new perspectives in early stage nsclc · reck et al. esmo 2017 a patients with a sensitising egfr...
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Immunotherapy for NSCLCs: Case Discussion
William N. William Jr., MD
Director of Oncology and Hematology, Hospital BP, a Beneficência Portuguesa de São Paulo
Adjunct Associate Professor, The University of Texas MD Anderson Cancer Center
72 year-old male, former smoker, PS 1
No significant co-morbidities
• Diagnosed with lung squamous-cell carcinoma, stage III in 2014
• Treated with concurrent carboplatin/paclitaxel and radiation therapy with CR
• In 2018 diagnosed with in-field recurrence in subcarinal lymph node not amenable for surgical resection or re-irradiation. Asymptomatic.
72 year old male with a possible SCC in-field recurrence after chemoXRT
What would be the next step?
A. Biopsy through EBUS and assessment of PD-L1 status
B. Biopsy through EBUS for pathology, and assessment of PD-L1 in the baseline sample (2016)
C. Liquid biopsy for next-generation sequencing
D. No biopsy or biomarker evaluation is necessary to initiate treatment
72 year old male with a possible SCC in-field recurrence after chemoXRT
What would be the next step?
A. Biopsy through EBUS and assessment of PD-L1 status
B. Biopsy through EBUS for pathology, and assessment of PD-L1 in the baseline sample (2016)
C. Liquid biopsy for next-generation sequencing
D. No biopsy or biomarker evaluation is necessary to initiate treatment
Recurrent SCC, PD-L1 5%
• The patient had an EBUS and pathology confirmed carcinoma.
• PD-L1 status was assessed in the baseline tissue specimen with a TPS = 5%
Recurrent SCC, PD-L1 5%
What would be the best treatment choice?
A. Pembrolizumab 200 mg IV q 3 weeks
B. Carboplatin and paclitaxel
C. Carboplatin, paclitaxel, and pembrolizumab
D. Docetaxel single agent
E. Docetaxel plus nintedanib
Recurrent SCC, PD-L1 5%
What would be the best treatment choice?
A. Pembrolizumab 200 mg IV q 3 weeks
B. Carboplatin and paclitaxel
C. Carboplatin, paclitaxel, and pembrolizumab
D. Docetaxel single agent
E. Docetaxel plus nintedanib
Phase III - Keynote 407First-line Carboplatin / Taxane ± Pembrolizumab
Paz Ares et al. ASCO 2018; NEJM
Phase III - Keynote 407First-line Carboplatin / Taxane ± Pembrolizumab
Paz Ares et al. ASCO 2018; NEJM
Phase III - Keynote 407First-line Carboplatin / Taxane ± Pembrolizumab
Paz Ares et al. ASCO 2018; NEJM
Recurrent NSCLC
• Before initiating treatment, you decide to send the specimens for pathology review and the reference lab identified an adenocarcinoma on both the baseline and re-biopsy specimens.
Recurrent adenocarcinoma, PD-L1 5%
What would be the best treatment choice?
A. Pembrolizumab 200 mg IV q 3 weeks
B. Carboplatin and pemetrexed
C. Carboplatin, pemetrexed, and pembrolizumab
D. Carboplatin, paclitaxel, bevacizumab
E. Carboplatin, paclitaxel, bevacizumab, and atezolizumab
Recurrent adenocarcinoma, PD-L1 5%
What would be the best treatment choice?
A. Pembrolizumab 200 mg IV q 3 weeks
B. Carboplatin and pemetrexed
C. Carboplatin, pemetrexed, and pembrolizumab
D. Carboplatin, paclitaxel, bevacizumab
E. Carboplatin, paclitaxel, bevacizumab, and atezolizumab
Phase III - Keynote 189First-line Platinum / Pemetrexed ± Pembrolizumab
Gandhi et al. AACR 2018; NEJM 2018
Gandhi et al. AACR 2018; NEJM 2018
Phase III - Keynote 189First-line Platinum / Pemetrexed ± Pembrolizumab
Gandhi et al. AACR 2018; NEJM 2018
Phase III - Keynote 189First-line Platinum / Pemetrexed ± Pembrolizumab
Reck et al. ESMO 2017
a Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance of treatment
with one or more approved targeted therapies. b Atezolizumab: 1200 mg IV q3w. c Carboplatin: AUC 6 IV q3w. d Paclitaxel: 200 mg/m2 IV q3w. e Bevacizumab: 15 mg/kg IV q3w.
