# Second-line treatment outcomes after first-line chemotherapy plus immunotherapy in Extensive-Stage small cell lung cancer (ES-SCLC) patients: A large French multicenter study

Elvire Pons-Tostivint, Remy Ezzedine, Thomas Goronflot, Perrine Crequit, Thierry Chatellier, Judith Raimbourg, Jaafar Bennouna, Etienne Giroux
Leprieur, Marie Porte

► To cite this version:

Elvire Pons-Tostivint, Remy Ezzedine, Thomas Goronflot, Perrine Crequit, Thierry Chatellier, et al. Second-line treatment outcomes after first-line chemotherapy plus immunotherapy in Extensive-Stage small cell lung cancer (ES-SCLC) patients: A large French multicenter study. Lung Cancer, 2024, 194, pp.107887. 10.1016/j.lungcan.2024.107887. hal-05071340

HAL Id: hal-05071340

https://hal.science/hal-05071340v1

Submitted on 16 May 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

# Second-line treatment outcomes after first-line chemotherapy plus immunotherapy in Extensive-Stage small cell lung cancer (ES-SCLC) patients: A large French multicenter study

Elvire Pons-Tostivint<sup>a,b,*</sup>, Remy Ezzedine<sup>c</sup>, Thomas Goronflot<sup>d</sup>, Perrine Crequit<sup>e</sup>, Thierry Chatellier<sup>f</sup>, Judith Raimbourg<sup>g</sup>, Jaafar Bennouna<sup>e</sup>, Etienne Giroux Leprieur<sup>c</sup>, Marie Porte<sup>a</sup>

## ABSTRACT

**Introduction:** Chemotherapy combined with immunotherapy (CT-IO) is the standard treatment for patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC). This study evaluates the effectiveness of second-line (2L) following CT-IO.

**Patients and Methods:** All patients from 10 centers who received a 2L after a first-line CT-IO were included. They were divided into 3 groups: platinum-based, lurbinectedin or others (topotecan, CAV, taxanes). We assessed overall survival (OS) and 2L progression-free survival (2L-PFS) according to treatment and platinum free-interval (PFI) < or ≥ 90 days.

**Results:** Among 82 patients included, median age was 67.0 years, 29.3 % had a Performans Status ≥ 2, 36.6 % had brain progression, 69.5 % were considered "platine-sensitive" and 30.5 % "platine-resistant" (PFI ≥ or < 90 days, respectively). As 2L, 37/82 patients (45.1 %) received platinum-doublet, 21/82 (25.6 %) lurbinectedin and 24/82 (29.3 %) others. Patients with a PFI ≥ 90 days received mainly platinum-based rechallenge (34/57, 59.6 %). With a median follow-up of 18.5 months, the median OS was 5.0 months (95 %CI, 1.5–7.9) / 6.8 months (95 %CI, 5.5–8.7) for platinum-resistant / sensitive, respectively (log rank p = 0.017). The median 2L-PFS was 1.9 months (95 %CI, 1.2–4.7) / 3.9 months (95 %CI, 2.9–6.0) for platinum-resistant / sensitive, respectively. Median OS was 8.1 (95 %CI, 6.3–12.9) / 4.9 (95 %CI, 3.7–6.8) / 5.1 months (95 %CI, 2.5–7.8) with platinum rechallenge / lurbinectedin / others, respectively (p = 0.017). Median 2L-PFS was 4.6 (95 %CI, 3.9–7.2) / 2.7 (95 %CI, 1.6–3.9) / 2.2 months (95 %CI, 1.5–4.1) with platinum rechallenge / lurbinectedin / others, respectively (p = 0.025).

**Discussion:** Platinum-based rechallenge after a first-line CT-IO showed promising results despite particularly unfavorable characteristics within our real-word population. Lurbinectedin when used after IO demonstrated as low efficacy as other platinum-free regimens.

## 1. Introduction

Small cell lung cancer (SCLC) is a neuroendocrine tumor accounting for about 12 % of newly diagnosed patients with lung cancer each year [1]. It is defined as an aggressive disease, with rapid tumor growth and early development of extra-thoracic metastases, explaining why approximately 70 % of patients are diagnosed at extensive stage (ES-SCLC) [2]. The therapeutic landscape of ES-SCLC has recently changed with the advent of first-line immunotherapy (IO) in combination with platinum-based chemotherapy (CT). Indeed, two randomized phase III

studies has recently demonstrated survival benefits over CT alone, establishing CT-IO as the new first-line standard [3–5]. However, despite a high initial response rate, progression after first-line therapy occurs among almost all patients [6–8]. In the CASPIAN trial, 24-months progression-free-survival (PFS) was only 11.0 % (95 % CI 7.5–15.2) with durvalumab plus platinum–etoposide, and only 17.6 % (95 % CI 13.3–22.4) of patients were alive at 3 years [6,8]. The time to progression, defined as treatment-free-interval or platinum-free-interval (PFI) from last CT to relapse, is a predictive factor for the response to second-line (2L) treatment, with a cut-off defined before the advent of first-line

