improving outcomes in advanced nsclc with immune ...•5-year survival rate is 19% (nsclc + sclc)...

Improving Outcomes in Advanced NSCLC with Immune Checkpoint Inhibitors

Pharmacist Implications

This educational activity is sponsored by Postgraduate Healthcare Education, LLC

and supported by an educational grant from Bristol-Myers Squibb.

Faculty

Melvin J. Rivera, PharmD, BCOP

Clinical Pharmacy Specialist

Thoracic/Head and Neck Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX

Dr. Rivera received his Doctor of Pharmacy degree from Northeastern

University, Bouve College of Health Sciences School of Pharmacy, in Boston.

He completed a PGY1 Pharmacy Practice Residency and a PGY2 Hematology/Oncology

Pharmacy Practice Residency at Boston University Medical Center. Currently, he is a

Clinical Pharmacy Specialist at The University of Texas MD Anderson Cancer Center in

Houston, TX specializing in Thoracic/Head and Neck Medical Oncology.

Faculty

Whitney E. Lewis, PharmD, BCOP

Clinical Pharmacy Specialist

Thoracic/Head and Neck Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX

Dr. Lewis is a clinical pharmacy specialist at The University of Texas MD Anderson Cancer

Center. She received her Doctor of Pharmacy degree from the University of Oklahoma

College of Pharmacy in Tulsa. Upon completion of a PGY2 oncology residency at MD

Anderson, she was hired to work with the Department of Thoracic/Head and Neck Medical

Oncology.

Disclosures

Drs. Rivera and Lewis have disclosed that they have no actual or potential conflicts of

interest in relation to this program.

The clinical reviewer, Lisa Holle, PharmD, BCOP, FHOPA, FISOPP has disclosed that

she has served as a consultant for McGraw Hill Education and has received honoraria

from HOPA and PharmCon.

Susanne Batesko, BSN, RN, Robin Soboti, RPh, and Susan R. Grady, MSN, RN, as

well as the planners, managers, and other individuals, not previously disclosed, who

are in a position to control the content of Postgraduate Healthcare Education (PHE)

continuing education activities hereby state that they have no relevant conflicts of

interest and no financial relationships or relationships to products or devices during the

past 12 months to disclose in relation to this activity. PHE is committed to providing

participants with a quality learning experience and to improve clinical outcomes without

promoting the financial interests of a proprietary business.

Postgraduate Healthcare Education, LLC is

accredited by the Accreditation Council for

Pharmacy Education as a provider of continuing

pharmacy education.

UAN: 0430-0000-20-109-H01-P

Credits: 1.5 hour (0.15 CEU)

Type of Activity: Application

Learning Objectives

• Discuss the standard-of-care options for patients with advanced

non–small-cell lung cancer (NSCLC), including immune-oncology

(I-O) therapies

• Examine the emerging data for I-O and I-O combination regimens in

the treatment of advanced NSCLC

• Identify appropriate prognostic and predictive biomarkers in the

treatment of advanced NSCLC with I-O alone or in combination

regimens

• Demonstrate pharmacist-driven strategies to recognize and prevent

or manage toxicities associated with I-O or I-O combination

therapies throughout the continuum of care

ARS Question #1

The combination of Nivolumab and Ipilimumab relative to chemotherapy alone for the frontline treatment of advanced NSCLC with PD-L1>1% has been associated with which of the following outcomes?

o Improvement in overall survival when compared to

chemotherapy

o Improvement in progression free survival when compared to

chemotherapy

o Similar overall survival when compared to chemotherapy

o Similar duration of response when compared to chemotherapy

ARS Question #2

SM comes to clinic for cycle 7 of pembrolizumab and a toxicity check. Her serum creatinine today is 1.4 mg/dL, elevated from a baseline of 0.6. She states she has been eating and drinking normally, has no peripheral edema, is taking no new medications, and has no symptoms of a urinary tract infection. A 24-urine collection is ordered and pembrolizumab therapy is on hold. The urine returns with 2.3 g/24 hours. What is the next step in managing her nephritis?

o Give intravenous fluids and resume pembrolizumab

o Initiate prednisone 2 mg/kg and admit to hospital

o Initiate prednisone 1 mg/kg and infliximab 5 mg

o Initiate prednisone 1 mg/kg and hold pembrolizumab

ARS Question #3

What is the best representation of a combined positive score (CPS) for PD-L1 expression?

oTotal number of mutations per coding area of tumor genome

oPD-L1 cells in the tumor microenvironment (tumor, lymphocytes, macrophages)

oConcentration of tumor-infiltrating lymphocytes

oRatio of neutrophils to lymphocytes

Background/Incidence

• Lung cancer is the leading cause of cancer death in the United States

• In 2020 there will be:

• 228,820 estimated new cases

• 135,720 estimated deaths

• 5-year survival rate is 19% (NSCLC + SCLC)

• From 2009–2015, the relative survival rate for NSCLC was 25%

• Recent overall 5-year survival rates for patients who can receive a targeted therapy or immunotherapy range from 15%–50%

Siegel RL, et al. CA Cancer J Clin. 2020;70:7-30.

SCLC, small-cell lung cancer.

Risk Factors

• Smoking tobacco

• Radon

• Secondhand smoke exposure

• COPD

• Asbestos

• Family history of lung cancer

• Carcinogen exposure• Arsenic, chromium, nickel, cadmium, beryllium, silica, diesel fumes

Torre AL, et al. Adv Exp Med Biol. 2016;893:1-19.

COPD, chronic obstructive pulmonary disease.

Pathology

NSCLC accounts for 80%–85% of all lung cancers

• Non-squamous NSCLC – about 60% of NSCLC cases• Adenocarcinoma, large cell, other less common subtypes

• Adenocarcinoma is most common histology in non-smokers and younger patients

• More likely to have EGFR, ALK mutations, etc.

• Squamous NSCLC – about 30%–40% of NSCLC cases• More likely to occur in smokers

• Generally centrally located

National Comprehensive Cancer Network. Non-Small Cell Lung Cancer. Version 8.2020.

