Optimal Treatment for Patients With Progressive

RCC After 1 or More Previous Lines of Therapy

Katy E. Beckermann, MD, PhD

Assistant Professor
Vanderbilt University
Department of Internal Medicine
Division of Hematology/Oncology
Nashville, Tennessee

Supported by educational grants from Aveo Oncology, Eisai Inc., Exelixis,

Merck Sharp & Dohme Corp., and Pfizer Inc.
About These Slides
 Please feel free to use and share some or all of these slides in your
noncommercial presentations to colleagues or patients
 When using our slides, please retain the source attribution:

Slide credit: clinicaloptions.com

 These slides may not be published, posted online, or used in

commercial presentations without permission. Please contact
permissions@clinicaloptions.com for details
Faculty
Katy E. Beckermann, MD, PhD
Assistant Professor
Department of Internal Medicine
Division of Hematology/Oncology
Vanderbilt University
Nashville, Tennessee

Katy E. Beckermann, MD, PhD, has disclosed that she has received consulting fees
from Aravive, AVEO, Bristol Myers Squibb, Exelixis, and Seagen and funds for research
from Bristol Myers Squibb.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer v.4.2022. © National Comprehensive Cancer Network, Inc
2022. All rights reserved. Accessed February 21, 2022. To view the most recent and complete version of the guideline, go online to nccn.org.
 Clinical Trial Data Supportive of Sequencing
VEGF Therapies Before the Era of IO Combinations
 Phase III METEOR Trial: Cabozantinib vs Everolimus in
After Prior VEGF TKI Therapy
1.0 Median Deaths,
OS, Mo n

0.8
Cabozantinib (n = 330)
Everolimus (n = 328)
21.4
17.1
198
232
 Overall, 5% of patients
received previous
Probability of OS

HR: 0.70 (95% Cl: 0.58-0.85; P = .0002)

0.6
therapy with an ICI
0.4  ORR with cabozantinib:
0.2
17% vs 3% with
everolimus alone
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Mo
Patients at Risk, n
Cabozantinib 330 318 297 266 240 213 188 163 114 76 30 6 3 0
Everolimus 328 308 364 231 205 177 148 121 82 54 23 3 0 0

Motzer. Br J Cancer. 2018;118:1176. Slide credit: clinicaloptions.com

 Randomized Phase II Lenvatinib, Everolimus, or
Lenvatinib + Everolimus After Prior VEGF TKI
100 Lenvatinib plus everolimus
Single-agent lenvatinib
Single-agent everolimus
80  Overall, 3% of patients
60
received previous
OS (%)

therapy with an ICI

40 Lenvatinib + everolimus vs everolimus
HR: 0.51 (95% CI: 0.30-0.88; P = .024)  ORR with lenvatinib +
Lenvatinib + everolimus vs lenvatinib
20 HR: 0.75 (95% CI: 0.43-1.30; P = .32) everolimus: 43% vs 6%
Lenvatinib vs everolimus
HR: 0.68 (95% CI: 0.41-1.41; P = .12) with everolimus alone
0
0 3 6 9 12 15 18 21 24 27
Patients at Risk, n OS (Mo)
Lenvatinib + everolimus 51 48 46 44 38 35 29 21 14 6
Single-agent lenvatinib 52 50 45 42 37 31 26 16 7 4
Single-agent everolimus 50 46 42 38 30 27 20 14 8 2

Motzer. Lancet Oncol. 2015;16:1473. Slide credit: clinicaloptions.com

 Phase II Trials Assessing Clinical Activity of VEGF
Following Checkpoint Inhibitor Therapy in Frontline
 Phase II Trial Assessing 18 mg vs 14 mg of Lenvatinib +
Everolimus After VEGF TKI (Prior IO Allowed)
 26% of patients received previous IO therapy; 81% with IMDC int/poor risk disease

1.0
OS in ITT Population 1.0
OS in Patients With Prior IO Tx

0.8 0.8
OS Probability

OS Probability
0.6 0.6

0.4 0.4 Median OS, Mo (95% CI)