<footnote><sup>a</sup> Nantes Université, Centre Hospitalier Universitaire Nantes, Medical oncology, F-44000 Nantes, France</footnote>

<footnote><sup>b</sup> Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA Nantes, France</footnote>

<footnote><sup>c</sup> Service de pneumologie et oncologie thoracique, CHU d'Ambroise-Paré, Boulogne-Billancourt, France</footnote>

<footnote><sup>d</sup> Nantes Université, CHU Nantes, Pôle Hospitalo-Universitaire 11 : Santé Publique, Clinique des données, INSERM, CIC 1413, F-44000 Nantes, France</footnote>

<footnote><sup>e</sup> Department of Medical Oncology, Hospital Foch, Suresnes, France</footnote>

<footnote><sup>f</sup> Medical Oncology Unit, Clinique Mutualiste de l'Estuaire, Saint-Nazaire, France</footnote>

<footnote><sup>g</sup> Department of Medical Oncology, Comprehensive Cancer Center, Institut de Cancérologie de l'Ouest, Saint-Herblain, France</footnote>

<footnote>* Corresponding author at: Hôpital Laennec, CHU de Nantes, Boulevard Professeur Jacques Monod, 44800 Saint Herblain, France.
E-mail address: elvire.pons@chu-nantes.fr (E. Pons-Tostivint).</footnote>
IO [9]. In guidelines, platinum-sensitive patients are defined by an initial response, followed by a relapse at least 90 days after completion of first-line CT. Platinum-resistant patients are defined by progression within 90 days after completion, while platinum-refractory patients are defined by the absence of any response to first-line therapy [5,10]. However, this cut-off has recently been discussed at the era of IO-first line, and a new 75-days cut-off has been proposed [11]. Until 2020, topotecan was the only drug approved in Europe and in the USA for patients who progressed after platinum-based CT [12,13]. Nevertheless, in platinum-sensitive patients, platinum rechallenge demonstrated a significantly longer median PFS compared to topotecan (4.7 versus 2.7 months; HR, 0.57, 95 %CI 0.41–0.73; p = 0.0041) [14]. Median overall survival (OS) was similar in the two treatment groups, around 7.5 months. Another drug named lurbinectedin, a selective inhibitor of oncogenic transcription, was recently approved as 2L regardless of platinum sensitivity based on a single arm phase II that reported an overall response rate of 35.2 % and a median PFS of 3.5 months (95 %CI 2.6 – 4.3). In this study, only eight patients had received prior IO, and 5 out of 8 of these patients exhibited durable responses to lurbinectedin. Furthermore, seven patients received additional IO, and their median OS appeared significantly longer than that of other patients. Although the number of patients was notably low, this raises questions about the impact of lurbinectedin on immunogenicity [15].

Importantly, all these 2L strategies have been explored before the era of front-line IO in ES-SCLC. Recent evidence in non-small cell lung cancer indicates that prior exposure to IO may result in a synergistic advantage for subsequent CT, potentially enhancing its efficacy [16–18]. We conducted this multicenter study to assessed real-world outcomes of 2L chemotherapies in patients previously treated with CT-IO in first-line for an ES-SCLC.

## 2. Patients and Methods

### 2.1. Study design and patients

All consecutive patients with newly histologically or cytologically diagnosed ES-SCLC from 10 French hospitals (university hospital, cancer center, and private clinic) were screened. All patients who received a first-line of CT-IO for an ES-SCLC were included and analyzed in two previous works [19,20]. IO was atezolizumab or durvalumab, followed by maintenance after completion of CT until disease progression, toxicities, or physician/patients' decision. In the current work, we selected patients with progressive disease following first-line CT-IO and who received at least 1 cycle of 2L systemic therapy between October 2019 and March 2023. 2L included platinum rechallenge, lurbinectedin (3.2 mg/m2 administered as intravenous (i.v.) infusion every three weeks), and “others” including topotecan (i.v. 1.5 mg/m2 on days 1–5 of 21-day cycles), cyclophosphamide/adriamycine/vincristine (CAV) (cyclophosphamide 1000 mg/m2, doxorubicin 45.0 mg/m2, and vincristine 2.0 mg on day 1 of 21-day cycles) or paclitaxel. Patients could be included whether progression occurred during IO maintenance or after cessation if IO was stopped. All clinical, radiological, and treatment information was manually extracted from medical records. This study was conducted in accordance with the local regulations. Protocol approval was obtained from an independent ethics committee at each site.

