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Table 1. Clinical trials of chemotherapy agents in the setting of recurrent/relapsed SCLC
Agent Clinical trial design Median Median progression Median overall Median duration
response rate free survival survival of response
Topotecan Phase III, IV topotecan vs. CAV [12] 24.3% 13.3 weeks 25 weeks 14.4 weeks
Phase III PO topotecan vs. supportive care [13] 7% 16.3 weeks 25.9 weeks Not reported
Phase III, IV vs. PO topoteca n[14] 18.3% - PO; 11.9 weeks -PO; 33 weeks - PO; 18.3 weeks - PO
21.9% - IV 14.6 weeks - IV 35 weeks - IV 25.4 weeks - IV
Lurbinectedin Phase II, single arm 2nd line [16] 35.2% 3.5 months 9.3 months 5.3 months
Irinotecan Phase II, single arm 2nd line [19] 47% Not reported 187 days 58 days
Phase II, single arm 2nd line [21] 41.3% 4.1 months 10.4 months Not reported
Paclitaxel Phase II, single arm ≥ 2nd line [22] 29% 65 days 100 days 108 days
Phase II, single arm ≥ 2nd line [23] 23.8% Not reported 5.8 months Not reported
Docetaxel Phase II, single arm [24] 25% 4.7 months Not reported 4.7 months
Temozolomide Phase II, single arm 2nd or 3rd line [26] 23% - sensitive 1.6 months 5.8 months 3.5 months
13% - refractory
Etoposide Phase II, PO etoposide ≥ 2nd line [29] 45.5% 4 months 3.5 + months 4 months
Phase II, single arm PO etoposide ≥ 2nd 23% Not reported 18 weeks CR = 16 weeks
line [30] PR = 9 weeks
Vinorelbine Phase II, single arm 2nd line [31] PR = 16% Not reported Not reported Not reported
SD = 28%
Bendamustine Phase II, single arm 2nd and 3rd line [34] 26% 4 months 4.8 months Not reported
Gemcitabine Phase II, single arm ≥ 2nd line [35] 13% 8 weeks 17 weeks 10-20 weeks
Amrubicin Phase III, Amrubicin vs. topotecan 2nd line [38] 31.1% 4.1 months 7.5 months 4.8 months
Vinflunine Phase II, single arm 2nd line [39] 19.6% 1.6 months 4.9 months 2.7 months
CIE Phase III, CIE vs. topotecan 2nd line [42] 84% 5.7 months 18.2 months Not reported
CAV Phase III, IV topotecan vs. CAV 2nd line [12] 18.3% 12.3 weeks 24.7 weeks 15.3 weeks

SCLC: small cell lung cancer; CAV: Cyclophosphamide, Doxorubicin, and Vincristine; PO: compare oral; CIE: cisplatin-irinotecan-
etoposide; PR: partial response; SD: stable disease; CR: complete response

eliminate the cancer cells due to inhibitory receptors and signals (checkpoints). Programmed death-1 (PD-1)
and cytotoxic lymphocyte antigen 4 (CTLA-4) are the most common checkpoints that have been studied
in solid malignancies . While immunotherapy is now recommended in the front-line setting, there have
[8]
been trials in immunotherapy naïve patients with relapsed SCLC, that were conducted prior to availibility
of IMPower 133 and CASPIAN results.

Nivolumab
[43]
The CheckMate 032 trial evaluated nivolumab in the setting of recurrent SCLC. In this study, patients
were randomized to three groups where they received either nivolumab 3 mg/kg alone every 2 weeks until
disease progression, nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks for 4 cycles followed by
maintenance nivolumab every 2 weeks, and nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks
for 4 cycles followed by maintenance nivolumab every 2 weeks. The number of patients in each group was
98, 61, and 54 respectively. A fourth group included only three patients who received nivolumab 1 mg/kg +
ipilimumab 1 mg/kg. The study showed a response rate of 10% for nivolumab alone, 23% for the nivolumab
1 mg/kg + ipilimumab 3 mg/kg, 19% for the nivolumab 3 mg/kg + ipilimumab 1 mg/kg, and 33% for
the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Interestingly the expression of programmed death-1
ligand (PD-L1) did not correlate with the response to therapy. Grade 3-4 treatment related toxicities were
most common in the nivolumab 1 mg/kg + ipilimumab 3 mg/kg group (30%) with diarrhea being the
most common . An updated analysis of the Checkmate 032 trial showed a higher response rate in the
[43]
combination of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg compared to nivolumab alone (21.9% vs.
[44]
11.6%; odds ratio 2.12; 95% CI: 1.06-4.26, P-value = 0.03) . However, it demonstrated similar OS between
the 2 groups. The median OS in the nivolumab group was 5.7 months (95%CI: 3.8-7.6 months) compared
to 4.7 months in the combination arm (95%CI: 3.1-8.3 months). Furthermore, toxicities were higher in the
combination arm. The last 2 findings led the NCCN panel to recommend nivolumab alone instead of the
combination .
[9]