What is the role of localized

therapies in metastatic RCC?

Axel Bex, MD, PhD

Royal Free London NHS Foundation Trust, UCL Division of Surgery and
Interventional Science, London, UK, The Netherlands Cancer Institute,
Amsterdam, The Netherlands

ESMO Educational Session, Madrid, 20 October 2023

DECLARATION OF INTERESTS
Axel Bex has the following disclosures

Type of affiliation / financial interest Name of commercial company

Receipt of grants/research supports: Pfizer
Receipt of honoraria or consultation fees: BMS, Roche, Ipsen
Participation in a company sponsored not applicable
speaker’s bureau:
Stock shareholder: not applicable
Spouse/partner: not applicable
Other support (please specify): not applicable

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The rationale for localized treatment in metastatic RCC

In localized disease in which complete resection is

achievable:
• Cure
• Improvement of DFS, PFS and OS
• Disease-free interval with delay or discontinuation
of systemic therapy

In symptomatic localized disease:

• Palliation of symptoms

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Entities and nomenclature for local therapeutic options
Single metastasis/
recurrence Surgery
Metastasis- (metastasectomy)
directed therapy EBRT
MDT SBRT
Oligometastasis Thermal ablation

Cytoreductive
Primary tumour in Cytoreductive nephrectomy/
mRCC therapy Partial nephrectomy
SABR

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Speaking the same language
What do we understand when we mean oligometastatic
disease ?

Quantitative (number of metastases) and developmental (time)

characteristics are most commonly used
• Is the metastasis de novo?
• Is it synchronous or metachronous?
• Did it occur under treatment?
• Do two or more organ sites qualify for oligometastatic
disease?

Guckenberger et al, Lancet Oncol 2020

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 Consensus meeting on the definition of oligometastasis
Prospective evaluation of
classification and nomenclature in
the EORTC OligoCare trial

Guckenberger et al, Lancet Oncol 2020

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5-Year survival rates following complete resection of
solitary or oligometastasis in RCC
Metastatic site Patient numbers 5-year survival in % References

Assouad et al. 2007 , Kavolius et

Lungs 48-149 37.5-74 al. 1998, Kanzaki et al. 2011 ,
Pfannschmidt et al. 2002, Alt et
al, 2011

Staehler et al. 2010 . Thelen et

Liver 31-68 38.9-62.2 al. 2007, Ruys et al. 2011

Althausen et al. 1997, Durr et al

Bone 9-38 40-55 1995, Kavolius et al. 1998,

Kavolius et al. 1998, Shuch et al.

Brain 11-138 12-18 2008,

Itano et al. 2000, Onishi et al.

Adrenal 5-30 51-100 2000,

Pantuck et al. 2003,

LN synchronous 129 20
Kavolius et al. 1998,
LN metachronous 15 63

Tanis et al. 2009, Adler et al.

Pancreas 250-321 57-70.4 2014

Iesalnieks et al 2008.
Thyroid 45 51
 Is ‘cure’ with localized therapy alone a realistic goal ?
The example of isolated lymph node metastasectomy
N=138 RCC patients after resection of N=50 RCC patients with resection of isolated LN with an
isolated (1-3) lymph node metastases IQR of 2.6 cm (1.9-5 cm)

median time to development of distant

metastases was only 4.2 months
(IQR 2.1–11.7)

Median PFS 19.5 months 3- and 5-year CSS

75.8% and 73.6%,

Cancer specific (CSS), overall (OS) and distant metastasis-free survival (MFS)
Gershman et al., Eur Urol. 2017 Aug;72(2):300-306. Russel et al., BJU Int 2016;117(6B):E60-6

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Comparison of incomplete or no metastasectomy versus
complete metastasectomy

Dabestani et al., Lancet Oncol 15(12):549-61, 2014

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The retrospective bias in metastasectomy series
Population A Population B

metastasectomy

Unfavourable tumourbiology
Favourable tumourbiology Rapid disease progression
with slow progression Probably never considered
for metastasectomy
•Low metastatic volume
•No sarcomatoid features
•Good performance
•MSKCC/IMDC intermediate

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Per-protocol resectable disease recurrence was defined as (1) solitary metastases, (2) oligometastases (1-3
at a single site), or (3) renal fossa or renal recurrence after radical or partial nephrectomy, respectively.

