Extensive-stage small cell lung cancer Tom Stinchcombe Duke - - PowerPoint PPT Presentation

Extensive-stage small cell lung cancer

Tom Stinchcombe Duke Thoracic Oncology Program

Extensive stage (ES) small cell lung cancer

• Patient with SCLC who presented with extensive-stage disease

and received carboplatin and etoposide as first-line therapy

• PCI completed
• Progressive disease 2 months after completing chemotherapy
• Treated with thoracic radiation for symptomatic disease
• Nivolumab x 4 cycles with progressive disease
• Topotecan daily x 5 days for 2 cycles with progressive disease
• Enrolled in phase 2 trial of rovalpituzumab tesirine (Rova-T)

Small cell lung cancer on clinical trial of Rova-T

Baseline Confirmatory scan

Extensive-stage small cell lung cancer

Tom Stinchcombe Duke Thoracic Oncology Program

PCI in ED-SCLC: EORTC 08993-22993

Slotman et al. NEJM 2007.

Chemotherapy (4-6 cycles) No response Any response PCI 20-30 Gy in 5-12 fractions R A N D O M I Z E No PCI Stratify by:

• Institution
• PS

< 5 weeks 4-6 weeks n=286

Primary endpoint: time to symptomatic brain metastases defined as signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms Secondary end-points: OS, Qol, toxicity, cost

(months) 4 8 12 16 20 24 28 32 36 10 20 30 40 50 60 70 80 90 100

PCI Control

1 year: 27.1% vs. 13.3% HR: 0.68 (0.52-0.88); p = 0.003

Ov Overall su surviv vival: al: me measu sured from

• m

rando randomizati ation

Slotman et al. NEJM 2007.

PCI in SCLC: Trial Design

Stratification by Age (<70 / ≥70), PS (0-1 / 2) Response (CR / PR+MR) Institutions

Follow-up by MRI imaging evaluated every 3 months

Primary endpoint: Overall Survival Secondary endpoints: Time to brain metastases (BM), Progression-Free Survival (PFS), Safety, Mini Mental State Examination (MMSE)

1st line chemo Platinum-based doublet R PCI: 25 Gy 10 fractions no PCI

• Any response
• No BM by MRI

assessment No response < 6 weeks 3-8 weeks

ASCO 2014 Abstract 7503: Presented by Takashi Seto

n=163

Overall Survival

10 20 30 40 50 60 70 80 90 100 3 6 9 12 15 18 21 24 27 30 33 36 39 Stratified log-rank test: P=0.091 (2-sided)

Arm B: No PCI Arm A: PCI

Arm A: PCI n=84 Arm B: no PCI n=79

• No. of OS Events

61 50 Hazard ratio (95%CI) 1.38 (0.95-2.02) Median OS (95%CI), mo 10.1 (8.5-13.2) 15.1 (10.2-18.7)

ASCO 2014 Abstract 7503: Presented by Takashi Seto

Trials of immunotherapy in SCLC

Treatment Patient population ORR (95% CI) Duration of response Nivolumab 3 mg/kg Unselected (n=98) 10% (5-18) Not reached (4.4 to NR) Nivolumab 3 mg/kg Ipilimuab 1 mg/kg Unselected (n=54) 19% (9-31) 4.4 (3.7 –NR) Nivolumab 1 mg/kg Ipilimumab 3 mg/kg Unselected (n=61) 23% (13-36) 7.7 (4.0-NR) Pembrolizumab 10 mg/kg PD-L1 ≥ 1%* (n=24) 33% (15.6-55.3) 19.4 (3.6+ to 20.0+)

Antonia et al. Lancet Oncology 2016; Ott et al. WCLC 2016. * 147 evaluable samples and 42 PD-L1 positive (28.6%)

Phase 2 trial of nivolumab alone and with ipilimumab

Progression-free survival Overall Survival

Antonia et al. Lancet Oncology 2016.

Median PFS Nivolumab: 1.4 months Nivolumab 3/ Ipilimumab 1: 1.4 months Nivolumab 1/ Ipilimumab 3: 2.6 months Median OS Nivolumab : 4.4 months Nivolumab 3/Ipilimumab 1: 6.0 months Nivolumab 1/ Ipilimumab 3: 7.7 months

Phase 2 trial of pembrolizumab

Progression-free survival Overall survival

Ott et al. WCLC 2016.

Rova-T

• Delta-like protein 3 (DLL-3), receptor that inhibits Notch signaling
• Over-expressed on SCLC and high grade neuroendocrine

carcinomas with limited expression on other tissues

• Rova-T is DLL-3 antibody drug conjugate with DNA cross-linking

agent

• Phase 1 trial: 74 patients with SCLC, 39 with 1 previous line (53%)

and 35 with 2 previous lines (47%)

• Schedule for phase 2 trials: 0.3 mg/kg every 6 weeks for 2 doses
• Treatment related grade 3 adverse events: low platelets (11%),

pleural effusions (8%), increased lipase (7%)

Rudin et al. Lancet Oncology 2016.

Rovalpituzumab Tesirine (Rova-TÔ, SC16LD6.5)

Rudin CM et al. Proc ASCO 2016;Abstract LBA8505.

Efficacy of Rova-T

Objective response rate Swimmer’s plot

DLL-3 0-49% (n=6): 0% DLL-3 ≥ 50% (n=26): 31% DLL-3 ≥ 50% Duration of response: 4.6 months Progression-free survival: 4.6 months Rudin et al. Lancet Oncology 2016.

Adverse Events Associated with Rova-T

Adverse event (n = 74) Grade 1-2 Grade ≥3 Thrombocytopenia 4 (5%) 8 (11%) Pleural effusion 17 (23%) 6 (8%) Increased lipase 1 (1%) 5 (7%) Fatigue 23 (31%) 3 (4%) Peripheral edema 18 (24%) 2 (3%) Pericardial effusion 7 (9%) 2 (3%) Acute kidney injury 0 (0%) 1 (1%)

Rudin et al. Lancet Oncology 2016.

Sample of ongoing trials in ES-SCLC

Disease setting Comparison Phase NCT trial # Primary end-point First line Platinum/etoposide +/- pembrolizumab 2 02580994 PFS First line Carboplatin/etoposide +/- atezolizumab 3 02763579 OS and PFS First line Cisplatin/etoposide + Rova-T in DLL-3 positive 1 0281999 Safety Maintenance Pembrolizumab 2 (single arm) 02359018 PFS Maintenance Nivolumab, nivolumab/ipilimumab or placebo 3 02538666 OS and PFS Second line Nivolumab vs topotecan or amrubicin 3 02481830 OS Second line Pembrolizumab vs topotecan 2 02963090 PFS Second line 3 arm: Rova-T+nivolumab, Rova-T+ipilimumab Rova-T+ nivolumab/ipilimumab 1/2 03026166 Safety

Take-home points

• PCI is an option in ES-SCLC but I personally rarely use it and only in

carefully selected patients

• Preliminary results of immunotherapy trials reveal low response rates

but durable responses

• Role of single agent immunotherapy, combination immunotherapy,

and chemotherapy-immunotherapy combinations will be defined by current trials

• Current NCCN recommendation 2A for immunotherapy for patients

with progression ≤ 6 months from primary therapy

• Rova-T has single agent activity, and is being investigated in a phase 2

trial as 3rd line therapy. Future development most likely a part of combination therapy

https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf

Extensive-stage small cell lung cancer

Tom Stinchcombe Duke Thoracic Oncology Program