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Checkpoint inhibitors and the changing landscape of Renal Cell Carcinoma therapeutics

Saby George, MD, FACP

Associate Professor of Medicine and OncologyGenitourinary Program

Roswell Park Cancer Institute02‐04‐2017

• I have consulted/worked in an advisory role for– Astellas– Bayer– Bristol‐Myers Squibb– Exelixis– Novartis– Onclive– Pfizer– Sanofi– Virtualscopics– Xcenda

• I (my institution) have received research funding from– Agensys– Acceleron– Bayer– Bristol‐Myers Squibb– Merck– Novartis– Pfizer

Disclosures

Objectives

• Treatment options for metastatic RCC

• Focused discussion of Nivolumab in RCC

• Some challenges in managing RCC patients with the introduction of such novel agents (with response evaluation including the dissociation between PFS and OS/ toxicities)

1

Heterogeniety in gene signature

Immunosuppression

Morphological Characteristics

Chemo and radiotherapy resistant

Different histologies

VEGF / HIF

CCRCC: Lipid / glycogen

accumulation

Stauffler’ssyndrome

Continuous tumor formation into IVC, RA and

RV

Familial syndromes

2


Current data in metastatic RCCSETTING TRIAL PFS (months) OS (months)

FRONT LINE Sunitinib vs Interferon 11 VS 5.1

P=<.000001

26.4 vs 21.4

P=.051

FRONT LINE Temsirolimus vs IFN vs

Combination

3.8 vs 1.9 10.9 vs. 7.3, hr=.73,

P=.008

FRONT LINE AVOREN/ CALGB90206 Bev+

IFN vs IFN or placebo

10.2 vs 5.4, HR=.63,

P=.0001

8.5 vs 5.2, HR=.71

23.3 vs 21.3

P=.1291

18.3 VS 17.4, P=.069

FRONT LINE CABOSUN: Cabozantinib vs

Sunitinib

8.2 vs 5.6 months

P=.012

HR=.66

30.3 VS 21.8

Not significant

FRONT LINE and SECOND‐

LINE

PAZOPANIB vs Placebo 9.2 vs 4.2, HR=.46,

P<.0000001

Not significant

SECOND‐LINE TARGET Sorafenib vs Placebo 5.5 VS 2.8, HR=.44,

P<.000001

17.8 VS 14.3

P=.0287

SECOND‐LINE RECORD‐1 Everolimus vs

Placebo

4 VS 1.9, HR=.3,

P<.0001

Not significant

SECOND‐LINE AXIS trial axitinib vs

sorafenib

6.7 vs 4.7, HR=0.665,

p<.0001

Not significant

SECOND LINE Nivolumab vs everolimus 4.4 vs 4.6 months, HR=0.88,

P=.11

25 vs 19.6, HR=.73, P=0.002

SECOND LINE Cabozantinib vs Everolimus 7.4 vs 3.8, HR=.58, P=<0.001 21.4 vs 16.5, HR=.66,

P=.0003

SECOND LINE LenvatInib plus everolimus vs

LEV vs Everolimus

14.6 (VS 7.4) VS 5.5, HR=.40,

p=.0005

25.5 vs 18.7 vs 17.5

3

Checkpoint inhibitor, Nivolumab; A drug with a novel mechanism of action

• Mechanism of action

• Data from Checkmate 025 trial

• Treatment beyond progression data 025

• Challenges with the response evaluation

• Unique Toxicities and implications

• Possible novel endpoints or radiographic assessments

4

• In patients on immune therapy, antitumor effects is due to immune response that indirectly attacks and clears the tumors.

Nivolumab mechanism of action

MHC

PD-L1

PD-1 PD-1

PD-1 PD-1

T-cellreceptorT-cell

receptor

PD-L1PD-L2

PD-L2

MHC

CD28 B7

T cell

NFκBOther

PI3KDendritic

cellTumor cell

IFNγ

IFNγR

Shp-2Shp-2

Nivolumab: PD-1 Receptor Blocking Antibody

75








6


7 8

9 10


11 12

13 14


15 16

17 18


19 20

21 22


23

Conclusions (1)

• Checkmate 025 met its primary endpoint, demonstrating superior OS with Nivolumab compared to Everolimus.

• This was the first trial to demonstrated OS advantage in second‐line of RCC.

• Survival benefit with Nivolumab was consistent across subgroups and irrespective of PD‐L1 expression.

• Nivolumab was associated with a higher objective response rate

24

Conclusions (2)

• Nivolumab was associated with fewer grade 3 and 4 treatment‐related AEs and fewer TRAEs leading to discontinuation that Everolimus.