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Without randomization inherent bias remains

Marconi et al., Eur Urol Open Scie 47: 65-72, 2023

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What is the true impact of metastasectomy on survival?
No randomized controlled trials in metastatic RCC to answer that question

tumorbiology metastasectomy

tumorbiology metastasectomy

tumorbiology metastasectomy

Contribution to survival time gained

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Selection is key
Multiple factors contribute to outcome

• Performance

• Site-specific factors

• Development over time

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Recurrence-free interval is a reflection of tumourbiology

Tosco L et al. Eur Urol. 2013;63(4):646-652.

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A simplified ‘uncertainty principle’ for oncology

Heisenberg and Bohr

We can know the position of a metastasis but
not the momentum of metastatic progression

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Drivers of RCC metastases

Turajlic et al., Cell 173:581-594, 2018

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‘Surgical’ metastasectomy comes at a price
In-hospital complications among 1102 patients undergoing metastasectomy, identified from 45 279 mRCC
patients in the National Inpatient Sample database (2000–2011).
Metastatic sites were the lungs (52%), bone (29%), liver (19%), lymph nodes (14%), adrenal glands (11%),
and brain (3.4%).

Meyer et al., Eur Urol 2017, 72:171-74

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Other local treatment modalities

Trial Design Setting Mets Nr Endpoint Therapy

NCT03575611 Phase 2 single- Treatment-naive 1-5 Feasibility and SBRT to all
(MDACC) arm PFS lesions
NCT02956798 Phase 2 single- Treatment-naive 1-3 Time to start SBRT to all
(UT arm systemic lesions
Southwestern therapy
NCT02542202 Phase 1 single- Treatment-naive 1-5 Grade 4 toxicity SBRT to all
(U Chicago) arm lesions
NCT04498767 Randomised Includes subset of 1-5 OS SBRT to all
(OligoCare phase 3 RCC lesions versus
EORTC) SOC
NCT04299646 Randomised Oligoprogressive 1-5 PFS ST and SBRT
(GETUG- phase 2 clear-cell RCC Versus ST only
StORM 01
Huynh et al., Eur Urol Oncol 2023

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Single-arm trials investigating SBRT in oligoprogression
N=38 patients treated with TKI (95% sunitinib 1st line)
Incidence of changing systemic therapy was 47% at 1 yr, with a
median time of 12.6 mo (95% CI 9.6–17.4 mo).
NCT02019576
Cheung et al., Eur Urol 2021
Axel Bex
N=20 patients treated with 1-4 prior lines (50% 2 lines)
The median time to changing systemic therapy was 11.1 mo
(95% CI: 4.5–19.3)
Hannan et al., Eur Urol Oncol 2022
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Trials combining SBRT with immunecheckpoint inhibition
Current results are from single-arm phase 2 trials only

1-/2-y OS 90%/74% 1-/2-y PFS 60%/45%

RAPPORT phase1/2
N=30 with 0-2 prior
treatments (73% surgery)
SBRT if feasible to all mets
Followed by 6 months
Huynh et al., Eur Urol Oncol 2023
Siva et al., Eur Urol 2022
pembrolizumab

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Adjuvant Pembrolizumab
Intermediate-high:
pT2 G4/sarcomatoid
pT3 Gany
High:
pT4 Gany
pTany Gany N1
M1 resected to NED
≦ 1 year after surgery

Choueiri TK et al. N Engl J Med. 2021;385:683–694.