### 2.2. Study endpoints

The study sample was divided into three groups according to the 2L therapy: platinum-doublet, lurbinectedin, or others. Patients were assessed with radiological imaging according to local monitoring requirements, every 9 to 12 weeks. OS was defined from the date of the 2L initiation to death of any cause. Second-line progression-free survival (2L-PFS) was defined as the time from 2L therapy initiation to clinical or radiological progression, death, or censoring. Patients who remained alive or showed no progression were censored at the date of last follow-up.

Best treatment response was assessed by investigators in accordance with RECIST version 1.1, defined as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). In case PD was clinically determined, the date of the clinical assessment was considered the PD date. Second-line objective response rate (2L-ORR) defined patients displaying PR or CR.

We performed subgroup analyses according to the PFI, defined by the time between the last platinum-based therapy during first-line and date of first progression. Patients were classified as platinum-resistant (PFI < 90 days) or sensitive (PFI ≥ 90 days). According to recent publication, we also performed exploratory analysis with a cut-off at 75 days [11].

### 2.3. Statistical analysis

Patients' characteristics were summarized as median plus interquartile range and percentage for continuous and categorical variables, respectively. We used Chi-square tests to compare distributions of categorical variables between groups of interest and Mann-Whitney-Wilcoxon tests for the continuous variables. Median follow-up time was calculated using the reverse Kaplan-Meier method, from the date of second-line initiation. OS and 2L-PFS were estimated using the Kaplan-Meier method. Estimated survival distribution between groups was compared using the log-rank test. Results were reported as median OS and median 2L-PFS with 95 % CIs. All statistical analyses were performed using R software (version 4.3.1).

## 3. Results

### 3.1. Patients and disease characteristics.

During the study period, 82 out of 132 patients treated with first-line CT-IO were included. Patients and disease characteristics are presented in Table 1. The median age was 67.0 years (Interquartile range (IQR), 60.3–71.0) and 67.1 % of patients were male. Performans Status (PS) prior to 2L initiation was ≥ 2 in 29.3 % of patients (24/82). Almost forty percent of the cohort had brain progression following first-line therapy.

All patients except one were treated by carboplatin during first-line CT-IO. IO was atezolizumab in 77 out of 82 patients (93.9 %). Median duration of IO first-line was 21.0 weeks (IQR, 15.0–29.0). At relapse, 69.5 % of patients (57/82) were considered “platinum-sensitive” with a PFI ≥ 90 days, and about a third (25/82, 30.5 %) were “platinum-resistant” with a PFI < 90 days. Among platinum-sensitive patients, 10/57 relapsed after 6 months.

As 2L treatment, 37 patients (45.1 %) received platinum-doublet, 21 (25.6 %) lurbinectedin and 24 (29.3 %) other chemotherapies (Fig. 1). As expected, nearly all patients treated with platinum had a PFI ≥ 90 days (34/37, 91.9 %). For patients treated with lurbinectedin, this proportion was 47.6 % (10/21), and for those treated with other chemotherapies, it was 54.2 % (13/24).

### 3.2. Survival according to treatment groups

After a median follow-up of 18.5 months (95 %CI, 12.5 – not reached), the median OS of the cohort was 6.1 months (95 %CI, 5.2–7.8). According to the treatment group, median OS was 8.1 months (95 %CI, 6.3–12.9) with platinum rechallenge, 4.9 months (95 %CI, 3.7–6.8) with lurbinectedin and 5.1 months (95 %CI, 2.5–7.8) with others chemotherapies (log rank p = 0.017) (Fig. 2). The 6-month OS rate was 67.6 % (95 %CI, 54.0–84.5) with platinum rechallenge, 40.0 % (95 %CI, 23.4–68.4) with lurbinectedin, and 33.3 % (95 %CI, 18.9–58.7) with other chemotherapies.

