Gefitinib versus gefitinib-pemetrexed-

carboplatin in EGFR mutated lung

cancer (Gef vs. Gef + C)
Vanita Noronha (@VanitaNoronha)
On behalf of Kumar Prabhash, Vijay Patil, Amit Joshi, Nandini Menon; and
Department of Medical Oncology and Thoracic oncology disease management group, Tata
Memorial Center (Mumbai, India)

Vanita Noronha, Tata Memorial Hospital 1

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Introduction

from:Flickr

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Vanita Noronha, Tata Memorial Hospital
Introduction
• Since IPASS1, molecular targeted therapy has become standard.
• NCCN: 5 EGFR-directed oral TKIs for first line Rx in EGFR mutant NSCLC
• Resistance inevitably develops within 8-12 months.
• Various strategies being tested to delay/ prevent resistance.
• One strategy: oral TKI + chemotherapy
• Synergistic: induce apoptosis, suppress Akt and Erk phosphorylation 2
• Two phase II trials testing chemo + oral TKI improved efficacy3

1. Mok et al. NEJM 2009; 2. Z. Yang, et al. Int J Biol Sci 2018; 3. Cheng Y et al, JCO 2016
2. Sugawara et al, Ann Oncol 2015

Vanita Noronha, Tata Memorial Hospital 4

Patients and Methods

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Vanita Noronha, Tata Memorial Hospital
Patients and Methods
• Conducted at Tata Memorial Center (TMC), Mumbai, India.
• Approved by Institutional Ethics Committee (IEC) of TMC.
• Monitored by Data Safety Monitoring Subcommittee (DSMSC).
• All patients provided written informed consent.
• Registered at Clinical Trials Registry-India: CTRI/2016/08/007149.

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 Gef vs Gef + C - Gefitinib 250mg daily
-Pem 500 mg/m2 +
ELIGIBILITY CRITERIA
• Age > 18 yrs n=174 Carbo AUC 5 Q21d x 4
• Histologic/ cytologic NSCLC  Pem 500 mg/m2
• Stage IIIB not amenable to Q21d
radical therapy or Stage IV
STRATIFY
• First-line palliative intent Randomized
•
• ECOG PS (0/1 v.2)
Activating EGFR mutation 1:1
(exon 19/ 21/ 18) • EGFR mutation Open Label
• ECOG PS 0 to 2 (exon 19 v. other)
• Adequate organ function
• No h/o ILD, radiation Gefitinib 250mg
pneumonitis that required n=176 daily
steroids or IPF

Evaluation: Clinical- Q 3 wks in Gef + C (pre-chemo), Q 2mth (gef); Radiologic-Q 2-3 mnth
Duration of Therapy: until PD, unacceptable toxicity or consent withdrawal.

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Aims and Objectives
• Primary endpoint: PFS
• Events for PFS: radiologic PD, symptom deterioration, death
without documented PD, lost to follow-up

• Secondary endpoints:
• OS
• Toxicity
• Response rate
• QoL*
*will be presented at a later date
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Sample size

• Baseline assumption: median PFS in gef arm-10 months 1

• Expectation: median PFS in gef + C arm-15 months 2
• Power 90%
• α error 5%
• Anticipated lost-to-follow-up 10%
• Planned sample size 350

1. Paz-Ares L. et al, J Cell Mol Med 2014; Feng-Che Kuan et al, Oncotarget 2017; Noronha V. et al, PLoS One 2013
2. Cheng Y. et al, JCO 2016

