Locally Advanced NSCLC: Standards and
Challenges
Martin J. Edelman, MD, FACPG. Morris Dorrance Professor of Medicine
Fox Chase Cancer Center
Disclosures• Scientific Advisory Board: Biomarker Strategies,
Neumedicines• Advisor: Windmil Therapeutics• Advisory boards: Armo, Bergen• Data Safety Monitoring Boards: Astra-Zeneca,
Takeda• Research funding: Apexigen, BMS, Nektar
Issues in the management of Stage III disease
• Role of surgery (to be discussed by Dr. Donington)
• Radiation dose and type• Chemotherapy regimen
– Cytotoxics– “Targeted therapies”– Immunotherapy
Lung Cancer Staging Made Ridiculously Simple
• Localized (I, II)– Tumor does not
invade major structure
– No or only peribronchial/hilarLN
• Locally Advanced (III)– Ipsilateral or
contralateral mediastinal nodes
– Invasion of major structures
• Advanced (IV)– Malignant effusions
(M1a)– Distant metastases
(M1b)
Stage III Disease• Superior outcome (cure rate) for
chemotherapy + radiotherapy vs. radiotherapy alone in locally advanced disease.( Dillman, NEJM, JNCI)
• Concurrent chemo/XRT improves outcome.
• Ongoing controversy regarding optimal chemotherapy, role of surgery
Dillman, NEJM
Sequential vs. Concurrent Chemoradiotherapy
Questions with chemoradiotherapy• Radiotherapy
– Optimal dose– Proton vs. Photon
• Chemotherapy– Optimal regimen– Duration? (consolidation, maintenance)
• Immunotherapy
RADIATION DOSE AND TYPE
Is there still a radiation question?• Approximately 30% of initial relapse is loco/regional. • Surgery (selected pts) may improve outcomes. Indicating a
role for improved local therapies.• Increased mortality in high dose arm appears related to
irradiation of other structures, i.e. heart.• Can dose to primary tumor/regional LN be increased without
damage to adjacent structures?
Schema
STRATIFY
RT Technique1. 3D-CRT2. IMRT
Zubrod1. 02. 1
PET Staging1. No2. Yes
Histology1. Squamous2. Non-
Squamous
RANDOMIZE
Concurrent Treatment Consolidation TreatmentArm AConcurrent chemotherapy*RT to 60 Gy, 5 x per wk for 6 wks
Arm AConsolidation chemotherapy*
Arm BConcurrent chemotherapy*RT to 74 Gy, 5 x per wk for 7.5 wks
Arm BConsolidation chemotherapy*
Arm CConcurrent chemotherapy* andCetuximabRT to 60 Gy, 5 x per wk for 6 wks
Arm CConsolidation chemotherapy* and Cetuximab
Arm DConcurrent chemotherapy* and CetuximabRT to 74 Gy, 5 x per wk for 7.5 wks
Arm DConsolidation chemotherapy* and Cetuximab
*Carboplatin and paclitaxel
RTOG 0617: 60 vs 74 Gy
Bradley, ESMO 2017
Photons (IMRT) vs. Protons
Nat Rev Cancer 2016
Yegya-Raman, J Thor Dis, 2018;10 (suppl 21): S2474-2491
Prospective, Randomized Trial• Objectives
– Radiation pneumonits (> or = grade 3)
• IMRT = 15%• 3DPT = 5%
– Local failure (PET, CT, biopsy)
• IMRT = 3DPT• 15% 6 mo, 25% 12 mo
Doses and ToxicityOAR Doses Radiation Pneumonitis
OutcomesOverall survival
Practice makes perfect….
CHEMOTHERAPY REGIMEN
Cisplatin/Etoposide vs. Carboplatin/Paclitaxel: Systematic Literature Review
• Systematic literature review
• 79 trials• No difference in
outcome• Substantially less
toxicity with CBDCA/Pac
Steuer JAMA Oncology 2016
CDDP/VP-16 vs. CBDCA/Pac with Radiotherapy for Stage III NSCLC: Meta-analysis of VA Data
• Analysis of 1,842 pts treated at VA facilities between 2001-2010.
• Increased toxicity, no survival advantage with CDDP based regimen.
• Critique: primarily male, primarily squamous
Santana-Davila R J Clin Oncol 33:567-574, 2015
“Consolidation” Chemotherapy after Concurrent Chemoradiotherapy
• S9504 tested the concept of docetaxel following PE/XRT (Gandara, JCO). PE =cisplatin 50 mg/m2 on days 1, 8, 29, and 36, etoposide 50 mg/m2 on days 1 through 5 and 29 through 33.
