What Is Next in Second- and Later-Line Treatment of Metastatic Renal Cell Carcinoma?

Review of the Recent Literature

Keiichiro Mori; Manuela Schmidinger; Fahad Quhal; Shin Egawa; Shahrokh F. Shariat; Viktor Grünwald

Curr Opin Urol. 2021;31(3):276-284.

Abstract and Introduction

Abstract

Purpose of Review: The current treatment landscape of metastatic renal cell carcinoma has changed dramatically from the dominance of single-agent tyrosine kinase inhibitor (TKI) therapy to immune-checkpoint inhibitor (ICI)-based combinations in recent years. However, the optimal subsequent therapy remains ill-defined owing to the novelty of this approach.

Recent Findings: Treatment with TKIs after failure of single or dual ICI therapies may result in robust clinical efficacy. Nonetheless, there is a trend toward lower efficacy of TKIs after previous ICI–TKI combination therapy. Currently, tivozanib is the only drug whose third- and later-line use after failure of TKI and ICI is supported by evidence, with significantly longer progression-free survival and higher objective response rates than sorafenib. Data from retrospective studies highlight the safety and clinical activity of ICI rechallenge.

Summary: Overall, the level of evidence remains low. Treatment after failure of dual ICI therapy is not well defined and may consist of any available TKI. Although first-line use of TKI is less common, strong evidence suggests cabozantinib or nivolumab as standard options in that setting. The recommendations after first-line TKI–ICI therapy failure mirror this recommendation, although the data are less robust.

Introduction

Renal cell carcinoma (RCC) is among the top 10 most frequently diagnosed cancers worldwide.^[1] Approximately 25% of patients with RCC present with metastatic disease at the time of initial diagnosis and require systemic treatment. Moreover, 20–50% of RCC patients with localized disease eventually develop metastatic RCC (mRCC).^[1,2]

The advent of immune-checkpoint inhibitors (ICIs) has transformed the treatment landscape of mRCC.^[3,4] In recent clinical trials, ICI-based combination therapies have markedly improved survival outcomes in mRCC patients compared with the previous standard of care (sunitinib) in first-line setting.^[5–9]

In an era of targeted therapy with antiangiogenic tyrosine kinase inhibitors (TKIs) for mRCC, approximately 52% and 35% of patients reach second- and third-line treatment, respectively.^[10] With the introduction of ICI combination therapy, the proportion of patients reaching later lines of treatment is expected to further increase, given the prolonged survival currently obtained.^[11]

Physicians are faced with the challenge of choosing an optimal treatment for the individual patient, especially in second and later lines of treatment. The choice of second and subsequent-line TKI or mammalian target of rapamycin (mTOR) inhibitor therapy is a subject of current debate, and data following prior ICI-based therapy is limited. Therefore, this review aims to summarize recent clinical evidence regarding second- and later-line treatment of mRCC.