Median OS, Mo (95% CI) Lenvatinib 14 mg + everolimus: 17.1 (10.6-NE)
0.2 Lenvatinib 14 mg + everolimus: 27.0 (18.3-NE) 0.2 Lenvatinib 18 mg + everolimus: 18.0 (13.1-NE)
Lenvatinib 18 mg + everolimus: NE (23.8-NE) HR : 1.28 (90% CI: 0.75-2.18)
0 0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 0 2 4 6 8 10 12 14 16 18 20
Patients at Risk, n Mo Mo
Len 14 mg + eve 156 147 138 124 108 89 75 71 56 48 34 20 10 8 43 40 39 34 29 23 18 18 12 10 7
Len 18 mg + eve 155 146 141 132 111 97 86 69 63 54 42 22 11 7 39 37 36 34 32 28 23 20 17 13 9

Pal. Eur Urol. 2022;[Epub]. Slide credit: clinicaloptions.com

 TIVO-3: Phase III Trial With Tivozanib vs Sorafenib in
Advanced RCC After VEGF TKI Therapy (Prior IO Allowed)
100
++ Tivozanib
+ Sorafenib  Overall, 26% of patients
80 + + Censored
received previous
+
60
therapy with an ICI + TKI
PFS (%)

49.6%
(42-57)a
++  ORR: 18% with tivozanib
40 + ++
vs 8% with sorafenib
31.2%
(24-39)a
24.2%
+ +
(18-31)a
18.3%
20 35.1% 18.4% (13-25)a 13.9% 12.3%
(27-43)a (12-25)a 8.8%
(5-14)a 4.8%
+ (9-20)a (8-18)a 9.2%
(5-15)a
7.6%

(2-10)a
3.2%
(1-7)a
2.4%
(1-6)a
1.6% + +0%
(4-13)a

(0-5)a
0
Patients at Risk, n 0 6 12 18 24 30 36 42 48
Tivozanib 175 79 45 34 25 18 16 12 9
Sorafenib 175 45 23 11 6 4 3 2 1

Rini. Lancet Oncol. 2020;21:95. Atkins. ASCO GU 2022. Abstr 362. Slide credit: clinicaloptions.com
 Phase II Trial Assessing Axitinib With
Individualized Dosing for RCC After IO Therapy
Baseline Characteristics Patients (N = 40) PFS
Median PFS: 8.8 mo (95% CI: 5.7-16.6)
No. of previous tx: 11 (28)/19 (48)/ 100
1/2/3/4, n (%) 9 (23)/1 (3)
Previous VEGF TKI, n (%) 28 (70) 75
Most recent tx, n (%)

PFS (%)
 Nivo/Nivo + Ipi/Nivo + HIF2a 25 (63)/6 (15)/3 (8)
 Atezo/Atezo + Bev 2 (5)/2 (5) 50
 Durva/Durva + Treme 1 (3)/1 (3)

Best response to IO: PR/SD/PD, n (%) 8 (20)/21 (53)/10 (25) 25

Duration on IO tx <6 mo, n (%) 25 (63) Median follow-up: 8.7 mo
Median duration, mo (IQR) 4.8 (2.0-8.7) 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Reason for IO d/c: PD/AEs, n (%) 37 (93)/3 (8) Time from Treatment (Mo)
Time from d/c to axitinib, mo (IQR) 1.1 (0.7-1.7) No. at risk 40 32 25 20 13 8 6 5 4 2 2 1 1 0
(Censored) (0) (0) (0) (0) (2) (6) (6) (7) (7) (8) (8) (9) (9) (10)
Axitinib starting dose: 5 mg BID; dose titration Q14D in 1-mg increments up to 10 mg BID max.

Ornstein. Lancet Oncol. 2019;20:1386. Slide credit: clinicaloptions.com

 Phase Ib/II KEYNOTE-146/Study 111: Response to
Lenvatinib + Pembrolizumab by Previous Therapy
 A multicenter, open-label phase Ib/II study, mRCC cohort (N = 145)
‒ Patients received 0-2 lines of previous therapy
IO Naive Previous IO
Event (n = 17) (n = 104)
ORR at 24 wk, % (95% CI) 41.2 (18.4-67.1) 55.8 (45.7-65.5)

Best objective response, %

 CR 0 0
 PR 52.9 62.5
 SD 41.2 29.8
 PD 5.9 3.8
 NE 0 3.8

ORR, % (95% CI) 52.9 (27.8-77.0) 62.5 (52.5-71.8)

