Patients with SCLC often have a variety of comorbidities associated with tobacco smoking, such as chronic obstructive pulmonary disease and cardiovascular disease, and these can be associated with poor performance status [
10]. Negative prognostic factors for OS identified in patients with SCLC include history of smoking, poor performance status, male sex, and older age (≥ 70 years), along with social factors, such as being unmarried and low socioeconomic status [
11,
12]. At the time of diagnosis, the majority of patients with SCLC present with extensive-stage disease [
7].
First-Line Treatment Options
First-line treatment of ES-SCLC with etoposide plus a platinum derivative (EP) chemotherapy has been a standard therapy for more than 30 years, with a general preference for carboplatin over cisplatin owing to a more tolerable toxicity profile and comparable efficacy [
6,
13]. However, despite high initial response rates to first-line EP therapy in patients with ES-SCLC, relapse rates are high and overall prognosis of relapsed disease is poor—most likely because of rapid development of drug resistance [
14]. In response to this challenge, a number of trials have explored the use of alkylating agents (e.g., ifosfamide), anthracyclines (e.g., epirubicin, amrubicin), antifolates (e.g., pemetrexed), camptothecins (e.g., irinotecan, topotecan), or taxanes (e.g., paclitaxel) in combination with platinum drugs as first-line treatment for ES-SCLC (Table
1) [
14‐
18]. However, none of these regimens have proven superiority over EP, which had remained the standard-of-care frontline treatment regimen until the advent of programmed death ligand 1 (PD-L1) immune-checkpoint therapy [
6,
14].
Table 1
First-line platinum-based combination chemotherapy phase 3 trials in ES-SCLC [
14‐
18]
Cisplatin-etoposide | 1985 | 20 | 88 | 29 | 9.1 | 30 | 18 | | | |
Cisplatin-etoposide | 1992 | 159 | 61 | 10 | 8.6 | 30 | 70 | 35 | 13 | 6a |
Cisplatin-etoposide-ifosfamide | 1995 | 171 | 73 | 21 | 9.0 | 36 | 52 | 52 | 35 | |
Cisplatin-etoposide-cyclophosphamide-epirubicin | 2001 | 226 | 76 | 21 | 10.5 | 40 | 99 | 51 | 78 | 22b |
Cisplatin-irinotecan (JCOG 9511) | 2002 | 154 | 84 | 3 | 12.8 | 58 | 65 | 27 | 5 | 16c |
Cisplatin-epirubicin | 2004 | 195 | 74 | | 10.9 | | 42 | | | |
Cisplatin-etoposide-paclitaxel | 2005 | 587 | 75 | 16 | 10.6 | 38 | 44 | 19 | 22 | |
Cisplatin-irinotecan | 2006 | 331 | 48 | | 9.3 | 35 | 36 | 5 | 4 | 21c |
Cisplatin-topotecan (oral) | 2006 | 784 | 63 | 6 | 10.0 | 31 | 59 | 38 | 38 | |
Carboplatin-irinotecan | 2008 | 209 | | 17 | 8.5 | 34 | 33 | 5 | 15 | 11c |
Cisplatin-irinotecan (S0124) | 2008 | 671 | 59 | 4 | 9.7 | 39 | 33 | 6 | 4 | 19c |
Cisplatin-topotecan (intravenous) | 2008 | 795 | 55 | 10 | 10.3 | 40 | 36 | 12 | 19 | |
Carboplatin-pemetrexed | 2008 | 733 | 25 | | 7.3 | | 9 | 10 | 10 | |
Cisplatin-irinotecan | 2010 | 405 | 39.1 | 4 | 10.2 | 41.9 | 38.1 | 6.9 | 5.4 | 17.3c |
Carboplatin-irinotecan | 2011 | 216 | 62.3 | 4 | 10.0 | 37.1 | | 17 | 23 | 14c |
Cisplatin-irinotecan | 2019 | 362 | 62.4 | 1.2 | 10.9 | | 62.3 | 27.0 | 12.6 | 20.4b 10.2c |
New First-Line Immunotherapy Treatment Options
More recently, improved OS was demonstrated in randomized phase 3 clinical trials of PD-L1 immunotherapies combined with EP regimens as first-line treatment for ES-SCLC [
19,
20]. This development represents a paradigm shift and the most significant move forward in this setting in the last 3 decades [
6,
21‐
23].
