S1630
11S2
Additionally, a phase III study is ongoing to determine the effectiveness
of nivolumab monotherapy compared to chemotherapy in relapsed
SCLC (Checkmate 331). As for atezolizumab, a phase I/III study is
underway to evaluate the efficacy of combination of atezolizumab and
carboplatin/etoposide as first-line treatment of ES-SCLC (IMPOWER
133). In terms of combination of PD-1 inhibitors and CTLA-4 blockade,
Checkmate 032, the first trial evaluating the combination of nivolumab
and ipilimumab in the treatment of patients with SCLC who had pro-
gressed after one or more treatment regimens was reported in ASCO
recently. Both nivolumab monotherapy and nivolumab plus ipilimumab
showed promising anti-tumor activity with durable responses and
manageable safety profiles10. These data prompted nivolumab alone or
nivolumab-ipilimumab combination regimen to be incorporated into
NCCN guidelines for SCLC as second line treatment recommendation.
Moreover, in 2017 ASCO, the updated data from Checkmate032 was
reported. With longer follow up in non-randomized cohort, the
response remains encouraging. 2-year OS could be achieved 14% and
26%, respectively in monotherapy and combination therapy11. In this
setting, a phase III trial, termed Checkmate451 assessing the role of
nivolumab monotherapy, nivolumab-ipilimumab combination and pla-
cebo as maintenance therapy in ES-SCLC and a phase II trial, STIMULI,
in LS-SCLC were initiated. Plus, a phase II trial regarding the trem-
elimumab and durvalumab with or without radiation in relapsed SCLC
patients is ongoing and more data are warranted . However, many
questions remain. The immune microenvironment in SCLC is distinct
from other tumor types for SCLC cells express low levels PD-L1, though
with high mutation burdens. In Checkmate032, there is no observation
on clear association between tumor PD-L1 expression and clinical
benefit. However, as mentioned above, patients with positive PD-L1
expression in the stromal interface had better PFS and OS observed in a
phase II trial9. The prediction value of PD-L1 expression is supposed to
be shifted from tumor cells to surrounding immune cells in SCLC. Thus,
it is important to define a specific biomarker to predict the response to
immunotherapy and explore the distinct tumor microenvironment in
SCLC. Moreover, potential toxicity is not supposed to be under-
estimated, especially the immune-related adverse effects. Immune
related side effects will happen in the course of the treatment. Close
monitoring is essential and oncologists are suggested to balance the
risks and benefits of immunotherapy in the clinical practice. Refer-
ences: 1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J
Med. 2008;359:1367-1380. 2. Rossi A, Di Maio M, Chiodini P, et al.
Carboplatin- or cisplatin-based chemotherapy in first-line treatment of
small-cell lung cancer: the COCIS meta-analysis of individual patient
data. J Clin Oncol. 2012;30:1692-1698. 3. Lehman JM, Gwin ME, Massion
PP. Immunotherapy and Targeted Therapy for Small Cell Lung Cancer:
There Is Hope. Curr Oncol Rep. 2017;19:49. 4. Reck M, Rodriguez-Abreu
D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-
Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823-
1833. 5. Robert C, Long GV, Brady B, et al. Nivolumab in previously
untreated melanoma without BRAF mutation. N Engl J Med.
2015;372:320-330. 6. Alexandrov LB, Nik-Zainal S, Wedge DC, et al.
Signatures of mutational processes in human cancer. Nature.
2013;500:415-421. 7. Gozzard P, Woodhall M, Chapman C, et al. Par-
aneoplastic neurologic disorders in small cell lung carcinoma: A pro-
spective study. Neurology. 2015;85:235-239. 8. Reck M, Luft A,
Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus Eto-
poside and Platinum Versus Placebo Plus Etoposide and Platinum in
Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol. 2016;10.1200/
JCO.2016.67.6601. 9. Gadgeel SM, Ventimiglia J, Kalemkerian GP, et al.
