A Review of Papillary Renal Cell Carcinoma and MET Inhibitors

INTRODUCTION

Renal cell carcinoma (RCC) is the sixth most commonly diagnosed cancer in men and the tenth in women with approximately 140,000 deaths yearly, ranking RCC as the 13th most common cause of cancer death worldwide [1–4]. The lifetime risk for developing RCC in Europe and North America is 1.3%–1.8%. In the United States, there are 15.9 cases per 100,000 each year with a 0.6% increase each year in new cases of kidney and renal pelvis cancer over the last decade [5]. Papillary renal cell carcinoma (PRCC) is the second most common type of RCC, following clear cell carcinoma (ccRCC), comprising 15–20% of RCC cases. PRCC is further subdivided into type 1 and type 2 based on histology. Although similar mutations are found within the two types of PRCC, each type has characteristic common mutations. Type 1 PRCC is more associated with MET alterations, either genetic mutations or gain of chromosome 7 where the MET gene is found. Type 2 PRCC tends to have mutations in CDKN2A, SETD2, BAP1, PBRM1, TERT, NF2, FH, and NRF2-ARE pathway genes. Type 2 is also associated with a CpG island methylator phenotype (CIMP) (Table 1) [6–8].

MET mutations in PRCC were first identified in hereditary PRCC as an autosomal dominant mutation in the MET gene on chromosome 7q31 [9, 10]. Since then, additional somatic mutations and chromosome duplications have been identified in sporadic renal carcinoma [8]. MET mutations are also found in other malignancies, such as hepatocellular carcinomas (HCC), lung cancer, breast cancer, colorectal cancer (CRC), head and neck squamous cell cancers (HNSCC), gastric carcinomas (GC), and cancers of unknown primary origin [7]. Increased expression of MET can occur via overexpression, gene amplification, activating point mutations, gene fusions, increased chromosome 7 copy number, paracrine signaling, autocrine loop formation, receptor mutations, and splice variants [10–13]. Although MET alterations are more common in type 1 PRCC, one study found a larger percentage of type 2 PRCC with MET mutations than previously identified, with 46% of type 2 and 81% of type 1 PRCC cases positive for MET mutation [14].

THE MET PATHWAY

MET is a tyrosine kinase receptor of hepatocyte growth factor/scatter factor (HGF/SF). This pathway is involved in a variety of normal functions, including: liver regeneration, wound healing, organ morphogenesis, and embryo development [11]. In normal tissues, HGF and MET are upregulated after renal injury as a mechanism of tissue repair and regeneration. In oncogenesis, MET is involved in invasion, anti-apoptosis, angiogenesis, and metastasis (Fig. 1)

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Fig.1

MET molecular pathway.

There is also influence from other growth factors, such as epidermal growth factor receptor (EGFR) activation of c-MET after stimulation of cells with EGF or transforming growth factor (TGF-α) (Fig. 1) [13]. This interaction is further evidenced in non-small cell lung carcinomas (NSCLC) with acquired resistance to EGFR inhibitors due to amplifications in MET.

PRCC OUTCOMES WITH CONVENTIONAL THERAPY

PRCC tends to have a less robust response to conventional therapy used in RCC compared with clear cell carcinoma (ccRCC) given that ccRCC is associated with distinct mutations not typically found in PRCC, such as VHL and PBRM1 [15–20]. Multiple large studies have found significantly lower response rates with shorter median progression-free survival (PFS) and overall survival (OS) in patients with non-ccRCC variants, such as PRCC, when compared to ccRCC. One large study of 5474 patients with metastatic RCC showed better OS, PFS, and objective response rate (ORR) for ccRCC compared to non-ccRCC with an OS 8 months longer for ccRCC [17]. Another large systematic review and meta-analysis evaluating 49 studies composed of 7771 patients found that non-ccRCC had significantly lower response rates compared with ccRCC, with a 10.5% overall response rate in non-ccRCC. Among patients with non-ccRCC, median PFS and OS were 7.4 and 13.4 months, respectively. For patients with ccRCC, these clinical outcomes were significantly higher with a PFS and OS of 10.5 months and 15.7 months, respectively [16]. Therapeutic interventions (including bevacizumab, sorafenib, sunitinib, temsirolimus, and sunitinib) were less effective for patients with non-ccRCC with a response rate of 9.2% compared to 14.8% in ccRCC [16].

When evaluating specific agents used in RCC, the efficacy is diminished for non-ccRCC compared to ccRCC. One example is everolimus. A shorter PFS was confirmed for non-ccRCC patients compared to ccRCC patients in the ASPEN, RECORD-3, and ESPN trials [18–21]. Other examples include VEGF inhibitors, such as sunitinib, which has a shorter PFS specifically in metastatic PRCC, ranging from 1.6–6.6 months, compared to 9–12 months in ccRCC [20, 22–26]. Data from meta-analyses support the use of sunitinib over everolimus and temsirolimus for metastatic non-ccRCCs in first-line treatment, but the difference in PFS is not statistically significant [27]. Based on this data, guidelines from the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) both recommend sunitinib as first line therapy in metastatic non-ccRCC [28, 29].