Durvalumab is a PD-L1 immunotherapy that was evaluated in the randomized, controlled, open-label, phase 3 CASPIAN trial that compared durvalumab (with or without tremelimumab, a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] inhibitor) in combination with EP (with either cisplatin or carboplatin) versus EP alone in treatment-naïve patients with ES-SCLC and a World Health Organization (WHO) performance status of 0 or 1 [
20]. Patients were randomly assigned to durvalumab plus EP, durvalumab plus tremelimumab plus EP, or EP alone. Treatment consisted of up to four cycles of durvalumab plus EP with or without tremelimumab every 3 weeks followed by maintenance treatment with durvalumab (with or without tremilimumab) every 4 weeks in the immunotherapy groups and up to six cycles of EP every 3 weeks in the EP-alone group. Durvalumab (without tremelimumab) plus EP significantly reduced the risk of death at the planned interim analysis (18 months) by 27% compared with EP alone (hazard ratio [HR] 0.73 [95% confidence interval (CI) 0.59, 0.91];
P = 0.0047) [
20].
Updated results after a median follow-up of 25.1 month (IQR 22.3–27.9) showed that durvalumab (without tremelimumab) plus EP produced a sustained improvement in OS versus EP alone (HR 0.75 [95% CI 0.62, 0.91]; nominal
P = 0.0032); median OS was 12.9 months (95% CI 11.3, 14.7) versus 10.5 months (95% CI 9.3, 11.2) [
24]. Importantly, the addition of tremelimumab to durvalumab plus EP did not improve OS compared with EP alone, suggesting that the combination immunotherapeutic approach has no added benefit in this setting [
24]. The lack of benefit with CTLA-4 inhibition was also shown with ipilimumab in combination with EP, which failed to prolong OS compared with EP alone in patients with newly diagnosed ES-SCLC [
25].
Atezolizumab, another PD-L1 monoclonal antibody, has also demonstrated effectiveness when used in combination with EP as first-line treatment for ES-SCLC [
19]. In the IMpower133 double-blind, placebo-controlled, phase 3 trial, treatment-naïve patients with ES-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomized to receive EP (with carboplatin) with either atezolizumab or placebo for four 21-day cycles (induction phase) followed by a maintenance phase during which they received either atezolizumab or placebo [
19]. Both primary endpoints of OS and investigator-assessed progression-free survival (PFS) were significantly improved when atezolizumab was added to EP as first-line therapy in patients with ES-SCLC compared with EP alone [
19]. A follow-up analysis showed that atezolizumab plus EP had a comparable safety profile to placebo plus EP and did not have a negative impact on health-related quality of life [
26]. In an updated OS analysis with a median follow-up of 22.9 months, median OS was 12.3 months (95% CI 10.8, 15.8) with atezolizumab plus EP versus 10.3 months (95% CI 9.3, 11.3) with placebo plus EP (HR 0.76 [95% CI 0.60, 0.95]; descriptive
P = 0.0154) in patients with ES-SCLC [
27]. At 18 months, 34% and 21% of patients were alive in the atezolizumab plus EP and placebo plus EP groups, respectively [
27].
It is worth noting that in both the CASPIAN and IMpower133 trials, the Kaplan–Meier curves for OS and PFS did not diverge until about 6 months, suggesting that only a subset of patients benefited from the addition of immunotherapy to EP and that the impact was somewhat delayed even in patients who derived benefit [
19,
20]. There are differences in the inclusion criteria regarding brain metastases between the studies, which is worth highlighting since patients with asymptomatic and untreated brain metastases were allowed in CASPIAN whereas they were excluded from IMpower133 [
19,
20]. Currently, no biomarkers exist to differentiate between patient subsets who may benefit from the addition of a PD-L1 inhibitor to standard EP chemotherapy and those who may not. Notably, patients derived similar benefit from the addition of atezolizumab to EP in IMpower133 independent of PD-L1 immunohistochemistry or blood-based tumor mutational burden (bTMB) status [
27]; however, the bTMB biomarker needs further refinement and validation as there are variable gene panel sizes, algorithms, and cutoffs that may vary on the basis of the tumor type such that a bTMB cutoff of 16 mutations per megabase may be sufficiently high for non-small cell lung cancer (NSCLC) but not for SCLC [
28,
29].