Molecular Targets in NSCLC

• Epidermal growth factor receptor (EGFR) gene mutations

• Anaplastic lymphoma kinase (ALK) fusion oncogene

• C-ros oncogene 1 (ROS1) gene fusion

• BRAF V600E point mutations

• Kirsten rat sarcoma (KRAS) mutations

• Neurotrophic tyrosine receptor kinase (NTRK) gene fusion

• Mesenchymal epithelial transition factor (MET) exon 14 skipping mutation

• Rearranged during transfection (RET) rearrangement

• Programmed death ligand (PD-L1) expression

• Human epidermal growth factor receptor 2 (HER2) mutations

• Tumor mutational burden (TMB)


First-Line Treatment: Metastatic –Breakdown

• First-line treatment of metastatic NSCLC largely dictated by histology and predictive biomarkers

• Driver mutations Preferred treatment recommendation• EGFR mutation Osimertinib*or other EGFR tyrosine kinase inhibitor (TKI)

• ALK translocation Alectinib* (or other ALK inhibitor)

• ROS 1 rearrangement Crizotinib or entrectinib

• BRAF V600E Dabrafenib/trametinib

• MET exon 14 skipping Capmatinib

• RET rearrangement Selpercatinib or pralsetinib

• NTRK gene fusion Larotrectinib or entrectinib


*category 1 recommendation.

Non-squamous NSCLC (no targetable mutations)

• PD-L1 status (preferred treatment recommendations)

• ≥50%: pembrolizumab alone* or platinum/pemetrexed/pembrolizumab*

• ≥1%–49%: platinum/pemetrexed/pembrolizumab*

•

Squamous cell NSCLC (no targetable mutations)

• PD-L1 status (preferred treatment recommendations)

• ≥50%: pembrolizumab alone or carboplatin/paclitaxel or nab-paclitaxel/pembrolizumab*

• ≥1%–49%: carboplatin/paclitaxel or nab-paclitaxel/pembrolizumab*

•

Immunotherapy in NSCLC

• Commercially available checkpoint inhibitors

Bold = FDA approved for NSCLC

PD-1 inhibitors PD-L1 inhibitors CTLA-4 inhibitors

Nivolumab Atezolizumab Ipilimumab

Pembrolizumab Durvalumab

Cemiplimab-rwlc Avelumab

CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FDA, United States Food and Drug Administration; PD-1, programmed cell death protein 1.

Timeline of FDA Approvalsof Checkpoint Inhibitors

2nd-line Frontline Frontline combo

3/2015Nivolumab2nd-line for

SQ met-NSCLC

10/2015 Nivolumab 2nd-line for met-NSCLC

5/2020Nivolumab +

ipilimumab 1st-line for patients with met-NSCLC with PD-L1 >1%

5/2020 Nivolumab + ipilimumab +

chemo 1st-line met-NSCLC

10/2015 Pembrolizumab 2nd-

line met-NSCLC

10/2016 Pembrolizumab 1st-line for met-NSCLC

PD-L1 >50%

5/2017 Pembrolizumab 1st-

line w/chemo for non-SQ met-NSCLC

10/2018 Pembrolizumab

with carboplatin/

paclitaxel or nab-paclitaxel 1st-line

for SQ NSCLC

4/2019Pembrolizumab

1st-line stage III/IV NSCLC if

PD-L1 >1%

10/2016Atezolizumab 2nd-

line met-NSCLC

12/2018Atezolizumab in

combo w/ bevacizumab +

chemo 1st-line for non-SQ met-NSCLC

12/2019Atezolizumab in

combo w/ carboplatin/

abraxane for 1st-line non-SQ met-NSCLC

5/2020Atezolizumab

approved 1st-line for met-NSCLC

with PD-L1 >50%

2/2018Durvalumab

stage III NSCLC after concurrent

chemoradiation

20

15

20

20

met, metastatic; non-SQ, non-squamous; SQ, squamous.

First-Line: Single-Agent Immunotherapy

KEYNOTE-024KEYNOTE-042IMpower110

KEYNOTE-024

Inclusion:

>18 years old

Advanced untreated NSCLC without sensitizing EGFR or ALK mutations

PD-L1 ≥50%

ECOG PS 0–1

Pembrolizumab 200 mg IVq 3 weeks x 35 cycles

(n=154)

Platinum doublet (investigator choice) x 4–6 cycles

(n=151)

Carboplatin/pemetrexedCisplatin/pemetrexed

Carboplatin/gemcitabineCisplatin/gemcitabineCarboplatin/paclitaxel

Phase 3, international, randomized, open-label trial

1:1

Primary endpoint: PFSSecondary endpoints: OS, ORR, safety

Reck M, et al. N Engl J Med. 2016;375(19):1823-33.

Maintenance pemetrexed (allowed

for non-squamous NSCLC)

ECOG PS, Eastern Cooperative Oncology Group Performance Status;ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

KEYNOTE-024

Pembrolizumab(N=154)

Chemotherapy doublet(N=151)

PFS 10.3 months 6 months HR 0.50 (95% CI, 0.37–0.68; p50% vs. standard chemotherapy doublet

CI, confidence interval; HR, hazard ratio; NR, not reported.

KEYNOTE-024

Adverse event (AE) Pembrolizumab (n=154)

Chemotherapy group(n=150)

Any grade (%) Grade 3–5 (%) Any grade (%) Grade 3–5 (%)

Any 113 (73.4) 41 (26.6) 135 (90) 80 (53.3)

Serious 33 (21.4) 29 (18.8) 31 (20.7) 29 (19.3)

Led to discontinuation 11 (7.1) 8 (5.2) 16 (10.7) 9 (6)

Led to death 1 (0.6) 1 (0.6) 3 (2) 3 (2)

AEs in ≥10% of subjects in both groups

Nausea 15 (9.7) 0 65 (43.3) 3 (2)

Anemia 8 (5.20 3 (1.9) 66 (44) 29 (19.3)

Diarrhea 22 (14.3) 6 (3.9) 20 (13.3) 2 (1.3)

Fatigue 16 (10.4) 2 (1.3) 43 (28.7) 5 (3.3)

Pyrexia 16 (10.4) 0 8 (5.3) 0


Immune-related adverse event (irAE)

Pembrolizumab (n=154)

Chemotherapy group(n=150)

Any grade (%) Grade 3–5 (%) Any grade (%) Grade 3–5 (%)

Any 45 (29.2) 15 (9.7) 7 (4.7) 1 (0.7)

Hypothyroidism 14 (9.1) 0 2 (1.3) 0

Hyperthyroidism 12 (7.8) 0 2 (1.3) 0

Pneumonitis 9 (5.8) 4 (2.6) 1 (0.7) 1 (0.7)

Infusion reactions 7 (4.5) 0 2 (1.3) 0

Severe skin reactions 6 (3.9) 6 (3.9) 0 0

Thyroiditis 4 (2.6) 0 0 0

Colitis 3 (1.9) 2 (1.3) 0 0

Myositis 3 (1.9) 0 0 0

Hypophysitis 1 (0.6) 1 (0.6) 0 0

Nephritis 1 (0.6) 1 (0.6) 0 0

Pancreatitis 1 (0.6) 0 0 0

Type 1 diabetes mellitus 1 (0.6) 0 0 0


KEYNOTE-024

• Treatment-related AEs occurred in 73.4% of the pembrolizumab group vs. 90% in the chemotherapy group