Arm A
Atezolizumabb +
Carboplatinc + Paclitaxeld
4 or 6 cycles
Atezolizumabb
Arm C (control)
Carboplatinc + Paclitaxeld
+ Bevacizumabe
4 or 6 cycles
Bevacizumabe
Su
rviv
al fo
llo
w-u
p
Stage IV or
recurrent metastatic
non-squamous NSCLC
Chemotherapy-naivea
Tumour tissue available
for biomarker testing
Any PD-L1 IHC status
Stratification factors:
• Sex
• PD-L1 IHC expression
• Liver metastases
N = 1202
R
1:1:1
Arm B
Atezolizumabb +
Carboplatinc + Paclitaxeld
+ Bevacizumabe
4 or 6 cycles
Atezolizumabb
+
Bevacizumabe
Maintenance therapy
(no crossover permitted)
Treated with
atezolizumab
until PD by
RECIST v1.1
or loss of
clinical benefit
AND/OR
Treated with
bevacizumab
until PD by
RECIST v1.1
The principal question is to assess whether the addition of atezolizumab to Arm C provides clinical benefit
Phase III – IMPOWER 150Chemotherapy ± Atezolizumab
Socinski et al. ASCO 2018
Phase III – IMPOWER 150Chemotherapy ± Atezolizumab
Socinski et al. ASCO 2018
Phase III – IMPOWER 150Chemotherapy ± Atezolizumab
Recurrent adenocarcinoma
• You really don’t believe the initial lab and the initial PD-L1 evaluation. You find out that the initial lab performed the PD-L1 testing with an unknown antibody.
• You request repeat PD-L1 testing in the reference lab using 22C3 antibody and results now come back with PD-L1 TPS 60%
• EGFR, ALK, ROS are wild-type
Recurrent adenocarcinoma, PD-L1 60%
What would be the best treatment choice?
A. Pembrolizumab 200 mg IV q 3 weeks
B. Carboplatin and pemetrexed
C. Carboplatin, pemetrexed, and pembrolizumab
D. Carboplatin, paclitaxel, bevacizumab
E. Carboplatin, paclitaxel, bevacizumab, and atezolizumab
Recurrent adenocarcinoma, PD-L1 60%
What would be the best treatment choice?
A. Pembrolizumab 200 mg IV q 3 weeks
B. Carboplatin and pemetrexed
C. Carboplatin, pemetrexed, and pembrolizumab
D. Carboplatin, paclitaxel, bevacizumab
E. Carboplatin, paclitaxel, bevacizumab, and atezolizumab
Phase III - Keynote 024First-line Platinum Doublet vs. Pembrolizumab
Reck et al. ESMO 2016; NEJM 2016
Reck et al. ESMO 2016; NEJM 2016
Phase III - Keynote 024First-line Platinum Doublet vs. Pembrolizumab
Brahmer et al. WCLC 2017
Overall Survival: Updated Analysis
0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
T im e , m o n th s
OS
, %
P e m b r o 1 5 4 1 3 6 1 2 1 1 1 2 1 0 6 9 6 8 9 8 3 5 2 2 2 5 0
C h e m o 1 5 1 1 2 3 1 0 7 8 8 8 0 7 0 6 1 5 5 3 1 1 6 5 0
N o . a t r is k
Median (95% CI)30.0 mo (18.3 mo–NR)14.2 mo (9.8 mo–19.0 mo)
70.3%54.8%
aEffective crossover rate from chemotherapy to anti-PD-L1 therapy, 62.3% (82 patients crossed over to pembrolizumab during the study and 12 received anti-PD-L1 therapy outside of crossover). bNominal P value. NR, not reached.Data cutoff: July 10, 2017.