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Results

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 Assessed for eligibility (n=712)
Aug 2016 to Aug 2018
Enrollment
PEM-CARBO-GEF ARM (GEF+C)
• Allocated to Gef + C arm (n=174)
• Received Gef + C (n=169)
• Did not receive Gef + C (n=5)
− Refused chemo, took only gef (n=3)
− Refused all therapy after randomization (n=1)
− Disease progression pre-therapy (n=1)
• Patients still on study treatment (n=71)
• Discontinued Gef + C (n=101)
• Disease progression (n=95)
• Patient decision (n=5)
• Death (n=1)
• Lost to follow-up (n=1)
• Did not take any therapy (n=1)
• Analyzed for outcome measures (PFS, OS) (n=174)
• Analyzed for toxicity (n=164)
• Took only gefitinib (n=3)
• Did not take any therapy (n=2)
• Did not return for clinical assessment (n=5)
Excluded (n=362)
• Already started on therapy (n=95)
• Declined to participate (n=76)
• Poor general condition (n=75)
Randomized (N=350) • Died before evaluation (n=26)
• Other reasons (n=90)
GEFITINIB ARM (GEF)
• Allocated to Gef arm (n=176)
• Received gefitinib (n=176)
Allocation
• Patients still on study treatment (n=37)
• Discontinued Gef (n=138)
Therapy • Disease progression (n=136)
• Patient decision (n=1)
• Death (n=1)
• Lost to follow-up (n=1)
• Analyzed for outcome measures (PFS, OS) (n=176)
Analysis • Analyzed for toxicity (n=170)
• Did not return for clinical assessment (n=6)
Median follow-up: 17 months (Range, 7 to 30)
Vanita Noronha, Tata Memorial Hospital
Demographics and baseline
disease characteristics

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Vanita Noronha, Tata Memorial Hospital
 Gef + C (n=174) Gef (n=176)
Age in years: Median (Range) 54 (27-75) 56 (27-78)
Male sex-No. (%) 88 (51) 93 (53)
Smoking history-No. (%)
• Never 145 (83) 150 (85)
• Former 19 (11) 21 (12)
• Current 10 (6) 5 (3)
ECOG PS-No. (%)
• 0 1 (1) 7 (4)
• 1 137 (79) 130 (74)
• 2 36 (21) 39 (22)
Comorbidities-No. (%)
• None 97 (56) 81 (46)
• Hypertension 21 (12) 32 (18)
• Diabetes mellitus 9 (5) 9 (5)
• COPD/ emphysema 8 (5) 5 (3)
• Prior tuberculosis 4 (2) 5 (3)
• Multiple (>1) 23 (13) 35 (20)
• Other 12 (7) 9 (5)

Vanita Noronha, Tata Memorial Hospital

 Gef + C (n=174) Gef (n=176)
Histology-No. (%)
• Adenocarcinoma 170 (98) 170 (97)
• Adenosquamous 3 (2) 4 (2)
• Squamous cell CA 1 (1) 1 (1)
• Sarcomatoid CA 0 1 (1)
Disease stage-No.(%)
• IV 171 (98) 171 (97)
• IIIB 3 (2) 5 (3)
Metastatic site-No. (%)
• Pleura/ pericardium 30 (17) 25 (14)
• Opposite lung 20 (12) 18 (10)
• Non-regional LNs 2 (1) 5 (3)
• Bones 24 (14) 25 (14)
• Brain 2 (1) 13 (7)
• Liver/ adrenal/ omentum 3 (2) 2 (1)
• Multiple (>1) 90 (52) 83 (47)
• Non-metastatic 3 (2) 5 (3)
Presence of brain metastases-No. (%) 30 (17) 34 (19)
Presence of pulmonary embolism-No. (%) 7 (4) 2 (1)

Vanita Noronha, Tata Memorial Hospital

 Gef + C (n=174) Gef (n=176)
EGFR mutation type-No. (%)
• Exon 19 in-frame deletion 107 (62) 109 (62)
• Exon 21 (L858R/ L861Q) 60 (35) 60 (34)
• Exon 18 (G719X) 1 (1) 2 (1)
• Exon 20 (T790M) with additional sensitizing mutation 4 (2) 2 (1)
• Dual sensitizing mutation 2 (1) 3 (2)
Additional cancer-directed therapy– No. (%)
• Palliative radiotherapy 49 (28) 51 (29)
• Whole brain radiotherapy 22 (13) 31 (18)
• Palliative surgery 2 (1) 4 (2)

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Treatment delivery

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Vanita Noronha, Tata Memorial Hospital
Gef + C arm (n=174)
• Induction phase:
• 169 patients (97%) started pem + carbo + gef
• 139 patients (80%) completed 4 cycles chemo
• 23 patients (13%) required dose reduction
• 39 patients (22%) had dose delays (>1 day), median length of 4.5 days (IQR, 3 to 9)
• 22 patients (13%) required growth factors.
• Maintenance phase:
• 137 patients (79%) started maintenance pem + gef
• Median number of maintenance cycles, 11 (IQR, 6 to 20)
• 18 patients (13%) had dose reductions
• 67 patients (49%) had dose delays (> 1 day), median length of 11 days (IQR, 6 to 16)
• Gefitinib:
• Gefitinib taken for median of 327 days (IQR, 205 to 518)
• Gefitinib held in 39 patients (22%) for a median of 7 days cumulatively (IQR, 2 to 16)

