La revolución de la inmunoterapia: dónde la posicionamos? Javier Puente, MD, PhD Hospital Universitario Clinico San Carlos Medical Oncology Department Thoracic & Urological Cancer Unit Complutense University Associate Professor of Medicine
Immunotherapy in Advanced RCC: A Renewed Level of Interest? McDermott DF, et al. Sem Oncol 2013
Resistance to antiangiogenic therapy is associated with an Immunosuppresive tumor microenviroment in mrcc Xian-De Liu, et al. Cancer Immunol Res 2015; 3(9): 1017-29
Resistance to antiangiogenic therapy is associated with an Immunosuppresive tumor microenviroment in mrcc Xian-De Liu, et al. Cancer Immunol Res 2015; 3(9): 1017-29
Key Late Stage Clinical Development of PD-1 Pathway Inhibitors Agent Target Tumor Type Clinical Development Stage Nivolumab Pembrolizumab Atezolizumab (MPDL3280A) Durvalumab (MEDI4736) Avelumab PD-1 PD-1 PD-L1 Melanoma, NSCLC, RCC Hodgkin s lymphoma Bladder/urothelial, brain, gastric/gej, HCC, HNSCC, SCLC Melanoma, NSCLC mcrc (MSI-high) Breast, bladder/urothelial, gastric/gej, HNSCC, multiple myeloma Bladder/urothelial, NSCLC Breast, RCC Approved (US) Breakthrough Therapy (US) Phase III Approved (US) Breakthrough Therapy (US) Phase III Breakthrough Therapy (US) Phase III PD-L1 Bladder, NSCLC, HNSCC Phase III PD-L1 Merkel cell NSCLC, gastric, ovarian, urothelial Breakthrough Therapy (US) Phase III
PD-1/PD-L1 Checkpoint Inhibitors in Advanced RCC
Clinical Activity of Nivolumab: Phase I Experience in Multiple Tumor Types Tumor Type N Dose, mg/kg ORR (CR/PR), n (%) SD 24 Wks, n (%) Melanoma 104 0.1-10 26 (28) 6 (6) NSCLC 76 1-10 14 (18) 5 (7) RCC 33 1 or 10 9 (33) 9 (27) 28 responses (16 melanoma, 6 RCC, and 6 NSCLC) lasted 1 yr among 54 pts with treatment initiation 1 yr before data analysis 13 pts (4 melanoma, 6 NSCLC, 3 RCC) demonstrated nonconventional patterns of response but were not included as responders Topalian SL, et al. N Engl J Med. 2012;366:2443-2454.
McDermott, et al J Clin Oncol 2015 Outcomes in patients with previously treated advanced RCC receiving Nivolumab
Nivolumab in RCC: phase 2 data Motzer et al J Clin Oncol 2015
McDermott et al. ASCO 2016 Long-term OS with nivolumab in previously treated RCC (from phase I and II studies)
Phase III trial: Check-Mate 025 Motzer R, et al. N Engl J Med. 2015
PFS in Check-Mate 025 Motzer R, et al. N Engl J Med. 2015
OS in Check-Mate 025 (primary end-point) Motzer R, et al. N Engl J Med. 2015
Phase Ib study of Pembrolizumab + Bevacizumab in mrcc (BTCR-GU14-003) Dudek et al. ASCO 2016
Phase Ib study of Pembrolizumab + Bevacizumab in mrcc (BTCR-GU14-003) Dudek et al. ASCO 2016
Maximum SLD Reduction From Baseline (%) Efficacy of Atezolizumab in Advanced RCC: Phase Ia Expansion Cohort 100 90 80 70 60 50 40 30 20 10 0-10 -20-30 -40-50 -60-70 -80-90 -100 20 mg/kg 15 mg/kg 10 mg/kg 3 mg/kg 1200 mg Clear-cell RCC (n = 62) ORR: 15% Median PFS: 5.6 mos Median OS: 28.9 mos Similar activity in VEGF-targeted therapy naive and refractory pts McDermott DF, et al. J Clin Oncol. 2016
Atezolizumab in Advanced RCC: preliminary ORR in patient subgroups Pt Subgroup ORR, n (%) No previous VEGFR TKI (n = 24) 3 (13) Previous VEGFR TKI (n = 38) 6 (16) Fuhrman grade 4 and/or sarcomatoid histology (n = 18) 4 (22) Fuhrman grade 4 (n = 16) 4 (25) Sarcomatoid histology (n = 6) 2 (33) MSKCC poor risk (n = 20) 5 (25) MSKCC intermediate/favorable risk (n = 42) 4 (10) McDermott DF, et al. J Clin Oncol. 2016
