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Abughanimeh et al. J Cancer Metastasis Treat 2020;6:50 I http://dx.doi.org/10.20517/2394-4722.2020.110 Page 3 of 13

patients who received topotecan had better improvement in symptoms including dyspnea (P = 0.002),
anorexia (P = 0.042), fatigue (P = 0.032), and hoarseness (P = 0.043).

[13]
Later in the early 2000s, a phase III clinical trial was conducted by O’Brien et al. to compare oral (PO)
topotecan to supportive care alone. This study demonstrated prolonged survival with topotecan compared
to supportive care. Moreover, it showed that patients who received topotecan had greater symptoms control
and slower quality of life deterioration.

[14]
Eckardt et al. performed a randomized phase III clinical trial to compare PO topotecan with IV
topotecan in relapsed SCLC. In this study, 309 patients were included, 153 patients received oral topotecan
2
2
2.3 mg/m daily for five consecutive days every three weeks whereas 151 received IV topotecan 1.5 mg/m
daily for five consecutive days every three weeks. The study showed similar ORR in both arms of 18.3%
vs. 21.9% respectively. There was no difference in median time to response (6.1 weeks for both), median
duration of response (18.3 weeks vs. 25.4 weeks), and median time to progression (11.9 weeks vs. 14.6 weeks).

Hematologic complications have been commonly reported with topotecan. Despite having lower risk
of grade 4 neutropenia compared to CAV, topotecan has higher risk of grade 4 thrombocytopenia and
[12]
anemia . Non-hematologic toxicities were also reported such as fatigue, alopecia, nausea, and other
gastrointestinal complications [11,12,14] .

2
Another study from Germany showed that a lower dose of topotecan 1.25 mg/m had a similar efficacy
2
[15]
to the traditional dose of 1.5 mg/m , but most importantly it was associated with reduced toxicity . It
is worth mentioning that there have been some studies which evaluated the usage of weekly topotecan
instead of the standard regimen, however the results were not conclusive and weekly topotecan is no longer
[9]
routinely used in clinical practice .
Lurbinectedin
Lurbinectedin is a synthetic analog of trabectedin, which acts through inhibition of the active transcription
protein-coding genes. This drug binds to CG-rich regions in the DNA causing irreversible arrest
of elongating RNA polymerase on the DNA template, leading to accumulation of DNA breaks and
apoptosis [10,16] .

[17]
This drug was first studied in humans in 2009 when Elez et al. conducted a phase I clinical trial in
patients with advanced solid tumors and showed both safety and anti-tumor effect. Later, lurbinectedin was
studied in combination with doxorubicin in patients with relapsed SCLC. The study showed tolerability and
[18]
an overall response rate of 57.7% .
Recently, a single arm, multicenter, phase II clinical trial was conducted on 105 patients who were treated
2
with 3.2 mg/m of IV lurbinectedin every 3 weeks. Among them, 45 patient were considered to have
resistant disease (defined as chemotherapy-free interval < 90 days) and 60 patients with sensitive disease
(defined as chemotherapy-free interval ≥ 90 days). The study showed an ORR of 35.2% (95%CI: 26.2-45.2).
Patients with sensitive disease had better ORR, [45% (95%CI: 32.1-58.4)] compared to the resistant disease
group [22.2% (95%CI: 11.2-37.1)]. The overall median duration of response was 5.3 months (95%CI: 4.1-
6.4), which was also higher in the sensitive disease group 6.2 (95%CI: 3.5-7.3) vs. 4.7 (95%CI: 2.6-5.6). In
this study, the median progression free survival (PFS) was 3.5 months (95%CI: 2.6-4.3) and the median
[16]
OS was 9.3 months (95%CI: 6.3-11.8), both were also better in the sensitive disease group . These results
led to accelerated approval by the FDA to be used in patients with metastatic SCLC after progression on
platinum-based chemotherapy. The National Comprehensive Cancer Network (NCCN) guidelines included
lurbinectedin as a “preferred” agent in the second line treatment options along with topotecan or clinical
[9]
trials .