new perspectives in early stage nsclc · reck et al. esmo 2017 a patients with a sensitising egfr...

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

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%

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

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

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%

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

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.

Atezolizumabb +

Carboplatinc + Paclitaxeld

4 or 6 cycles

Atezolizumabb

Arm C (control)

+ Bevacizumabe

4 or 6 cycles

Bevacizumabe

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

Atezolizumabb +

+ 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

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

Phase III - Keynote 024First-line Platinum Doublet vs. Pembrolizumab

Reck et al. ESMO 2016; NEJM 2016

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

T im e , m o n th 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

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

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3

T im e , m o n th sO

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.

• 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.

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

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

• 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

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

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

• You initiate antibiotics and prednisone for 10 days and the patient experiences a significant improvement in the cough.

Pembro

months

Prednisone

X 10 days

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

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

• 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

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

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

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

• 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

• 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.

Do you resume pembrolizumab at this point?

A. Yes

Do you resume pembrolizumab at this point?

A. Yes

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

C. I don’t know

Duration of Therapy

Do you stop pembrolizumab at this point?

A. Yes

C. I don’t know

Phase III - CheckMate 153Nivolumab Continuous vs. 1 Year

Spiegel et al. ESMO 2017

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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