Unresectable stage

III NSCLC
PACIFIC and beyond

Maarten Lambrecht MD, PhD

University Hospitals Leuven
 DISCLOSURE INFORMATION

Advisory board: Astra Zeneca

Speaker engagement: Astra Zeneca
Travel expenses: Astra Zeneca, Roche
 Stage III disease
Heterogeneous disease: unresectable

Postmus et al. Ann Oncol 2017

 … before IO (Pacific)
Concurrent CRT: standard of care No role for dose escalation

Bradley et al. Lancet Oncol. 2015

Systemic treatment
- Platinum based
- No role for consolidation or induction
- Hanna et al. J Clin Oncol. 2008
- Vokes et al. J Clin Oncol. 2007
- No role for Targeted agents
Aupérin A, et al. J Clin Oncol. 2010 - Kelly et al. J Clin Oncol. 2008
PACIFIC trial
 Study Design
Phase III Randomized, Double-blind, placebo-controlled,multicenter, international study

• Patients with stage III, locally

Durvalumab Co-primary endpoints
advanced, unresectable
NSCLC who have not 10 mg/kg q2w for • PFS by BICR using
progressed following definitive up to 12 months RECIST v1.1*
N=476 • OS
platinum-based cCRT
(≥2 cycles) 1–42 days 2:1 randomization,
post-cCRT stratified by age, sex, Key secondary endpoints
• 18 years or older R and smoking history
N=713 • ORR (per BICR)

• WHO PS score 0 or 1 • DoR (per BICR)

Placebo
• Safety and tolerability
10 mg/kg q2w for
• Estimated life expectancy of up to 12 months • PROs
≥12 weeks N=237

• Archived tissue was collected

 UPDATED PFS (BICR; ITT)
No. of events/ Median PFS
total no. of patients (%) (95% CI), months

Durvalumab 266/476 (55.9) 17.2 (12.3–23.8)

1.0
0.9 Placebo 174/237 (73.4) 5.6 (4.6–7.7)

0.8 Stratified HR for progression or death, 0.55 (95% CI, 0.44–0.67)

Stratified HR from the primary analysis,1 0.52 (95% CI, 0.42–0.65)
0.7
Probability of PFS

55.3%
0.6
0.5
44.8%
39.8%
34.4% 35.3%
0.4
0.3
0.2
PFS HR = 0.55 24.8%
0.1 (95% CI, 0.44–0.67) 20.5% 19.5%
0
0 1 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63
Time from randomisation (months)
No. at risk
Durvalumab 476 377 301 266 213 189 165 146 136 127 119 110 103 97 92 80 59 37 18 8 1 0
Placebo 237 163 105 86 67 55 47 40 36 35 29 26 25 24 23 22 16 11 5 1 0 0

Data cutoff: 20 March 2020 (median follow up, 34.2 months [range, 0.2–64.9]). BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; PFS, progression-free survival. Faivre-Finn C, ESMO 2020
1. Antonia SJ, et al. New Engl J Med 2017;377:1919–29.
 UPDATED OS (ITT)
No. of events/ Median OS
total no. of patients (%) (95% CI), months

1.0 Durvalumab 247/476 (51.9) 47.5 (38.4–52.6)

0.9
83.1% Placebo 149/237 (62.9) 29.1 (22.1–35.1)

0.8 Stratified HR for death, 0.71 (95% CI, 0.57–0.88)

66.3% Stratified HR from the primary analysis,1,2 0.68 (95% CI, 0.53–0.87)
0.7
Probability of OS

0.6
74.6% 56.7%
49.6%
0.5
55.3%
0.4
43.6%
0.3
36.3%
0.2
OS HR = 0.71
0.1 (95% CI, 0.57–0.88)

0
01 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66
Time from randomisation (months)
No. at risk
Durvalumab 476 464 431 414 385 364 343 319 299 290 274 265 252 241 235 225 195 138 75 36 15 2 0
Placebo 237 220 199 179 171 156 143 133 123 116 107 99 97 93 91 83 75 53 29 15 7 2 0

Data cutoff: 20 March 2020 (median follow up, 34.2 months [range, 0.2–64.9]). CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; OS, overall survival.
Faivre-Finn C, ESMO 2020
1. Antonia SJ, et al. New Engl J Med 2018;379:2342–50; 2. European Medicines Agency. Durvalumab (Imfinzi). Summary of product characteristics 2020 [Accessed August 2020]. Available from: https://www.ema.europa.eu/en/documents/product-information/imfizi-epar-product-information_en.pdf.
 OS throughout the years
Trial Regimen Median OS (months) 2 y OS 5 y OS
Meta-Analysis 2006
RT Alone - 12 months 21% 6%
Concurrent CRT Carbo-etoposide 14 months 25% 8%
Meta-Analysis 2010
Sequential Cisplatin + vinca or 14 months 30% 11%
Concurrent etoposide 18 months 36% 15%

RTOG 0617 standard arm Carbo-paclitaxel 29 months 58% 31%

PROCLAIM standard arm Cis-etoposide 25 months 52% NA

PACIFIC Durvalumab 47.5 months 66% NA

Auperin et al. Ann Oncol 2006

Auperin et al. JCO 2010
Bradley et al. Lancet Oncol 2015 and JCO 2020
Senan et al. JCO 2016
Time to death or distant metastases

Antonia et al. NEJM 2018

 Toxicity

Immune mediated AE:

