Disease Analysis: Renal Cell Carcinoma (RCC)
Author: Tom Tyler
Publisher: Datamonitor Healthcare
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Disease Overview
Renal cell carcinoma (RCC) is defined as a kidney cancer where the primary tumor emerges in renal tubular epithelial cells. This distinguishes RCC from other cancers of the renal parenchyma and renal pelvis cancers. RCC is the most common form of kidney cancer, comprising over 90% of all cases. RCC accounts for 2% of cancers worldwide, and 3.5% of new cancer diagnoses in the US.
Latest key takeaways
- Datamonitor Healthcare estimates that in 2018, there were 338,000 incident cases of renal cell carcinoma (RCC) worldwide in those aged 40 years and older, and forecasts that number to increase to 384,000 cases by 2027.
- The majority (75%) of RCC cases have a clear cell histology (ccRCC), to which most first-line treatment regimens are specialized. The next most common histology is papillary RCC, comprising 15% of RCCs.
- Nearly all pharmacological interventions are administered in metastatic RCC. Sutent may occasionally be prescribed as a postoperative adjuvant therapy in locoregional disease, but the typical approach is nephrectomy alone.
- Patients receiving first-line treatment are organized by prognostic risk criteria, as determined by several clinical parameters. This is used to stratify patients into poor, intermediate, and favorable risk categories, which subsequently guide physicians in choosing the appropriate treatment regimen.
- The most prominent drug class in RCC currently is tyrosine kinase inhibitors (TKIs). While Nexavar inhibits both intracellular and cell surface kinases, other agents (Sutent, Votrient, Lenvima, Cabometyx, and Inlyta) block members of the receptor tyrosine kinase (RTK) superfamily associated with angiogenesis and tumor cell proliferation, most notably VEGFR and PDGFR. In addition to targeting VEGFR/PDGFR, Cabometyx targets the RTKs MET and AXL. Inlyta and Tivopath, on the other hand, are specific for members of the VEGFR family.
- Other drug classes in RCC include inhibitors of the mammalian target of rapamycin (mTOR), a serine-threonine kinase. The mTOR pathway is dysregulated in several human cancers, and Afinitor (an mTOR inhibitor) was the first pharmacological agent available as a therapy for subsequent-line metastatic RCC. Inhibition of mTOR has also been shown to reduce expression of VEGF.
- PD-1 antagonist Opdivo was the first immune checkpoint inhibitor (ICI) approved in RCC and has quickly become a standard of care (SOC) in many treatment settings after showing demonstrable clinical benefits over earlier therapies. Recently, the agent has been challenged in first-line ccRCC by rival PD-1/PD-L1 antagonists Keytruda and Bavencio, but has been boosted by the approval of the CheckMate 9ER regimen and remains the only drug of its class in subsequent-line settings.
- Combinations of checkpoint inhibitors and TKIs dominate in first-line ccRCC. Opdivo is approved in combination with Yervoy or Cabometyx, while Keytruda and Bavencio are approved in combination with Inlyta. Moreover, a similar doublet of Keytruda and Lenvima is also likely to be launched.
- Sutent is set to lose ground due to both newer, more effective treatments and imminent biosimilar erosion. Previously the SOC across many treatment settings, the pivotal trials of several newer therapies, which include checkpoint inhibitors Keytruda, Opdivo, and Bavencio, and the RTK inhibitor Cabometyx, have demonstrated significant clinical benefit over Sutent in the first-line setting. Keytruda and Cabometyx have also demonstrated benefit over Sutent in subsequent-line settings.
- Sutent is also threatened by the expansion of ICIs for postoperative treatment of locoregional disease, where it is infrequently used but has largely been able to avoid competition. Approval in this area has proven difficult, with several other TKIs previously failing to expand into the setting. Due to concern over its risk/benefit profile, Sutent is only listed as a Category 3 treatment in this setting by the NCCN and was rejected by the EMA. It is thus infrequently administered. Phase III trials of ICIs Keytruda, Opdivo, and Tecentriq are ongoing, and one or more of these agents could finally displace Sutent and perhaps renew interest in adjuvant treatment of locally advanced RCC. Recently, the KEYNOTE-564 trial of adjuvant Keytruda recorded a 32% reduction in disease recurrence or death against placebo, becoming the first PD-1 antibody to demonstrate a conclusive benefit in the setting.
- Sutent, along with Cabometyx, remains commonly prescribed in first-line non-ccRCC, although this is partly due to a lack of data for newer treatments in the less common histological subtypes of RCC. Opdivo and Yervoy are the only checkpoint inhibitors available in this setting but are only recommended for sarcomatoid RCCs.
- mTOR inhibitors along with most TKI monotherapies are being gradually eclipsed in metastatic RCC by ICI-based combination therapies. However, some TKIs will be able to retain market share through incorporation into these combination regimens. This has been the case with Inlyta, which has seen improved uptake through use in first-line combination therapies that also incorporate checkpoint inhibitors Keytruda and Bavencio.
