medicalmanagement(of( advanced(bladder(cancer:( overview...

MEDICAL MANAGEMENT OF ADVANCED BLADDER CANCER:

OVERVIEW AND RECENT ADVANCES

Arushi Khurana Fellow, Hematology/Oncology

5/5/2017

OBJECTIVES:

• Epidemiology, Staging and Pathology • Initial Approach • Management of bladder cancer -‐ overview • Management of advanced bladder cancer -‐ overview• Immunotherapy – basics and beyond• Recent Advances – newly approved drugs

EPIDEMIOLOGY – SEER DATABASE

• 9th most common cancer.• 6th most common – new cases

American Cancer Society Database

• 4th most frequentlydiagnosed cancer inmales.• 3 times more likely inmales than females.• 8th most common causeof cancer-‐related deathin males.

• 7th – 8thdecade. • Median age at diagnosis 73 years.

PRESENTATION AND 5-‐ YR RELATIVE SURVIVAL

OVER THE YEARS:

• Not muchimprovement insurvival over thelast 3 decades.

STAGING – AJCC (7th ed., 2010):

Morphological and Histological Subtypes:

Urothelial Ca91%

SCC5%

Adeno Ca2% Undifferentiated

2%

Prevalance %

Urothelial Ca SCC Adeno Ca Undifferentiated

INITIAL APPROACH

MANAGEMENT OF BLADDER CANCER: OVERVIEW

70% 25% 5%-‐ Neo adjuvant chemo is standard of care in MIBC (non metastatic)

MANAGEMENT OF NON METASTATIC MIBC:

AUA/ASCO/ASTRO/SUO Guideline 2017

METASTATIC BLADDER CANCER:

• 4-‐5% of patients havemetastatic disease at the time of diagnosis.• Half of all patients relapse after cystectomy of which distantmetastases 50-‐60%.• The presence of both visceral metastases and ECOG performancescore ≥2 strongly predict poor outcomewith chemotherapy.• Participation in clinical trials of new or more tolerable therapy isrecommended.

ASCO Key Recommendations for MIBC and Metastatic Bladder Cancer -‐ 2016• Multidisciplinary input via tumor board discussions and/or directedconsultations is critical to the optimal management.

Guideline on Muscle-‐Invasive and Metastatic Bladder Cancer (European Association of Urology Guideline): American Society of ClinicalOncology Clinical Practice Guideline Endorsement. Milowsky MI, Rumble RB, Booth CM, Gilligan T, Eapen LJ, Hauke RJ, Boumansour P, Lee CT.J Clin Oncol. 2016 Jun 1; 34(16):1945-‐52.

For cis eligible (fit) patients

1. GC, 2. MVAC or 3. high-‐dose MVAC growth factor support.

Patients ineligible (unfit) for cisplatin

1. Carboplatin combination 2. single agents.

Patients experiencing progression after platinum-‐based

treatment1. clinical trial2. Single agent –

paclitaxel, docetaxel, vinflunine

NCCN 2.2017 – First Line Treatment

UPDATE APRIL 2017: Atezolizumab as first line in cis-‐ineligible patients

NCCN 2.2017: Subsequent Treatment

UPDATE MAY 2017: Durvalumab in 2nd line for progression after platinum based regimens

First Line Treatment: Cisplatin Based Regimens• DEFINE MEDICAL FITNESS: 1. WHO/ECOG PS 2 or greater2. CrCl less than 60 mL/min3. Hearing loss (measured at audiometry) of 25 dB at two contiguous

frequencies4. Grade 2 or greater peripheral neuropathy5. NYHA class III or greater heart failure

Cisplatin Based Regimens:

• MVAC – Methotrexate, Vinblastine, Doxorubicin and Cisplatin q 4 weeks X 6 cycles• GC – Gemcitabine and Cisplatin q4 weeks X 6 cycles• ddMVAC – q2weeks with growth factor support

MVAC:• overall response rate (ORR; 39 versus 12 percent)• median progression-‐free survival (PFS; 10 versus 4 months)• median overall survival (OS; 13 versus 8 months)

Loehrer PJ Sr, Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or in combination with methotrexate,vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992;10:1066.

