Immunotherapy and Small-Cell Lung Cancer

Dr.Yasar Ahmed
 Small-Cell Lung Cancer
 SCLC accounts for ~ 13% of all lung cancer Lung Cancer Incidence by Histology
2010-2014
 Previously called oat-cell carcinoma
Other Large-cell carcinoma
3% 2%
 Associated with a history of significant Small-cell
Adenocarcinoma
carcinoma
tobacco use
Other 13%
 Unique biology: rapid proliferation, non-small- 47%
cell 12%
abrupt presentation, bulky central tumor carcinomas

, hematogenous metastases at onset 23%

 Poor outcomes Squamous and

transitional cell carcinoma
Historic Management of Small-Cell Lung Cancer
 Historic standard therapy has been platinum + etoposide
‒ Phase II studies of cisplatin/etoposide date back to the 1970s
‒ Initially very effective (high response rates, symptom improvement)
‒ Transient benefit
‒ Progression expected within 6 mos of starting therapy
‒ Median survival limited to 8-10 mos
‒ At relapse, fairly refractory to therapy
‒ > 40 phase III trials challenging first-line treatment of SCLC have failed to
show improved OS
History of Cancer Immunotherapy:
Key Milestones Atezolizumab
IFN-α as adjuvant Pembrolizumab and
nivolumab approved approved for
Discovery of therapy for melanoma advanced UC and
dendritic cell for advanced
melanoma metastatic NSCLC
BCG Discovery of checkpoint
approved inhibitors
for bladder
Tumor-specific cancer
monoclonal Abs First immunotherapy Nivolumab Nivolumab
approved for prostate approved approved
cancer (sipuleucel-T) for RCC for HL
Adoptive T-cell
immunotherapy

1970s 1980s 1990s 2000s 2011 2014 2015 2016

Immune component IL-2 approved Nivolumab

for RCC and Pembrolizumab
to spontaneous First checkpoint approved for
melanoma (US) approved for
regressions in inhibitor (ipilimumab) NSCLC HNSCC
melanoma approved for
advanced melanoma Pembrolizumab
First tumor-associated
antigen cloned (MAGE-1) approved for
PD-L1+ NSCLC

References in slidenotes.
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 High expectations for immunotherapy in SCLC

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Immunotherapy and Small-Cell Lung Cancer

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Genetic Alterations in SCLC: No Clear Targetable
Oncogenic Driver
 Nearly all tumors have loss or
inactivation of TP53 and RB1
 MYC family member amplification is
common
‒ MYC-L1 > N-MYC > C-MYC
‒ Recurrent RFL-MYCL1 fusions have
been described
 Additional alterations include:
‒ FGFR1 amplification (6%)
‒ SOX2 amplification (27%)
‒ Recurrent point mutations in
chromatin modifiers: CREBBP, EP300,
MLL (~ 10-20%)
‒ Inactivating mutations in NOTCH
family genes (25%)
‒ EZH2, regulator of chromatin
remodeling implicated in acquired
resistance
Immunotherapy and SCLC: High Expectations,
Modest Outcomes: KEYNOTE 158
 KEYNOTE 158: Single-arm phase II study of pembrolizumab
‒ 107 patients with previously treated SCLC
‒ ORR (primary endpoint): 18.7%
‒ Median PFS: 2.0 mos (95% CI: 1.9-2.1)
‒ Median OS: 8.7 mos (95% CI: 5.6-12.0)
CheckMate 032: Phase I/II Study of Nivolumab ±
Ipilimumab in Multiple Tumor Types
 CheckMate 032: multiarm, open-label trial included cohort of patients
with SCLC that progressed after ≥ 1 platinum-based therapy
Endpoint Nivolumab Nivolumab 1 mg/kg + Nivolumab 3 mg/kg +
3 mg/kg ipilimumab 3 mg/kg ipilimumab 1 mg/kg
(n = 98) (n = 61) (n = 54)
ORR, % 10 23 19
Median PFS, mos 1.4 2.6 1.4
1-yr OS, % 33 43 35
Median OS, mos 4.4 7.7 6.0
Grade ≥ 3 AEs, % 13 30 19
CheckMate 032: Results
 CheckMate 032: nivolumab monotherapy for third (or later)-line
treatment of SCLC
‒ Included patients from randomized and nonrandomized cohorts who had
received ≥ 2 prior lines of therapy (n = 109)
‒ Median follow-up: 28.3 mos
‒ ORR: 11.9% (95% CI: 6.5% to 19.5%)
‒ Median DoR: 17.9 mos (range: 3.0-42.1)
‒ Median OS: 5.6 mos (95% CI: 3.1-6.8)
‒ Grade ≥ 3 AEs: 11.9%
 CheckMate 032: Third (or Later)-line Nivolumab in
Small-Cell Lung Cancer
100
August 16, 2018: FDA accelerated approval
80 Nivolumab indicated for patients with metastatic SCLC with
progression after platinum-based chemotherapy and at least
1 other line of therapy[2]
60
OS (%)[1]