The median 2L-PFS of the cohort was 3.4 months (95 %CI, 2.8–4.5). According to the treatment, median 2L-PFS was 4.6 months (95 %CI, 3.9–7.2) with platinum rechallenge, 2.7 months (95 %CI, 1.6–3.9) with lurbinectedin and 2.2 months (95 %CI, 1.5–4.1) with others chemotherapies (log rank p = 0.025) (Fig. 3). The 3-month 2L-PFS was 72.8 %
<table><caption>**Table 1**

Patient and disease characteristics.</caption><thead><tr><th>Characteristics, n (%)</th><th>Study sample (n = 82)</th><th>Platinum-doublet (n = 37)</th><th>Lurbinectedin (n = 21)</th><th>Others (n = 24)</th></tr></thead><tbody><tr><td>Age, median [IQR]</td><td>67.00 [60.25, 71.00]</td><td>69.00 [65.00, 72.00]</td><td>63.00 [58.00, 71.00]</td><td>69.00 [58.75, 70.00]</td></tr><tr><td>Sex</td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>55 (67.1)</td><td>25 (67.6)</td><td>14 (66.7)</td><td>16 (66.7)</td></tr><tr><td>Female</td><td>27 (32.9)</td><td>12 (32.4)</td><td>7 (33.3)</td><td>8 (33.3)</td></tr><tr><td>Platinum-based therapy 1L</td><td>81 (98.8)</td><td>36 (97.3)</td><td>21 (100.0)</td><td>24 (100.0)</td></tr><tr><td>Carboplatin</td><td></td><td></td><td></td><td></td></tr><tr><td>Immunotherapy 1L</td><td></td><td></td><td></td><td></td></tr><tr><td>Atezolizumab</td><td>77 (93.9)</td><td>34 (91.9)</td><td>20 (95.2)</td><td>23 (95.8)</td></tr><tr><td>Durvalumab</td><td>5 (6.1)</td><td>3 (8.1)</td><td>1 (4.8)</td><td>1 (4.2)</td></tr><tr><td>Median duration of IO 1L, weeks [IQR]</td><td>21.00 [15.00, 29.00]</td><td>25.00 [21.00, 34.00]</td><td>16.00 [15.00, 21.00]</td><td>15.00 [12.50, 19.00]</td></tr><tr><td>Best response 1L</td><td></td><td></td><td></td><td></td></tr><tr><td>CR</td><td>4 (4.9)</td><td>3 (8.1)</td><td>0 (0.0)</td><td>1 (4.2)</td></tr><tr><td>PR</td><td>69 (84.1)</td><td>32 (86.5)</td><td>19 (90.4)</td><td>18 (75.0)</td></tr><tr><td>SD</td><td>6 (7.3)</td><td>2 (5.4)</td><td>1 (4.8)</td><td>3 (12.5)</td></tr><tr><td>PD</td><td>3 (3.7)</td><td>0 (0.0)</td><td>1 (4.8)</td><td>2 (8.3)</td></tr><tr><td>Brain radiation therapy before or during 1L</td><td>16 (19.5)</td><td>11 (29.7)</td><td>1 (4.8)</td><td>4 (16.7)</td></tr><tr><td>Pattern of progression at 1L</td><td></td><td></td><td></td><td></td></tr><tr><td>Cerebral</td><td>11 (13.4)</td><td>7 (18.9)</td><td>2 (9.5)</td><td>2 (8.3)</td></tr><tr><td>Extracerebral</td><td>52 (63.4)</td><td>19 (51.4)</td><td>15 (71.4)</td><td>18 (75.0)</td></tr><tr><td>Both</td><td>19 (23.2)</td><td>11 (29.7)</td><td>4 (19.1)</td><td>4 (16.7)</td></tr><tr><td>Performance status at 2L</td><td></td><td></td><td></td><td></td></tr><tr><td>0-1</td><td>58 (70.7)</td><td>28 (75.7)</td><td>13 (61.9)</td><td>17 (70.8)</td></tr><tr><td>≥ 2</td><td>24 (29.3)</td><td>9 (24.3)</td><td>8 (38.1)</td><td>7 (29.2)</td></tr><tr><td>PFI</td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 90 days</td><td>25 (30.5)</td><td>3 (8.1)</td><td>11 (52.4)</td><td>11 (45.8)</td></tr><tr><td>≥ 90 days</td><td>57 (69.5)</td><td>34 (91.9)</td><td>10 (47.6)</td><td>13 (54.2)</td></tr></tbody></table>

Abbreviations: 1L First-line; 2L Second-line; IO Immunotherapy; PFI Platinum-free-interval.

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Histogram plot illustrating the distribution of patients by PFI and treatment group.</figcaption></figure>

(95 %CI, 59.7–88.7) with platinum, 42.3 % (95 %CI, 25.6–70.1) with lurbinectedin, and 41.7 % (95 %CI, 26.0–66.9) with other chemotherapies.