24% (Durvalumab) vs. 8.1%
(placebo)
Pneumonitis:
3.4% ≥ grade 3

Antonia et al. NEJM 2017

Quality of Life

Hui et al. Lancet Oncol 2019

 Some unanswered questions
PD-L1 status
– PD-L1 testing was not required and 37% of all randomised patients had unknown PD-L1 status
– PD-L1 status was determined from tumour tissue obtained pre-CRT (getting a sample post-CRT medically not feasible)
– PD-L1 expression-level cutoff of 1% was part of an unplanned post-hoc analysis requested by the EMA

OS PFS (BICR)
# events / # events /
# patients (%) HR and 95% CI # patients (%) HR and 95% CI
All patients 396/713 (55.5) 440/713 (61.7)
PD-L1 status ≥25% 76/159 (47.8) 92/159 (57.9)
(pre-specified) <25% 164/292 (56.2) 181/292 (62.0)
Unknown 156/262 (59.5) 167/262 (63.7)
PD-L1 status 1–<25% 75/144 (52.1) 85/144 (59.0)
(post-hoc) ≥1% 151/303 (49.8) 177/303 (58.4)
<1% 89/148 (60.1) 96/148 (64.9)

0.2 0.6 1 1.4 1.8 0.2 0.6 1 1.4 1.8

Durvalumab better Placebo better Durvalumab better Placebo better

Faivre-Finn C, ESMO 2020

 Some unanswered questions
EGFR mutation

Faivre-Finn C, ESMO 2020

Lisberg et al. J Thorac Oncol, 2018
 CONCLUSION PACIFIC
• Practice changing, with impressive PFS and OS data and manageable toxicity
• All eligible unresectable stage III NSCLC should be considered for the pacific
regimen

• However:
• Selected patient population
• Biomarkers: none!
• What about sequential CRT/elderly patients?
And Beyond
 How do we move forward?

1. BIOLOGY: Optimize IO/RT combination

• Improve Timing
• Improve Radiotherapy
• Improve Immunotherapy

2. CLINICAL: Implications for resectable stage III NSCLC?

Improve timing

Van Limbergen EJ et al. Br J Radiol 2017

Dovedi et al. Cancer Res 2014
Faivre-Finn. ESMO 2020
 Timing: ETOP 6-14 NICOLAS
79 patients
Medians FUP: 21 months 12 months PFS: 54.8%
Toxicity:
43% any pneumonitis
10% ≥ grade 3

Trial Type Agent N Primary endpoint Outcome Pneumonitis

DETERRED Phase II A: Atezolizumab adjuvant 40 Time to toxicity Median PFS Any pneumonitis 25%
B: Atezolizumab concurrent + A: 12.5 months 10% ≥ grade 3
adjuvant B: 13.2 months

KEYNOTE-799 phase II Pembro concurrent + adjuvant A: 112 ORR 6 months PFS: ≥ grade 3 pneumonitis
A: paclitaxel-carbo B: 73 ≥ grade 3 pneumonitis A: 81.4% A: 8%
B: Cis-Pem B: 85.2% B: 5,5%
Peters S et al. ESMO 2019
Lin. et al. JTO 2020
Jabbour ASCO 2020
Improvements in radiotherapy

1. Optimal dose/fractionation
A. Dose (de-)escalation
B. Hypofractionation
C. Acceleration
2. Advanced RT techniques
A. ↓Toxicity => ↑Eligibility
B. Lymphopenia?

Brown et al. BJR 2019

Lymphopenia

1. Association between lymphopenia and OS

2. Critical structures associated with severe

lymphopenia
• Heart
• Lung
• Thoracic vertebrae

Abravan et al. JTO 2020

 Improve Immunotherapy?

Trial Type Agent Strategy N Primary endpoint

Intr@pid LUNG 005 Phase II M7824 Concurrent + adjuvant vs 330 PFS

PACIFIC

COAST Phase II Oleclumab Adjuvant vs PACIFIC 189 ORR

Monalizumab

CheckMate73L Phase III Nivolumab Concurrent + adjuvant Nivo 1400 PFS/OS

Ipilimumab With or without ipilimumab vs
PACIFIC

PACIFIC 2 Phase III Durvalumab Concurrent + Adjuvant vs 300 PFS

PACIFIC

…
What about resectable patients?
 Historical stage IIIA data
INT 0139 ESPATUE

5-yr OS: 27% 5 yr OS: 40%

Albain KS, et al. Lancet 2009

Eberhardt, et al. JCO 2015
LUNG-ART data

Le Pechoux, ESMO 2020

 ICI in surgical patients
Trials Agent N MPR pCR PFS
Forde et al. Nivolumab 21 pts IA-IIIA 45% 14% NA

LCMC3 Atezolizumab 82 pts IB-IIIB 18% 5% NA

NEOSTAR Nivolumab ± ipilimumab 44 pts IA-IIIA 24% 15% NA

Shu et al. Atezolizumab +paciltaxel/carbo 30 pts IIA-IIIA 57% 33% NA

NADIM
Stage IIIA NSCLC
Neo-adjuvant chemotherapy-Nivolumab
Phase II trial
46 patients
24 months follow-up
MPR rate: 83%
PFS at 2 years: 77.1% Provencio et al. Lancet Oncol 2020
Forde et al. NEJM 2018
Kwiatkowski et al. JCO 2019
Cascone et al. JCO 2019
Shu et al. Lancet Oncol
 Final Thoughts

• PACIFIC was practice changing for stage III unresectable patients

• Who (doesn’t) benefit?
• Biomarkers
• Patient selection

• Better understanding of the underlying biology to further improve immuno/RT combination

• Treatment strategy in stage III (un-)resectable disease?

THANK YOU

2
Acknowledgements

• Department of Pulmonology
• Els Wauters
• Johan Vansteenkiste

• Radiotherapy Oncology
• Patrick Berkovic