Chair, Jacob Sands, MD, Ticiana Leal, MD, and Taofeek K. Owonikoko, MD, PhD, prepared useful Practice Aids pertaining to small cell lung cancer for this CME/MOC activity titled “Facilitating Progress in the Treatment of SCLC: How to Optimize the Use of Current Systemic Options and Accelerate the Clinical Transition of Investigational Approaches.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3WP47ze. CME/MOC credit will be available until March 22, 2024.

1. Dosing
3.2 mg/m2
via intravenous infusion every 21 d
Consider premedication with corticosteroids and serotonin antagonists
NCCN Guidelines3
Lurbinectedin (Selective Inhibitor of Oncogenic Transcription)1,2
• Category 2A recommended option for patients who relapse ≤6 mo or >6 mo following
first-line platinum-based CT
• Recommended option for patients who relapse ≤6 mo with ECOG PS 0-2
• Synthetically produced agent,
originally derived from
Ecteinascidia turbinata
• A selective inhibitor of
oncogenic transcription
Other common adverse events include
lymphopenia, fatigue, increased creatinine,
increased alanine aminotransferase,
increased glucose, nausea, decreased appetite,
musculoskeletal pain, decreased albumin,
constipation, dyspnea, decreased sodium,
increased aspartate aminotransferase,
vomiting, cough, decreased magnesium, and
diarrhea
Indicated for the treatment of adult patients with
metastatic SCLC with disease progression on or
after platinum-based chemotherapy
Granted accelerated FDA
approval on June 15, 2020
based on overall response
rate and duration of response
Neutropenia Leukopenia
Anemia Thrombocytopenia
M
o
s
t
C
o
m
m
o
n
G
r
a
d
e
3
/
4
A
E
s
1
M
e
c
h
a
n
is
m
o
f
A
c
t
io
n
1
46%
9%
29%
7%
ORR by
Investigator
Assessment1
All patients
35.2%
Chemotherapy-free
interval ≥90 d
45.0%
Chemotherapy-free
interval <90 d
22.2%
Tumor
CCL2
Induction of
apoptosis
Monocyte
CCL2
CXCL8
VEGF
Reduced
cancer-related
inflammation
TAM
Inhibition of
cell migration
LURBINECTEDIN
Lurbinectedin: The Newest FDA-Approved Second-Line
Treatment Option in SCLC
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/FSN40
1. Zepzelca (lurbinectedin) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213702s000lbl.pdf. 2. https://www.fda.gov/drugs/drug-approvals-and-databases/
fda-grants-accelerated-approval-lurbinectedin-metastatic-small-cell-lung-cancer. 3. NCCN Clinical Practice Guidelines. Small Cell Lung Cancer. Version 3.2023. https://www.nccn.org/professionals/
physician_gls/pdf/sclc.pdf.

2. Immune Checkpoints
• Activated T cells recognize cognate antigen presented by cancer
cells  TCR triggered  negative regulatory receptor PD-1
expressed  IFN-γ produced  reactive expression of PD-L1
 antitumor T-cell responses turned off
This negative interaction can be blocked by anti–PD-1 or
anti–PD-L1 antibody therapies
– Examples of anti–PD-1 antibodies: nivolumab,
pembrolizumab, cemiplimab-rwlc
– Examples of anti–PD-L1 antibodies: durvalumab,
atezolizumab, avelumab
• CTLA-4 is a negative regulator of costimulation that is required for
initial activation of an antitumor T cell in a lymph node upon
recognition of tumor antigen
This negative interaction can be blocked by anti–PD-1 or
anti–PD-L1 antibody therapies
– Examples of anti–CTLA-4 antibodies: ipilimumab,
tremelimumab
Tumor Microenvironment Lymphoid Tissue
Elimination of tumor cells
Tumor escape
With
Immunotherapy
Without
Immunotherapy
Elimination of tumor cells
Tumor escape
With
Immunotherapy
Without
Immunotherapy
• Proteins on T cells or cancer cells that need to be
activated/inactivated to start/stop an immune response
– Examples include PD-1, PD-L1, CTLA-4
• Serve as “brakes” that help keep immune responses in check and can
prevent T-cell response against cancer cells
• Can be blocked by immune checkpoint inhibitors
– The “brakes” on the immune system are released and T cells are
able to attack and kill cancer cells
PD-1/PD-L1 Checkpoint Inhibition1
CTLA-4 Checkpoint Inhibition1
The Immunotherapy Era in SCLC: Treatment, Adverse
Events, and PD-1/PD-L1 Checkpoint Inhibition
Full abbreviations, accreditation, and disclosure information available at PeerView.com/FSN40

