Phase 3 Perioperative Nivolumab in M0 RCC (PROSPER RCC, ECOG ACRIN 8143) A UROLOGIST S PERSPECTIVE Mohamad E. Allaf, MD Associate Professor of Urology, Oncology, & BME MEA Endowed Director, Minimally Invasive Surgery Johns Hopkins Medicine Fifteenth International Kidney Cancer Symposium November 4-5, 2016 Marriott Miami Biscayne Bay, Miami, Florida, USA
Team Science
Disclosures American Urological Association Kidney Cancer Guideline Committee Agency for Healthcare Research and Quality (AHRQ) Funded Investigator Management of Renal Masses and Localized Renal Cancer Bristol-Myers-Squibb Drug and science funding Brady Urological Institute Patients Buerger Family, Kovler Family, Allaf Endowment Fund and many others for trial costs No relevant financial relationships to disclose. Will discuss experimental neoadjuvant Nivolumab for localized RCC in this presentation.
Outline Rationale for neoadjuvant therapy Is neoadjuvant therapy safe / feasible in localized disease? Does nivolumab reach the tumor? Is there a global increase in CD8 T cell activation / proliferation? Is there a reflex up-regulation in other checkpoints?
Surgical Monotherapy Fails to Cure a Number of Patients with Localized Disease
Adjuvant Trials = NOT A HOME RUN (YET)
Nivolumab Works When Tumor is Present (& Well Tolerated!)
NOT TESTING NEOADJUVANT THERAPY IS A HUGE LOST OPPORTUNITY
Neoadjuvant Efficacy: Preclinical Evidence is Growing & Strong! Almost ALL neoadjuvant treated mice exhibit long-term survival versus adjuvant treatment (19/20 vs. 5/20) No lung micromets in neoadjuvant treatment arm (by IHC and qpcr) Liu et al., Cancer Discovery, Sept 2016
Johns Hopkins Neoadjuvant Phase I Trial
Johns Hopkins Trial Design PI: Allaf; Team: Gorin, Drake, Nirschl
Johns Hopkins Neoadjuvant Phase I Trial 5 patients have successfully received full 3 doses of drug. There have been no dose delays or reductions. Preoperative Biopsies = safe, no complications.
Study Cohort Characteristics Variable Median (range) / n (%) Age 67 (60-73) Male Sex 3 (60) White Race 5 (100) Tumor Diameter on Imaging 7.1 (5.7-8.1) Clinical T Stage ct2a 4 (80) ct2b 0 (0) ct3a 1 (20) Clinical N0 5 (100)
Johns Hopkins Neoadjuvant Phase I Trial: Early Results Following completion of 3 cycles of nivolumab patients were restaged: All had stable disease with NO progression. All underwent surgery within 1 week of their final cycle of nivolumab (median 17 days). No surgical complications observed due to drug.
Post-nivolumab Pathology Variable Median (range) / n (%) Clear cell Histology 5 (100) ISUP Grade 2 2 (40) 3 3 (60) Tumor Diameter 6.5 (5.0-9.0) Pathologic T Stage pt1b 2 (40) pt2a 0 (0) pt2b 0 (0) pt3a 3 (60)
Adverse Events Prior to Surgery Adverse Event Grade n (%) Arthralgia Grade 2 1 (20) Erythema / Rash / Flushing Grade 1 3 (60) Fatigue Grade 1 4 (80) Hypersensitivity Grade 1 1 (20) Hyperthyroidism Grade 1 1 (20) Pyelonephritis Grade 3 1 (20) Postnasal Drip Grade 2 1 (20) Pruritus Grade 1 3 (60) Any Grade 1-2 --- 5 (100) Any Grade 3-4 --- 1 (20)
Adverse Events Following Surgery Adverse Event Grade n (%) Dyspnea Grade 1 1 (20) Erythema / Rash / Flushing Grade 1 1 (20) Hyperthyroidism Grade 1 1 (20) Malaise Grade 1 1 (20) Pain Grade 2 1 (20) Urinary Retention Grade 2 1 (20) UTI Grade 2 2 (40) Weight Loss Grade 1 1 (20) Any Grade 1-2 --- 3 (60) Any Grade 3-4 --- 0 (0) Median follow-up = 48 days (31-133)
Early Correlative Studies
TIL PBMC Neoadjuvant Nivolumab Blocks PD-1 in RCC Tumor Microenviroment Untreated 12.3% Neo-Adjuvant Anti-PD1 0.7% 51.3% 3.5% CD8