• Grade ≥3 AEs occurred twice as often in chemotherapy vs. pembrolizumab group (53.3% vs. 26.6%)

• Discontinuation of treatment occurred in 7.1% of pembrolizumab patients vs. 10.7% of chemotherapy patients

• Most common AEs:• Pembrolizumab: diarrhea (14.3%), fatigue (10.4%), and pyrexia (10.4%)

• Chemotherapy: anemia (44%), nausea (43.3%), and fatigue (28.7%)

KEYNOTE-024


KEYNOTE-042

Inclusion:

≥18 years old

Advanced untreated NSCLC with no sensitizing EGFR or ALK mutation

PD-L1 >1%

ECOG PS 0–1

Life expectancy >3 months

Pembrolizumab 200 mg IV q 21 daysup to 35 cycles

(n=637)

Carboplatin (AUC 5–6) +paclitaxel 200 mg/m2 or

pemetrexed 500 mg/m2 IVq 21 days x 4–6 cycles

(n=637)

Phase 3, international, randomized, open-label study

1:1

Primary endpoint: OS (PD-L1 ≥50%, ≥20%, and ≥1%)Secondary endpoint: PFS, ORR

Mok TSK, et al. Lancet. 2019;393(10183):1819-30.

Maintenance pemetrexed (allowed for non-squamous NSCLC)

KEYNOTE-042


Platinum doublet(n=637)

OS: TPS ≥50% 20 months 12.2 months HR 0.69 (95% CI, 0.56–0.85), p=0.0003

OS: TPS ≥20% 17.7 months 13 months HR 0.77 (95% CI, 0.64–0.92), p=0.0020

OS: TPS ≥1% 16.7 months 12.1 months HR 0.81 (95% CI, 0.71–0.93), p=0.0018

OS: TPS 1%–49% 13.4 months 12.1 months HR 0.92 (95% CI, 0.77–1.11)

TPS, tumor proportion score.


KEYNOTE-042



PFS: TPS ≥50% 7.1 months 6.4 months HR 0.81 (95% CI, 0.67–0.99), p=0.017

PFS: TPS ≥20% 6.2 months 6.6 months HR 0.94 (95% CI, 0.80–1.11)

PFS: TPS ≥1% 5.4 months 6.5 months HR 1.07 (95% CI, 0.94–1.21)



ORR: TPS ≥50% 39% 32%

ORR: TPS ≥20% 33% 29%

ORR: TPS ≥1% 27% 27%


KEYNOTE-042

• Adverse effect of interest:• Pembrolizumab group (n=636): 28% (grade ≥3, 8%)• Chemotherapy group (n=615): 7% (grade ≥3, 1%)

• Grade ≥3 immune-mediated toxicities that occurred in >5 patients in pembrolizumab group:

• Pneumonitis• Severe skin reactions• Hepatitis only


IMpower110

Inclusion:

Stage IV NSCLC

PD-L1 >1%

Measurable disease by RECIST

ECOG PS 0–1

Atezolizumab 1200 mg IVq 21 days up to 58 months

(n=550)

Platinum doublet q 21 days x 4–6 cycles(n=537)

Non-squamous: Cisplatin 75 mg/m2 or carboplatin AUC 6 on day 1 + pemetrexed 500 mg/m2

Squamous: Cisplatin 75 mg/m2 day 1 + gemcitabine 1250 mg/m2

(days 1 & 8)Carboplatin AUC 5 day 1 + gemcitabine 1000 mg/m2

(days 1 & 8)


1:1

Primary outcome: OSSecondary outcome: PFS, ORR, DOR

Spigel D, et al. Ann Oncol. 2019;30(5):v915.

Maintenance pemetrexed (allowed for non-squamous NSCLC)

DOR, duration of response; RECIST, Response Evaluation Criteria in Solid Tumours.

IMpower110

Atezolizumab(n=550)


PD-L1 >50% 20.2 months 13.1 months HR 0.595 (95% CI, 0.398–0.890), p=0.0106



Spigel D, et al. Ann Oncol. 2019;30(5):v915.

IMpower110

Adverse event (%)

Atezolizumab(n=286)

Chemotherapy (n=263)

Grade 3/4 86 (30.1) 138 (52.5)

Related grade 3/4 (%) 37 (12.9) 116 (44.1)

Grade 5 11 (3.8) 11 (4.2)

Related grade 5 0 1 (0.4)

AE leading to any therapy withdrawal

18 (6.3) 43 (16.3)

irAE 115 (40.2) 44 (16.7)

Grade 3 or 4 irAE 19 (6.6) 4 (1.5)

irAE requiring steroids 30 (10.5) 3 (1.1)

Jassem, et al. J Clin Oncol. 2020;38:suppl.e21623.

First-Line: Chemotherapy-Immunotherapy Combinations

KEYNOTE-189

KEYNOTE- 407

CHECKMATE 9LA

IMpower150

IMpower130

IMpower131

Combining Cytotoxic Chemotherapy and Checkpoint Inhibitors

• Combining chemotherapy with immunotherapy• Cytotoxic agents may enhance antigen cross-presentation by dendritic cells

after destruction of tumor cells

• Inhibiting myeloid-derived suppressor cells

• Increased ratio of cytotoxic lymphocytes to regulatory T-cells

• Blocking STAT 6 pathway, which conversely suppresses dendritic cell activity

Gandhi L, et al. N Engl J Med. 2018;378(22):2078-92.

Inclusion:

≥18 years old

Metastatic non-squamous NSCLC w/o sensitizing EGFR or ALK mutations

No previous systemic therapy

ECOG PS 0–1

Tumor evaluable by RECIST

Provide sample for PD-L1 status

Pembrolizumab 200 mg IV q 3 weeks for up to 35 cycles

+ cisplatin 75 mg/m2 or carboplatin AUC 5+ pemetrexed 500 mg/m2 IV q 3 weeks

x 4 cycles(n=410)

Placebo IV q 3 weeks for up to 35 cycles+

cisplatin 75 mg/m2 or carboplatin AUC 5+ pemetrexed 500 mg/m2 IV every 3

weeks x 4 cycles(n=206)

Phase 3, international, randomized, double-blind study

2:1

Primary endpoint: OS, PFSSecondary endpoints: ORR, DOR, safety

Gandhi L, et al. N Engl J Med. 2018;378(22):2078-92.