In a meta-analysis of four immune-checkpoint-inhibitor trials, including two with PD-L1 inhibitors that are currently approved by the FDA for the first-line treatment of patients with ES-SCLC (CASPIAN [durvalumab] and IMpower133 [atezolizumab]) and two with programmed death 1 (PD-1) inhibitors that are not currently approved by the FDA (KEYNOTE-604 [pembrolizumab] and ECOG-ACRIN EA5161 [nivolumab]), a pooled analysis of all four of these trials showed that frontline immune-checkpoint inhibitors provide significant survival benefits when combined with EP chemotherapy in patients with ES-SCLC [
30]. Further, in the pooled analysis of all four trials, the addition of a PD-1/PD-L1 inhibitor to EP chemotherapy led to a significant benefit in OS (HR 0.76 [95% CI 0.68, 0.85];
P < 0.00001), PFS (HR 0.75 [95% CI 0.68, 0.84];
P < 0.00001), and objective response rate (ORR; odds ratio 1.28 [95% CI 1.04, 1.57];
P = 0.02) compared with EP chemotherapy alone [
30]. Despite the promising results noted in the phase III KEYNOTE-604 trial, it should be noted that the
P value did not meet the required significance threshold in the planned hierarchical OS analysis, and pembrolizumab is not currently FDA approved as a frontline option in patients with ES-SCLC [
30,
31].
In summary, on the basis of the results from the CASPIAN and IMpower133 trials, the FDA approved either durvalumab or atezolizumab in combination with EP as first-line treatment of patients with ES-SCLC [
32,
33], introducing a treatment paradigm shift in frontline therapy. However, even with these advances, almost all patients with ES-SCLC who respond to first-line systemic treatment will eventually develop progressive disease and require second-line therapy, with very few patients achieving long-term response to maintenance PD-L1 therapy [
6,
13]. For these patients with disease progression, therapeutic options are limited, long-term survival is often less than 10 months [
13,
34], and the general goal of systemic therapy is to palliate symptoms and prolong quality of life [
6].
Second-Line Treatment Options
Two time-based criteria (i.e., 90 days or 180 days) are most commonly used to characterize relapsed ES-SCLC according to the duration of treatment-free interval since the last platinum dose given as part of frontline treatment. Thus, a tumor with durable tumor response lasting longer than 90 days from the last dose of frontline platinum doublet is termed “platinum sensitive,” while recurrence within 90 days of chemotherapy is termed “platinum resistant.” A “refractory” case is one in which the patient’s tumors either never responded or progressed within 45 days of treatment [
4]. These are not definitive cutoffs as other studies have used various thresholds (e.g., 60 days) for classifying a relapsed SCLC as chemotherapy sensitive [
35]. In general, a prolonged treatment-free interval beyond 6 months typically leads to the consideration of platinum-doublet re-treatment at the time of relapse.
Prognosis for patients who relapse or progress after first-line chemotherapy is poor: a median survival of 2–3 months was observed in patients who did not receive second-line therapy and typically 6 months or less in those who did receive second-line therapy [
36]. Hence, second- or third-line treatment for ES-SCLC is primarily considered palliative, with a focus on maintaining or improving quality of life to the extent possible. Treatment options, and the likelihood of their success, may vary depending on whether the initial tumor response was considered platinum sensitive, resistant, or refractory [
36]. A systematic analysis of second-line chemotherapy efficacy in sensitive and refractory SCLC determined that patients with SCLC whose tumors were platinum-sensitive (> 90 days’ relapse-free interval after first-line therapy) derived greater benefit compared with those whose tumors were platinum-resistant (< 90 days’ relapse-free interval after first-line therapy) [
37].
Because of first-line use of immunotherapy (durvalumab or atezolizumab) plus EP, the treatment landscape for second-line therapy is rapidly evolving, albeit with limited long-term data. Most of what is currently known about second-line therapy outcomes involves patients treated only with first-line EP chemotherapy without a PD-L1 inhibitor. Moreover, whether it is beneficial to continue immunotherapy into the second-line setting for patients progressing while on maintenance immunotherapy administered as part of frontline treatment remains to be determined.
Topotecan
Since its initial approval in 1996 and until recently, topotecan has been the only FDA-approved agent as a second-line treatment option for patients with SCLC and is only approved for those with chemotherapy-sensitive, relapsed SCLC [
38,
39]. Topotecan is a topoisomerase I inhibitor with cytotoxic effects [
38] that has demonstrated efficacy in several second-line therapy trials of patients with relapsed SCLC, with ORRs ranging from 8% to 27% and a median OS ranging from 3.7 to 12.5 months, although the efficacy reported is largely limited to chemotherapy-sensitive disease (Table
2) [
35,
40‐
48]. Topoisomerase I expression, as evaluated by immunohistochemistry, has been shown to be highly prevalent in patients with SCLC and has been shown to be associated with increased disease control in patients with platinum-sensitive, relapsed SCLC who received topotecan as second-line therapy [
49]. Topotecan is available for injection or oral administration [
38,
39], with similar efficacy and tolerability between the two formulations (Table
2) [
44].