 Median PFS: 12.2 mo (95% CI: 9.5-17.7)
Lee. Lancet Oncol. 2021;22:946. Slide credit: clinicaloptions.com
Investigating Novel Targets in RCC
Post Immunotherapy Progression
 ASCO 2022 Update

Belzutifan in Advanced Clear-Cell RCC: Study Design

 Dose-escalation/expansion phase I/II study of belzutifan (MK-6482), a potent, selective,
oral small-molecule HIF-2α inhibitor with antitumor activity in clear-cell RCC
‒ Current analysis: updated follow-up of dose-expansion cohort in advanced clear-cell RCC
Adult patients with previously
treated advanced clear-cell RCC Until PD or
with ≥1 previous therapy; Belzutifan 120 mg PO QD* unacceptable
ECOG PS 0/1 toxicity
(N = 55) *21-day DLT period in dose-escalation.

Belzutifan Normal Oxygen Levels Hypoxia

Structure HIF-α HIF-2α HIF-β
inhibitor

CACGTG CACGTG
HRE site
Proteasomal degradation HIF complex
Bauer. ASCO GU 2021. Abstr 273. Choueiri. Nat Med. 2021;27:802. Jonasch. ASCO 2022. Abstr 4509. Slide credit: clinicaloptions.com
 ASCO 2022 Update
Belzutifan in Advanced RCC: Max Change
From Baseline in Target Lesions
ORR: 25% (CR: 2%; PR: 24%); DCR: 80% PFS
Events, Median PFS,
n (%) mos (range)
Belzutifan (n = 55) 27 (49) 14.5 (7.3-22.1)

Jonasch. ASCO 2022. Abstr 4509. Slide credit: clinicaloptions.com

 Belzutifan in Advanced RCC: All-Cause AEs
All-Cause AEs in ≥20% (N = 55), Any Grade All-Cause AEs in ≥20% (N = 55), Any Grade
n (%) Grade Grade 3 4/5 Grade 3
n (%) Grade 4/5
Any 55 (100) 33 (60) 6 (11) Arthralgia 14 (25) 0 (0) 0 (0)
Anemia 42 (76) 15 (27) 0 (0) Blood creatinine increased 14 (25) 1 (2) 0 (0)
Fatigue 39 (71) 3 (5) 0 (0) Headache 14 (25) 1 (2) 0 (0)
Dyspnea 27 (49) 3 (5) 0 (0) Dizziness 13 (24) 0 (0) 0 (0)
Nausea 20 (36) 1 (2) 0 (0) Back pain 12 (22) 1 (2) 0 (0)
Cough 17 (31) 0 (0) 0 (0) Diarrhea 12 (22) 0 (0) 0 (0)
Hypoxia 17 (31) 9 (16) 0 (0) Hyperkalemia 12 (22) 1 (2) 0 (0)
Vomiting 16 (29) 0 (0) 0 (0) Constipation 12 (22) 0 (0) 0 (0)
Edema, peripheral 15 (27) 0 (0) 0 (0) Dehydration 11 (20) 1 (2) 0 (0)

 Grade 4 AEs: 4 events in 2 patients (4%)
‒ Sepsis (2), hypercalcemia (1),
respiratory failure (1)
Bauer. ASCO GU 2021. Abstr 273.
 Grade 5 AEs: 4 events in 4 patients (7%)
‒ Acute kidney injury (1), disease progression (1),
malignant neoplasm progression (1),
cardiac arrest (1)
Slide credit: clinicaloptions.com
Clinical Trials Recently Closed or Actively
Recruiting in the Post-IO Setting
 Ongoing Phase III Trials in the Post-IO Setting
Title Inclusion Treatment Arms
MK-6482-005: Phase III Trial of  Clear-cell RCC Belzutifan
Belzutifan vs Everolimus in  Prior therapy with PD-1/PD-L1 inhibitor and VEGF
vs
Advanced RCC After PD-1/PD-L1 TKI, as monotherapy or in combination Everolimus
and TKI Therapy (n = 736)1  ≤3 prior therapies
 Clear-cell RCC or non–clear-cell RCC
CONTACT-03: Phase III Trial (papillary or unclassified) Atezolizumab +
of Atezo + Cabo vs Cabo in  Prior first- or second-line therapy with cabozantinib
Advanced RCC After PD-1/PD-L1 PD-1/PD-L1 inhibitor as immediate vs
Therapy (n = 500)2 preceding therapy Cabozantinib
 No more than 1 previous PD-1/PD-L1 inhibitor
TiNivo-2: Phase III Trial of Tivozanib  Clear-cell RCC Nivolumab +
+ Nivolumab vs Tivozanib in  PD during or following ≥6 wk of treatment tivozanib
Advanced RCC with an IO therapy vs
After IO Therapy (n = 326)3  ≤2 previous lines of therapy Tivozanib