Maintenance pemetrexed

Maintenance pemetrexed

KEYNOTE-189

Pembrolizumab + platinum doublet Platinum doublet + placebo

Median OS NR 11.3 months HR 0.49 (95% CI, 0.38–0.64); p

• Grade ≥3 AEs occurred in 67.2% of patients receiving pembrolizumab + chemo vs. 65.8% of chemotherapy alone

• Discontinuation rate due to toxicity higher in pembrolizumab combination group than in chemotherapy alone

• 13.8% vs. 7.9%

• Nausea, anemia, and fatigue were the most common AEs in both groups

• irAEs in the pembrolizumab combination group vs. chemotherapy alone: 22.7% vs. 11.9%, respectively

• Grade ≥3: 8.9% vs. 4.5%, respectively

Gandhi L, et al. N Engl J Med. 2018;378:2078-92.

KEYNOTE-189

IMpower150

Inclusion:

Stage IV or recurrent metastatic non-squamous NSCLC

No prior treatment

ECOG PS 0–1

Tissue tumor available for biomarker testing

Eligible to receive bevacizumab

Any PD-L1 status eligible

Atezolizumab 1200 mg + carboplatin AUC 6 + paclitaxel 200 mg/m2 (ACP) IV

q 21 days x 4–6 cycles (n=402)

Atezolizumab 1200 mg + bevacizumab 15 mg/kg +

carboplatin AUC 6 + paclitaxel 200 mg/m2 (ABCP)

IV q 21 days x 4–6 cycles(n=400)

Bevacizumab 15 mg/kg + carboplatin AUC 6 + paclitaxel 200 mg/m2 (BCP) IV

q 21 days x 4–6 cycles(n=400)


Primary endpoint: PFS, OSSecondary endpoints: PFS and OS in patients with EGFR or ALK mutations; PFS in PD-L1 subgroups

1:1:1

Socinski M, et al. N Engl J Med. 2018;378(24):2288-301.

Maintenance atezolizumab


and bevacizumab

Maintenance bevacizumab

Atezolizumab + bevacizumab + carboplatin +

paclitaxel (ABCP)

Bevacizumab + carboplatin +

paclitaxel (BCP)

OS* 19.2 months 14.7 months HR 0.78 (95% CI, 0.64–0.96); p=0.02

PFS 8.3 months 6.8 months HR 0.62 (95% CI, 0.52–0.74); p

IMpower150

• Subgroup analysis• PFS in EGFR mutations and ALK translocations

• 9.7 months vs. 6.1 months (HR 0.59; 95% CI, 0.37–0.94)

• PFS in low or negative PD-L1 (50%)


• PFS in patients with liver metastases


• PFS in KRAS mutation positive



IMpower150

• Safety• Grade 1 or 2 AEs more common in BCP than in ABCP group

• 45.4% vs. 35.9%

• Most common grade 3/4 AEs in both groups were neutropenia, decreased neutrophil count, febrile neutropenia, and hypertension

• 5 deaths in ABCP group attributed to pulmonary hemorrhage or hemoptysis

• 4 of 5 occurred in patients with high-risk features

• Tumor cavitation of great vessels, centrally located tumor, hemoptysis at baseline


IMpower130

Inclusion:

≥18 years old

Stage IV non-squamous NSCLC

ECOG PS 0–1

No previous chemotherapy

Known PD-L1 tumor status

Treated asymptomatic CNS mets

Adequate end-organ function

ALK or EGFR sensitizing mutation who progressed on at least 1 TKI allowed on trial

Atezolizumab 1200 mg IV q 3 weeks + carboplatin AUC 6 IV q 3 weeks + nab-

paclitaxel 100 mg/m2 IV weeklyx 4–6 cycles

(n=451)

Carboplatin AUC 6 IV q 3 weeks + nab-paclitaxel 100 mg/m2 IV weekly

x 4–6 cycles(n=228)

2:1

Phase 3, international, randomized, open-label trial

Primary endpoint: PFS and OSSecondary endpoint: PFS and OS in per PD-L1 expression, ORR, DOR

West H, et al. Lancet Oncol. 2019;20(7):924-37.

Best supportive

care or

switch pemetrexed maintenance


CNS, central nervous system.

IMpower130

Atezolizumab + chemotherapy (n=451)

Chemotherapy alone(n=228)

PFS 7 months 5.5 months HR 0.64 (95% CI, 0.54–0.77)

OS 18.6 months 13.9 months HR 0.79 (95% CI, 0.64–0.98)

RR 49.2% 31.9%

PFS at 6 months 56.1% 42.5%

PFS at 12 months 29.1% 14.1%

OS at 12 months 63.1% 55.5%

OS at 24 months 39.6% 30%

• Subgroup analysis found OS and PFS benefits regardless of PD-L1 expression• Patients with liver metastasis or EGFR mutation or ALK translocation were not found to

have benefits with the addition of atezolizumab


RR, response rate.

IMpower130

• Safety• Grade 3/4 AEs occurred at a higher rate in the atezolizumab/chemotherapy

group than the chemotherapy group • 81% vs. 71%

• Most common AEs (grade ≥3) were neutropenia, anemia, and decreased neutrophil count

• Serious AEs among atezolizumab/chemotherapy patients vs. chemotherapy alone occurred: 51% vs. 38%, respectively

• irAEs occurred in 45% of atezolizumab/chemotherapy patients • Rash (24%), hypothyroidism (15%), and hepatitis (10%) were the most common irAEs


KEYNOTE-407

Inclusion:

Metastatic squamous NSCLC

Treatment-naïve

ECOG PS 0–1

(n=559)

Carboplatin + paclitaxel ORcarboplatin + nab-paclitaxel

with placebo(n=281)

Maintenance placebo

Carboplatin + paclitaxel ORcarboplatin + nab-paclitaxel

with pembrolizumab(n=278)

Maintenance pembrolizumab

Phase 3, randomized, double-blind, placebo-controlled trial

1:1 randomization

Paz-Ares L, et al. N Engl J Med. 2018;379(21):2040-51.

x 4 cyclesPrimary outcomes: OS, PFSSecondary outcomes: ORR, DOR x 35 cycles

Chemotherapy doses per 21-day cycle:• Carboplatin AUC 6 day 1• Paclitaxel 200 mg/m2 day 1 or nab-paclitaxel 100 mg/m2 days 1, 8, & 15• Pembrolizumab 200 mg day 1

KEYNOTE-407

• Overall survival• 15.9 months (95% CI, 13.2 to NR) vs. 11.3 months (95% CI, 9.5–14.8), p

KEYNOTE-407


KEYNOTE-407

Adverse events Pembrolizumab + chemo (%) Placebo + chemo (%)

Grade 3–5 69.8 68.2

Any grade event leading to discontinuation of treatment:

Pembrolizumab/placeboCarboplatinPaclitaxel/nab-paclitaxel

17.311.215.8

7.97.5

10.0

Event leading to death attributed to treatment

3.6 2.1


KEYNOTE-407


IMpower131

Inclusion:

Metastatic squamous NSCLC

Treatment-naïve

ECOG PS 0-1

(n=1021)

Carboplatin + nab-paclitaxel(n=340)

Carboplatin + nab-paclitaxelwith atezolizumab

(n=343)


Carboplatin + paclitaxel +atezolizumab

(n=338)


Phase 3, randomized, double-blind trial

Jotte R, et al. J Thorac Oncol. 2020;15(8):1351-60.