### 3.3. Survival according to platinum-free-interval

OS and 2L-PFS according to PFI < or ≥ 90 days were showed in Fig. 4. Median OS was 6.8 months (95 %CI, 5.5–8.7) for PFI ≥ 90 days and 5.0 months (95 %CI, 1.5–7.9) for PFI < 90 days (log rank p = 0.017) The median 2L-PFS was longer in patients with a PFI ≥ 90 days than those with a PFI < 90 days, respectively 3.9 months (95 %CI 2.9–6.0) and 1.9 months (95 %CI 1.2–4.7) (log rank p = 0.025).

We also explored the cut-off of 75 days. Seventeen patients had a PFI < 75 days. Median OS was 2.2 months (95 %CI, 1.2–8.0) for these patients, while 6.8 months (95 %CI, 5.5–8.7) for patients with a PFI ≥ 75 days (Table 2). The median 2L-PFS was 3.8 months (95 %CI, 2.9–4.7) patients with a PFI ≥ 75 days, and 1.4 months (95 %CI, 1.1–4.7) in patients with a PFI < 75 days.

### 3.4. Response rate, and pattern of relapse

2L-ORR was 39.0 % in the total sample and was numerically higher in the platinum rechallenge group than in the lurbinectedin group (62.2 % and 19.0 % respectively, p = 0.026) (Suppl Table 1). Pattern of progression was comparable between treatment groups (Suppl table 2). On the whole cohort, 39 patients (47.6 %) received a third line, 56.8 % (21/37) of patients in the rechallenge group, 38.1 % in the lurbinectedin-group and 41.7 % in the other-group, with no statistical differences between groups (p = 0.268) (Suppl table 2).

## 4. Discussion

Although immunotherapy has, for the first time in decades, enabled improved survival in a limited subset of patients with ES-SCLC, the majority of patients will experience rapid relapse within the first few months of treatment. Indeed, in the CASPIAN and the IMpower133 trials, progression rates were at 18%/22% respectively within the first 3 months, 55%/69% at 6 months and 82%/87% at 12 months [3,4]. Guidelines have established a 90-day cut-off from the last platinum injection to distinguish between platinum-sensitive and resistant cases [5,10]. Several options are available in patient with platinum-sensitive disease, including rechallenge with platinum plus etoposide, CAV, lurbinectedin or topotecan [5]. It has been well-documented that outcomes are particularly poor in platinum-resistant patients, defined as having a PFI < 90 days, with no established standard of care demonstrating significant benefit. Our real-world study revealed that French physicians equally proposed lurbinectedin or other chemotherapies (CAV, topotecan, or taxanes) for this population.

The impact of first-line IO on the efficacy of 2L therapies remains uncertain. It is plausible that IO alters the disease's natural history and microenvironment, influencing the pattern of relapse, particularly well reported in non-small cell lung cancer patients with oligo-progression [21,22]. A third of our real-word cohort was considered platinum-resistant, defined as experiencing a relapse within 90 days after the last administration of platinum-based therapy. The median OS of this group 5.0 months (95 %CI, 1.5–7.9) for PFI < 90 days versus 6.8 months (95 %CI, 5.5–8.7) for PFI ≥ 90 days (log rank p = 0.017). A recent publication in the Journal of Thoracic Oncology questioned the cut-off value for defining platinum-sensitivity in ES-SCLC patients [11]. The authors found that a 75-day cutoff might be more accurate than the 90-day one in defining sensitive relapse. However, patients in their cohort were exclusively Japanese, and they mostly received amrubicin as 2L, a third-generation anthracycline and potent topoisomerase II inhibitor not used in Europe. The authors reported that the results of platinum rechallenge and amrubicin monotherapy were comparable with the 75-day cut-off, but very few patients in their cohort received platinum-
<figure><img src="image_5.png" /><figcaption>Fig. 2. Kaplan-Meier graph of overall survival by treatment group.</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>Fig. 3. Kaplan-Meier graph of 2L-PFS by treatment group.</figcaption></figure>

based therapy as 2L. We did exploratory analyses by using this 75-days cut-off. The median OS appeared shortened in the group of patients experiencing a relapse within 75 days (2.2 months (95 %CI, 1.2–8.0)), compared to those who relapse after 75-days (6.8 months (95 %CI, 5.5–8.7)). Our two studies highlighted the importance of accurately categorizing relapsed in ES-SCLC patients in the era of IO-based first line therapy. The question of whether patients experiencing a relapse between 75 and 90 days after the last injection of platinum could benefit from a new rechallenge with platinum remains unresolved to date. In our cohort, we observed only 3 patients who underwent rechallenge with a PFI < 90 days. Interestingly, their median OS was comparable to

those with a PFI greater than 90 days, with values of 7.9 months (95 % CI, 6;8 – NR) and 7.4 months (95 %CI, 5.7 – 14.8), respectively. Of course, we cannot draw conclusions from such small sample sizes. The challenge is not to exclude patients who might be sensitive to 2L treatment, thanks to a potential modification of their response profile following exposure to immunotherapy. Interestingly, Torasawa *et al.* showed that patients in the post-ICI era tend to have longer OS even after the initiation of second-line treatment than those in the pre-ICI era.