% C D 8 + T -c e lls E x p re s s in g P D -1 Neoadjuvant Nivolumab Blocks PD-1 on CD8+ T-cells in RCC Tumor Microenviroment PD-1 Untreated: N=10 Neoadjuvant Nivolumab: N=5 1 0 0 P < 0.0 0 1 P = 0.0 0 3 8 0 6 0 4 0 2 0 0 P B M C N o T r e a tm e n t P B M C N iv o T IL N o T r e a tm e n t T IL N iv o
T o ta l E ffe c to r C D 4 T -c e ll/g ra m o f tis s u e # Effector CD4 t cells/gram of tissue 2.0 P = 0.1 5 5 3 1 0 7 N o T re a tm e n t 1.5 1 0 7 N ivo lu m ab 1.0 1 0 7 5.0 1 0 6 0 N o T r e a tm e n t N iv o lu m a b
Does Neoadjuvant Nivolumab GLOBALLY affect the Functionality of CD8 T Cells in RCC? CD8+ T cells IFN-γ TNF-α IL-2 Granzyme B
TIL PBMC CD8 TIL in RCC are Refractory to Physiological Stimulation (CD3/CD28) IFNg TNFa IL2 GZMb CD8 CD8
TIL PBMC CD8 TIL in RCC Treated with Neoadjuvant Nivolumab are STILL Relatively Refractory to Physiological Stimulation (CD3/CD28) IFNg TNFa IL2 GZMb CD8 CD8
% C D 8 + T -c e lls E x p r e s s in g IL 2 % C D 8 + T -c e lls E x p re s s in g G Z M b % C D 8 + T -c e lls E x p re s s in g IF N g % C D 8 + T -c e lls E x p re s s in g T N F a Nivolumab Does Not Globally Alter Effector Function for CD8+ T-cells in the Tumor Microenvironment 1 0 0 8 0 IFNg N S 1 0 0 8 0 TNFa Untreated: N=7 Neo-Adjuvant Nivolumab: N=5 6 0 6 0 4 0 4 0 P = 0.0 1 5 7 2 0 2 0 0 0 P B M C N o T r e a tm e n t P B M C N iv o T IL N o T r e a tm e n t T IL N iv o P B M C N o T r e a tm e n t P B M C N iv o T IL N o T r e a tm e n t T IL N iv o 1 0 0 8 0 IL-2 N S 1 0 0 8 0 GZMb N S 6 0 6 0 4 0 4 0 2 0 2 0 0 0 P B M C N o T r e a tm e n t P B M C N iv o T IL N o T r e a tm e n t T IL N iv o P B M C N o T r e a tm e n t P B M C N iv o T IL N o T r e a tm e n t T IL N iv o
Is There a Reflex Up-Regulation of Additional Checkpoint Molecules in Response to Anti-PD-1 Treatment? LAG-3 CTLA-4 Tim-3 CD8+ T cells
Neo-Adjuvant Ant-PD-1 CD8 TIL Untreated CD8 TIL Neoadjuvant Nivolumab DOES NOT Result in a Reflex Up-Regulation of LAG-3 / TIM-3 / CTLA-4 LAG-3 CTLA-4 TIM-3 19.4% 2.39% 45.1% CD8 17.4% 0.4% 23.1 CD8
% C D 8 + T -c e lls E x p re s s in g L A G -3 % C D 8 + T -c e lls E x p re s s in g C T L A -4 % C D 8 + T -c e lls E x p re s s in g T IM -3 Nivolumab Tx DOES NOT Result in Compensatory Upregulation of Other Checkpoint Molecules Naïve Tumor: N=10 Nivolumab: N=5 LAG-3 CTLA-4 TIM-3 1 0 0 8 0 1 0 0 8 0 N S 1 0 0 8 0 P < 0.0 0 1 P = 0.0 0 2 8 N S 6 0 4 0 P < 0.0 0 1 N S N S 6 0 4 0 6 0 4 0 2 0 2 0 2 0 0 P B M C N o T r e a tm e n t P B M C N iv o T IL N o T r e a tm e n t T IL N iv o 0 P B M C N o T r e a tm e n t P B M C N iv o T IL N o T r e a tm e n t T IL N iv o 0 P B M C N o T r e a tm e n t P B M C N iv o T IL N o T r e a tm e n t T IL N iv o
Conclusions Surgical monotherapy does not cure a significant number of patients with high risk localized RCC Adjuvant trials to date have been disappointing including S-TRAC IMO Sound preclinical data on efficacy of neoadjuvant dosing Neoadjuvant Nivolumab: Reaches the tumor? Increases CD8 cells and decreases Tregs in tumor Opportunity for good science and implications for other tumors The Answer: EA8143 the PROSPER Trial (PI: Harshman)
The Answer: EA8143 Phase III- Perioperative PD-1 Blockade In Non-metastatic RCC (The PROSPER Trial) PI: Lauren Harshman
We Need Neoadjuvant and WE CAN DO IT!
Meeting at KCA: 5pm Friday Nov 4 Marco Island Rm (3 rd Fl) On the PROSPER RCC Team Opening via CIRB and NCTN Intergroup mechanism. Please contact us welcome correlative proposals and involvement on many levels LaurenC_Harshman@dfci.harvard.edu