• The concept in Fig 1 was proposed and rejected by CTEP
• HOG tested the concept in Fig 2. (Hanna, JCO 2008)
• Neither approach tested full dose chemotherapy consolidation after low dose CBDCA/Paclitaxel
Fig 1
Fig 2
“Low dose carboplatin/paclitaxel”• Used in most RTOG
trials• Widely applicable: no
fluid load, no limitations for cardiac or renal disease.
• Fully validated in RTOG 0617
• Had consolidation as part of the regimen.
TARGETED THERAPY
“Targeted Therapy”• Vaguely defined.• Has come to mean inhibition of specific
pathways (particularly with mutations).• Also VEGF
SWOG 0023
CDDP 50 mg/2d 1,8,29,36
VP-16 50 mg/m2d1-5, 29-33
XRT 1.8- 2 Gy/d61 Gy
DOCETAXEL75 mg/m2x 3 cycles
PLACEBO
GEFITINIB500 mg/day250 mg/day
(5-1-03)
Definitive TX Consolidation MaintenanceReg #1 Reg #2 Reg #3
Projected 840 pts 642 pts (80%)
Eligible: 571 pts 429 pts (75%) 243 pts (43%)243 pts/ 429 pts (57%)
RANDOMIZE
SWOG 0023: Overall Survival From Randomization
0%
20%
40%
60%
80%
100%
0 12 24 36 48 60Months After Randomization
GefitinbPlacebo
N118125
Events7154
Medianin Months
2335
P = .01
Bevacizumab with Chemoradiotherapy: NSCLC Trials
SITE REGIMEN STATUS
Ca Consortium (IIIB/IV)
RT → CP/Bev Closed - 1 gr 5 hemorrhage
Northwestern (IIIB/IV)
RT → CP/Bev Never Opened
Dana Farber CP wkly + Bev q3 wk + RT → CP/Bev q3 wk → Bev x 1 yr
Closed 4 pt – 1 gr 5 hemorrhage, 1 PE
NCI 7213 (Vokes)
C/P/Bev/RT Closed; 1 pt accrued
Sarah Cannon(Spigel)
Carbo/Pem/Bev/RT → Carbo/Pem/Bev → Bev
Closed – 5 pt – 2 TE fistulas
UNC (Socinski) CP/Bev → CP/Bev/RT → Bev/Erlotinib
Active – 21 pt – 1 gr 5 and 1 gr 3 hemorrhage
1306 Redesign - Submitted to CTEP 10/24/16; Study Terminated
IMMUNOTHERAPY
Immunotherapy in Stage III NSCLC: PACIFIC
Paz-Arres, ESMO 2017; Antonia NEJM 2017
PACIFIC: Results
Paz-Arres, ESMO 2017; Antonia NEJM 2017, 2018
Issues with PACIFIC• Chemoradiation regimen not standardized.• No quality control for XRT.• Entry to study was after completion of
chemoradiation (i.e. half way into the race).
PACIFIC Subgroup Analysis: Proceed with Caution
• Not planned.• No adjustments for
other prognostic factors (e.g. tumor size, co-morbidities, sex etc).
A few points…• Cisplatin vs. Carboplatin
– Pt’s receiving cisplatin by definition have good cardiac and renal function, no neuropathy etc.
– Automatically selects for a better group of pts.
• Time from end of chemoradiotherapy– Larger tumor (a know prognostic
factor) = greater risk of toxicity (e.g. esophagitis)
– = longer recovery time,– = worse outcome.
Lieu, Cancer Med 2013
Did the PACIFIC Control Underperform?• Difficult to compare to
other trials as started after completion of chemoXRT.
• Similar to START vaccine trial.
Butts, Lancet Oncol 2014; 15: 59–68
Where do we go from here with • Immunotherapy concurrent with chemoradiotherapy?• Immunotherapy combinations?• Immunotherapy followed completion of
chemoradiotherapy within 42 days.– Could it be done concurrently with “full dose”
chemotherapy (as in the CBDCA/Paclitaxel regimen)?• Test with other regimens? (e.g. carboplatin/paclitaxel).