40
12-mo OS: 28.3%
18-mo OS: 20.0%
20

3L+ nivolumab
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Mos
1. Ready. J Thorac Oncol. 2019;14:237. 2. Nivolumab PI. 2018.
Immunotherapy as Monotherapy in SCLC: Conclusions
 High expectations tempered by modest outcomes
 Durable responses possible, but not likely
 Nivolumab approved as later-line therapy based on CheckMate 032
ORR of 11.9%
 Greatest opportunity to affect disease is in first-line setting
‒ More patients able to derive benefit (high attrition in SCLC).
‒ Leverage initial response to chemotherapy
Combination Immunotherapy Regimens in SCLC
First-line Immunotherapy/Chemotherapy Combinations
in SCLC
 Combination strategies appealing
‒ Chemotherapy can promote antigen release to antigen-presenting cells
‒ Chemotherapy can suppress regulatory T-cell activity
‒ Atezolizumab can be safely combined with platinum-based therapy [1]
 Led to development of IMpower 133 trial
IMpower133: Atezolizumab + Chemotherapy for
Advanced SCLC
 Double-blind, randomized, placebo-controlled phase I/III trial

Stratified by sex,
ECOG PS 0 vs 1, brain Induction: 4 x 21-day cycles Maintenance
metastases: yes vs no
Atezolizumab 1200 mg IV on Day 1 +
Carboplatin AUC 5 mg/mL/min IV on Day 1 +
Etoposide 100 mg/m² on Days 1-3 Atezolizumab
Patients with
(n = 201) PD or
measurable ES-SCLC;
ECOG PS 0 or 1; no
loss of
earlier systemic clinical
Placebo + benefit
therapy for ES-SCLC
Carboplatin AUC 5 mg/mL/min IV on Day 1 + Placebo
(N = 403)
Etoposide 100 mg/m² on Days 1-3
(n = 202)

 Coprimary endpoints: OS, PFS by investigator assessment

 Secondary endpoints: ORR, DoR, safety
IMpower133: Baseline Characteristics

Characteristic Atezolizumab + Carbo/Etop Placebo + Carbo/Etop

(n = 201) (n = 202)
Median age, yrs (range) 64 (28-90) 64 (26-87)
Age, n (%)    
 < 65 yrs 111 (55) 106 (52)
 ≥ 65 yrs 90 (45) 96 (48)
Male sex, n (%) 129 (64) 132 (65)
Smoking status, n (%)
 Current smoker 74 (36.8) 75 (37.1)
 Former smoker 118 (58.7) 124 (61.4)
ECOG PS, n (%)    
0 73 (36) 67 (33)
1 128 (64) 135 (67)
Brain metastases present, n (%) 17 (9) 18 (9)
Liver metastases present, n (%) 77 (38) 72 (36)
 IMpower133: Response Rates
 No difference in response rate 70
64.4
60.2
60 Atezolizumab + CP/ET
 Ongoing responses* Placebo + CP/ET
50
‒ Atezolizumab: 15%

Response (%)
40
‒ Placebo: 5.4%
30
20.9 21.3
20
10.9
10 6.9
2.5 1.0
0
CR CR/PR SD PD

*Data cutoff April 24, 2018.