Exploratory analysis of OS by subgroup Motzer R, et al. N Engl J Med. 2015
Toxicities Associated with PD- 1/PD-L1 Checkpoint inhibitors
CheckMate-025: Treatment-Related Aes ( 10% of Pts) AE, % Nivolumab (n = 406) Everolimus (n = 397) Any Grade Grade 3/4 Any Grade Grade 3/4 Treatment-related AEs 79 19 88 37 Fatigue 33 2 34 3 Nausea 14 < 1 17 1 Pruritus 14 0 10 0 Diarrhea 12 1 21 1 Decreased appetite 12 < 1 21 1 Rash 10 < 1 20 1 Cough 9 0 19 0 Anemia 8 2 24 8 Dyspnea 7 1 13 < 1 Edema peripheral 4 0 14 < 1 Pneumonitis 4 1 15 3 Mucosal inflammation 3 0 19 3 Dysgeusia 3 0 13 0 Hyperglycemia 2 1 12 4 Stomatitis 2 0 29 4 Hypertriglyceridemia 1 0 16 5 Epistaxis 1 0 10 0
Safety in Check-Mate 025 Motzer R, et al. N Engl J Med. 2015
Emerging select TRAEs over time in phase II studies Motzer et al J Clin Oncol 2015
CheckMate-025: Change From Baseline in QoL Scores (FKSI-DRS) A clinically meaningful and statistically significant improvement in QoL was seen with nivolumab vs everolimus for the duration of the study 4 Nivolumab 2 0 Worse Better -2-4 -6 Questionnaire completion rate: 80% during the first yr of follow-up Everolimus 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 Pts at Risk, n Nivolumab 362 334 302 267 236 208 186 164 159 144 132 119 112 97 90 89 81 72 63 59 53 44 43 31 30 26 20 Everolimus 344 316 270 219 191 157 143 122 102 97 87 74 73 63 58 49 44 35 30 28 24 21 15 12 12 9 9 Motzer R, et al. N Engl J Med. 2015 Wks
CheckMate-025: Change From Baseline in QoL Scores (HR-QoL) Cella D, et al. ASCO 2016
PD-L1 Expression and Patient Selection in Advanced RCC
Cancer-Specific Survival Relevance of Tumor PD-L1 Expression in RCC Tumoral PD-L1 expression may be associated with: Impaired antitumor immunity More aggressive disease High tumor grade Shorter survival 100 80 60 40 20 PD-L1 expression < 10% PD-L1 expression 10% 0 0 1 2 3 Yrs From Nephrectomy to Last Follow-up Thompson RH, et al. Proc Natl Acad Sci USA. 2004;101:17174-17179. Thompson RH, et al. Clin Cancer Res. 2007;13:1757-1761. Krambeck AE, et al. Clin Cancer Res. 2007;13:1749-1756. Frigola X, et al. Clin Cancer Res. 2011;17:1915-1923.
CheckMate-025: OS by PD-L1 Expression Motzer R, et al. N Engl J Med. 2015
Differential expression of PD-L1 between primary and metastatic sites in clear cell RCC Callea M, et al. Cancer Immunol Res 2015; 3(10): 1158-64
Differential expression of PD-L1 between primary and metastatic sites in clear cell RCC
Combination Therapy: Overcoming Innate/Acquired Resistance
Change in SLD From Baseline (%) Phase Ib Study of Atezolizumab + Bev: First-line Therapy for Advanced ccrcc Atezolizumab 20 mg/kg + Bev 15 mg/kg q3w Safety Treatment-related grade 3 AEs occurred in 3% of pts (1 case of neutropenia) No grade 4 AEs or deaths were attributed to atezolizumab Efficacy (n = 10) ORR: 40% IC 1 (2 pts), 1 pt each IC 0 or IC unknown SD 24 wks: 50% 100 80 60 40 20 0-20 -40-60 -80-100 IC 3 IC 3: 10% PD-L1+ IC 2: 5% to < 10% PD-L1+ IC 1: 1% to < 5% PD-L1+ IC 0: < 1% PD-L1+. IC 1 IC 0 IC 1 IC 1 0 42 84 126 168 210 Days on Study IC 0 IC 0 IC 1 IC 0 252 Lieu C, et al. ESMO 2014. Abstract 1049O.