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M1 NED subgroup in Keynote 564

Exploratory DFS HR of 0.29 is suggestive of treating

(subclinical) systemic disease with systemic therapy
Choueiri TK et al. ASCO GU. 2022

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ICI monotherapy with ipilimumab rescue

Titan HCRN-GU16-260 Omnivore Fraction

ESMO 2019 ASCO 2020 ASCO 2020 ASCO 2020
Number 207 123 83 46
Prior TKI yes no yes yes
Sequence Nivo followed by Ipi Nivo followed by Ipi Nivo followed by Ipi Nivo followed by Ipi
Number of Ipi doses 4 4 2 4
ORR 12 % 13 % 4% 15 %
CR 2.7 % 0 0 0

CheckMate 214 demonstrated in 425 patients who were treatment naïve at the 32-months update a ORR of
42.1 % and CR of 10.1 %

Motzer et al., J Immunother Canc 2020

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Surveillance of Oligometastatic Disease

Harrison MR et al. Cancer. 2021;127(13):2204-2212. Rini BI et al. Lancet Oncol. 2016;17(9):P1317-1324.

In the Real-World-Setting, surveillance of metastases is frequent (32%) and a safe

alternative to immediate systemic therapy with median time-to-therapy of 16
months

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Trial of local therapy versus no local therapy of metastases

Any kind Adjuvant

of focal pembrolizumab 1
therapy year
Patients with
synchronous or
metachronous*
R
clear cell M1
Single/oligomet
WHO 0-1 Surveillance
1st line ICI
until
Primary endpoint combination
necessity to
• Overall survival therapy
treat
Secondary endpoints
• Event-Free survival
• Time on systemic therapy
• Adverse events *stratified by <1 and >1 year after (partial) nephrectomy
• Quality of life

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Observation for patients with primary mRCC

• N=40 patients with primary mRCC

• Retrospective analysis
• 100% ccRCC, 52% ≥ 2 metastatic sites
IMDC favorable 18%
IMDC intermediate 60%
IMDC poor 22%
• Median time to progression 6 months Short TTP with
• Median time to targeted therapy 16 months - Higher IMDC risk
- Higher Fuhrman grade
De Bruijn et al., Urology109: 127–133, 2017

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 Primary metastatic RCC patients in ICI trials
Trial Number and % of Patients treated with the primary Subgroup analyses (hazard ratios
patients treated with tumour in place (ICI with 95% confidence intervals)
primary tumour in place combination versus sunitinib)
ICI combination sunitinib PFS OS

CM 214 187/847 (22 %) 84 103 NA 0.63 (0.42-0.94)

CM 9ER 196/651 (30.1 %) 101 95 0.63 (0.43-0.92) 0.79 (0.48-1.29)

Javelin 101 75/660 (11.4 %) 37 38 0.63 (0.31-1.29) NA

Keynote 426 146/861 (16.9 %) NA NA NA 0.57 (0.36-0.89)

Clear 175/712 (24.6%) 93 82 0.44 (0.28-0.68) 0.52 (0.31-0.86)

Summary of evidence table EAU RCC guideline 2021

Motzer et al. NEJM 2018
Choueiri et al. ESMO 2020
Motzer et al. NEJM 2019
Rini et al. NEJM 2019
Motzer et al., NEJM 2021

https://uroweb.org/guideline/renal-cell-carcinoma/#7_3
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Indications for deferred CN discussed at MDTs

The patient develops a durable complete/ near complete response at metastatic

sites and can be rendered disease free by removal of the primary

The patient has developed durable response or stable disease at metastatic sites
but the primary tumour progresses locally

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Arguments for deferred CN

• Complete pathological response in the

primary tumour is rare1 and vital tumour
may remain in patients with CR at
metastatic sites
• Removal of the primary tumour may
abrogate rapidly metastasizing clones2
and potentially prolong survival
• Patients with CR may potentially stop ICI
therapy after CN
• Currently confirmation of pathological CR
of the primary tumour requires full
histopathological examination of the 1Graafland et al., Eur Oncol 2022; 2Turajlic et al., Cell 2018
specimen