3. Indicated in combination with etoposide and either carboplatin or cisplatin,
as first-line treatment of adult patients with extensive-stage SCLC
Granted FDA approval in combination with etoposide and
either carboplatin or cisplatin as first-line treatment of
patients with extensive-stage SCLC on March 27, 2020
Indicated in combination with etoposide and either carboplatin or cisplatin,
as first-line treatment of adult patients with ES-SCLC
Granted FDA approval in combination with etoposide and
either carboplatin or cisplatin as first-line treatment of
patients with ES-SCLC on March 27, 2020
Indicated in combination with etoposide and either carboplatin or cisplatin,
as first-line treatment of adult patients with extensive-stage SCLC
Granted FDA approval in combination with etoposide and
either carboplatin or cisplatin as first-line treatment of
patients with extensive-stage SCLC on March 27, 2020
Indicated in combination with carboplatin and etoposide for
first-line treatment of adult patients with ES-SCLC
Granted FDA approval in combination with carboplatin and
etoposide for first-line treatment of adult patients with
ES-SCLC on March 18, 2019
Dosing2
1,500 mg every 3 weeks prior to chemotherapy in combination with etoposide and either carboplatin or cisplatin
and then every 4 weeks as a single agent
Most Common AEs (All Grades)2
Nausea
(34%)
Fatigue/
asthenia (32%)
Alopecia
(31%)
Most Common AEs (All Grades)8
Nausea
Fatigue/
asthenia
Alopecia
Diarrhea
Constipation
Decreased
appetite
Outcomes From the CASPIAN Trial: A Randomized, Controlled, Open-Label, Phase 3 Trial4-7
Confirmed Objective Response, n (%)a
Median Duration of Response, mo (95% CI)
Durvalumab +
Platinum-etoposide
(n = 268)
Platinum-
etoposide
(n = 269)
182 (68)
5.1 (4.9-5.3)
156 (58)
5.1 (4.8-5.3)
a
Objective response by investigator review
per RECIST 1.1 is defined as pts with complete
response or partial response on at least one
visit (unconfirmed responses); for confirmed
responses, a confirmatory scan was
required no sooner than 4 weeks after the
initial response.
Outcomes From the IMpower33 Trial: A Double-Blind, Placebo-Controlled, Phase 3 Trial10
b
Assessed in pts in the ITT population who had
measurable disease at baseline. Defined as
confirmed complete response or partial
response by investigator review per RECIST 1.1.
c
Assessed in pts who had a confirmed objective
response. Defined as the time from first
occurrence of a documented objective response
to the time of disease progression as determined
by the investigator (according to RECIST) or
death from any cause, whichever occurred first.
Dosing for ES-SCLC8
1,200 mg every 3 weeks prior to chemotherapy with carboplatin and etoposide; 840 mg every 2 weeks, 1,200 mg every 3 weeks,
or 1,680 mg every 4 weeks following completion of 4 cycles of carboplatin and etoposide
Confirmed Objective Response, n (%)b
Median Duration of Response, mo (range)c
Median Overall Survival, mo (95% CI)
Median PFS, mo (95% CI)
Atezolizumab
(n = 201)
Placebo
(n = 202)
121 (60.2)
4.2 (1.4-19.5)
12.3 (10.8-15.9)
5.2 (4.4-5.6)
130 (64.4)
3.9 (2.0-16.1)
10.3 (9.3-11.3)
4.3 (4.2-4.5)
Durvalumab (PD-L1–Blocking Antibody)2,3
Atezolizumab (PD-L1–Blocking Antibody)8,9
Median Overall Survival, mo (95% CI)
Median PFS, mo (95% CI)
12.9 (11.3-14.7)
5.1 (4.7-6.2)
10.5 (9.3-11.2)
5.4 (4.8-6.2)
The Immunotherapy Era in SCLC: Treatment, Adverse
Events, and PD-1/PD-L1 Checkpoint Inhibition
Full abbreviations, accreditation, and disclosure information available at PeerView.com/FSN40

4. Endocrine
Hyper- or hypothyroidism
Hypophysitis
Adrenal insufficiency
Diabetes
Hepatic
Hepatitis
Renal
Nephritis
Dermatologic
Rash
Pruritus
Psoriasis
Vitiligo
DRESS
Stevens-Johnson
Hematologic
Hemolytic anemia
Thrombocytopenia
Neutropenia
Hemophilia
Ocular
Uveitis
Conjunctivitis
Scleritis, episcleritis
Blepharitis
Retinitis
Respiratory
Pneumonitis
Pleuritis
Sarcoid-like granulomatosis
Cardiovascular
Myocarditis
Pericarditis
Vasculitis
Gastrointestinal
Colitis
Ileitis
Pancreatitis
Gastritis
Neurologic
Neuropathy
Guillain-Barré syndrome
Myelopathy
Encephalitis
Myasthenia
Musculoskeletal
Arthritis
Dermatomyositis
Prevention Anticipation
Treatment
Monitoring Detection
What Are irAEs?
Immune-Related Adverse Events (irAEs)11-14
• Immune checkpoint inhibitors are associated with important clinical benefits, but general immunologic enhancement can also lead
to a unique spectrum of immune-related adverse effects
• Any organ system can be affected, but more commonly occurring are pulmonary (pneumonitis), dermatologic (rash, pruritus,
blisters, ulcers, vitiligo), gastrointestinal (diarrhea, enterocolitis, transaminitis, hepatitis, pancreatitis), and endocrine (thyroiditis,
hypophysitis, adrenal insufficiency) irAEs
The Immunotherapy Era in SCLC: Treatment, Adverse
Events, and PD-1/PD-L1 Checkpoint Inhibition
Full abbreviations, accreditation, and disclosure information available at PeerView.com/FSN40