CheckMate-016: Phase I Study of Nivolumab + Ipilimumab in mrcc mrcc; no previous systemic therapy other than cytokine therapy for mrcc or 1 prior adjuvant/neoadjuvant therapy with recurrence 6 mos after last treatment (N = 100) Primary endpoint: Safety Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV q3w x 4 doses (n = 47) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV q3w x 4 doses (n = 47) Nivolumab 3 mg/kg + Ipilimumab 3 mg/kg IV q3w x 4 doses (n = 6) Secondary endpoints: ORR, DoR, PFS, OS Nivolumab 3 mg/kg IV q2w Hammers H, et al. ASCO 2015. Abstract 4516.
CheckMate-016: Response Outcomes Tumor Response, n (%) Nivo 3 mg/kg + Ipi 1 mg/kg (n = 47) Nivo 1 mg/kg + Ipi 3 mg/kg (n = 47) Nivo 3 mg/kg + Ipi 3 mg/kg (n = 6) ORR 18 (38.3) 19 (40.4) 0 CR 4 (8.5) 1 (2.1) 0 PR 14 (29.8) 18 (38.3) 0 SD 17 (36.2) 17 (36.2) 5 (83.3) Median duration of response: Nivolumab 3 mg/kg + ipilimumab 1 mg/kg: 67.7 wks (range: 4.1-91.1) Nivolumab 1 mg/kg + ipilimumab 3 mg/kg: 81.1 wks (range: 6.1-81.1) Hammers H, et al. ASCO 2015. Abstract 4516.
CheckMate-016: Select Treatment-Related AEs AE, n (%) Nivo 3 mg/kg + Ipi 1 mg/kg (n = 47) Nivo 1 mg/kg + Ipi 3 mg/kg (n = 47) Nivo 3 mg/kg + Ipi 3 mg/kg (n = 6) Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4 Skin disorder 18 (38.3) 0 24 (51.1) 1 (2.1) 3 (50.0) 0 GI disorder 11 (23.4) 1 (2.1) 21 (44.7) 11 (23.4) 3 (50.0) 2 (33.3) Endocrinopathy 11 (23.4) 1 (2.1) 20 (42.6) 0 5 (83.3) 0 Hepatic 7 (14.9) 2 (4.3) 15 (31.9) 10 (21.3) 3 (50.0) 0 Renal disorder 5 (10.6) 1 (2.1) 7 (14.9) 1 (2.1) 2 (33.3) 0 Infusion reaction 4 (8.5) 0 3 (6.4) 0 1 (16.7) 0 Pulmonary 2 (4.3) 0 3 (6.4) 0 0 0 Hammers H, et al. ASCO 2015. Abstract 4516.
Nivolumab plus Sunitinib/Pazopanib
Nivolumab plus Sunitinib/Pazopanib Hans Hammers at Genitourinary Cancers Symposium 2016
Long Term Responders: PD1 vs PD1/TKI vs PD1/CTLA4 (CAUTION!!!)
Ongoing Trials of PD-1/vaccines + VEGF Pathway Blockade in Advanced RCC Agent Phase Intervention Anti-PD1 Nivolumab III Nivolumab + ipilimumab vs sunitinib (CheckMate 214) (NCT02231749) Pembrolizumab I/II Pembrolizumab +/- Pazopanib (NCT02014636) Ib Pembrolizumab + Axitinib (NCT02133742) Ib/II Pembrolizumab + Bevacizumab (NCT02348008) Anti-PD-L1 Atezolizumab II Atezolizumab ± bevacizumab vs sunitinib (RAPID) (NCT01984242) III Atezolizumab + bevacizumab vs sunitinib (IMmotion) (NCT02420821) Avelumab III Avelumab + axitinib vs sunitinib (JAVELIN Renal 101) (NCT02684006) Cancer vaccines AGS-003 III AGS-003 + sunitinib vs sunitinib (ADAPT) (NCT01582672)
EAU Guidelines for ccrcm1 2016 Ljungberg al. EAU guidelines. Available online
Conclusions Single-agent PD-1 pathway blockade is efficacious in advanced RCC Nivolumab is approved for pts following progression on antiangiogenic therapy Vigilance for iraes by the entire healthcare team and well-educated pts along with rapid intervention is key to optimal management Biomarkers that predict response are being investigated Tumor grade and mutational load may add value Combination regimens appear to improve outcomes at a cost of increased toxicity Management algorithms will need to be refined Vaccine strategies likely need more work
THANK YOU Javier Puente, MD, PhD Hospital Universitario Clinico San Carlos Medical Oncology Department Thoracic & Urological Cancer Unit Complutense University Associate Professor of Medicine javier.puente@salud.madrid.org @docjavip