Gef arm (n=176)

• Gefitinib taken for a median of 260 days (IQR, 182 to 356)
• Gefitinib was held in 34 patients (19%) for a median of 5 days cumulatively (IQR, 2 to 10)
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Toxicities

From: pngimg.com

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OVERALL TOXICITIES Gef + C arm (n=164) Gef arm (n=170) P-value

All > grade 3 toxicities 123 (75%, 95% CI, 67.8 to 81) 84 (49.4%, 95% CI, 42 to 56.9) <0.001

Clinically relevant > gr 3 toxicities 83 (50.6%, 95% CI, 43 to 58.2) 43 (25.3%, 95% CI, 19.4 to 32.4) <0.001
(excluding asympt lab abnormalities)

Fatal toxicities 1 (0.6%)-FN 1 (0.6%)-ILD 1.0

Discontinuation due to toxicities

• Pemetrexed 30 (16.7%) N/A
• Gefitinib 0 2 (1.1%)

Vanita Noronha, Tata Memorial Hospital

HEMATOLOG Gef + C arm (n=164) Gef arm (n=170) P
Gr 1 Gr 2 Gr 3 Gr 4 Gr 5 Gr 1 Gr 2 Gr 3 Gr 4 Gr 5
Anemia 71 (43) 55 (34) 30 (18) 2 (1) 0 83 (49) 28 (17) 2 (1) 0 0 <0.001
Neutropenia 35 (21) 29 (18) 23 (14) 3 (2) 0 1 (1) 1 (1) 0 0 0 <0.001
Thrombocytop 68 (42) 16 (10) 6 (4) 2 (1) 0 25 (15) 2 (1) 0 0 0 0.003
FN N/A N/A 9 (6) 8 (5) 1 (1) 0 0 0 0 0 <0.001
GASTROINTES Gef + C arm (n=164) Gef arm (n=170) P
Nausea/ vom 54 (33) 24 (15) 9 (6) 0 0 27 (16) 6 (4) 3 (2) 0 0 0.069
Anorexia 81 (49) 32 (20) 2 (1) 0 0 46 (27) 21 (12) 0 0 0 0.242
Diarrhea 40 (24) 29 (18) 22 (13) 1 (1) 0 26 (15) 21 (12) 13 (8) 1 (1) 0 0.092
Constipation 46 (28) 8 (5) 0 0 0 14 (8) 2 (1) 0 0 0 N/A
Mucositis 36 (22) 19 (12) 2 (1) 0 0 19 (11) 15 (9) 0 0 0 N/A
Hiccups 12 (7) 4 (2) 1 (1) 0 0 3 (2) 1 (1) 0 0 0 N/A
Pancreatitis 0 1 (1) 0 0 0 0 0 0 0 0 N/A
Transaminitis 83 (51) 18 (11) 8 (5) 0 0 63 (37) 16 (9) 4 (2) 1 (1) 0 0.360
Incr bilirubin 18 (11) 6 (4) 0 0 0 25 (15) 3 (2) 0 0 0 N/A