Table 2
Select topotecan trials in relapsed SCLC [
35,
40‐
48]
von Pawel et al. (1999) [ 40] | 211 (S) | IV topotecan versus CAV | 24 | 13 weeks | 25 weeks | 89 | 58 | 42 |
18 | 12 weeks | 25 weeks | 87 | 15 | 20 |
von Pawel et al. (2001) [ 41] | 106 (S) | Oral topotecan versus IV topotecan | 23 | 15 weeks | 32 weeks | 57 | 53 | 31 |
15 | 13 weeks | 25 weeks | 94 | 49 | 30 |
O’Brien et al. (2006) [ 42] | 141 (76 R; 65 S) | BSC versus oral topotecan + BSC | NR | NR | 14 weeks | NR | NR | NR |
O: 7 R: 10 S: 3 | 16 weeks | 26 weeks | 61 | 38 | 25 |
| 22 (S) | Weekly IV topotecan + chemotherapy | 0 | 6 weeks | 20 weeks | 0 | 9 | 0 |
Eckardt et al. (2007) [ 44] | 309 (S)b | Oral topotecan versus IV topotecan | 18 | 12 weeks | 33 weeks | 71 | 48 | 22 |
22 | 15 weeks | 35 weeks | 86 | 43 | 30 |
Spigel et al. (2011) [ 45] | 38 (R or S) | Weekly IV topotecan | O: 8 R: 0 S:16 | R: 1.5 months S: 2.5 months | R: 3.7 months S: 8.6 months | 53 | 37 | 13 |
von Pawel et al. (2014) [ 46] | 637 (R or S)c | IV amrubicin versus IV topotecan | 31 | O: 4.1 months R: 2.8 months S: 5.5 months | O: 7.5 months R: 6.2 months S: 9.2 months | 41 | 21 | 16 |
17 | O: 3.5 months R: 2.6 months S: 4.3 months | O: 7.8 months R: 5.7 months S: 9.9 months | 54 | 54 | 31 |
| 180 (S) | IV topotecan versus IV cisplatin + etoposide + irinotecan | 27 | 3.6 months | 12.5 months | 86 | 28 | 28 |
84 | 5.7 months | 18.2 months | 83 | 41 | 84 |
| 164 (S)d | IV carboplatin + etoposide versus oral topotecan | 49 | 4.7 months | 7.5 months | 14 | 31 | 25 |
25 | 2.7 months | 7.4 months | 25 | 36 | 21 |
In patients with platinum-sensitive, platinum-resistant, or platinum-refractory relapsed SCLC, the main adverse event with topotecan infusions is myelosuppression [
40,
41,
44‐
47]. The standard intravenous (IV) dosing of topotecan is 1.5 mg/m
2 daily on days 1–5 of a 21-day cycle [
39]. A less burdensome schedule of a higher weekly dose of topotecan (6 mg/m
2 IV for 6 weeks) in 38 patients with relapsed SCLC yielded no responses in those with refractory tumors and three responses (all partial, none complete) in those with sensitive tumors, which was offset by even higher levels of hematologic toxicity [
45]. Irinotecan, another topoisomerase I inhibitor, is sometimes used as an alternative to topotecan in the second-line setting owing to its less frequent dosing (i.e., weekly) and lower probability of myelosuppressive adverse events [
50].
Re-treatment with Platinum Chemotherapy for Platinum-Sensitive Relapse
Until recently, in both the USA and Europe, topotecan has been the go-to second-line therapy for patients with platinum-sensitive, relapsed SCLC. However, in platinum-sensitive patients (relapse ≥ 90 days) with ECOG performance status 0–2, a recent study has shown platinum-based chemotherapy rechallenge to be superior to topotecan. This multicenter, open-label, randomized, phase 3 trial conducted in Japan (JCOG0605) compared topotecan alone with combination chemotherapy consisting of EP (with cisplatin) plus irinotecan [
47]. OS was significantly longer in the combined chemotherapy arm versus the topotecan arm (median 18.2 months vs 12.5 months; HR 0.67 [90% CI 0.51, 0.88];
P = 0.0079), as was PFS (median 5.7 months vs 3.6 months; HR 0.50 [95% CI 0.37, 0.68];
P < 0.0001). However, grade 3 or 4 febrile neutropenia, thrombocytopenia, and anemia were more common in the combination chemotherapy arm [
47]. Given the unfavorable toxicity profile of this triplet regimen, it is unlikely to be widely adopted.