• FKSI‐DRS results demonstrated a consistent improvement in QOL with Nivolumab compared to Everolimus.

• These results led to the approval of Nivolumab in December 2015 for use in advanced RCC patients who had received VEGF TKI in the past.

25








26


• With immunotherapy, tumor flare (growth of existing lesions or the appearance of the new lesions) may precede antitumor effects1

• This phenomenon may result in RECIST–defined progression leading to premature discontinuation of therapy

Tumor flare with immunotherapy

T cells infiltrating the

tumor site

Immune therapy

Tumor cells

1. Wolchok JD et al. Clin Cancer Res. 2009;15:7412-7420.

T cells infiltrating the

tumor site

Immune therapy

Tumor cells

27

Introduction

• Response patterns of immunotherapies like nivolumab differ from those seen with other approved targeted therapies1,2

– Immune cell infiltration into the tumor or tumor growth that can occur as the immune system is priming for a responsemakes interpretation by Response Evaluation Criteria in Solid Tumors (RECIST) more challenging and may result in patients discontinuing therapy prematurely3

• In a phase II study, 69% (25/36) of previously treated patients with advanced renal cell carcinoma (aRCC) who were treated beyond progression experienced tumor burden reduction or stabilization in the size of target lesions after first progression4

• We investigated nivolumab treatment beyond RECIST progression in the large, randomized, phase III study of previously treated patients with aRCC (NCT01668784; Figure 1)

4. George S, Motzer R, et al., Safety and efficacy of Nivolumab TBP in RCC patients. JAMA Oncol. 2016 May 28

MethodsFigure 1. Study design, subgroup definitions, and disposition

Study Design and Patients

Nivolumab 3 mg/kg

intravenously every 2 weeksN=406 treated

Everolimus10 mg orally once daily

N=397 treated

Ran

do

miz

e 1:

1

ORR = objective response rate; OS = overall survival

Did not progressN=90

ProgressedN=316

Did not progressN= 77

ProgressedN= 320

Treated beyond progressionN=65

Treated briefly beyond progressionN=111

Not treated beyond progressionN=144

Treated beyond progressionN=153

Treated briefly beyond progressionN=18

Not treated beyond progressionN=145

Niv

olu

mab

Eve

rolim

us

Endpoints: OS (primary), ORR (key secondary)

Study design Subgroup definitions and disposition

Eligibility Criteria

aRCC with clear-cell component

One or two prior anti-angiogenic

therapies

Progression within 6 months

29Motzer et al. ASCO 2016

Methods

Figure 1 cont.

First progression

Treatment ≥4 weeks after progression

Treatment < 4 weeks after progression

Treated beyond progressionTreated briefly beyond progressionNot treated beyond

progression



Methods (cont’d)Assessments for subgroup analysis

• Efficacy:

– Baseline to first RECIST‐defined progression

• Disease characteristics, duration of treatment, ORR, best overall response, time to response

– At first progression

• Disease characteristics

– From first progression to death or study discontinuation

• Duration of treatment, ≥30% tumor burden reduction, OS

• Safety

– Baseline to first RECIST‐defined progression

– After first progression

• This analysis primarily focuses on the nivolumab arm of the study


Demographics and baseline characteristicsa

Patients treated beyond progression(n = 153)

Patients not treated beyond progression(n = 145)

Median age (range), years 62 (29–85) 63 (23–85)

Sex, n (%)MaleFemale

116 (76)37 (24)

116 (80)29 (20)

MSKCC risk groupb, n (%)FavorableIntermediatePoor

58 (38)70 (46)25 (16)

44 (30)75 (52)26 (18)

KPS, n (%)70 or 80≥90

43 (28)110 (72)

54 (37)90 (62)

Tumor burden5, n (%)Small (<13 cm)Bulky (≥13 cm)

126 (82)27 (18)

108 (74)37 (26)

Prior radiotherapy, n (%) 39 (25) 42 (29)

Number of prior systemic antiangiogenicregimensb, n (%)12

113 (74)38 (25)

118 (81)27 (19)

Quality of life score (FKSI-DRS), median (Q1, Q3)c

31.5 (27.0–34.0) 31.0 (26.0–33.0)

aPatients who did not have a progression event or who were treated briefly beyond progression (<4 weeks) were excluded from analysis; bResults based on case report form data; Cn = 135 treated beyond progression and n = 52 not treated beyond progression. FKSI‐DRS = Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease Related Symptoms; KPS = Karnofsky performance status; MSKCC = Memorial Sloan Kettering Cancer Center; Q1 = first quartile; Q3 = third quartile 32