- A minority of other TKIs are also well positioned to improve their uptake through use as combination therapies alongside checkpoint inhibitors in a similar manner to Inlyta. Already well appraised as a monotherapy in second-line disease and in combination with Opdivo in first-line disease, Cabometyx has prospective label expansions as a combination therapy alongside Tecentriq and also alongside pipeline histone deacetylase inhibitor abexinostat. Similarly, Lenvima, presently available either as a monotherapy or a combination therapy with everolimus, may also be employed in the coming years in a combination therapy alongside Keytruda.
- Many older drugs are subject to patent expiries. VEGF inhibitor Avastin is already facing erosion from bevacizumab biosimilars, and the mTOR inhibitor Afinitor has been widely genericized. Other drugs set to follow in the near future include mTOR inhibitor Torisel, along with TKIs Sutent, Nexavar, and Votrient.
- Pipeline therapies of note include the PD-L1 inhibitor Tecentriq and the potential first-in-class launch of the HIF-2α antagonist belzutifan.
CONTENTS
8 OVERVIEW
8 Latest key takeaways
10 DISEASE BACKGROUND
10 Definition
10 Risk factors
11 Symptoms
11 Diagnosis
12 Patient segmentation
13 Prognosis
14 TREATMENT
14 Referral patterns
14 Recommended pharmacological therapy for locoregional disease
14 Recommended first-line regimens for metastatic ccRCC
15 Preferred subsequent-line regimens for metastatic ccRCC
16 Preferred pharmacological therapy for metastatic non-ccRCC
20 EPIDEMIOLOGY
20 Incidence methodology
24 MARKETED DRUGS
30 PIPELINE DRUGS
39 KEY REGULATORY EVENTS
39 More US FDA Enforcement Of Clinical Trial Reporting Is Expected After Acceleron’s ‘Clerical Oversight’
39 Biocon And Viatris Ready To Launch EU Bevacizumab
39 FDA Accepts New Drug Application For Merck’s Belzutifan
39 Persistence Pays Off With US Approval Of Aveo’s Fotivda In RCC
40 Six Drugs Recommended For EU-Wide Use
40 Exelixis Has Renewed Momentum Heading Into 2021
40 Stada-Mabxience Bevacizumab Is Latest To Receive EU Nod
41 Accord Picks Up European Nods
41 Mystery Surrounds Second Samsung Bioepis Avastin Biosimilar
41 SMC Recommends Bavencio/Axitinib Combo For Advanced RCC
42 Centus Gets European Bevacizumab Approval
42 Samsung Bioepis Receives EU Bevacizumab Approval
42 MK-6482 Brings New Mechanism To Merck’s Renal Cancer Franchise
42 Centus Biotherapeutics’s Equidacent Gets CHMP Nod
42 Samsung Bioepis’ Bevacizumab Nod Sets Stage For EU Throwdown
44 PROBABILITY OF SUCCESS
45 LICENSING AND ASSET ACQUISITION DEALS
45 Kazia Therapeutics Acquires Worldwide License to Evotec’s VEGFR3 Receptor Inhibitor
45 Could SillaJen Get Back On Track Via M2N’s Acquisition?
45 Immunotech Obtains Chinese Rights To T-Cure’s RCC Candidate
45 Biomm Backs Bio-Thera’s Brazilian Bevacizumab
46 Bristol Licenses Dragonfly’s IL-12 Program To Boost Immunotherapies
47 CLINICAL TRIAL LANDSCAPE
48 Sponsors by status
49 Sponsors by phase
50 Recent events
53 DRUG ASSESSMENT MODEL
58 MARKET DYNAMICS
59 FUTURE TRENDS
59 TKIs will remain a common prescribing option when used in combination
59 Sutent to be largely replaced by newer therapies
60 Patients resistant to anti-PD-1/PD-L1 therapy may have more options
60 Competition in first-line metastatic ccRCC will intensify
60 Race for ICI launch in adjuvant treatment of locally advanced tumors
62 CONSENSUS FORECASTS
67 RECENT EVENTS AND ANALYST OPINION
67 Telaglenastat for Renal Cell Cancer (June 7, 2021)
67 Multiple Drugs for Renal Cell Cancer (June 4, 2021)
69 Keytruda for Renal Cell Cancer (June 3, 2021)
70 Keytruda for Renal Cell Cancer (April 8, 2021)
71 Ilixadencel for Renal Cell Cancer (February 22, 2021)
73 Lenvima for Renal Cell Cancer (February 13, 2021)
74 Telaglenastat for Renal Cell Cancer (January 4, 2021)
76 Multiple Drugs for Renal Cell Cancer (November 10, 2020)
76 Multiple Drugs for Renal Cell Cancer (September 19, 2020)
78 Ilixadencel for Renal Cell Cancer (August 18, 2020)