While the phase 2 study that have assessed lurbinectedin as 2L raised the hypothesis that lurbinectedin might be particularly effective in patients pre-treated with IO, we do not necessarily confirm this hypothesis
<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /><figcaption>**Fig. 4.** Kaplan-Meier graph of (A) overall survival and (B) 2L-Progression-Free-Survival by Platinum-Free-Interval groups < or ≥ 90 days.</figcaption></figure>

based on our findings [15]. Importantly, our study reflects a real-world cohort, encompassing patients with co-morbidities, a PS ≥ 2 for 29.3 %, and 36.6 % of patients had brain progression after first-line therapy. We found that lurbinectedin when used after IO demonstrated efficacy comparable to other platinum-free regimens, yielding median PFS values of 2.7 months (95 %CI, 1.6–3.9) and 2.2 months (95 %CI, 1.5–4.1), respectively. In our cohort, lurbinectedin was used both in platinum-resistant patients (n = 11/21, 52.4 %) and platinum-sensitive patients. However, our cohort sharply contrasts with the patient profile

in the phase 2 trial assessing lurbinectedin efficacy, where only 8 % had a PS of 2, and known brain metastases were excluded [15]. Moreover, 30 % of patients received first-line at localized-stage, while all our cohort had ES-SCLC disease at diagnosis. The median OS in the phase 2 was 5.0 months (95 %CI, 4.1–6.3) in PFI < 90 days, and 11.9 months (95 %CI, 9.7–16.2) in PFI ≥ 90 days. It was previously showed *in vitro* that cell death induced by lurbinectedin could enhance systemic anti-cancer immune responses [23]. *In vivo*, lurbinectedin efficacy were boosted in combination with PD-1 and CTLA-4 double immune
<table><caption>**Table 2**
Overall survival and 2L-Progression free survival Based on a 75-Day PFI Cut-off.</caption><thead><tr><th>Overall survival</th><th>Median (months)</th><th>95 % CI</th><th>2L-Progression Free Survival</th><th>Median (months)</th><th>95 % CI</th></tr></thead><tbody><tr><td>Study sample</td><td>6.1</td><td>5.2 – 7.8</td><td>Study sample</td><td>3.4</td><td>2.8 – 4.5</td></tr><tr><td>&lt; 75 days</td><td>2.2</td><td>1.2 – 8.0</td><td>&lt; 75 days</td><td>1.4</td><td>1.1 – 4.7</td></tr><tr><td>≥ 75 days</td><td>6.8</td><td>5.5 – 8.7</td><td>≥ 75 days</td><td>3.8</td><td>2.9 – 4.7</td></tr></tbody></table>

Supplementary table 1: Overall survival and 2L-Progression free survival Based on a 75-Day PFI Cut-off.

checkpoint blockade. Several trials are ongoing assessing the combination of lurbinectedin plus immunotherapy in SCLC (NCT05572476) [24]. Further research and larger cohorts are warranted to delineate the relationship between IO and lurbinectedin efficacy.