IMpower133: PFS
100 Rate of PFS, % (95% CI)
At 6 Mos At 12 Mos
Atezolizumab 30.9 (24.3-37.5) 12.6 (7.9-17.4)
80
Placebo 22.4 (16.6-28.2) 5.4 (2.1-8.6)
HR: 0.77 (95% CI: 0.62-0.96; P = .02)
60
PFS (%)

Median in the atezolizumab group:

40 5.2 mos (95% CI: 4.4-5.6)

Median in the
20 placebo group,
4.3 mos (95% CI:
4.2-4.5)
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Mos
IMpower133: OS
100 Rate of OS at 12 Mos, % (95% CI)
Atezolizumab 51.7 (44.4-59.0)
80 Placebo 38.2 (31.2-45.3)

HR: 0.70 (95% CI: 0.54-0.91; P = .007)

60
OS (%)

40

20
Median in the placebo group, Median in the atezolizumab group,
10.3 mos (95% CI: 9.3-11.3) 12.3 mos (95% CI: 10.8-15.9)
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Mos
IMpower 133: Adverse Events

Events, n (%) Atezolizumab + Carbo/Etop Placebo + Carbo/Etop

(n = 198) (n = 196)
≥ 1 AE 198 (100) 189 (96.4)
Grade 3/4 AEs  133 (67.2) 125 (63.8) 
Treatment-related AEs 188 (94.9) 181 (92.3)
Serious AEs 74 (37.4) 68 (34.7)
Immune-related AEs 79 (39.9) 48 (24.5)
AEs leading to withdrawal from any study medication 22 (11) 6 (3.1)
 Atezolizumab or placebo 21 (10.6) 5 (2.6)
 Carboplatin 5 (2.5) 1 (0.5)
 Etoposide 8 (4.0) 2 (1.0)
Treatment-related deaths  3 (1.5)  3 (1.5)

 Median duration of treatment with atezolizumab: 4.7 mos (range: 0-21)

 Median no. of doses received: atezolizumab: 7 (range: 1-30); chemotherapy: carboplatin: 4; etoposide: 12
IMpower 133: Treatment- and Immune-Related AEs

AEs, n (%) Atezolizumab + Carbo/Etop Placebo + Carbo/Etop

(n = 198) (n = 196)
Treatment-related AEs > 5% in either group Gr 1/2 Gr 3/4 Gr 5 Gr 1/2 Gr 3/4 Gr 5
 Neutropenia 26 (13.1) 45 (22.7) 1 (0.5) 20 (10.2) 48 (24.5) 0
 Anemia 49 (24.7) 28 (14.1) 0 41 (20.9) 24 (12.2) 0
 Decrease in neutrophil count 7 (3.5) 28 (14.1) 0 12 (6.1) 33 (16.8) 0
 Thrombocytopenia 12 (6.1) 20 (10.1) 0 14 (7.1) 15 (7.7) 0
 Leukopenia 15 (7.6) 10 (5.1) 0 10 (5.1) 8 (4.1) 0
 Febrile neutropenia 0 6 (3.0) 0 0 12 (6.1) 0
Immune-related AEs > 1% in either group
 Rash 33 (16.7) 4 (2.0) 0 20 (10.2) 0 0
 Hepatitis 11 (5.6) 3 (1.5) 0 9 (4.6) 0 0
 Infusion-related reaction 7 (3.5) 4 (2.0) 0 9 (4.6) 1 (0.5) 0
 Pneumonitis 3 (1.5) 1 (0.5) 0 3 (1.5) 2 (1.0) 0
 Colitis 1 (0.5) 2 (1.0) 0 0 0 0
 Pancreatitis 0 1 (0.5) 0 0 2 (1.0) 0
First-line Chemotherapy + Immunotherapy in SCLC
 Addition of concurrent atezolizumab to carboplatin and etoposide
‒ Improved OS (HR for death: 0.70)
‒ No new safety signals identified
‒ Did not compromise ability to complete 4 full cycles of chemotherapy
 Atezolizumab plus carboplatin and etoposide: approved by FDA on
March 18, 2019, for first-line treatment of extensive-stage SCLC
 New standard of care and the first improvement in SCLC survival in
> 30 yrs
Optimal Sequencing of Immunotherapy in SCLC:
CheckMate 331
 Can immunotherapy be reserved for later lines of therapy?
 CheckMate 331: phase III trial of nivolumab vs chemotherapy for second-line treatment of SCLC