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Next Section

Abstract and Introduction
Evidence Synthesis
Conclusion
References
Sidebar

Table 1. Summary of the oncological outcomes of tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma pretreated with ICIs
Author	Year	Design	N	Privious ICI Treatment	Treatment	ORR	PFS (months)	OS (months)
Albiges	2015	R	56 (TKI:44/mTOR: 12)	ICI monotherapy	Axitinib, Bevacizumab, Everolimus, Pazopanib, Sorafenib, Sunitinib, Temsirolimus	13% (TKI: 16%, mTOR: 0%)	TTF 6.6 (TKI: 6.9, mTOR: 5.7)	1 year OS rate 58% (TKI: 66%, mTOR: 35%)
Auvray	2019	R	33	Nivolumab plus Ipilimumab	Axitinib, Cabozantinib, Pazopanib, Sunitinib	36%	8	1 year OS rate 54% 2 year OS rate 37%
Barata	2018	R	31	Atezolizumab plus bevacizumab, Nivolumab plus Ipilimumab, Axitinib plus Avelumab	Axitinib, Cabozantinib, Pazopanib, Sunitinib	29%	6.4 (after ICI plus TKI: 6.2, after ICI plus ICI: 7.6)	NR
Cao	2020	R	258 (2nd line: 182, 3rd and later line: 76)	Nivolumab, Nivolumab plus Ipilimumab, Pembrolizumab, Ipilimumab	Pazopanib	NR	13.5 (2nd line: 16.0, 3rd and later line: 13.5)	1 year OS rate 89% (2nd line: 91%, 3rd and later line: 85%)
Dudani	2019	R	188 (ICI plus TKI: 113, Nivolumab plus Ipilimumab: 75)	ICI plus TKI, Nivolumab plus Ipilimumab	Axitinib, Cabozantinib, Lenvatinib plus Everolimus, Nivolumab, Pazopanib, Sunitinib	22% (after ICI plus TKI: 15%, after Nivolumab plus Ipilimumab: 45%)	TTF (after ICI plus TKI: 3.7, after Nivolumab plus Ipilimumab: 5.4)	NR
Ged	2020	R	59	Atezolizumab plus bevacizumab, Pembrolizumab plus Lenvatinib, Pembrolizumab plus Pazopanib, Pembrolizumab plusAxitinib, Nivolumab plus Sunitinib, Nivolumab plus bevacizumab, Axitinib plus Avelumab	Axitinib, Cabozantinib, Everolimus, Lenvatinib plus Everolimus, Pazopanib, Sorafenib, Sunitinib	25%	12	24.5 1 year OS rate 63%
Graham	2019	R	314 (TKI: 276, mTOR: 38)	ICI monotherapy or in combinations	Axitinib, Bevacizumab, Cabozantinib, Everolimus, Pazopanib, Sorafenib, Sunitinib, Temsirolimus	19% (all TKI: 30%, mTOR: 4%, 2nd line TKI: 36%, mTOR: 0%)	TTD (all TKI: 6.1, mTOR: 2.8, 2nd line TKI: 7.5, mTOR: 4.1)	1 year OS rate (all TKI: 65%, mTOR: 47%, 2nd line TKI: 78%, mTOR: 50%)
Grande	2020	P	20	PD-1/PD-L1 plus TKI or CTLA-4	Sunitinib	10%	6.8	NR
Iacovelli	2020	R	84 (2nd line: 39, 3rd and later line: 45)	Nivolumab	Cabozantinib	52%	11.5 (2nd line: NRE, 3rd and later line: 11.1)	17.3 (2nd line: NRE, 3rd and later line: 14.7)
McGregor	2020	R	86 (after ICI plus ICI or ICI: 55, after ICI plus TKI: 25, after ICI plus other: 6)	ICI monotherapy or in combinations (ICI plus ICI, ICI plus TKI, ICI plus other)	Cabozantinib	36% (after ICI plus TKI: 28%, after ICI plus ICI or ICI: 42%, after ICI plus other: 17%)	TTF 6.5 (after ICI plus TKI: 4.7, after ICI plus ICI or ICI: 8.1, after ICI plus other: 5.7)	median OS 13.1 1year OS rate 55% (after ICI plus TKI: 40%, after ICI plus ICI or ICI: 63%, after ICI plus other: 42%)
Nadal	2016	R	70 (Nivolumab: 32, Nivolumab plus Ipilimumab: 17, Nivolumab plus Pazopanib or Sunitinib: 21)	Nivolumab, Nivolumab plus Ipilimumab, Nivolumab plus Pazopanib, Nivolumab plus Sunitinib	Axitinib, Pazopanib, Sorafenib, Sunitinib	28% (after ICI plus TKI: 10%, after ICI: 36%, after Nivolumab plus Ipilimumab: 31%)	6.4 (after ICI plus TKI: 5.6, after ICI: 8.4)	16.9 (after ICI plus TKI: 24.9, after ICI: 16.3)
Ornstein	2019	P	40 (2nd line: 11, 3rd and later line: 29)	Nivolumab, Nivolumab plus Ipilimumab, Nivolumab plus HIFI, Atezolizumab, Atezolizumab plus bevacizumab, Durvalumab, Durvalumab plus tremelimumab	Axitinib	45% (2nd line: 36%, 3rd and later line: 48%)	8.8	NR
Powles	2020	P	62 (2nd line: 47, 3rd and later line: 15)	ICI, ICI plus TKI	Pazopanib	2nd line: 19%, 3rd line: 0%	2nd line: 7.4, 3rd line: 4.6	1 year OS rate 2nd line: 65.8%, 3rd line: 75.8%
Powles	2018	R	32 (Cabozantinib: 18, Everolimus: 14)	Nivolimab or Atezolizumab	Cabozantinib Everolimus	22% vs 0%	NRE vs 4.1 (HR: 0.22, 95%CI: 0.07–0.65)	NRE vs 16.3 (HR: 0.56, 95%CI: 0.21–1.52)
Rini	2020	R	91 (Tivozanib: 47, Sorafenib: 44)	PD-1, PD-L1	Tivozanib Sorafenib	NR	7.3 vs 5.1 (HR: 0.55, 95%CI: 0.32–0.94)	NR
Shah	2019	R	70	Nivolumab, Nivolumab plus Ipilimumab, Nivolumab plus Bevacizumab, Atezolizumab plus Bevacizumab, Atezolizumab	Axitinib, Cabozantinib, Pazopanib, Sunitinib	41%	13.2	1 year OS rate 80% 2 year OS rate 58%

CTLA-4, cytotoxic T-lymphocyte-associated protein 4; HIFI, hypoxia-inducible factor inhibitor; ICI, immune-checkpoint inhibitors; mTOR, mammalian target of rapamycin; NR, not reported; NRE, not reached; ORR, objective response rate; OS, overall survival; P, prospective; PD-1, programmed cell death-1; PD-L1, programmed cell death- ligand 1; PFS, progression free survival; R, retrospective; TKI, tyrosine kinase inhibitor.

