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.