highlights in immunoncologia: carcinoma della...

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


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


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

https://clinicaltrials.gov/ct2/show/NCT02302807?term=IMvigor211&rank=1

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



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



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


Ongoing selected immunotherapy trials in BC


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

Research is engaged in combination of immune checkpoints and these latter with chemotherapy

Take home messages

Thank you

for your attention!

highlights in immunoncologia: carcinoma della...

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