Study Population
• Patients with unresectable, Stage III NSCLC
• All-comers(PD-L1 expression-agnostic)
• ECOG PS 0-1
Randomised N = 300 patients
Durvalumab 1500 mg Q4W + CRT(N = 200)
Placebo + CRT(N = 100)
R
Stratification• Age (<65, ≥65)• Stage (IIIA vs IIIB/C)
• Primary Endpoints: ORR, PFS• Key Secondary Endpoints: OS, OS24
2
1
For subjects with SD, PR, CR
Durvalumab 1500 mg Q4W
Placebo
• Treat to progression
PACIFIC 2: A Phase III, Randomized, Placebo-controlled, Double-blind, Multi-center, International Study of Durvalumab Given Concurrently with Platinum-based Chemoradiation Therapy in Patients with Locally Advanced, Unresectable Non-small Cell Lung Cancer (Stage III)
• Early IDMC safety assessment in first 15 and 60 TOTAL subjects (CRT+28 days)• In Japan, assessment after first 9 TOTAL subjects (CRT+28 days)
PACIFIC 2 – Chemotherapy Regimens for CRT
40
Physician choice one of four regimens
• Paclitaxel + Carboplatin– Paclitaxel 45-50mg/m2 + Carboplatin AUC 2 weekly during CRT x up to 6 cycles– +/- 1 optional induction cycle at “full dose” (Paclitaxel 200mg/m2 + Carboplatin AUC 6 administered
3 weeks before start of CRT)
• Cisplatin + Etoposide– Cisplatin 50mg/m2 on days 1, 8 + Etoposide 50mg/m2 on Days 1-5 of each 28 day cycle x 2 – +/- 1 optional induction cycle
• Cisplatin + Pemetrexed (Nonsquamous only)– Cisplatin 75mg/m2 + Pemetrexed 500mg/m2 Day 1 of each 21 day cycle x 3 cycles – +/- 1 optional induction cycle
• Carboplatin + Pemetrexed (Nonsquamous only)– Carboplatin AUC 5 + Pemetrexed 500mg/m2 Day 1 of each 21 day cycle x 4 cycles
PACIFIC 2: Radiation Therapy Quality Assurance
41
• Plan requirement: 60Gy delivered in 30 fractions via IMRT or 3DCRT• Exclusion criteria for radiation plans with excessive exposure to organs at risk
• Whole lung V20 >35%• Cardiac dose V50 >25%
• Protocol appendix with detailed radiation delivery specifications• Prospective review of radiation plans
• Plan submitted via online portal • Independent review of each individual plan by third party agency (Radialogica)• Radialogica triage of plans to expert review by radiation therapist• Feedback provided to sites in timely manner• Feedback may have expert recommendations from radiation oncologist if plan is outside of protocol
specifications• Sites encouraged to make corrections before or during radiation administration and submit new plan
Immunotherapy and surgery• Neoadjuvant nivolumab
3mg/kg q 2 wks x 2 followed by resection.
• 21 pts (JHU and MSKCC)• Radiologic response
– PR = 2 (10%)– SD = 18 (86%)– PD = 1 (5%)
• Pathological downstaging in 40%
NADIM Study (Spanish Lung Cancer Group)
ASCO 2018 (JCO 36:15 suppl, 8521)
Referral Populations
• Referral populations inherently do better.
• Possible reasons:– Socioeconomics– Nutrition– Inherent biology
Lamont, JNCI 2001
Phase II data, even when they are qualitatively correct, are invariably quantitatively far below the phase III
results
Authors Phase Response Rate (%)
MST (mo) 1-yr Survival Rate (%)
Langer et al II 62 12 54
Natale et al I-II 62 10.5 43
Belani et al III 23 7.7 32
Schiller er al III 15 8.2 35
Langer C+T+Herceptin
II 21 10.1 43
Langer et al. J Clin Oncol. 1995;13:1860-1870. Langer et al. ECCO, 2001
Natale et al. Semin Oncol. 1996;23(6 suppl 16):51-54.
Belani et al. PASCO, 1998 Schiller et al. PASCO 2000
Phase II vs. Phase III in the IO EraStudy Study N RR PFS OS
Langer (KN-021, cohort G)
CBDCA/PEMCBDCA/PEM/Pem
6360
1833
9.324
21.1NR
Gandhi, (KN-189)
Plat/PemPlat/Pem/Pem
206410
18.947.6
4.98.8
11.3NR
ASCO 2018NEJM
Questions for future trialsChemo
XRTIO drug
combination or chemoIO
IO or combination
ChemoXRT/IO
Sequential 1
Sequential 2
Sequential 3 IO or combination
ChemoXRT+/-IO
Conclusions• Stage III disease is potentially curable with definitive
chemoradiotherapy• Optimal radiotherapy dose: 60 Gy
– IMRT preferred over 3D-CRT– No role for protons etc at this time other than on trial.
• Optimal chemotherapy regimen: ? Carboplatin/paclitaxel– Immunotherapy (durvalamab) improves PFS, OS.– In PACIFIC trial, followed chemoXRT within 42 days
• Surgery in selected cases, high volume centers with experienced surgeons can be considered.