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CUTANEOUS Gef + C arm (n=164) Gef arm (n=170) P
Gr 1 Gr 2 Gr 3 Gr 4 Gr 5 Gr 1 Gr 2 Gr 3 Gr 4 Gr 5
Rash 81 (49) 26 (16) 7 (4) 1 (1) 0 59 (35) 29 (17) 8 (5) 0 0 0.941
Dry skin 98 (60) 27 (17) 0 0 0 89 (53) 17 (10) 1 (1) 0 0 1.0
Pruritus 90 (55) 13 (8) 0 0 0 85 (50) 22 (13) 0 0 0 N/A
Skin fissures 31 (19) 4 (2) 0 0 0 13 (8) 1 (1) 0 0 0 N/A
Hyperpigment 74 (45) 12 (7) 0 0 0 22 (13) 3 (2) 0 0 0 N/A
Ulceration 0 2 (1) 1 (1) 0 0 0 0 0 0 0 0.486
Paronychia 23 (14) 20 (12) 0 0 0 16 (10) 11 (7) 1 (1) 0 0 1.0
OPTHALMOL Gef + C arm (n=164) Gef arm (n=170) P
Conjunctivitis 14 (9) 3 (2) 0 0 0 7 (4) 0 0 0 0 N/A
Eyelash chang 2 (1) 1 (1) 0 0 0 3 (2) 0 0 0 0 N/A
Epiphora 21 (13) 0 0 0 0 5 (3) 0 0 0 0 N/A
Decreas vision 6 (4) 0 0 0 0 1 (1) 0 0 0 0 N/A
CONSTITUTIO Gef + C arm (n=164) Gef arm (n=170) P
Fatigue 72 (44) 55 (34) 8 (5) 0 0 56 (33) 30 (18) 5 (3) 0 0 0.360
Weight loss 38 (23) 25 (15) 6 (4) 0 0 26 (15) 17 (10) 5 (3) 0 0 0.713
Pedal edema 26 (16) 10 (6) 0 0 0 5 (3) 7 (4) 0 0 0 N/A
Giddiness 27 (17) 7 (4) 1 (1) 0 0 14 (8) 3 (2) 0 0 0 0.491
ELECTROLYTE Gef + C arm (n=164) Gef arm (n=170) P
Gr 1 Gr 2 Gr 3 Gr 4 G 5 Gr 1 Gr 2 Gr 3 Gr 4 Gr 5
Hyponatremia 81 (49) N/A 36 (22) 3 (2) 0 61 (36) N/A 23 (14) 4 (2) 0 0.070
Hypokalemia 39 (24) 1 (1) 12 (7) 1 (1) 0 14 (8) 0 1 (1) 1 (1) 0 0.003
Hyperkalemia 19 (12) 9 (6) 2 (1) 0 0 16 (9) 5 (3) 1 (1) 0 0 0.617
Hypomag 84 (51) 5 (3) 1 (1) 0 0 56 (33) 0 0 1 (1) 0 1.0
Hypocalcemia 59 (36) 26 (16) 2 (1) 3 (2) 0 28 (17) 10 (6) 1 (1) 0 0 0.116

MISCELLAN Gef + C arm (n=164) Gef arm (n=170) P

Non-neutr inf 0 36 (22) 13 (8) 5 (3) 0 0 16 (9) 7 (4) 3 (2) 0 0.093
Hypertension 4 (2) 81 (49) 43 (26) 0 0 6 (4) 86 (51) 40 (24) 0 0 0.570
ILD 1 (1) 0 1 (1) 0 0 2 (1) 2 (1) 0 0 1 (1) 0.623
Weight loss 38 (23) 25 (15) 6 (4) 0 0 26 (15) 17 (10) 5 (3) 0 0 0.713
Periph neurop 25 (15) 6 (4) 0 0 0 9 (5) 3 (2) 0 0 0 N/A
Pedal edema 26 (16) 10 (6) 0 0 0 5 (3) 7 (4) 0 0 0 N/A
Hemoptysis 1 (1) 1 (1) 1 (1) 0 0 1 (1) 1 (1) 0 0 0 0.491
Nephrotoxicit 6 (4) 16 (10) 10 (6) 0 0 4 (2) 1 (1) 1 (1) 0 0 0.005
Thromboemb 0 3 (2) 2 (1) 1 (1) 0 0 4 (2) 1 (1) 1 (1) 0 0.680
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 Response rate

Gef + C arm (n=174) Gef arm (n=176) P-

value
No. of pts who had restaging scans-No. (%) 162 (93) 161 (92)
Best radiologic response-No. (%)
• CR 5 (2.9) 1 (0.6)
• PR 126 (72.4) 109 (61.9)
• SD 22 (12.6) 39 (22.2)
• PD 9 (5.2) 12 (6.8)

ORR (CR + PR) 75.3% (95% CI, 68.3 to 81.1) 62.5% (95% CI, 55.1 to 69.3) 0.01
Median depth of response -56.4 (IQR, -41.2 to -69) -43.5 (IQR, -25.2 to -60) 0.002

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Comparison of depth of response
Gefitinib + pemetrexed + carbo arm Gefitinib arm