5. How Should irAEs Be Diagnosed and Managed?
• In general, immunotherapy should be continued with close monitoring, with the exception of some neurologic,
hematologic, and cardiac toxicities
Minimal or No Symptoms; Diagnostic Changes Only
Grade 1
Mild to Moderate Symptoms
Grade 2
• Hold checkpoint inhibitor therapy for most grade 2 toxicities
• Consider resuming immunotherapy when symptoms and/or lab values revert to grade 1
• Corticosteroids (initial dose of 0.5-1 mg/kg/day of prednisone or equivalent) may be administered
Severe or Life-Threatening Symptoms
Grade 3/4
Grade 3 toxicities
• Hold checkpoint inhibitor therapy
• Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/day or methylprednisolone IV 1-2 mg/kg/day)
• If symptoms do not improve within 48-72 hours of high-dose corticosteroid, infliximab may be offered for some toxicities
• Taper corticosteroids over the course of at least 4-6 weeks
• When symptoms and/or laboratory values revert to grade 1, rechallenging with immunotherapy may be considered;
however, caution is advised, especially in those patients with early-onset irAEs; dose adjustments are not recommended
Grade 4 toxicities
• In general, permanent discontinuation of checkpoint inhibitor therapy is warranted, with the exception of
endocrinopathies that have been controlled by hormone replacement
irAEs are often
diagnosed by exclusion;
other causes should be
ruled out (including AEs
of other therapies used),
but immunotherapy-
related toxicity should
always be included in
the differential
There should be a high
level of suspicion that
new symptoms are
treatment related; early
recognition, evaluation,
and treatment of irAEs
plus patient education
are essential for the
best outcome
Depending on severity
of irAEs, management
may require
corticosteroid or other
immunosuppressive
treatment and
interruption or
discontinuation of
therapy
If appropriate
immunosuppressive
treatment is
used, patients generally
recover from irAEs
Use of
immunosuppressive
therapy to manage
irAEs does not appear to
impact response to
immunotherapy
The Immunotherapy Era in SCLC: Treatment, Adverse
Events, and PD-1/PD-L1 Checkpoint Inhibition
Full abbreviations, accreditation, and disclosure information available at PeerView.com/FSN40

6. How Should Pulmonary irAEs Be Diagnosed and Managed?
 Hold immunotherapy with radiographic evidence of pneumonitis progression
 May offer one repeat CT in 3-4 weeks; in patients who have had baseline testing, may offer
a repeat spirometry/DLCO in 3-4 weeks
 May resume immunotherapy with radiographic evidence of improvement or resolution; if no
improvement, should treat as grade 2
 Monitor patients weekly with history, physical examination, and pulse oximetry; may also offer CXR
Grade 3: Severe symptoms
requiring hospitalization; involves
all lung lobes or >50% of lung
parenchyma; limiting self-care
Grade 4: Life-threatening
respiratory compromise; urgent
intervention indicated (intubation)
 Hold immunotherapy until resolution to grades ≤1
 Prednisone 1-2 mg/kg/day and taper by 5-10 mg/week over 4-6 weeks
 Consider bronchoscopy with BAL
 Consider empiric antibiotics
 Monitor patients every 3 days with history, physical examination, and pulse oximetry; consider CXR;
if no clinical improvement after 48-72 hours of prednisone, treat as grade 3
 Discontinue immunotherapy
 Empiric antibiotics; methylprednisolone IV 1-2 mg/kg/day; if no improvement after 48 hours, may add
infliximab 5 mg/kg, or mycophenolate mofetil IV 1 g 2x/day, or IVIG x 5 days, or cyclophosphamide
 Taper corticosteroids over 4-6 weeks
 Pulmonary and infectious disease consults if necessary
 Bronchoscopy with BAL ± transbronchial biopsy
 Patients should be hospitalized for further management
 Pneumonitis: Focal or diffuse inflammation of the lung parenchyma (typically identified on CT imaging)
 Diagnostic work-up: CXR, CT, pulse oximetry; for grade ≥2, may include infectious work-up
Grade 1: Asymptomatic; confined to
1 lobe of lung or <25% of lung
parenchyma; clinical or diagnostic
observations only
Additional considerations
Grade 2: Symptomatic; >1 lobe
of lung or 25%-50% of lung
parenchyma; medical intervention
indicated; limiting instrumental ADL
• GI and pneumocystis prophylaxis may be offered to patients on prolonged steroid use (>12 weeks)
• Consider calcium and vitamin D supplementation with prolonged steroid use
• Bronchoscopy + biopsy; if clinical picture is consistent with pneumonitis, no need for biopsy
The Immunotherapy Era in SCLC: Treatment, Adverse
Events, and PD-1/PD-L1 Checkpoint Inhibition
Full abbreviations, accreditation, and disclosure information available at PeerView.com/FSN40
1. Adapted from: Soularue E et al. Gut. 2018;67:2056-2067. 2. Imfinzi (durvalumab) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761069s035lbl.pdf. 3. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-
durvalumab-extensive-stage-small-cell-lung-cancer. 4. Paz-Ares L et al. Lancet. 2019;394:1929-1939. 5. Goldman JW et al. Lancet Oncol. 2021;22:51-65. 6. Paz-Ares L et al. ESMO Open. 2022;7:100408. 7. Paz-Ares LG et al. ESMO 2021. Abstract LBA61. 8. Tecentriq (atezolizumab)
Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761034s043lbl.pdf. 9. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-extensive-stage-small-cell-lung-cancer. 10. Horn L et al. N Engl J Med.
2018;379:2220-2229. 11. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1786. 12. Postow MA et al. N Engl J Med. 2018;378:158-168. 13. Gordon R et al. Clin J Oncol Nurs. 2017;21(suppl 2):45-52. 14. Champiat S et al. Ann Oncol. 2016;27:559-574.