Immunotherapy also has a role in treating RCC. Nivolumab, a PD-L1 inhibitor, is approved for metastatic RCC, but this was based on studies excluding patients with non-ccRCC [30, 31]. For ccRCC, nivolumab improves OS with patients surviving 25 months with nivolumab versus 19.6 months with everolimus [30]. For non-ccRCC, a few case reports describe responses of patients with PRCC to nivolumab [32–34]. In 2018, a study from Koshkin et al. evaluated nivolumab in non-ccRCC with 16 of 41 patients having PRCC. The study found clinical response to nivolumab seen as an ORR of 20% and stable disease (SD) in 29% of all patients in the study. Results specific to the 16 patients with PRCC, included PR of 14% and SD in 21% [35].

Given the limited response of PRCC to conventional therapies used in all RCC, MET-targeted therapy alone or combination with other agents could provide better outcomes for these patients. Several agents targeted to MET have been tested in RCC with varying outcomes, including tyrosine kinase inhibitors (TKI) and monoclonal antibodies (Table 2).

TKIs TARGETING MET

MONOCLONAL ANTIBODIES TARGETING MET

IMMUNE CHECKPOINT INHIBITORS AND COMBINATION THERAPIES

There are recent studies indicating the role of immune checkpoint inhibitors specifically in non-cc RCC. A phase II study of pembrolizumab in non-ccRCC with 72% of participants having PRCC, found an overall ORR of 24.8% and an ORR for PRCC of 25.4% [68]. A recent phase II study evaluating atezolizumab and bevacizumab in participants with non-ccRCC or sarcomatoid variant RCC (sscRCC) with 38.9% of participants having PRCC, found an overall ORR of 31% and an ORR for non-ccRCC of 26% [69]. SD was seen in 44% in overall population and 50% in non-ccRCC. A study of combination therapy with durvalumab and savolitinib in metastatic PRCC was recently presented and showed an ORR of 27%, SD in 39%, and a PFS of 3.3 months. For MET positive patients, ORR was 20% [70]. There are also other ongoing combination trials for PRCC. One study, MEDI4736 Combinations in Metastatic RCC (CALYPSO), investigates the use of durvalumab, savolitinib, tremelimumab alone or in combination in PRCC (NCT02819596) [71]. Another phase II study, ANZUP1602 (UNISON) looks at sequential treatment of single agent nivolumab followed by nivolumab with ipilimumab if single agent treatment is not effective in PRCC (NCT03177239) (Table 3) [72].

OTHER AGENTS

In addition to the TKIs and mAbs described, several additional MET inhibitors are at an early stage of investigation in pre-clinical studies or are undergoing testing in other malignancies that may have potential role in treatment of PRCC in the near future. Glesatinib, golvatinib, and AMG208 are MET TKIs shown to have activity and tolerability in phase I trials in malignancies other than PRCC [73–80]. Capmatinib is another MET TKI with in vitro activity against cells harboring METex14 alterations [81]. Although prior studies have focused on NSCLC, there is a phase II trial of capmatinib in PRCC that is ongoing [82].

There are also several mAbs targeting c-MET in early developmental stages that have largely been tested in other malignances as well. These agents include emibetuzumab and DN30 [83–91]. SAIT301 is a humanized mAb that promotes MET degradation that has shown activity and tolerability in MET positive patients; however, the study focused mostly on colorectal cancer [92–94]. Another drug under investigation, ABT-700, is a humanized bivalent monoclonal antibody that inhibits MET dimerization and activation with activity in cancer cell lines [91, 95]. In 2017, a phase I study was completed of ABT-700 alone and in combination with docetaxel, 5-fluorouracil, folinic acid, irinotecan and cetuximab (FOLFIRI/cetuximab) or erlotinib in patients with advanced solid tumors, with some patients harboring MET amplification or overexpression [96]. Additionally, a phase I study of telisotuzumab vedotin (Teliso-V), an antibody-drug conjugate of ABT-700 and monomethyl auristatin E, in NSCLC patients who carried a MET alteration found a PFS of 5.7 months in three of 16 patients with c-MET-positive NSCLC [97]. Phase II studies are underway [98].

CONCLUSION

MET is an appealing drug target given its prevalence in PRCC. Developing effective MET targeted therapies is needed since outcomes are typically worse for PRCC when treated with conventional therapies. Therapeutic interventions targeted to the MET pathway in PRCC are still under active investigation, such as, MET TKIs and MET-directed antibodies. There is a need for continued research into MET-targeted therapy and more studies to include patients with PRCC. Additionally, recent studies indicate that there may be a role for immune checkpoint inhibitors alone or combination with MET inhibitors in treatment of PRCC. Going forward, PRCC patients may benefit from targeting multiple components of the MET pathway, targeting pathways that are known to interact with the MET pathway, and incorporating immune checkpoint inhibitors.

CONFLICTS OF INTEREST

M.A. Bilen has a consulting/advisory role with Exelixis, Nektar, Genomic Health, EMD Serono and Sanofi and receives institutional research funding from Bayer, Bristol-Myers Squibb, Genentech/Roche, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peloton, and Pfizer.