51.5%34.5%
Events, n HR (95% CI)
Pembrolizumaba 73 0.63
(0.47–0.86)
P = 0.002bChemotherapy 96
Phase III - Keynote 024First-line Platinum Doublet vs. Pembrolizumab
0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
T im e , m o n th sO
S,
%
P e m b r o 1 5 4 1 3 6 1 2 1 1 1 2 1 0 6 9 6 8 9 8 3 5 2 2 2 5 0
C h e m o 1 5 1 1 2 3 1 0 7 8 8 8 0 7 0 6 1 5 5 3 1 1 6 5 0
N o . a t r is k
70.3%54.8%
.
51.5%34.5%
Keynote-189 Keynote-024
TPS ≥ 50%
Keynote-189 vs Keynote-024
Gandhi L, et al. AACR 2018; N Engl J Med 378:2078, 2018; Brahmer JR, et al. WCLC 2017.
Keynote-189PD-L1 ≥ 50%
Keynote-024PD-L1 ≥ 50%
Keynote-189 vs Keynote-024
Gandhi L, et al. AACR 2018; N Engl J Med 378:2078, 2018; Reck R, et al. ESMO 2016; N Engl J Med 375:1823, 2016.
Recurrent adenocarcinoma, PD-L1 60%
• You initiate carboplatin, pemetrexed and pembrolizumab every 3 weeks and the patient experiences a partial response.
• After 4 cycles, there is no evidence of disease progression and the patient has no side effects.
Recurrent adenocarcinoma, PD-L1 60%
What would be the next step?
A. Continue with carboplatin, pemetrexed and pembrolizumab for 4 more cycles and repeat scans
B. Discontinue carboplatin and maintain pemetrexed and pembrolizumab
C. Discontinue carboplatin and pemetrexed and maintain pembolizumab single agent
D. Discontinue treatment and resume pembrolizumab at the time of disease progression
Recurrent adenocarcinoma, PD-L1 60%
What would be the next step?
A. Continue with carboplatin, pemetrexed and pembrolizumab for 4 more cycles and repeat scans
B. Discontinue carboplatin and maintain pemetrexed and pembrolizumab
C. Discontinue carboplatin and pemetrexed and maintain pembolizumab single agent
D. Discontinue treatment and resume pembrolizumab at the time of disease progression
Recurrent adenocarcinoma, PD-L1 60%
• You continue pemetrexed and pembrolizumab for 4 additional cycles and the patient experiences significant fatigue. Thyroid function tests and cortisol levels are within normal limits.
• You discontinue pemetrexed and continue pembrolizumab 200 mg IV single agent. The patient continues to experience no evidence of disease progression and fatigue significantly improves.
• After 2.5 months, he develops a dry cough and worsening fatigue. He denies any fever.
• O2 sat is 94% in room air• Angio-CT is negative for pulmonary embolism
Pulmonary infiltrates on pembrolizumab
Pembrolizumab
single agent
for 2.5 months
Pulmonary infiltrates on pembrolizumab
What would be the next step?
A. Obtain a biopsy to rule out disease progression
B. Obtain broncho-alveolar lavage
C. Continue pembrolizumab and repeat scans in 4 weeks
D. Discontinue pembrolizumab and monitor
E. Discontinue pembrolizumab, initiate antibiotics and prednisone 1 mg/kg/day
Pulmonary infiltrates on pembrolizumab
What would be the next step?
A. Obtain a biopsy to rule out disease progression
B. Obtain broncho-alveolar lavage
C. Continue pembrolizumab and repeat scans in 4 weeks
D. Discontinue pembrolizumab and monitor
E. Discontinue pembrolizumab, initiate antibiotics and prednisone 1 mg/kg/day
Management of Pneumonitis
Brahmer et al., JCO 2018
Pulmonary infiltrates on pembrolizumab
• You initiate antibiotics and prednisone for 10 days and the patient experiences a significant improvement in the cough.