7. SCLC Treatment Algorithm1
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/FSN40
1. Created by Aakash Desai, MBBS, MPH. Used with permission from the author. 2. Paz-Ares L et al. ESMO Open. 2022;7:100408. 3. Paz-Ares LG et al. ESMO 2021. Abstract LBA61.
SCLC treatment algorithm
Cancer confined to one hemithorax and
regional lymph nodes?
(can be treated with single radiation field)
Stage and workup
CT abd/pelvis, PET/CT scan (if needed), MRI
brain, PFTs, bone marrow biopsy (select cases),
mediastinal staging (stage I-IIA)
Prophylactic cranial irradiation in patients achieving remission (ALL stages);
take into account performance status, comorbidities, and age
Meta-analysis: PCI vs no PCI, RR of death HR: 0.84 (P = .01)
EXTENSIVE STAGE
(stage III or IV disease not eligible for
treatment of curative intent)
LIMITED STAGE
(eligible for treatment
of curative intent)
Stage I-IIA
Pathologic mediastinal
staging
Stage IIB-IIIC
Lobectomy +
mediastinal LN
dissection
>6 mo treatment-free interval?
Platinum-based
chemotherapy
1L: Chemoimmunotherapy
• Carboplatin + etoposide +
atezolizumab with maintenance
atezolizumab
(IMpower133: Chemo + atezo vs
chemo mOS: 12.3 vs 10.3 mo
[HR, 0.70])
• Carboplatin or cisplatin +
etoposide + durvalumab with
maintenance durvalumab
(CASPIAN: Chemo + durva vs
chemo mOS: 12.9 vs 10.5 mo
[HR, 0.71])2,3
Platinum-based
chemotherapy
+ concurrent RT
(JCOG 9104: Concurrent
RT vs sequential RT
mOS: 27.2 vs 19.7 mo,
HR, 0.70)
Best supportive care in consult
with palliative medicine
If ineligible for immunotherapy,
use platinum-based chemotherapy
T1–2, N1, M0
T3–4, Nx, M0
Performance status ≤1
or ≥2 due to SCLC
Performance status ≥2
due to comorbidities
cT1–2, N0, M0
Negative
Limited disease Extensive disease
Yes No
Platinum-based
chemotherapy +
mediastinal RT
pT1-2, N0-1, R0 N2 and/or R1-2
Positive
Relapse
Yes
No
2L: Chemotherapy 2L: Chemotherapy
Rechallenge with original platinum-
based chemotherapy (preferred)
Lurbinectedin
PMB1183-B005014: Single arm
(ORR: 35%, mDOR: 5.1 mo)
Topotecan cyclophosphamide +
doxorubicin + vincristine (CAV)
Lurbinectedin (preferred)
PMB1183-B005014: Single arm
(ORR: 35%, mDOR: 5.1 mo)
Topotecan (preferred)
Trial: Topotecan vs CAV ORR: 23.3%
vs 18.3%
Clinical trials (preferred)
Cyclophosphamide + doxorubicin +
vincristine (CAV)