Similar results were shown for PFS in a randomized, open-label, phase 3 French study that compared orally administered topotecan with EP in patients with platinum-sensitive, relapsed SCLC [
48]. Although median PFS was significantly longer in the combination EP chemotherapy arm compared with the topotecan arm (4.7 months [90% CI 3.9, 5.5] vs 2.7 months [90% CI 2.3, 3.2; HR 0.57 [90% CI 0.41, 0.73];
P = 0.0041), there were no significant differences between the treatment arms for median OS. Unlike the JCOG0605 triplet regimen, there were no major differences between the platinum-doublet chemotherapy and topotecan treatment arms with respect to percentages of grade 3 or 4 neutropenia, thrombocytopenia, anemia, or febrile neutropenia in this study [
48]. Given the importance of platinum-based chemotherapy in SCLC—including platinum-sensitive, relapsed disease—there are agents being developed to induce or re-induce platinum sensitivity [
51].
Lurbinectedin
Lurbinectedin is an alkylating drug and selective inhibitor of oncogenic transcription and DNA repair machinery in tumor cells, triggering tumor cell apoptosis and altering the inflammatory tumor microenvironment [
52‐
54]. Lurbinectedin received an orphan drug designation in 2018 [
55], and on the basis of the results of a phase 2 basket trial, received an accelerated approval in June 2020 as a second-line treatment option in patients with ES-SCLC who develop disease progression on or after platinum-based chemotherapy [
52,
56].
The phase 2 basket trial was a single-arm, open-label study of lurbinectedin 3.2 mg/m
2 every 21 days as second-line treatment for patients with relapsed SCLC and documented progression after treatment with only one prior chemotherapy (prior immunotherapy was allowed but only 8% of patients received prior immunotherapy) [
57]. All patients in the study had an ECOG performance status of 2 or better. At data cutoff, with a median follow-up of 17.1 months, responses were observed in 37 of 105 study participants, for an ORR of 35.2% (95% CI 26.2, 45.2) (Table
3) [
57]. The ORR was higher for patients with platinum-sensitive tumors (45.0%) compared with those with platinum-resistant tumors (22.2%). Moreover, 43% of all patients with a response had a durable response of 6 months or longer. The median OS was 11.9 months for patients with platinum-sensitive tumors versus 5.0 months for those with platinum-resistant tumors, and the median OS of the entire cohort was 9.3 months [
57]. The most common grade 3 or 4 adverse events were neutropenia (46%), leukopenia (29%), abnormal γ-glutamyl transferase (15%), anemia (9%), fatigue (7%), and thrombocytopenia (7%) [
57].
Overall response, % | 45.0 (32.1, 58.4) | 22.2 (11.2, 37.1) | 35.2 (26.2, 45.2) |
Median duration of response, months | 6.2 (3.5, 7.3) | 4.7 (2.6, 5.6) | 5.3 (4.1, 6.4) |
Patients responding at 6 months, % | 55.3 (34.5, 76.0) | 11.7 (0.0, 33.1) | 43.0 (25.6, 60.5) |
Median overall survival, months | 11.9 (9.7, 16.2) | 5.0 (4.1, 6.3) | 9.3 (6.3, 11.8) |
The phase 3 ATLANTIS open-label, randomized, multicenter trial examined lurbinectedin in patients with ES-SCLC but did not include an investigational treatment arm of lurbinectedin alone. The trial treatment arms compared the combination of lurbinectedin plus doxorubicin with standard of care (investigator’s choice of topotecan or cyclophosphamide/doxorubicin/vincristine [CAV]) in 613 patients with SCLC, disease progression after one prior platinum-containing chemotherapy regimen, and a chemotherapy-free interval of 30 days or more [
58,
59]. In December 2020, a press release reported that the trial did not meet the primary endpoint of OS for significance in the intent-to-treat patient population. The safety and tolerability data of ATLANTIS were consistent with the known safety profile of lurbinectedin, and there were no new safety signals in the lurbinectedin treatment arm [
59]. The ATLANTIS trial has not yet been published since the press release, and without the full study outcomes, a full understanding of the implications of the results is not possible. On the basis of the limited information currently available, it is hypothesized that the lower lurbinectedin dose used in the phase 3 trial (2.0 mg/m
2 every 21 days) compared with the phase 2 trial (3.2 mg/m
2 every 21 days) may have affected the outcomes [
57‐
59]. This hypothesis is in line with an exposure–response analysis of lurbinectedin dosage in SCLC that determined the 3.2 mg/m
2 dose every 21 days (same dose as used in the phase 2 trial and FDA approved) provided the most benefit in patients with SCLC who had disease progression on or after platinum-based chemotherapy and had a manageable risk of grade 4 neutropenia [
60]. Given that the single-arm, open-label, phase 2 study in 105 patients resulted in conditional accelerated approval of lurbinectedin by the FDA on the basis of ORR and duration of response, “continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials” [
61].