Pembro
X 2,5
months
Prednisone
X 10 days
Pulmonary infiltrates on pembrolizumab
What would be the next step?
A. Permanently discontinue pembrolizumab
B. Discontinue prednisone on day 15 and resume pembrolizumab
C. Continue prednisone at the same dose and initiate chemotherapy
D. Taper prednisone slowly over 4-6 weeks and resume pembrolizumab when prednisone < 10 mg/day
Pulmonary infiltrates on pembrolizumab
What would be the next step?
A. Permanently discontinue pembrolizumab
B. Discontinue prednisone on day 15 and resume pembrolizumab
C. Continue prednisone at the same dose and initiate chemotherapy
D. Taper prednisone slowly over 4-6 weeks and resume pembrolizumab when prednisone < 10 mg/day
Pulmonary infiltrates on pembrolizumab
• You decide to taper prednisone slowly and when the dose is at 10 mg/day, you resume pembrolizumab
• Six weeks later the patient has recurrent cough, shortness of breath and SO2 88% in room air
Pembro
X 2
doses
Rechallenge after Toxicities
• 40 patients rechallenged• 18 (45%) did not experience further irAEs• 17 patients (42.5%) experienced a recurrence of the same type of irAE• 5 patients (12.5%) experienced a different type of irAE
Simonaggio et al., JAMA Oncol 2019
Pulmonary infiltrates on pembrolizumab
What would be the next step?
A. Increase prednisone dose to 1 mg/kg/day
B. Methylprednisolone IV 1-2 mg/kg
C. Initiate infliximab
D. Start antibiotics and continue prednisone 10 mg/day and pembrolizumab in order to maintain tumor response
Pulmonary infiltrates on pembrolizumab
What would be the next step?
A. Increase prednisone dose to 1 mg/kg/day
B. Methylprednisolone IV 1-2 mg/kg
C. Initiate infliximab
D. Start antibiotics and continue prednisone 10 mg/day and pembrolizumab in order to maintain tumor response
Management of Pneumonitis
Brahmer et al., JCO 2018
Pulmonary infiltrates on pembrolizumab
• You admit the patient to the hospital, screen for Tb, hepatitis B and C, and HIV, and initiate methylprednisolone 2 mg/kg IV
• You consider bronchoscopy and BAL, but the patient is too ill for the procedures
• After 48 hours the patient does not improve
Pulmonary infiltrates on pembrolizumab
Pulmonary infiltrates on pembrolizumab
• You initiate infliximab 5 mg/kg
• The patient has an excellent clinical response and resolution of the infiltrates on CT scan
• Eight weeks later, he is on prednisone 5 mg/day and has no evidence of disease progression. He is asymptomatic.
Pulmonary infiltrates on pembrolizumab
Do you resume pembrolizumab at this point?
A. Yes
B. No
Pulmonary infiltrates on pembrolizumab
Do you resume pembrolizumab at this point?
A. Yes
B. No
Duration of Therapy
• The patient seeks care elsewhere and another medical oncologist resumes pebrolizumab
• After 2 years of pembrolizumab therapy, the patient has no evidence of disease progression and no side effects
• He returns to your office for an opinion on duration of therapy
Duration of Therapy
Do you stop pembrolizumab at this point?
A. Yes
B. No
C. I don’t know
Duration of Therapy
Do you stop pembrolizumab at this point?
A. Yes
B. No
C. I don’t know
Phase III - CheckMate 153Nivolumab Continuous vs. 1 Year
Spiegel et al. ESMO 2017
Phase III - CheckMate 153Nivolumab Continuous vs. 1 Year
Spiegel et al. ESMO 2017.
Phase III - CheckMate 153Nivolumab Continuous vs. 1 Year
Spiegel et al. ESMO 2017.
Phase II/III - Keynote 010Pembrolizumab vs. Docetaxel in NSCLC
Herbst et al. ESMO 2018
Phase II/III - Keynote 010Pembrolizumab vs. Docetaxel in NSCLC
Herbst et al. ESMO 2018
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