1. NCT04195750. 2. NCT04338269. 3. NCT04987203. Slide credit: clinicaloptions.com

Ongoing Trials in RCC Presented at
ASCO 2022 With Novel Agents
Trial Name Phase Novel Mechanism
Batiraxcept (AVB-S6-500) with cabozantinib in patients with advanced or
metastatic clear-cell RCC who have received front-line treatment Ib/II GAS6/AXL signaling inhibition

First-in-human study of SRF388, a first-in-class IL-27 targeting antibody, as

monotherapy and in combination with pembrolizumab in patients with I/Ib IL-27
advanced solid tumors
STARLITE 2: Phase II study of nivolumab plus 177Lutetium-labeled
anti-carbonic anhydrase IX (CAIX) monoclonal antibody girentuximab ( 177Lu- II Lutetium-CAIX
girentuximab) in patients with advanced clear-cell RCC
Antibody–drug conjugate targeting
Two-part, multicenter, first-in-human (FIH) study of DS-6000a in subjects I CDH6 with MAAA-1181 cytotoxic
with advanced RCC and ovarian tumors (OVC)
payload
Randomized, double blind trial of axitinib +/- PF‑04518600, an Monoclonal antibody
OX40 antibody (PFOX) after PD1/PDL1 antibody (IO) therapy (Tx) in II
metastatic renal cell carcinoma (mRCC) targeting OX40

Slide credit: clinicaloptions.com

 Phase Ib/II Trial of Batiraxcept (AVB-S6-500) +
Cabozantinib for ccRCC After Frontline Therapy
 Phase Ib/II study with batiraxcept (AVB-S6-500) + cabozantinib for advanced or metastatic
ccRCC after frontline treatment (N = 26)
88% of patients had reduction in target
lesions at 8-wk response assessment

Shah. ASCO 2022. Abstr 4511. Slide credit: clinicaloptions.com

 First-in-Human Study of Anti–IL-27 SRF388 Alone or
With Pembrolizumab in Solid Tumors
 First-in-human study with IL-27–targeting antibody SRF388 as monotherapy or in
combination with pembrolizumab
SRF388 Monotherapy in ccRCC: SRF388 + Pembro:
Dose Expansion Cohort (n = 13) Dose Expansion Cohort (n = 9)

31% disease control rate 67% disease control rate

Naing. ASCO 2022. Abstr 2501. Slide credit: clinicaloptions.com

 Phase II Study of Axitinib ± Anti-OX40 Antibody
PF‑04518600 in mRCC After Previous IO Therapy
 Phase II study of axitinib ± anti-OX40 antibody PF‑04518600 for patients with metastatic
RCC after previous treatment with PD-1 or PD-L1 inhibitors Median OS,
mos (95% CI)
Median PFS, Axitinib + Ox40 Ab 22.5 (14.8-NA)
mos (95% CI) Axinitib + placebo 20.3 (12.3-NA)
Axitinib + Ox40 Ab (n = 29) 10.2 (6.0-15.8)
Axinitib + placebo (n = 30) 8.5 (5.5-11.6)

Sadeghi. ASCO 2022. Abstr 4529. Slide credit: clinicaloptions.com

 Go Online for More CCO
Coverage of RCC!
Downloadable slidesets from today’s symposium
On-demand webcast of today’s symposium (on education.NCCN.org)
ClinicalThought commentary with expert perspective on managing RCC (coming soon)

clinicaloptions.com/oncology
education.nccn.org/RCC2022