Highlights in
immunoncologia:
carcinoma della vescica
Dr. Antonello Veccia
Introduction
Scher et al, Harrison's Hematology and Oncology 2016
Non muscle invasive bladder cancer
(NMIBC) (75%)
Muscle invasive bladder cancer
(MIBC) (25%)
The prognosis of bladder cancer is poor
The treatment has been changed by the use of immunotherapy
Bacillus of Calmette-Guerin (BCG) is the standard of care in early stages since 1990
In last years checkpoints inhibitors demonstrated their impact on survival in
advanced stages
BCG in NMIBC
Redelman-Sidi et al, Nat Rev Urol 2014
The mechanism of action of BCG is not fully elucidated but it is thought to elicit an immune response in much the same way as native TB
Checkpoint inhibitors in MIBC/advanced BC
Sanli et al, Nat Rev Dis Primers 2017
Monoclonal antibodies block the negative co-signaling molecules that prevent an effective immune response, causing reinvigoration of T-cell-mediated antitumor activity
PD-L1 in bladder cancer
Glaser AP et al, Nat Rev Urol 2017 Bellmunt et al, Cancer Treat Rev 2017
Bladder cancer is characterized by a high mutational burden and seems to benefit the most from checkpoint blockade
PD-L1 expression correlates with a higher stage, but not with response rate
PD-L1 is associated with increased resistance to BCG therapy
Atezolizumab: phase 2 study
Rosenberg et al, Lancet 2016 Balar et al, Lancet 2017
Indication ORR (%) Response by PD-L1 score (%)
IC0 (< 1%) IC1 (≥1 but <5%) IC 2/3 (≥5%)
Cohort 1: I line,
cisplatin ineligible 23 21 21 28
Cohort 2:
postplatinum 15 8 10 26
Rosenberg et al, Lancet 2016 Balar et al, Lancet 2017
DoR (%) NR NR
Atezolizumab: phase 2 study
Rosenberg et al, Lancet Oncol 2016 Balar et al, Lancet Oncol 2017
mFU: 11.7 and 15.9 months, respectively
The rate of G3-4 AEs was 16% in both cohorts; G3-4 irAEs were reported in 5% of patients
Based on results of cohort 2 of the IMvigor 210, FDA granted atezolizumab accelerated approval as II line treatment for platinum pretreated patients (May 2016)
Base on results of cohort 1, FDA granted atezolizumab accelerated approval as first line treatment for platinum ineligible patients (April 2017)
Kaplan-Meier overall survival curves in cohort 2 Kaplan-Meier overall survival curves in cohort 1
Atezolizumab: phase 3 study
The Phase 3 trial, called IMvigor211 (NCT02302807), was a randomized, open-label, multicenter study designed to evaluate the safety and efficacy of atezolizumab versus investigator’s choice of chemotherapy (vinflunine, paclitaxel, or docetaxel) in 931 patients with metastatic urothelial cancer and progression despite platinum-based chemotherapy.