1:1:1

Primary outcomes: OS, PFSSecondary outcomes: OS and PFS in PD-L1 subgroups, safety, ORR, DOR

Chemotherapy doses per 21-day cycle:• Carboplatin AUC 6 day 1• Paclitaxel 200 mg/m2 day 1 or nab-paclitaxel 100 mg/m2 days 1, 8, & 15• Atezolizumab 1200 mg day 1

x 4–6 cycles

x 4–6 cycles

x 4–6 cycles

Score Percentage of PD-L1–expressing cellsTC3 or IC3 ≥50% of TC or ≥10% of IC

TC2/3 or IC2/3 ≥5% of TC or IC

TC1/2/3 or IC1/2/3 ≥1% of TC or IC

TC1/2 or IC1/2 ≥1% of TC or IC and

• Overall survival: 14.2 months vs. 13.5 months (p=0.15)• PD-L1 ≥50%: 23.4 vs. 10.2 months, HR 0.48 (95% CI, 0.29–0.81)

• Progression-free survival by independent review: 6.9 months vs. 5.7 months (HR 0.8 [95% CI, 0.67–0.96], p

Investigator-assessed PFS (A) and OS (B) in the intention-to-treat population


IMpower131

PD-L1 subgroups Atezo + chemo Chemo HR (95% CI)

TC3 or IC3 23.4 10.2 0.48 (0.29–0.81)

TC2/3 or IC2/3 20.4 14.5 0.72 (0.52–1.00)

TC1/2/3 or IC 1/2/3 14.8 15.0 0.86 (0.67–1.11)

TC 1/2 or IC 1/2 12.8 15.5 1.08 (0.81–1.45)

TC0 or IC0 14.0 12.5 0.87 (0.67–1.13)

OS in biomarker subgroups in the intention-to-treat population at final analysis


IMpower131

Immune-related adverse eventA+CP (%) A+CnP (%) CnP (%)

All grades Grades 3–5 All grades Grades 3–4 All grades Grades 3–4

Rash 24.7 1.8 23.1 1.8 11.7 0.3Hepatitis (lab abnormality) 16.9 3.3 17.7 5.7 8.1 0.9Hypothyroidism 10.5 0 11.1 0.6 0.9 0Pneumonitis 7.5 3 7.5 1.5 1.5 0.9Hyperthyroidism 3.6 0 3.6 0.3 0.3 0Infusion-related reaction 3.3 0.3 0.6 0 0 0Hepatitis (diagnosis) 1.8 0.6 0.9 0.3 0.9 0.3Colitis 1.5 0.6 1.8 1.2 0 0Diabetes mellitus 0.9 0.3 1.2 0.9 0.3 0Adrenal insufficiency 0.6 0 0.6 0.3 0 0Meningitis 0.3 0.3 0.9 0 0 0Meningoencephalitis 0.3 0.3 0.9 0 0 0Severe cutaneous reaction 0.3 0.3 0.6 0 0.3 0Myositis 0.3 0 0.3 0 0.3 0Pancreatitis 0.3 0.3 0.6 0.3 0 0Ocular inflammatory toxic 0.3 0 0.3 0.3 0 0Autoimmune hemolytic anemia 0 0 0.3 0.3 0 0Guillain-Barré syndrome 0.3 0.3 0 0 0 0Nephritis 0.3 0 0 0 0 0Vasculitis 0.3 0.3 0 0 0 0Rhabdomyolysis 0 0 0.3 0 0 0

A+CP, atezolizumab+carboplatin+paclitaxel; A+CnP, atezolizumab+carboplatin+nab-paclitaxel; CCOD, clinical cutoff date; CnP, carboplatin+nab-paclitaxel.


IMpower131

First-Line: Dual Checkpoint Inhibition

CheckMate 227

CheckMate 9LA

CheckMate 227

Inclusion:

Metastatic NSCLC

Treatment-naïve, ECOG PS 0–1

No EGFR or ALK mutation

(n=1739)

PD-L1 ≥1%

Nivo + ipi(n=396)

Chemo (n=397)

Nivo (n=396)

PD-L1

CheckMate 227

Ramalingam S, et al. ASCO 2020:A9500.

3-year update: OS with nivolumab + ipilimumab vs. chemo vs. nivolumab + chemo PD-L1 ≥ 1%

CheckMate 227

3-year update: PFS of PD-L1

CheckMate 227

PD-L1 ≥1% PD-L1

CheckMate 227

Nivolumab + ipilimumab (n=139) Chemo (n=160)

1-year PFS (%) 42.6 13.2

Median PFS (months) 7.2 (95% CI, 5.5–13.2) 5.5 (95% CI, 4.4–5.8)

ORR (%) 45.3 26.9

OS (months) 23.03 16.72

Grade 3/4 ADEs (%) 31.2 36.1

Hellman M, et al. N Engl J Med. 2018;378(22):2093-104.

OS for patients with high TMB was not statistically significant (95% CI, 0.61–1.00)

Outcomes reported for high-TMB population

*Inclusion criteria: ≥10 mutations/megabase

ADE, adverse drug event.

CheckMate 9LA

Reck M, et al. ASCO 2020:A9501.

Inclusion:

Metastatic NSCLC

No EGFR or ALK mutation

Treatment-naïve, ECOG PS 0–1

(n=719)

Nivolumab 360 mg q 3 weeks + ipilimumab 1 mg/kg q 6

weeks + chemo(n=361)

Nivolumab + ipilimumab

for up to 2 years

Chemo (n=358)Maintenance pemetrexed

(optional for non-squamous) or observation

1:1 randomization

Phase 3, randomized, open-label trial

Primary endpoint: OSSecondary endpoints: PFS, ORR, efficacy by PD-L1 expression

2 cycles

4 cycles

Non-squamous: carboplatin or cisplatin + pemetrexedSquamous: carboplatin + gemcitabine

CheckMate 9LA


CheckMate 9LA

Ipi + nivo + chemo Chemo Statistical significance

OS by histology (months):SquamousNon-squamous

14.5 (95% CI, 13.1–19.4)17.0 (95% CI, 14.0 to NR)

9.1 (95% CI, 9.9–14.1)11.9 (95% CI, 7.2–11.6)

HR 0.62HR 0.69

Median PFS (months) 6.7 (95% CI, 5.6–7.8) 5.0 (95% CI, 4.3–5.6) HR 0.68

ORR (%) 38 25 OR 1.9

DOR (months) 11.3 (95% CI, 8.5 to NR) 5.6 (95% CI, 4.4–7.5) NR


NR, not reached; OR, odds ratio.