GC vs MVAC

• Similar ORR (49 vs 46 %).• Similar TTP (7 months)• Similar OS (14 vs 15 months). • Similar 5 yr survival rate (13 and 15 %) • Similar quality of life, • Less serious (grade 3/4) toxicity

von der Maase H, Hansen SW, Roberts JT , et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin inadvanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000; 18:3068.

ddMVAC vs MVAC EORTC 30924 study:

Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-‐dose intensity M-‐VACchemotherapy and G-‐CSF versus classic M-‐VAC in advanced urothelial tract tumours. Eur J Cancer 2006; 42:50.

263 patientsCR 21% vs. 9%, ORR 62% vs. 50%

Cisplatin ineligible patients: Gem+CarboEORTC 30986 study

• No difference in medianOS (9 vs 8 months, HR 0.94• No difference in medianPFS (6 vs 4 months, HR1.04.• Higher ORR (41 versus 30%, not statisticallysignificant.• 1-‐ yr OS ~ 37%

De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/ca rboplatin andmethotrexate/ca rboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-‐based chemotherapy: EORTCstudy 30986. J Clin Oncol 2012; 30:191.

2nd Line Treatment (Before the immunotherapy)• The only agent approved anywhere worldwide for second-‐linetherapy was vinflunine in Europe.• This drug did not improve survival in its pivotal phase 3 trial whencompared with best supportive care.• No agents were approved by the US FDA, and• Cytotoxic chemotherapy agents, such as docetaxel, paclitaxel, orpemetrexed were used.• Response rates of around 10%, and are associated with substantialtoxicity, and do not improve survival.

2nd Line therapy formetastatic urothelialcancer

Second-‐line systemic therapy and emerging drugs for metastatic transitional-‐ce ll carcinoma of the urothelium. Sonpavde G, Sternberg CN,Rosenberg JE, Hahn NM, Galsky MD,Vogelzang NJ. Lancet Oncol. 2010 Sep;11(9):861-‐70.

NCCN 2.2017: Subsequent Treatment

UPDATE MAY 2017: Durvalumab in 2nd line for progression after platinum based regimens

PD-‐1 pathway

Anti PD-‐1 and PD-‐L1

Atezolizumab (PD-‐L1)

• Atezolizumab (1200 mg intravenously every 3 weeks) was approved by the FDA in May 2016. IMvigor210

Rosenberg JE, Hoffman-‐Cens its J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial ca rcinoma whohave progressed following treatment with platinum-‐based chemotherapy: a single-‐arm, multicentre, phase 2 trial. Lancet 2016; 387:1909.

Atezolizumab• co-‐primary endpoints1. independent review facility-‐assessedobjective response rate according to RECIST v1.1 and2. the investigator-‐assessed objective response rate according to immune-‐modified RECIST, analyzed by

intention to treat.

Rosenberg JE, Hoffman-‐Cens its J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial ca rcinoma whohave progressed following treatment with platinum-‐based chemotherapy: a single-‐arm, multicentre, phase 2 trial. Lancet 2016; 387:1909.

Results:

• Compare to historical RR of 10% with 2ndline chemo.

• OS: 11.4 months (IC2/3), 8.8 months (IC 1/2/3).

Toxicities:• No treatment-‐related deaths• No cases of febrile neutropenia• 93 (30%) patients had an adverseevent leading to dose interruption.

• 11 (4%) patients had an adverseevent that led to treatmentwithdrawal.

• 69 (22%) of 310 patients had anadverse event that necessitatedsystemic steroid use.

Nivolumab: (PD-‐1)• Nivolumab (240 mg intravenously every two weeks) was approved by the FDA in February 2017.

Sharma P, Retz M, Siefker-‐Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-‐arm, phase 2 trial. Lancet Oncol 2017.