The primary efficacy endpoint was OS and key secondary endpoints included ORR, PFS, duration of response and safety
Nivolumab: phase 2 study
Sharma P et al, Lancet Oncol 2017
The primary end point of CheckMate 275 study was achieved:
OR in 19.6% of 265 pts (CR 2% and PR 17%)
Time to response: 1.87 months
Duration of response: NR (7.43 – NR)
G3-4 AEs: 18% (most common irAEs were skin and endocrine)
mFU: 7 months
FDA approval on February 2017
mOS: 8.74 months (95% CI 6.05 – NR)
Avelumab: phase 1b study
Apolo et al, J Clin Oncol 2017
44 patients with locally advanced or metastatic urothelial carcinoma who failed to respond to platinum- based chemotherapy and unselected for PD-L1 expression were enrolled in the JAVELIN study
13 pts (29.5%) had PD-L1 + tumors (≥5% staining in TC)
Avelumab was given at 10 mg/kg IV every 2 wks until progression or unacceptable toxicity
Primary end points: PFS and best ORR
Avelumab: phase 1b study
Apolo et al, J Clin Oncol 2017 FDA approval on May 2017
ORR was 53.8% in PD-L1 + tumors (7 of 13 pts) and 4.2% in PD-L1 – tumors (1 of 24 pts)
mFU: 16.5 months
Durvalumab: phase 1/2 study
Massard et al, J Clin Oncol 2017
Early response (median time 6.3 weeks) in the 13 responders
Durable response; median not reached (range 4.1+ to 49.3+ wks)
mFU: 4.3 months FDA approval on May 2017
The study included 61 patients (40 PD-L1 positive and 21 PD-L1 negative) with inoperable or metastatic urothelial carcinoma, highly pretreated; first 20 pts were enrolled regardless of PD-L1 status, the others with PD-L1 expression on TC of ≥5%
Durvalumab was given at 10 mg/kg IV every 2 wks until progression or unacceptable toxicity
Primary end points: safety (only 4.9% of G3 AEs)
Secondary: ORR 31% and disease control rate at 12 weeks 47.6%
Pembrolizumab: phase 3 study
Bellmunt et al, NEJM 2017
164 pts (including 74 in pembrolizumab group and 90 in chemotherapy group) had PD-L1 ≥ 10% (30.3%)
mFU: 14.1 months
Median duration of study treatment was 3.5 months (< 0.1 - 20.0) in pembrolizumab group vs 1.5 months (<0.1 – 14.2) in chemotherapy group
Bellmunt et al, NEJM 2017
Pembrolizumab: phase 3 study
Benefit of pembrolizumab over chemotherapy in:
- mOS (10.3 vs 7.4 months)
- OS rate at 12 months (43.9% vs 30.7%)
- all subgroups of pts
mPFS was inferior with pembrolizumab (2.1 vs 3.3 months)
PFS rate at 12 mos was better with pembro (16.8% vs 6.2%)
PFS may not be a surrogate of clinical benefit of immunotherapy
Bellmunt et al, NEJM 2017
Pembrolizumab: phase 3 study
FDA approval on June 2017
Pembro (n = 266) Chemo (n = 255)
irAEs Any G (%)
G 3-5 (%)
Any G (%)
G 3-5 (%)
Any 16.9 4.5 7.5 1.6
Hypothyroidism 6.4 0 1.2 0
Hyperthyroidism 3.8 0 0.4 0
Pneumonitis 4.1 2.3 0.4 0
Colitis 2.3 1.1 0.4 0
Infusion reaction 0.8 0 3.9 0
Skin reaction 0.8 0.4 1.2 1.2
Guidelines
Treatment algorithm for NMIBC
Kamat et al, Journal for ImmunoTherapy of cancer 2017
Treatment algorithm for MI and metastatic BC
Kamat et al, Journal for ImmunoTherapy of cancer 2017
Ongoing selected immunotherapy trials in BC
Kamat et al, Journal for ImmunoTherapy of cancer 2017
Molecular subtypes and immunotherapy
Sanli O et al, Nat Rev Dis Primers 2017
Basal tumors (TCGA II, TCGA IV, urobasal B or Squamous Cell Carcinoma-like) have worse prognosis than luminal
Moreover, they are enriched for a tumor-initiating cell expession signature, have an EMT phenotype and high immune infiltration response to immune checkpoint inhibitors
Exloratory analyses showed that TGCA subtypes and mutation load are independently predictive for response to atezolizumab
Immunotherapy is a step forward in bladder cancer treatment and the current guidelines will be soon radically changed
The best immune checkpoint inhibitor in second-line is not definable
Current ongoing trials will clarify the role of immunotherapy as first-line treatment
Checkpoint inhibitors, which seem to be able to achieve unprecented long term survival rates, should confirm these exciting results with long-term data
Clinical trials should explore the potential role of biomarkers to select patients most likely to benefit