Patients with SCLC and  Negative study

recurrence or PD after
≥ 4 cycles of platinum  Did not improve survival: HR: 0.86 (95% CI: 0.72-1.04;
CT or CRT; ECOG PS 0 Nivolumab P = .11)
or 1; no symptomatic (n = 284)
CNS metastases and Nivolumab Chemotherapy
no earlier therapy with (n = 284) (n = 285)
anti–CTLA-4, anti- Topotecan or
CD37, or anti–PD-L1 or Amrubicin Median PFS, mos 1.5 3.8
anti–PD-L2 agents (n = 285)
Median OS, mos 7.5 8.4
(N = 569)
ORR, % 13.7 16.5
Primary endpoint: OS
Optimal Sequencing of Immunotherapy in SCLC
(IMpower133: OS)
100 Rate of OS at 12 Mos, % (95% CI)
Atezolizumab 51.7 (44.4-59.0)
80 Placebo 38.2 (31.2-45.3)

HR: 0.70 (95% CI: 0.54-0.91; P = .007)

60
OS (%)

40

20
Median OS in the placebo group: Median OS in the atezolizumab group:
10.3 mos (95% CI: 9.3-11.3) 12.3 mos (95% CI: 10.8-15.9)
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Mos
 Is concurrent use necessary or is maintenance therapy sufficient?
Optimal Sequencing of Immunotherapy in SCLC:
Maintenance Pembrolizumab
 Can immunotherapy be reserved for later lines of therapy?
 Maintenance pembrolizumab 200 mg IV Q3W studied in patients with
ES-SCLC with response to or SD after platinum + etoposide
chemotherapy (N = 45)
‒ Primary endpoint: PFS
‒ Target: 3 mos (based on historical data)
‒ Negative trial (median PFS: only 1.4 mos; 95% CI: 1.3-2.8)
Optimal Sequencing of Immunotherapy in SCLC:
CheckMate 451
 Can immunotherapy be reserved for later lines of therapy?
 CheckMate 451: randomized, double-blind phase III study of maintenance
nivolumab vs nivolumab + ipilimumab vs placebo

Patients with ES-SCLC and Nivolumab

SD after first-line platinum-  Negative study
based CT; ECOG PS 0 or 1;
no symptomatic Nivolumab + Ipilimumab  Did not improve survival
CNS metastases; no
autoimmune disease
(N = 940)
Placebo
Brain Metastases
 Common site of disease involvement in SCLC
‒ For asymptomatic brain metastases, clinical practice has typically been standard
chemotherapy and whole-brain radiation therapy after chemotherapy started or
complete
 IMpower133 excluded patients with untreated brain metastases[1]
‒ Patients with treated asymptomatic brain metastases could be included
 How should these patients be managed?
‒ Given typical pace of disease, there is a need to avoid delays in starting
chemotherapy for patients with extracranial symptoms (particularly dyspnea,
SVC syndrome)
Brain Metastases
 Although more data needed, available evidence from IMpower133 did
not identify any significant safety signals in patients treated with
prophylactic cranial irradiation or palliative radiation on therapy
 How should these patients be managed?
‒ Chemotherapy alone followed by WBRT
‒ Chemotherapy plus atezolizumab followed by WBRT
‒ Extrapolation of existing data
Toxicity Management
Pneumonitis With Immune Checkpoint Therapy
 Potentially fatal complication
‒ Early recognition and intervention is critical
‒ New/worsening hypoxia or symptoms must be assessed quickly
Management of Immune-Mediated Adverse Events
 Management generally based on severity of symptoms
‒ Mild (grade 1): supportive care, consider holding drug
‒ Moderate (grade 2): hold drug, redose if toxicity improves, consider
low-dose steroids (prednisone 0.5-1 mg/kg/day)
‒ Severe (grade 3): discontinue drug, monitor closely (likely inpatient), start
high-dose steroids (prednisone 1-2 mg/kg/day) with a slow taper (≥ 1 mo)
‒ If not improving in 1-3 days, increase immunosuppression
 Dose reduction is not a recommended strategy
 Avoid delays in recognition and intervention
Summary: Immunotherapy in SCLC
 Atezolizumab + carboplatin and etoposide followed by atezolizumab
maintenance therapy as first-line therapy for ES-SCLC
‒ Improved OS (HR for death: 0.70); first improvement in decades
‒ No significant impact on tolerability or toxicity
‒ New standard of care for ES-SCLC
 Second-line and maintenance strategies have failed
 There remains room for improvement
‒ Need to build on the success of IMpower 133
 Prevention will have the biggest impact!
Take home message