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Local therapy of the primary tumour and ICI therapy
Randomised controlled phase 3 trials of deferred CN with primary endpoint OS

NORDIC-SUN
NCT03977571

N=364
PROBE
NCT04510597
SWOG S1931

Bakouny Z, et al. Presented at ASCO GU. February 2020

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 Local therapy of the primary tumour and ICI therapy
SAMURAI and CYTOSHRINK randomized controlled phase 2 trials with primary endpoint PFS
Key Inclusion criteria
mRCC
IMDC >/=1 factor N=240
Primary tumour < 8 cm
And amenable to SBRT
Not a surgical candidate
SAMURAI NCT05327686
Key Inclusion criteria
Advanced treatment naïve
RCC N=78
IMDC int/poor
Primary tumour amenable to
SBRT
Not a surgical candidate
CYTOSHRINK NCT04090710
Axel Bex
Standard immunotherapy based regimen
(allow for cytoreductive nephrectomy)
R
1:2
Standard immunotherapy based regimen
+SABR to primary (42Gy/3)
(allow for cytoreductive nephrectomy)
Nivolumab plus ipilimumab
R
1:2
Nivolumab plus ipilimumab + upfront
SABR to primary (30-40Gy/5)
(allow for cytoreductive nephrectomy)
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Randomised trial landscape for local treatment of mRCC
Modality Trial Design Endpoint Outcome Reference

Objective: to compare local therapy to observation alone (time to systemic therapy/OS) ?

Surgery X
SBRT X

Objective: to compare local therapy + systemic therapy at progression to upfront systemic therapy
Surgery X

SBRT NCT05863351 Phase 3, n=472 OS recruiting clinicaltrials.gov/study

(SOAR) 1-5 oligomets /NCT05863351

Objective: to compare local therapy + systemic therapy to local therapy alone

Surgery NCT03142334 Phase 3, n=58 DFS, OS HR 0.29 Choueiri TK et al. N
(Keynote-564) Single mets favouring Engl J Med. 2021
pembrolizumab
SBRT X

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Randomised trial landscape for local treatment of mRCC
Modality Trial Design Endpoint Outcome Reference

Objective: to compare systemic therapy + local therapy at progression to systemic therapy alone
Surgery X
SBRT NCT04299646 Phase 2, n=114 PFS recruiting clinicaltrials.gov/study/
(GETUG-StORM- 1-5 oligo- NCT04299646
01) progressive mets

Objective: to compare systemic therapy + local therapy to systemic therapy alone

Surgery NCT03977571 Phase 3, n=400 OS recruiting clinicaltrials.gov/study/
(NORDIC-SUN) Local tumour NCT03977571

Surgery NCT04510597 Phase 3, n=364 OS recruiting clinicaltrials.gov/study/

(PROBE) Local tumour NCT04510597

SBRT NCT05327686 Phase 2, n=240 PFS recruiting clinicaltrials.gov/study/

(SAMURAI) Local tumour NCT05327686

SBRT NCT04090710 Phase 2, n=78 PFS recruiting clinicaltrials.gov/study/

(CYTOSHRINK) Local tumour NCT04090710

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Conclusion

• The role of localized therapy in mRCC is ill defined

• The evidence base has largely emerged from retrospective studies of metastasectomies using surgery
by default but remains poor due to absence of RCT data
• Prolonged disease-free intervals with delay or discontinuation of systemic therapy are more realistic
objectives than cure
• High recurrence rates and surgical adverse events following metastasectomy minimal-invasive
approaches such as SBRT and ablation are gaining ground
• Oligometastatic disease comprises different clinical presentations and dynamics which need to be
recognized in the design of trials
• Randomised controlled trials for different clinical settings are ongoing to improve the evidence base

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