Patient disposition and duration of treatment

Patients treated beyond progression

(n = 153)

Patients not treated beyond progression

(n = 145)

Discontinued treatment, n (%) 134 (88) 145 (100)

Reasons for discontinuation, n (%)Disease progression Study drug toxicity AE unrelated to study drug Other

123 (80)8 (5)1 (1)2 (1)

122 (84)13 (9)6 (4)4 (3)

Median duration of treatment, months (95% CI)

OverallRandomization to first progressionPost-progression

8.8 (7.4–10.2)2.7 (1.9–3.8)3.4 (3.0–5.1)

2.3 (1.7–3.3)2.3 (1.8–3.3)

Not applicable

Continue to be followed, n (%) 92 (60) 50 (34)AE = adverse event; CI = confidence interval

33

Anti‐tumor activity of Nivolumab from Randomization to First Progression

Patients treated beyond progression

(n = 153)


ORR, % (95% CI) 20 (14‒28) 14 (9‒21) Best overall response, n (%)

Complete responsePartial responseStable diseaseProgressive diseaseUnable to determine

031 (20)51 (33)70 (46)

1 (1)

1 (1)20 (14)55 (38)58 (40)11 (8)

Median time to response, months (range)

1.9 (1.7‒9.2) 3.7 (1.4‒11.1)

Median duration of response, months (95% CI)

5.6 (3.9‒7.5) 7.0 (2.2‒7.9)

34


Results: At First ProgressionPatients treated beyond

progression(n = 153)


KPS, n (%)a

<7070 or 80≥90

1 (1)41 (27)111 (73)

3 (2)72 (50)70 (48)

Quality of life score (FKSI-DRS), median (range)b

31.0 (28.0–33.0) 27.0 (24.0–32.5)

Change in KPS, n (%)DeteriorationImprovement

26 (17)24 (16)

39 (27) 11 (8)

Target lesion status at progression, n (%)Increase in target lesionsc

Appearance of new lesionsIncrease in target lesions and appearance of new lesions

84 (55)63 (41)18 (12)

62 (43)64 (44)22 (15)

Site of new lesions, n (%)d

LungLymph node BoneLiver

21 (14)15 (10)8 (5)8 (5)

17 (12)14 (10)21 (14)11 (8)

Change in tumor burden, n (%)Bulky (≥13 cm) to small (<13 cm)5

Small (<13 cm) to bulky (≥13 cm)56 (4)

10 (7)5 (3)

19 (13)

aDefined as the performance status at or prior to and closest to the time of progression; bn = 135 treated beyond progression and n = 52 not treated beyond progression; cAt least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; d% based on all patients treated and not treated beyond progression. FKSI‐DRS = Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease Related Symptoms 35

Tumor burden change post‐progression

Figure 2. Best reduction in target lesions

Plus signs represent responders before first progression

• 142 of 153 patients treated beyond progression had tumor measurements pre‐ and post‐progression• Of these 142 patients,15% (n=21) had ≥30% tumor burden reduction post‐progression (Figure 2)


Overall survival

Treated beyond progression

Not treated beyond progression

Median OS, months (95% CI)Treated beyond progression

28.1 (23.2–NE)


15.0 (12.1–18.2)

HR (95% CI), 0.41 (0.29–0.57)


Landmark Analysis of OS



Median OS, months (95% CI)


20.4 (17.3–NE)


11.4 (9.4–14.6)

HR (95% CI), 0.42 (0.30–0.59)



Tumor burden change post‐progression based on best overall response

41

N≥30% tumor burden

reduction post‐progression, n (%)

Best response prior to progression

Complete or partial response

Stable diseaseProgressive disease

29

47

66

8 (28)

3 (6)

9 (14)


Tumor burden change based on best overall response

Complete/partial response Stable disease Progressive disease

Asterisks represent patients who were treated beyond progression but who did not have scans beyond first progression to document tumor burden

**

*

*n = 31 n = 51 n = 70


Results: Tumor burden change post‐progression with everolimus

Of 52 patients treated beyond progression with tumor measurements pre‐ and post‐progression, 0% had ≥30% tumor burden reduction post‐progression (Figure 5)

43

Figure 5. Best reduction in target lesions with everolimus

PatientsAsterisks represent responders before first progression 41Motzer et al. ASCO 2016

Safety

44

From Randomization to First Progression Post‐Progression

Treated beyond progression(n = 153)

Not treated beyond progression(n = 145)

Treated beyond progression(n = 153)

System Organ Class, n (%)

Any Grade

Grade 3 or 4

Any Grade

Grade 3 or 4

Any Grade

Grade 3 or 4

Total patients with an event

108 (71) 12 (8) 102 (70) 24 (17) 91 (59) 22 (14)