Phase II study of maintenance pembrolizumab (pembro) in extensive
stage small cell lung cancer (ES-SCLC) patients (pts). Journal of Clinical
Oncology. 2017;35:8504-8504. 10. Antonia SJ, Lopez-Martin JA, Bendell
J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent
small-cell lung cancer (CheckMate 032): a multicentre, open-label,
phase 1/2 trial. Lancet Oncol. 2016;17:883-895. 11. Hellmann MD, Ott
PA, Zugazagoitia J, et al. Nivolumab (nivo) ± ipilimumab (ipi) in
advanced small-cell lung cancer (SCLC): First report of a randomized
Journal of Thoracic Oncology Vol. 12 No.
expansion cohort from CheckMate 032. Journal of Clinical Oncology.
2017;35:8503-8503. Keywords: small cell lung cancer, Immuno-
therapy, Immune checkpoint inhibitors
ES 09.05
Management of Paraneoplastic Syndromes in SCLC
L. Crinò Medical Oncology- Istituto Scientifico Romagnolo Per Lo
Studio e La Cura Dei Tumori (IRST) IRCCS, Meldola/IT
Small cell lung cancer (S.C.L.C.) represents approximately 15% of lung
cancers and offers a unique profile of clinical and biological features)
S.C.C.L. is a fast growing tumor with are estimated doubling time of
10 days, high propensity to metastatic diffusion since the early
beginning of the disease, high sensitivity to chemoradiotherapy but
early and common development of pleiotropic drug resistance. Un-
fortunately in the past 30 years very few advances have been realized
in the treatment of S.C.L.C. which in most of the patients is a fatal
disease with a median survival of 16-18 months in limited thoracic
and 11 months in extensive disease. S.C.L.C. is the most common
cancer associated with paraneoplastic syndromes because of its pro-
pensity to release endocrine peptides, ectopic hormones and neo-
antigens that can develop the para neoplastic syndromes.
Paraneoplastic syndromes constitutes different and heterogeneous
clinical conditions associated with cancer development, affecting
various tissues at remote locations from the primary tumor , with an
unpredictable clinical behavior. In SCLC, a large number of paraneo-
plastic syndromes have been reported, involving different organ
functions and complicating the clinical course of the disease, including
endocrine, neurological and miscellaneous less frequent manifesta-
tions. The most common paraneoplastic syndromes in SCLC, can be
divided in ectopic hormone-associated syndromes, and immunome-
diated neurologic syndromes. According to the S.C.L.C. produced
hormones we can recognized among the ectopic hormone-associated
syndromes, the Hyponatremia (10%) of S.C.L.C., the ectropic Cushing
syndrome (5%) Hypertension reninrelated (1%), galactorrhea (1%)
and hyperamylasemia (1%). S.C.L.C. has the unique feature to be often
heralded or accompanied by a number of immune-mediated neuro-
logic syndromes, the Lambert-Eaton myastemic syndrome 1%, the
limbic encephalopaty and the encephalomyelitis, the sensory poly-
neuropathy, the cerebellar degeneration the opsoclonus myoclonus,
all accounting for less than 1%. In most of the cases the neurological
symptoms develop before the onset of clinical overt S.C.L.C manifes-
tation and the stage seems not to be related to the presence of
paraneoplastic neurological syndrome, whose evolution usually mir-
rors the behavior and the clinical manifestation. In most of the cases
the starting of systemic chemotherapy can induce a dramatic
improvement of neurological symptoms in advance to clinical
response, and vice versa the worsening of the neurological condition
can indicate progressive disease and resistance to the treatment. The
study and the improved understanding of pathophisiolgy mechanisms
of paraneoplasic syndromes in SCLC can contribute to elucidate the
natural history of a fascinating and still largely unknown disease
which was erroneously predicted to be a potential curable disease in
the eighty years. From that time the treatment strategies and the
therapeutic results have been only marginally improved and the
undersanding and resolution of paraneoplastic syndromes can
contribute substantially to the cure improvement of SCLC.
ES 09.06
NCI’s Small Cell Lung Cancer Consortium: New
Answers to Old Questions
P. Ujhazy National Cancer Institute, Rockville, MD/US
The worldwide toll in mortality due to small cell lung cancer (SCLC) is
still unacceptable. Based on an analysis conducted by the National