CheckMate 9LA

Ipi + nivo + chemo Chemo

Any grade Grade 3/4 Any grade Grade 3/4

Any ADE (%) 92 47 88 38

ADEs leading to discontinuation

19 16 7 5

Treatment-related deaths

2 2


Summary of Trials

PD-L1 ≥50% PD-L1 1%–49% Chemo + immuno Dual immuno

Regimen • Pembrolizumab• Atezolizumab

• Pembrolizumab • Platinum/peme/pembro• Carbo/pacli/atezo/bev• Carbo/n-pac/atezo• Carbo/pacli/pembro

• Ipi + nivo*• Ipi + nivo +

chemo

ORR 44.8% pembrolizumab, not reported for atezolizumab

NR 47.6%–63.5% 36.4%–45.3%

Median PFS(months)

10.3 for pembrolizumab, not reported for atezolizumab

7.1 6.4–8.8 5.1–7.2

Median OS(months)

NR (HR for death 0.6) for pembro, 20.2 for atezo

13.4 14.2–19.2 15.6–23.0

DOR (months) NR 20.2 7.3–11.2 11.3–23.2

*Including PD-L1 ≥1% and TMB-high populations

Therapeutic Considerations

• Treatment landscape of NSCLC is more complicated than ever

• For treatment planning, consider:• PD-L1 %

• Histology

• Performance status

• Comorbid conditions

• Mutational status

Subsequent-Line TherapyCHECKMATE 017

CHECKMATE 057

KEYNOTE-010

OAK Trial

Checkpoint Inhibitors asSubsequent-Line Therapy Options

• Role of immunotherapy in the “subsequent” line of treatment is largely dependent on whether patients received previous treatment with checkpoint inhibitors

• PD-1 checkpoint inhibitors nivolumab and pembrolizumab are FDA approved for use in NSCLC that has progressed following platinum-based therapy

• Pembrolizumab requires TPS ≥1%

• PD-L1 checkpoint inhibitor atezolizumab is FDA approved for use in

NSCLC that has progressed following platinum-based therapy

CHECKMATE 017/057 — Nivolumab

5-year follow-up found sustained benefit for nivolumab in both OS and PFS• 5-year OS: 13% vs. 3% (HR 0.68 [95% CI, 0.59–0.78])• 5-year PFS: 8% vs. 0% (HR 0.79 [95% CI, 0.68–0.92])

CHECKMATE 017 CHECKMATE 057

Borghaei H, et al. N Engl J Med. 2015; 373(17):1627-39.; Brahmer J, et al. N Engl J Med. 2015;373(2):123-35.; Gettinger S, et al. J Thor Oncol. 2019;14(10):S244-5.

KEYNOTE-010 — Pembrolizumab

• Long-term follow-up (median 42 months) showed continued benefit of pembrolizumab in metastatic NSCLC patients who received pembrolizumab as subsequent therapy

• 36-month OS: PD-L1 ≥50%: 34.5% vs. 12.7% and PD-L1 >1%: 22.9% vs. 11%• 79 of 690 patients (11%) completed 35 cycles (2 years) of therapy

Herbst RS, et al. J Clin Oncol. 2020;38(14):1580-90.; Herbst RS, et al. Lancet. 2016;387(10027):1540-50.

OAK Trial — Atezolizumab

Atezolizumab Docetaxel

Pop. N (%) mOS(months)

2-year OS (%)

N (%) mOS(months)

2-year OS (%)

OS HR (95% CI)

PR/CR 62 (15) NE 77 57 (13) 22.7 48 0.35 (0.19–0.64)

SD 148 (35) 17.3 33 177 (42) 13 27 0.73 (0.57–0.97)

PD 185 (44) 7.2 17 117 (28) 6.4 7 0.76 (0.59–0.98)

ITT 425 (100) 13.8 31 42 (100) 9.6 21 0.75 (0.64–0.88)

Rittmeyer A, et al. Lancet. 2017;389(10066):255-65.;Von Pawell J, et al. Eur J Cancer. 2019;107:124-32.

Update: Long-term survival by best overall response

CR, complete response; ITT, intention-to-treat; mOS, median overall survival; PD, progressive disease; PR, partial response; SD, stable disease.

Summary of Second-Line Treatment Recommendations

• Non-Squamous Cell NSCLC• No previous checkpoint inhibitor

• PD-L1 ≥1%: pembrolizumab, nivolumab, or atezolizumab

• PD-L1

Predictive/Prognostic Biomarkersin NSCLC

Predictive/Prognostic Biomarkers in NSCLC

• Biomarker: a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions

• Current biomarkers of interest include:• PD-L1

• TMB

• Tumor-infiltrating lymphocytes (TILs)

• Tumor-specific genotypes (EGFR, ALK, KRAS, etc.)

• Gene expression signatures (IFN-gamma)

• Serum-based biomarkers (NLR, bTMB)

Bodor JN, et al. Cancer. 2020;126(2):260-70.;McKean WB, et al. American Society of Clinical Oncology Educational Book. 2020;40:e275-91.

Predictive/Prognostic Biomarkers in NSCLC — PD-L1

• Measured by IHC• TPS: tumor proportion score

• Percentage of viable tumor cells showing partial or complete membrane staining at any intensity

• CPS: combined positive score

• Number of PD-L1 staining tumor and immune cells relative to all viable tumor cells

• Only biomarker validated for its predictive utility in NSCLC in both treatment-naïve patients and in those who progressed on standard chemotherapy

• Remains controversial: different testing platforms, different cutoff points for expression among different agents, and heterogenous nature of PD-L1 expression on tumors

• Inconsistent predicter of response – not all high PD-L1 expressors respond to therapy while some with low expression have benefits


Predictive/Prognostic Biomarkers in NSCLC — TMB

• Total number of mutations, including both base substitutions and short insertions/deletions, per coding area of a tumor genome

• Assessed with whole-exome sequencing or NGS (FoundationOne CDxassay)

• High TMB and response to immune checkpoint therapy has been correlated in studies

• CheckMate227• PFS: increased in high TMB (>10 mutations/megabase), irrespective of PD-L1, in patients who

received combination immunotherapy in first-line setting (HR 0.58; 95% CI, 0.41–0.81)• OS: statistically nonsignificant benefit of ipilimumab with nivolumab in patients with high TMB

(HR 0.77; 95% CI, 0.56–1.06)

• Limitations• Lack of assay standardization• Lack of fixed definition of “high” TMB threshold


NGS, next-generation sequencing.