Table 2. Summary of the oncological outcomes of ICIs in patients with metastatic renal cell carcinoma pretreated with ICIs
Author	Year	Design	N	Privious ICI Treatment	Treatment	ORR	PFS (months)	OS (months)	irAE
Gul	2020	R	45	ICI monotherapy, ICI plus TKI	Nivolumab plus Ipilimumab	20%	4	NR	13%
Ravi	2020	R	69	ICI monotherapy, ICI plus TKI, ICI plus ICI, ICI plus chemotherapy, ICI plus investigational agent	Atezolizumab, Durvalumab, Nivolumab, Nivolumab plus Ipiilimumab, Nivolumab plus Ipiilimumab plus Cabozantinib, Pembrolizumab, Pembrolizumab plus Axitinib, Pembrolizumab plus Bevacizumab, Spartalizumab	23%	5.7	NR	16%
Lee	2020	P	104	ICI monotherapy, ICI plus TKI, Nivolumab plus Ipilimumab	Lenvatinib plus Pembrolizumab	53.8%	11.8	NRE	NR

ICI, immune-checkpoint inhibitors; irAE, immune-related adverse event; NR, not reported; NRE, not reached; ORR, objective response rate; OS, overall survival; P, prospective; PFS, progression free survival; R, retrospective; TKI, tyrosine kinase inhibitor.

Authors and Disclosures

Keiichiro Mori^a,b, Manuela Schmidinger^a, Fahad Quhal^a,c, Shin Egawa^b, Shahrokh F. Shariat^{a,d,e,f,g,h,i} and Viktor Grünwald^j

^aDepartment of Urology, Medical University of Vienna, Vienna, Austria, ^bDepartment of Urology, The Jikei University School of Medicine, Tokyo, Japan, ^cDepartment of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia, ^dDivision of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan, ^eInstitute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia, ^fDepartment of Urology, Weill Cornell Medical College, New York, New York, USA, ^gDepartment of Urology, University of Texas Southwestern, Dallas, Texas, USA, ^hKarl Landsteiner Institute of Urology and Andrology, Vienna, Austria, ⁱDepartment of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic and ^jClinic for medical oncology and Clinic for Urology, West German Cancer Center Essen, University Hospital Essen, Essen, Germany

Correspondence to
Viktor Grünwald, University Hospital Essen, West-German Cancer Center Essen, Clinic for Medical Oncology and Clinic for Urology, Hufelandstraße 55, D-45147 Essen, Germany. Tel: +49 201/723 2637; fax: +49 201/723 5851; e-mail: viktor.gruenwald@uk-essen.de

Conflicts of interest
V.G. reports grants, personal fees and nonfinancial support from Astra Zeneca, grants, personal fees and nonfinancial support from Bristol-Myers Squibb, personal fees from MSD Sharp & Dohme, grants, personal fees and nonfinancial support from Ipsen, personal fees from Merck Serono, grants, personal fees and nonfinancial support from Pfizer, personal fees from EUSAPharm, personal fees from Novartis, personal fees from Eisai; grants and nonfinancial support from Astra Zeneca, grants, personal fees and nonfinancial support from Bristol-Myers Squibb, personal fees and nonfinancial support from Bayer, grants and personal fees from MSD Sharp & Dohme, personal fees from Roche, personal fees from Janssen-Cilag, personal fees from Asklepios Clinic, personal fees from Diakonie Clinic, personal fees from Lilly, personal fees from PharmaMar, personal fees from Dortmund Hospital, personal fees from Clinic of Oldenburg, personal fees from Onkowissen, grants from Novartis, personal fees from Janssen-Cilag, grants and personal fees from MSD Sharp & Dohme.S.S. owns or co-owns the following patents: Methods to determine prognosis after therapy for prostate cancer. Granted 2002–09-06. Methods to determine prognosis after therapy for bladder cancer. Granted 2003–06-19. Prognostic methods for patients with prostatic disease. Granted 2004–08-05. Soluble Fas: urinary marker for the detection of bladder transitional cell carcinoma. Granted 2010–07-20. He has a consulting or advisory role for the following: Astellas, Astra Zeneca, Bayer, BMS, Cepheid, Ferring, Ipsen, Jansen, Lilly, MSD, Olympus, Pfizer, Pierre Fabre, Roche, Sanochemia, Sanofi, Takeda, Urogen, Wolff.