79 Tivopath for Renal Cell Cancer (May 29, 2020)
81 Belzutifan for Renal Cell Cancer (May 13, 2020)
83 Opdivo for Renal Cell Cancer (April 20, 2020)
86 KEY UPCOMING EVENTS
87 KEY OPINION LEADER INSIGHTS
88 UNMET NEEDS
89 BIBLIOGRAPHY
90 APPENDIX
LIST OF FIGURES
13 Figure 1: AJCC prognostic groups for renal cell carcinoma
13 Figure 2: Definitions of the diagnostic criteria for primary tumor (T), regional lymph nodes (N), and distant metastasis (M) in kidney cancer
15 Figure 3: First-line therapy for clear cell renal cell carcinoma
16 Figure 4: Subsequent-line therapy for renal cell carcinoma
17 Figure 5: First-line therapy for non-clear cell renal cell carcinoma
22 Figure 6: Trends in incident cases of renal cell carcinoma, 2018–27
30 Figure 7: Overview of pipeline drugs for renal cell carcinoma in the US
31 Figure 8: Pipeline drugs for renal cell carcinoma, by company
31 Figure 9: Pipeline drugs for renal cell carcinoma, by drug type
32 Figure 10: Pipeline drugs for renal cell carcinoma, by classification
44 Figure 11: Probability of success in the renal cell carcinoma pipeline
47 Figure 12: Clinical trials in renal cancer
47 Figure 13: Top 10 drugs for clinical trials in renal cancer
48 Figure 14: Top 10 companies for clinical trials in renal cancer
48 Figure 15: Trial locations in renal cancer
49 Figure 16: Renal cancer trials status
50 Figure 17: Renal cancer trials sponsors, by phase
53 Figure 18: Datamonitor Healthcare’s drug assessment summary for renal cell carcinoma
58 Figure 19: Market dynamics in renal cell carcinoma
59 Figure 20: Future trends in renal cell carcinoma
69 Figure 21: Cabometyx / Cometriq and Opdivo for Renal Cell Cancer (June 4, 2021): Phase II – w/Cabozantinib + Nivolumab – Non-Clear Cell RCC (MSKCC)
70 Figure 22: Keytruda for Renal Cell Cancer (June 3, 2021): Phase III – KEYNOTE-564
73 Figure 23: Ilixadencel for Renal Cell Cancer (February 22, 2021): Phase II – MERECA
74 Figure 24: Lenvima for Renal Cell Cancer (February 13, 2021): Phase III – CLEAR (First Line)
76 Figure 25: Telaglenastat for Renal Cell Cancer (January 4, 2021): Phase II – CANTATA (w/Cabozantinib)
78 Figure 26: Cabometyx / Cometriq and Opdivo for Renal Cell Cancer (September 19, 2020): Phase III – CheckMate 9ER
81 Figure 27: Tivopath for Renal Cell Cancer (May 29, 2020): Phase III – TIVO-3
83 Figure 28: Belzutifan for Renal Cell Cancer (May 13, 2020): Phase II – VHL-Associated RCC
85 Figure 29: Opdivo for Renal Cell Cancer (April 20, 2020): Phase III – CheckMate 9ER (w/Cabozantinib)
86 Figure 30: Key upcoming events in renal cell carcinoma
88 Figure 31: Unmet needs in renal cell carcinoma
LIST OF TABLES
18 Table 1: Preferred/recommended branded treatment regimens for patients with renal cell carcinoma
21 Table 2: Incident cases of renal cell carcinoma, 2018–27
23 Table 3: Incident cases of renal cell carcinoma, by gender, 2018
25 Table 4: Marketed drugs for renal cell carcinoma
33 Table 5: Pipeline drugs for renal cell carcinoma in the US
63 Table 6: Historical global sales, by drug ($m), 2016–20
65 Table 7: Forecasted global sales, by drug ($m), 2021–25
67 Table 8: Telaglenastat for Renal Cell Cancer (June 7, 2021)
68 Table 9: Multiple Drugs for Renal Cell Cancer (June 4, 2021)
69 Table 10: Keytruda for Renal Cell Cancer (June 3, 2021)
71 Table 11: Keytruda for Renal Cell Cancer (April 8, 2021)
72 Table 12: Ilixadencel for Renal Cell Cancer (February 22, 2021)
73 Table 13: Lenvima for Renal Cell Cancer (February 13, 2021)
75 Table 14: Telaglenastat for Renal Cell Cancer (January 4, 2021)
76 Table 15: Multiple Drugs for Renal Cell Cancer (November 10, 2020)
77 Table 16: Multiple Drugs for Renal Cell Cancer (September 19, 2020)
78 Table 17: Ilixadencel for Renal Cell Cancer (August 18, 2020)
80 Table 18: Tivopath for Renal Cell Cancer (May 29, 2020)
82 Table 19: Belzutifan for Renal Cell Cancer (May 13, 2020)
84 Table 20: Opdivo for Renal Cell Cancer (April 20, 2020)
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