Predictive/Prognostic Biomarkers in NSCLC — TILs

• Checkpoint inhibition leads to T-cell activity by blockade of PD-1 and CTLA-4, leading to infiltration of CD4+ and CD8+ within tumoral parenchyma

• High density of TILs is considered to reflect greater immune recognition of tumor cells in a patient and represents a T-cell–inflamed tumor microenvironment

• Continued research necessary to determine thresholds of TIL density


Predictive/Prognostic Biomarkers in NSCLC —Gene Expression Signatures

• Rapidly expanding tool for evaluation of tumoral response to ICI

• Immune gene signature, in particular IFN-gamma, may predict response to immunotherapy

• POPLAR • Patients with tumors with high IFN-gamma–associated gene signature found improved

survival with atezolizumab treatment (HR 0.43; 95% CI, 0.24–0.77)

• IMpower150• Low expressors of IFN-gamma found to have benefit (HR 0.76; 95% CI, 0.60–0.96)

• High expressors found to have more robust benefit (HR 0.51; 95% CI, 0.38–0.68)


Predictive/Prognostic Biomarkers in NSCLC —Tumor-Specific Genotypes

• Single-driver mutation testing potential for determining response to therapy

• EGFR- and ALK-positive tumors: lower levels of response in single-agent checkpoint inhibitor trials

• Lower levels of PD-L1 expression

• High density of inactive TILs

• Many early checkpoint inhibitor trials excluded patients with EGFR or ALK mutations

• KRAS-mutant NSCLC may have increased response to immunotherapy• STK11/LKB1 co-mutations may have inferior response to immunotherapy

• IMpower150 retrospective analysis of ALK+ or EGFR+ patients• Improved PFS compared to standard chemotherapy (HR 0.59; 95% CI, 0.37–

0.94) with addition of VEGF inhibitor to platinum doublet and immunotherapy


Predictive/Prognostic Biomarkers in NSCLC —Serum-Based Biomarkers

• Neutrophil to lymphocyte ratio (NLR): easily calculated from differential

• High baseline ratio potentially a negative prognostic indicator• High neutrophil/low lymphocyte infiltration is thought to promote angiogenesis and

inhibit cell apoptosis → tumorigenesis and poorer outcomes

• Potential role as early marker of response• Small retrospective studies to date

• Blood tumor mutational burden (bTMB)• Positive correlation between blood and tumor samples in second-line

atezolizumab in the NSCLC population• Retrospective analysis found greater bTMB to be predictive of longer PFS

• Analysis suggested bTMB of >16 mutations per megabase may be clinically meaningful cutoff point for “high” TMB


Biomarkers and Adverse Effects

• Cytokines appear to be important markers of irAEs• Melanoma patients with high IL-6: risk of toxicity increased

• Decreased levels of pretreatment circulating IL-6, IL-8, soluble IL-2, and IL-17: associated with increased risk of ipilimumab-induced colitis

• Presence of autoantibodies: may predict increase in toxicity (anti-thyroidglobulin); diabetes autoantibodies hastened the development of clinical diabetes

• Role of biomarkers for predicting toxicity undefined and requires further investigation


IL, interleukin.

Pitfalls of Current Biomarker Use

• Intratumoral heterogeneity• Diversity and subclonal population within tumor may not be adequately biopsied • May not represent actual response to immunotherapy• NSCLC and melanoma studies suggest subclonal neoantigen heterogeneity is enriched in poor response• May limit predictive yield of certain biomarkers (TMB)

• Tumor microenvironment• Interplay between tumor cell and microenvironment plays role in response

• Interpatient variation/host immunity• Polymorphisms amongst HLA alleles• TCR sequence diversity may be related to immune therapy response

• Chronologic change• Dynamic change of tumoral subpopulation over time limit use of static biomarkers

• Sample collection and evaluation• Variable preanalytical processing and clinical interpretation

• Example: PD-L1 IHC has multiple assays and not always interchangeable

• NSCLC samples in studies have shown poor concordance

HLA, human leukocyte antigen; IHC, immunohistochemistry; TCR, T-cell receptor.


Future Implications of Biomarkers

• Unlikely a single biomarker will be predictive enough for all types of therapies

• Future biomarkers should be multifaceted and comprehensive, including guidance of which immunotherapeutic agent to use

• Development of early-on biomarkers to determine response or lack thereof

• Development of non-invasive methods of assessment


Toxicity Management

National Comprehensive Cancer Network. https://www.nccn.org/about/news/newsinfo.aspx?NewsID=1008.

Toxicity Management Guidelines/Resources

• National Comprehensive Cancer Network (NCCN)• Management of Immunotherapy-Related Toxicities

• Society for Immunotherapy of Cancer (SITC)• Immune Checkpoint Inhibitor-Related Adverse Events

• American Society of Clinical Oncology (ASCO)• Management of Immune-Related Adverse Effects in Patients

Treated with Immune Checkpoint Inhibitor Therapy

• European Society for Medical Oncology (ESMO)• Management of Toxicities from Immunotherapy

American Society of Clinical Oncology. https://ascopubs.org/doi/10.1200/jco.2017.77.6385.;European Society for Medical Oncology. https://www.esmo.org/guidelines/supportive-and-palliative-care/toxicities-from-immunotherapy.;National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.;Society for Immunotherapy of Cancer. https://www.sitcancer.org/research/cancer-immunotherapy-guidelines/irae/immune-checkpoint-inhibitor-related-adverse-events.

https://ascopubs.org/doi/10.1200/jco.2017.77.6385https://www.esmo.org/guidelines/supportive-and-palliative-care/toxicities-from-immunotherapyhttps://www.nccn.org/professionals/physician_gls/pdf/nscl.pdfhttps://www.sitcancer.org/research/cancer-immunotherapy-guidelines/irae/immune-checkpoint-inhibitor-related-adverse-events

Toxicity: Timing of Onset

Ramalingam S, et al. ASCO 2020:A9500.

Toxicity Management Monitoring

Body system Baseline assessment Follow-up monitoring Monitoring after discontinuation

General bloodwork Baseline CBC, CMP Every 4 weeks Every 6–12 weeks, or as indicated

Pancreatic None None if asymptomatic N/A

Thyroid TSH, free T4 Every 4–6 weeks Every 12 weeks as indicated

Adrenal/pituitary Serum cortisol, TSH, free T4 Prior to each treatment or every 4 weeks

Every 6–12 weeks

CBC, complete blood count; CMP, comprehensive metabolic panel; TSH, thyroid-stimulating hormone.