There was also preliminary data from the phase 1b/2 study of lurbinectedin in combination with irinotecan among 21 patients with SCLC with disease progression after no more than two prior therapies which reported an ORR of 62% and a median PFS of 6.2 months (95% CI 4.3, 8.5) [
62,
63], suggesting that additional combination studies may be warranted. Given the limited treatment options in the second-line setting and the lethality of previously treated ES-SCLC, in spite of the phase 3 lurbinectedin plus doxorubicin combination failing to meet the primary endpoint with the caveats mentioned above, lurbinectedin monotherapy offers preliminary efficacy with a favorable safety profile, a facile dosing schedule, and is a reasonable second-line treatment option for patients with relapsed SCLC.
Immunotherapies
SCLC has long been considered an immunogenic disease because of high tumor mutational burden secondary to tobacco exposure related to tumor development and the occurrence of paraneoplastic disorders in 15–20% of newly diagnosed cases, providing a rational basis for consideration of immunotherapies in the treatment of SCLC [
64‐
66]. As previously discussed, the immune-checkpoint inhibitors durvalumab and atezolizumab have an established efficacy as part of frontline therapy for ES-SCLC in combination with EP [
19,
20]. Although pembrolizumab and nivolumab, both PD-1 monoclonal antibodies, had received accelerated FDA approval for patients with relapsed SCLC who had received two prior lines of treatment (including platinum-based chemotherapy), both applications have been recently withdrawn [
67‐
69]. Pembrolizumab initially received accelerated approval based on the pooled data from two basket trials (KEYNOTE-028 and KEYNOTE-158) [
68,
70,
71]. In a pooled analysis of SCLC cohorts (
N = 83) from KEYNOTE-028 (enrolled patients with PD-L1-positive tumors) and KEYNOTE-158 (enrolled patients irrespective of PD-L1 status of tumors), the ORR was 19.3% (95% CI 11.4, 29.4) [
68]. The confirmatory phase 3 KEYNOTE-604 trial, however, did not reach statistical significance for the primary endpoint of OS, leading to voluntary withdrawal by the manufacturer of the US SCLC indication for pembrolizumab in March 2021 [
31,
72].
Nivolumab was initially studied alone or in combination with ipilimumab in patients with relapsed ES-SCLC in the Checkmate-032 phase 1/2 trial. Although the study treatments were not initially designed to be compared with one another, the ORRs of nivolumab monotherapy versus nivolumab plus ipilimumab in patients with relapsed SCLC were 11.6% and 21.9%, respectively. Median OS was 5.7 months with nivolumab monotherapy versus 4.7 months with nivolumab plus ipilimumab combination therapy. Not surprisingly, combining ipilimumab with nivolumab increased grade 3–4 toxicity from 12.9% with nivolumab monotherapy to 37.5% with nivolumab plus ipilimumab [
73]. In the confirmatory phase III trial comparing nivolumab with chemotherapy (topotecan or amrubicin) in patients with relapsed SCLC, Checkmate 331, the primary endpoint of superior OS was not met [
74,
75]. In addition, examination of immunotherapy maintenance strategies after first-line chemotherapy of nivolumab plus ipilimumab or nivolumab monotherapy in patients with ES-SCLC in the randomized, phase III Checkmate 451 study did not result in a prolongation of OS versus placebo [
74]. On the basis of these results, the nivolumab indication for relapsed ES-SCLC was withdrawn in January 2021 from the USA by its manufacturer [
69].
Since no immune-checkpoint inhibitors are FDA approved in relapsed SCLC and the current use of PD-L1 inhibitors is in the frontline setting in combination with EP and as continuation maintenance therapy, there is very limited use for immunotherapies in the standard-of-care second-line setting despite some preliminary efficacy results.