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Page 8 of 13 Abughanimeh et al. J Cancer Metastasis Treat 2020;6:50 I http://dx.doi.org/10.20517/2394-4722.2020.110
[45]
The CheckMate 331 trial (NCT02481830) is an ongoing phase III clinical trial that is comparing
nivolumab to topotecan and amrubicin. The trial estimated complete date is in mid-2021, however, preliminary
data showed no significant difference in overall survival between nivolumab (median of 7.5 months)
and chemotherapy (median of 8.4 months) with a hazard ratio of 0.86 (95%CI: 0.72-1.04).

Pembrolizumab
[46]
The KEYNOTE-028 trial (NCT02054806) , is a phase Ib study that evaluated the safety of pembrolizumab
10 mg/kg every 2 weeks in patients with advanced PD-L1 positive ES-SCLC. This study revealed a promising
[46]
efficacy of pembrolizumab in SCLC with an ORR of 33% (95%CI: 16%-55%) . The KEYNOTE-158
[47]
trial (NCT02628067) , is an ongoing phase II trial, to evaluate the benefit of pembrolizumab in advanced
SCLC. The preliminary results showed an ORR of 18.7% (95%CI: 11.8%-27.4%). The response was higher
in patients who had PD-L1 positive tumor compared to PD-L1 negative tumor (35.7% vs. 6%) . A recent
[47]
[48]
paper was published by Chung et al. who performed a combined analysis of both KEYNOTE-028 and
KEYNOTE-158. The results demonstrated an ORR of 19.3% (95%CI: 11.4%-29.4%) with a median OS of
7.7 months (95%CI: 5.2-10.1 months). As revealed by the KEYNOTE-158 trial, patients who had PD-L1
positive tumor had better ORR and OS. Nevertheless, the NCCN panel added pembrolizumab as a second
[9]
line therapy regardless of the PD-L1 results .
Durvalumab
Durvalumab is another immunotherapy agent that was approved by the FDA in 2020 to be used with
[7]
combined chemotherapy in the first line setting based on the CASPIAN trial . A phase I study evaluated
the use of durvalumab and tremelimumab in patients who had disease progression on at least one
[49]
treatment. The results of this study showed an ORR of 13.3%, PFS of 1.8 months and an OS of 7.9 months .
However, a phase II study did not show sufficient response of durvalumab and tremelimumab when it was
[50]
used with or without radiation .
Atezolizumab
Atezolizumab was approved by the FDA to be used in the front line setting based on the IMpower-133
trial which demonstrated significant improvement in the PFS and OS by adding atezolizumab to
[2]
chemotherapy . However, the use of it in the second line setting is still under study. A recent phase I
trial on 17 patients showed that atezolizumab was tolerated and it had some efficacy with a median OS of
[51]
5.9 months .
There are no doubts that the field of immunotherapy will continue to expand, with many different clinical
trials curently ongoing. Table 2 summarizes some of the trials that investigated immunotherapy in relapsed
small cell lung cancer based on reported studies in literature.

Targeted therapy
Targeted therapy has been an exciting field for different malignancies. Until recently, its use in SCLC
has not been successful . Several trials were done to assess targeted therapies as a single agent or in
[8]
[8]
combination with chemotherapy but many of them did not reach their primary endpoint . These therapies
included bevacizumab, vandetanib, aflibercept, vismodegib, cixutumumab, panobinostat, oblimersen, and
obatoclax [52-58] . However, there are some targeted therapies that have shown some promising results.

Alisertib
Alisertib is an oral aurora kinase A inhibitor . Melichar et al. performed a study to evaluate alisertib use
[8]
[59]
in different relapsed solid malignancies including SCLC. A total of 48 patients with SCLC were enrolled,
with a total overall response rate of 21%. However, the time to progression was only 2.6 months.