The primary objective of our cohort was not to compare the efficacy of lurbinectedin versus other regimens or platinum-based therapies, as the patient profiles differed significantly, impacting the results. Although platinum-based rechallenge remained the most efficient therapy, it was predominantly administered to sensitive patients, thus including a selection bias. It was well known that platinum-sensitive patients had better responses with second-line chemotherapy, defined as higher objective response rate and longer overall survival [9]. In previous randomized studies, topotecan showed response rate of 24%, globally similar to CAV which had response rate of 18%. Median OS was similar for both therapies, around 6.2 months [13]. In our cohort, we found ORR of 18.2% with these therapies, and median OS of 5.1 months (95%CI, 2.5–7.8). For patients who relapse after 90 days, rechallenge with platinum-based chemotherapy showed better results than topotecan in a French phase 3 comparing these two strategies [14]. Importantly in this phase 3 study, mean age was 64 years, only 6% of patients had a PS of 2, and 30% of the cohort had PFI ≥ 180 days. Moreover, 36% of the patients were previously treated for a localized stage SCLC. Platinum-based rechallenge improved both response rate (49% v 25%; P = 0.002) and PFS (4.7 v 2.7 months; p = 0.004), though there was no significant difference in OS (median, 7.5 v 7.4 months; p = 0.94). A retrospective multicentre analysis conducted before the era of IO found, among 112 ES-SCLC treated with platinum-etoposide rechallenge at progression, a median PFS of 5.5 months (95CI, 4.4–6.3) and a median OS of 7.9 months (95% CI, 6.9–9.7) [25]. Median age was 64, 82% of patients had a PS 0–1, 44% were primarily treated at localized stage. While characteristics of our cohort treated with platinum-based rechallenge was much more pejorative, with older patients (median age 69 years), all treated first-line at extensive stage, 24.3% of PS ≥ 2, and only 18.9% had PFI ≥ 180 days, we observed a very similar median PFS of 4.6 months (95%CI, 3.9–7.2) and a median OS of 8.1 months (95%CI, 6.3–12.9). At 6-months in the phase 3 trial, 31% (95%CI, 25–35) of patients were free-from progression with platinum-based therapies. This proportion was untiringly high up to 43.1% (95%CI 29.3–63.4) in our cohort. Objective response rate with platinum-based rechallenge was 62.2% in our cohort. Further data will be necessary to explore if first-line IO could increase sensitivity to platinum-based rechallenge.

Our study has several limitations. Firstly, the patient cohort was small, despite screening numerous centers. Many patients did not receive 2L therapies for ES-SCLC. Importantly, we included both low- and high-volume centers to better highlight the heterogeneity between local practices and to provide a more accurate representation of real-world clinical practices. Then, this was a retrospective study, and it may have led to an imperfect assessment of PFI. However, relapses of SCLC are most often rapidly symptomatic, prompting regular and close radiological evaluations to be performed. Our study also has several strengths. We included patients from several centers, and to our knowledge, this is the largest study in a Caucasian population to assess the outcomes of 2L in patients with ES-SCLC who received CT-IO as first-line treatment.

Other studies were conducted in Asia, mostly exploring impact of 2L amrubicin [11,26,27].

In conclusion, our work provided data on the efficacy of 2L following CT-IO progression. Our study demonstrated interesting results within the population treated with platinum, despite particularly unfavorable characteristics within our real-word population. We also found that lurbinectedin when used after IO demonstrated as low efficacy as other platinum-free regimens. We showed that survival appeared comparable for patients experiencing relapse beyond 75 or 90 days, and that the survival of patients relapsing within the first 75 days was significantly unfavorable. The question of the optimal cut-off for defining the relevance of a platinum-based rechallenge after CT-IO remains unresolved.

## Funding

The authors declare that no funds, grants or other support were received during the preparation of this manuscript.

## Authors contributions

- Conception and design of the study: MP and EPT

- Acquisition of data: MP

- Analysis and interpretation of data: MP, EPT, TG

- Drafting the article: MP and EPT

All authors gave final approval of the version to be submitted.

## CRediT authorship contribution statement

**Elvire Pons-Tostivint:** Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Formal analysis, Conceptualization.
**Remy Ezzedine:** Writing – review & editing, Investigation, Data curation.
**Thomas Goronflot:** Writing – review & editing, Formal analysis, Data curation.
**Perrine Crequit:** Writing – review & editing, Validation, Data curation.
**Thierry Chatellier:** Writing – review & editing, Validation, Data curation.
**Judith Raimbourg:** Writing – review & editing, Validation, Data curation.
**Jaafar Benbouna:** Writing – review & editing, Validation, Data curation.
**Etienne Giroux Leprieur:** Writing – review & editing, Validation, Data curation.
**Marie Porte:** Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation, Data curation, Conceptualization.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.lungcan.2024.107887.

## References

[1] D. Debieuvre, O. Molinier, L. Falchero, C. Locher, D. Templement-Grangerat, N. Meyer, et al., Lung cancer trends and tumor characteristic changes over 20 years (2000–2020): Results of three French consecutive nationwide prospective cohorts' studies, Lancet Reg Health Eur. 22 (2022 Nov) 100492.

[2] L.A. Byers, C.M. Rudin, Small cell lung cancer: where do we go from here? Cancer. 121 (5) (2015 Mar 1) 664–672.

[3] L. Horn, A.S. Mansfield, A. Szczęsna, L. Havel, M. Krzakowski, M.J. Hochmair, et al., First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer, N Engl J Med. 379 (23) (2018 Dec 6) 2220–2229.