Nivolumab:• Multicenter, phase 2, single-‐arm study • The primary endpoint was overall objective response• Median OS of 8·∙74 months.• Responses were seen irrespective of tumor PD-‐L1 expression


PEMBROLIZUMAB: (PD-‐1)

Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-‐Line Therapy for Advanced Urothelial Carcinoma. N Engl JMed 2017.

PEMBROLIZUMAB• open-‐label, international, phase 3 trial, • The co-‐primary end points were OS and PFS.


PEMBROLIZUMAB• median OS 10.3 vs 7.4 months.• Fewer AEs 60.9% vs 90.2%.• Benefit of Pembrolizumab was seen regardless of the PD-‐L1 expression.


PEMBROLIZUMAB

• Expecting FDA approval soon – June 2017

Latest Approval – DURVALUMAB !!!

• May 1, 2017, the U.S. FDA granted accelerated approval to durvalumab (IMFINZI).• one single-‐arm trial of 182 patients with locally advanced or metastatic urothelialcarcinoma whose disease progressed after prior platinum-‐containingchemotherapy.• ORR per RECIST 1.1, was 17.0% (95% CI: 11.9, 23.3).• median response durationwas not reached (range: 0.9+ to 19.9+ months).• ORR was 26.3% (95% CI: 17.8, 36.4) in 95 patients with a high PD-‐L1 score and4.1% (95% CI: 0.9, 11.5) in 73 patients with low or negative PD-‐L1 score.• Grade 3-‐4 adverse events were seen in 43% of patients.

NEXT IN LINE: AVELUMAB (PD-‐L1) JAVELIN SOLID TUMOR Phase Ib trial

Avelumab (MSB0010718C; anti-‐PD-‐L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial:Analysis of safety, clinical activity, and PD-‐L1 expression. ASCO – 2016 abstract

• N=44• 8 pts had a response 1 CR and 7 PR• 17 pts – Stable disease• Early and durable responses were seen • Median OS 12.9 months• 1 yr survival rate 53.5%

SUMMARY:• First-‐ line cisplatin-‐based chemo yields a median OS of 14 to 15 months• 5-‐year survival 5 to 15% of patients. • salvage chemo with vinflunineor a taxane after platinum-‐based chemo – response 10%.• median OS of 6 to 8 months. • PD-‐1/PD-‐L1 – RR ~15-‐20%, higher with inc PD expression.• AE-‐ 16-‐18%, much more tolerable

Questions that are unanswered??

• Is there a preferred agent among pembrolizumab, nivolumab, and atezolizumab? Oh and durvalumab !!!• When should PD-‐1 or PD-‐L1 inhibitor therapy be discontinued? (Pseudo progression) • Tumor PD-‐L1 expression, genomic subtype, interferon-‐γ gene expression, chemokine signature, and mutation burden may be prognostic for response. • Which assay for PD-‐1 or PD-‐L1 is standard of care? And do they correlate?• Should we use these agents in first line setting?

Cisplatin ineligible patients: Atezolizumab(PD-‐L1) in First Line Setting.

Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-‐ line treatment in cisplatin-‐ineligible patients with locally advanced andmetastatic urothelial carcinoma: a single-‐arm, multicentre, phase 2 trial. Lancet 2017; 389:67.

Atezolizumab (PD-‐L1) in First Line Setting.

• ORR-‐ 23%• CR -‐ 9% (n=11)• Duration of Response – not reached• Response observed regardless of PD-‐L1 expression

Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-‐ line treatment in cisplatin-‐ineligible patients with locally advanced andmetastatic urothelial carcinoma: a single-‐arm, multicentre, phase 2 trial. Lancet 2017; 389:67.

PROGNOSTIC MARKERS:

• Tumor PD-‐L1 expression, • Genomic subtype – Luminal vs Basal – The cancer genome atlas.• Interferon-‐γgene expression : inc responders and PD-‐L1 expression• Chemokine signature, and • Mutation burden – inc responders.

CURRENT PHASE III TRIALS:

THANK YOU!!

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