overall cohort and 12 months in the subgroup of previously untreated patients. Molecular analysis showed that 14 of the enrolled patients had METdriven disease, in whom the response rate was 57% [52].
Other combination strategies in this setting include bevacizumab (a monoclonal antibody targeting VEGF) in combination with atezolizumab, which was assessed in a multicenter phase II study [53]. With a total of 60 patients enrolled, papillary histology was identified in 12 (20%) patients with a response rate of 25%. Similarly, KEYNOTE-B61 was a phase II single-arm trial of the combination of pembrolizumab and lenvatinib, which demonstrated considerable activity in pRCC, with an ORR of 52.9% (95% CI, 38.5-67.1) across 51 patients [50].
Given the promising potential for these treatment modalities, there is an urgent need for predictive biomarkers. A study of PD-L1 expression on formalin-fixed paraffinembedded tumor samples from 101 patients with nccRCC was reported in 2014, showing low tumor cell expression and modest tumor-infiltrating mononuclear cell expression of PD-L1 [54]. Tumor mutational burden (TMB) has not been an effective biomarker in pRCC, as it tends to be relatively low, with one study showing a median TMB of 2.7 Mb in patients with pRCC in both the type 1 and type 2 diseases [14]. Whole exome sequencing was performed on tumor samples in the aforementioned study of cabozantinib/nivolumab showed that 10 of 12 patients who harbored NF2 or FH mutations exhibited an objective response to the combination [47]. Of note, only 1 of 6 patients with a SETD2 had a response. Larger studies are needed to validate these molecular findings as potential markers of responses to TKI/ICI combinations.

Ongoing Trials in pRCC
At present, there are three highly anticipated prospective trials of VEGF/ICI, doublet-ICI, and MET-inhibitor/ICI combination strategies in pRCC. As a follow-up to the impressive results of cabozantinib in the PAPMET trial, PAPMET 2 (NCT02761057) is a randomized phase II study of cabozantinib with or without atezolizumab in pRCC. This trial has a target enrollment of 200 patients who have had < 1 line of prior therapy with a primary endpoint of PFS (Figure 1).
Although there appears to be promising evidence for doublet-ICI based on singlearm and retrospective data in pRCC, prospective randomized data comparing the combination to standard-of-care regimens is needed. SUNIFORCAST (NCT03075423) is an ongoing phase II multicenter study comparing the combination of ipilimumab/nivolumab to standard-of-care physician's-choice regimens in patients with advanced nccRCC [55]. Target accrual is 306 patients, with a primary endpoint of 12-month OS. Secondary endpoints include the 6-month and 18-month OS, median OS, PFS, ORR, and quality-of-life metrics. This trial is expected to include a considerable number of patients with advanced/metastatic pRCC.
Building off the success of CALYPSO, SAMETA (NCT05043090) is a randomized phase III, three-arm trial comparing the combination of savolitinib and durvalumab against monotherapy with either sunitinib or durvalumab in patients with advanced/metastatic pRCC. Target enrollment is 220 participants, with a primary endpoint of PFS of the combination versus sunitinib (Figure 2).

Conclusions
pRCC is the second-most common histologic subtype of kidney cancer and has benefited from the therapeutic advances of its more-prevalent clear-cell counterpart. Historically, early phase or subgroup analyses spurred the development of nccRCC-or pRCCspecific phase II trials from which treatment algorithms were largely devised. However, there remains a paucity of pRCC-specific randomized phase III trials. The current standard for metastatic pRCC should theoretically be cabozantinib, but guidelines remain vague around whether this or sunitinib are the most appropriate options. Thus, ongoing studies such as SAMETA, which is structured as a phase III registration trial, will be helpful. Other phase III studies in this space are eagerly anticipated.

Conclusions
pRCC is the second-most common histologic subtype of kidney cancer and has benefited from the therapeutic advances of its more-prevalent clear-cell counterpart. Historically, early phase or subgroup analyses spurred the development of nccRCC-or pRCCspecific phase II trials from which treatment algorithms were largely devised. However, there remains a paucity of pRCC-specific randomized phase III trials. The current standard for metastatic pRCC should theoretically be cabozantinib, but guidelines remain vague around whether this or sunitinib are the most appropriate options. Thus, ongoing studies such as SAMETA, which is structured as a phase III registration trial, will be helpful. Other phase III studies in this space are eagerly anticipated.

Conclusions
pRCC is the second-most common histologic subtype of kidney cancer and has benefited from the therapeutic advances of its more-prevalent clear-cell counterpart. Historically, early phase or subgroup analyses spurred the development of nccRCC-or pRCC-specific phase II trials from which treatment algorithms were largely devised. However, there remains a paucity of pRCC-specific randomized phase III trials. The current standard for metastatic pRCC should theoretically be cabozantinib, but guidelines remain vague around whether this or sunitinib are the most appropriate options. Thus, ongoing studies such as SAMETA, which is structured as a phase III registration trial, will be helpful. Other phase III studies in this space are eagerly anticipated.
On the horizon, there are several clinical trials that seek to leverage the potential synergies of VEGF/ICI, doublet-ICI, and MET-inhibitor/ICI combinations. As we chart a path forward in pRCC, it will be of utmost importance to design large-scale clinical trials that adequately evaluate and validate the nuanced biology and demography of this disease state. Author Contributions: Authors N.S.C. and N.S. contributed to this manuscript equally. Conceptualization, N.S.C., N.S., S.P. and E.C.; writing-original draft preparation, N.S.C., N.S., S.P. and E.C.; writing-review and editing, N.S.C., N.S., S.K.P. and A.C.-R. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.

Conflicts of Interest:
The authors declare no conflict of interest.