General Principles of irAE Management

• Grade 1: continue and monitor closely

• Grade 2: hold and initiate symptomatic management (i.e., topical steroids for rash), consider steroids

• Grade 3–4: Hold or permanently discontinue and start steroids

• For endocrine-related side effects, steroids are generally not recommended


General Principles of Corticosteroids

• Steroids are the main treatment for irAEs

• Steroid use for irAE management has not been shown to mitigate patient response to immune checkpoint therapy

• If no resolution on steroids after a few days to 1 week, add concomitant immunomodulatory therapies

• DO NOT taper off steroids just because another agent is being added and patient did not have adequate response to steroid therapy

• Taper steroids over 4 weeks only after resolution to grade ≤1• Longer tapers may be required to prevent flares—particularly with

hepatitis and pneumonitis

• Consideration of rechallenge is organ-specific

Prophylaxis for Corticosteroids

• Consider PJP prophylaxis for patients on ≥20 mg prednisone for 4 weeks

• Consider fluconazole prophylaxis for patients on ≥20 mg prednisone for 6–8 weeks

• Consider H2 receptor antagonist or proton pump inhibitor for patients at high risk of gastritis (concomitant NSAIDs, anticoagulation)

• Consider calcium and vitamin D, physical therapy, and weight-bearing exercises for osteoporosis prevention

• Consider herpes zoster prophylaxis for reactivation

NSAIDs, non-steroidal anti-inflammatory drugs; PJP, Pneumocystis jirovecii pneumonia.


Non-Steroidal Agents for Grade 3–4 irAE Management

Toxicity Agents Toxicity Agents

Pruritus • Gabapentin, pregabalin• Aprepitant• Omalizumab

Myocarditis • Anti-thymocyte globulin• Infliximab• IVIG• Mycophenolate

Bullous dermatitis

• IVIG• Prednisone + rituximab

Myasthenia gravis • IVIG• Plasmapheresis• Rituximab (if refractory)

Colitis • Vedolizumab• Infliximab

Guillain-Barretransverse myelitis

• IVIG• Plasmapheresis

Hepatitis • Mycophenolate mofetil 0.5–1 g BID Arthritis • Rheumatology consult for additional agents

Pneumonitis • Infliximab• IVIG• Mycophenolate mofetil 1–1.5 g BID

Nephritis • Azathioprine• Monthly cyclosporine• Cyclosporine• Infliximab• Mycophenolate

IVIG, intravenous immune globulin.


• JP comes to clinic for a scheduled follow-up appointment for toxicity check prior to cycle 5 of carboplatin/paclitaxel/pembrolizumab with a recent decline in PS.

• JP complains of new, persistent headaches and profound fatigue.

• Routine bloodwork reveals CBC WNL, electrolytes WNL (with the exception of mild hyponatremia), TSH 0.2 mcU/mL, and free T4 0.7 ng/dL. Physical exam reveals orthostatic hypotension.

• The team is concerned for hypophysitis and orders brain MRI with pituitary cuts, ACTH, and a cortisol-stimulation test. Brain MRI reveals inflammation in the pituitary gland; bloodwork comes back with ACTH 4 pg/mL and the stimulation test is low.

Case #1

ACTH, adrenocorticotropic hormone; MRI, magnetic resonance imaging; WNL, within normal limits.

Case Question #1

What is the appropriate management for JP’s newly diagnosed hypophysitis?

oContinue chemoimmunotherapy; initiate levothyroxine and hydrocortisone supplementation

oHold chemoimmunotherapy; initiate 1 mg/kg prednisone, levothyroxine, and hydrocortisone

oHold chemoimmunotherapy; initiate hydrocortisone today and initiate levothyroxine in 5 days

oContinue chemoimmunotherapy and initiate prednisone

Hypophysitis Education Pearls

• Educate patient on need for medical alert bracelet and stress-dose steroids

• Endocrinology consult

• Consider also checking LH, FSH, testosterone, estradiol, and prolactin

• OK to resume immunotherapy once symptoms resolve

FSH, follicle-stimulating hormone; LH, luteinizing hormone.

• PC is a 64-year-old female with metastatic adenocarcinoma of the lung, Kras G12C-mutation positive. She presents to clinic today for cycle 6 of carboplatin/pemetrexed/pembrolizumab with a restaging CT showing stable disease with 1 station 7 LN with 2-mm growth. Her blood counts are as follows:

• PC is admitted to the hospital, chemotherapy is on hold, and she is started on 1.5 mg/kg/day IV methylprednisolone.

Case #2

WBC 9.5k/mcL Cl 109 Phos 2.7 mg/dL

Hgb 8.9 mg/dL CO2 31 mEq/L Mag 2.0 mg/dL

Plt 153k/mcL SCr 1.05 mg/dL AST 357 U/L

Na 137 mg/dL BUN 15 ALT 409 U/L

K 4.7 mg/dL Calcium 8.5 mg/dL Bili 0.9 mg/dL

CT, computed tomography; LN, lymph node.

Case Question #2

72 hours after her admission, PC’s AST is 709, ALT is 1020, and bili is stable at 0.9 mg/dL. What is the appropriate next step?

o Continue steroids and add infliximab 5 mg IV x 1

o Increase steroids to 2 mg/kg IV daily

o Discontinue steroids and start tacrolimus

o Continue steroids and add mycophenolate mofetil 1 g BID

AST, aspartate aminotransferase; ALT, alanine aminotransferase; bili, bilirubin.

Agents in the Pipeline

• CITYSCAPE: atezolizumab + tiragolumab (anti-TIGIT antibody)• First-line treatment with PD-L1+ NSCLC

• Improved ORR (37.3% vs. 20.6%) and PFS (5.6 vs. 3.9 months) vs. atezolizumab alone

• Durvalumab + tremelimumab ± chemotherapy• No OS benefit—not likely to see in practice

• Tislelizumab (anti–PD-1) + carboplatin + paclitaxel/nab-paclitaxel vs. chemo in squamous NSCLC

• Combination had improved ORR, PFS, DOR but OS immature in all 3 arms

• Pembrolizumab + vorinostat: improved ORR and disease control rate 91%

• Docetaxel + nintedanib for 2L NSCLC: ORR 50%, mPFS 6.5 months, mOS12.4 months; 52% had grade 3 AEs and 30% discontinued due to AEs

Leighl NB, et al. ASCO 2020;A9502.; Grohe C et al. ASCO 2020;A9604.;Rodriguez-Abreu D, et al. J Clin Oncol. 2020;38(15):A9503.; Saltos AN, et al. ASCO 2020;A9567.; Wang J, et al. ASCO 2020;A9554.

mOS, median overall survival;mPFS, median progression-free survival.

Questions & Answers

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