Fatigue 48 (31) 0 37 (26) 4 (3) 31 (20) 4 (3)

Diarrhea 18 (12) 1 (1) 13 (9) 2 (1) 11 (7) 0

Pruritus 17 (11) 0 7 (5) 0 12 (8) 0

Nausea 12 (8) 0 17 (12) 0 11 (7) 0

Decreased appetite 11 (7) 0 12 (8) 1 (1) 15 (10) 0

Table 6. Treatment‐related AEs occurring in ≥10% of patients



Conclusions

• In patients who were treated with nivolumab beyond progression, 14% (20/142) experienced ≥30% tumor shrinkage post‐progression

• Patients with progressive disease as their best response prior to treatment beyond progression also experienced tumor shrinkage

• At first progression, patients with favorable disease characteristics were selected for treatment beyond progression

• No new safety concerns were identified with treatment beyond progression

• These data provide further evidence that some patients benefit from nivolumab treatment beyond first progression

• Evaluating disease characteristics at first progression may facilitate decision making to continue nivolumab treatment beyond progression


References

1. de Velasco G, et al. Cancer Immunol Res 2016;4:12–17.

2. Raman R, Vaena D. Biomed Res Int 2015:367354.

3. Chiou VL, Burotto M. J Clin Oncol 2015;33:3541–3.

4. George S, et al. JAMA Oncol 2016; accepted for publication.

5. Basappa NS, et al. Cancer 2011;117:1183‐89.

44

Radiographs representing Treatment beyond progression experience

45

11/2011 1/2012

Patient SB

46


1/2012 3/2015

47








48

49 50


Disconnect between PFS and OS

• PFS was not different between Nivolumab and Everolimus, but the OS was significantly more in patients who were treated with Nivolumab

• Was there an effect of TBP which was not measured by the RECIST based PFS approach?

• What does the late separation of the curves mean in terms of PFS?

51






• Unique Toxicities and their implications


52

Immune‐mediated toxicities

• Identification

• Efficient therapy

• Fatality/ Irreversible nature of some toxicities

• Prophylactic antibiotics

• Financial burden

• Inability to continue therapy in most situations

53






• Unique Toxicities and their implications


54


Novel endpoints or radiographic assessments

• If PFS is not a reliable surrogate of OS, what could be used as an interim endpoint.

• Proposal to use median duration of treatment instead of PFS as a surrogate

• Novel radiographic assessments that could assess the T‐cell infiltration accurately in cases of Flare/ pseudoprogression

55

Summary

• We have novel drugs with varying mechanism of action for use in met RCC

• Nivolumab is efficacious in the second‐line setting of metastatic RCC and can prolong survival.

• There is some value in treatment beyond progression given the inability of RECIST in accurately assessing response with novel agents line Nivolumab.

• Unique toxicities and their management require expertise

• This class of drugs may lead to long term control and possible cures in a small subset of patients.

56

Available Clinical Trials at RPCI for advanced RCC

Treatment naive 1/2

A Phase I/ II Trial of Pazopanib Alternating with Bevacizumab in Treatment‐Naive Metastatic Clear Cell Renal Cell Carcinoma Patients George, Saby

Treatment refractory 2

A Multi‐center, Open Label, Randomized Phase 2 Study of AGS‐16C3F vs. Axitinib in Metastatic Renal Cell Carcinoma

George, Saby

Treatment refractory (brain mets, non‐clear cell) 3/4

(CA209374) A Phase 3b/4 Safety Trial of Nivolumab (BMS‐936558) in Subjects with Advanced or Metastatic Renal Cell Carcinoma

George, Saby

Treatment naive

A Phase III Randomized Open‐label Study to Evaluate Efficacy and Safety of Pembrolizumab (MK‐3475) in Combination with Axitinib versus Sunitinib Monotherapy as a First‐line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC)

George, Saby

Treatment refractory (post checkpoint inhibitor)

2 B0001014; A MULTI CENTER, MULTI COHORT, OPEN LABEL PHASE 2 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB* (MSB0010718C)

George, Saby

57

Acknowledgements

• All my co‐investigators especially:

– Robert Motzer, MD (MSKCC)

– Bernard Escudier, MD (IGR)

– Padmanee Sharma, MD (MDACC)

• Mentors:

– Brian Rini, MD (CCF)

– Ronald Bukowski, MD (CCF)

• All my patients and colleagues

58

checkpoint inhibitors george s 2 4 17cme.uthscsa.edu/courses/panao/2017/online syllabus... ·...

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