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Discussion

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Vanita Noronha, Tata Memorial Hospital
 Earlier studies…
• Early trials with oral TKI + chemo (TRIBUTE1, TALENT2) were negative,
but in unselected population of NSCLC patients.
• Randomized phase II studies in EGFR mutant patients were positive:
• Cheng et al.3: Gef vs Gef + Pem PFS increased from 10.9 to 15.8 months, HR-0.68 (95%
CI, 0.48 to 0.96), P=0.014
• NEJ0054-Concurrent vs sequential gef and pem/carboPFS increased from 15.3 to 18.3
months, HR-0.71 (95% CI, 0.42 to 1.20), P=0.20
• NEJ009-phase III randomized trial presented last year at ASCO:
1.Herbst, JCO
2005;
2. Gatzemeier,
JCO 2007
3. Cheng,
JCO 2016;
4. Sugawara
Ann Oncol 2015

Vanita Noronha, Tata Memorial Hospital

Overall survival
benefit
• All the landmark trials comparing oral
TKI to chemotherapy/ TKI
• prolong PFS,
• but no prolongation of OS.

Vanita Noronha, Tata Memorial Hospital

• Dacomitinib prolonged OS compared to gefitinib in ARCHER 1050.
• Gefitinib + pem/ carbo one of the only regimens that prolongs overall
survival in EGFR mutant NSCLC.

Vanita Noronha, Tata Memorial Hospital

So where does gef + C fit in the current treatment
algorithm?
• Gefitinib, erlotinib and afatinib have comparable efficacies (ORR, PFS, OS)
• Osimertinib, dacomitinib, erlotinib + bev and gef + chemo: better PFS
• PFS in our study-17 months, similar to 18.9 months from osimertinib in
FLAURA
• But we included PS 2 (20%), FLAURA enrolled only PS < 1
• Thus, several first-line options with comparable efficacy exist.
• Osimertinib has efficacy in T790M mutation, therefore may be better
positioned in relapsed setting.
• To maximize survival, sequencing of effective therapies is important.

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Optimal sequencing…
Combination of oral TKI + chemo/ VEGF inhibitor

PD Oligoprogression Radical therapy

Multiprogression

T790M MET/ PIK3CA/ BRAF No targetable

SCLC
mutation
Non-cross resistant chemo Platinum
Osimertinib Clinical trial
+/- VEGF inhibitor + etopo
+/- immunotherapy
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Vanita Noronha, Tata Memorial Hospital
Critique of our trial
• Negatives:
• Single institution
• Open label design
• Demographic pattern may vary from other countries (84% non-smokers)
• No centralized independent radiology review
• QOL data not analyzed yet
• Positives:
• Use of easily available, accessible and affordable medications
• Use of standard of care chemo (pem + platinum induction  pem maint)
• All EGFR testing done in the molecular lab of medical oncology dept of
TMH
• Included PS 2 pts, brain mets, rare EGFR mutations: L861Q, S761I, G791X
Vanita Noronha, Tata Memorial Hospital
Conclusions
• Gef + pem + carbo doubled PFS from 8 months  16 months;
HR, 0.51 (95% CI, 0.39-0.66), P<0.001
• Gef + pem + carbo led to 25% absolute increase in 18-month OS
from 48.7%  78.3%
• Gef + pem + carbo doubled serious clinically relevant toxicities
from 25% to 51%
• Gef + pem + carbo represents a new first-line therapy option for
EGFR mutant NSCLC

Vanita Noronha, Tata Memorial Hospital

Acknowledgements

Dr. Vijay Patil

Dr. Amit Joshi

Dr. Kumar Prabhash

Dr. Nandini Menon
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Our team with research coordinators and research staff

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Team of Medical Oncology-Molecular Laboratory

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Vanita Noronha, Tata Memorial Hospital
 Gef vs Gef + C
Acknowledgements

Entire Thoracic Disease Management Group

&
Department of Medical Oncology
Tata Memorial Hospital

Funding
TRAC, Dr. Reddy’s, Fresnius Kabi, Alkem, Natco, BDR, Lung Cancer Consortium Asia

PATIENTS AND THEIR FAMILIES

Vanita Noronha, Tata Memorial Hospital
 THANK YOU!
@VanitaNoronha

vanita.noronha@gmail.com

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Vanita Noronha, Tata Memorial Hospital