[4] L. Paz-Ares, M. Dvorkin, Y. Chen, N. Reinmuth, K. Hotta, D. Trukhin, et al., Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised,
controlled, open-label, phase 3 trial, The Lancet. 394 (10212) (2019 Nov 23) 1929-1939.

[5] A.M.C. Dingemans, M. Früh, A. Ardizzoni, B. Besse, C. Faivre-Finn, L.E. Hendriks, et al., Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann Oncol. 32 (7) (2021 Jul 1) 839-853.

[6] J.W. Goldman, M. Dvorkin, Y. Chen, N. Reinmuth, K. Hotta, D. Trukhin, et al., Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial, Lancet Oncol. 22 (1) (2021 Jan 1) 51-65.

[7] S.V. Liu, M. Reck, A.S. Mansfield, T. Mok, A. Scherpereel, N. Reinmuth, et al., Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMPower133), J Clin Oncol off J Am Soc Clin Oncol. 39 (6) (2021 Feb 20) 619-630.

[8] L. Paz-Ares, Y. Chen, N. Reinmuth, K. Hotta, D. Trukhin, G. Statsenko, et al., Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN, ESMO Open. 7 (2) (2022 Apr) 100408.

[9] T.K. Owonikoko, M. Behera, Z. Chen, C. Bhimani, W.J. Curran, F.R. Khuri, et al., A Systematic Analysis of Efficacy of Second-Line Chemotherapy in Sensitive and Refractory Small-Cell Lung Cancer, J Thorac Oncol. 7 (5) (2012 May 1) 866-872.

[10] H. Khurshid, N. Ismaila, J. Bian, R. Dabney, M. Das, P. Ellis, et al., Systemic Therapy for Small-Cell Lung Cancer: ASCO-Ontario Health (Cancer Care Ontario) Guideline, J Clin Oncol. 41 (35) (2023 Dec 10) 5448-5472.

[11] M. Torasawa, H. Horinouchi, S. Nomura, S. Igawa, M. Asai, H. Ishii, et al., Reconsidering the Cutoff Value for Sensitive and Refractory Relapses in Extensive-Stage SCLC in the Era of Immunotherapy, J Thorac Oncol off Publ Int Assoc Study Lung Cancer. 19 (2) (2024 Feb) 325-336.

[12] M.E.R. O'Brien, T.E. Ciuleanu, H. Tsekov, Y. Shparyk, B. Cuceviá, G. Juhasz, et al., Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer, J Clin Oncol off J Am Soc Clin Oncol. 24 (34) (2006 Dec 1) 5441-5447.

[13] J. von Pawel, J.H. Schiller, F.A. Shepherd, S.Z. Fields, J.P. Kleisbauer, N. G. Chrysson, et al., Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer, J Clin Oncol off J Am Soc Clin Oncol. 17 (2) (1999 Feb) 658-667.

[14] N. Baize, I. Monnet, L. Greillier, M. Geier, H. Lena, H. Janicot, et al., Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial, Lancet Oncol. 21 (9) (2020 Sep) 1224-1233.

[15] J. Trigo, V. Subbiah, B. Besse, V. Moreno, R. López, M.A. Sala, et al., Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial, Lancet Oncol. 21 (5) (2020 May) 645-654.

[16] L. Heraudet, T. Delon, R. Veillon, C. Vergnenègre, H. Lepetit, A. Daste, et al., Effect of prior immunotherapy on the efficacy of chemotherapy in advanced non-small

cell lung cancer: A retrospective study, Thorac Cancer. 13 (9) (2022 May) 1391-1400.

[17] S.E. Park, S.H. Lee, J.S. Ahn, M.J. Ahn, K. Park, J.M. Sun, Increased Response Rates to Salvage Chemotherapy Administered after PD-1/PD-L1 Inhibitors in Patients with Non-Small Cell Lung Cancer, J Thorac Oncol off Publ Int Assoc Study Lung Cancer. 13 (1) (2018 Jan) 106-111.

[18] G. Schvartsman, S.A. Peng, G. Bis, J.J. Lee, M.F.K. Benveniste, J. Zhang, et al., Response rates to single-agent chemotherapy after exposure to immune checkpoint inhibitors in advanced non-small cell lung cancer, Lung Cancer Amst Neth. 112 (2017 Oct) 90-95.

[19] R. Ezzedine, A. Canellas, C. Naltet, M. Wislez, R. Azarian, A. Seferian, et al., Evaluation of Real-Life Chemoimmunotherapy Combination in Patients with Metastatic Small Cell Lung Carcinoma (SCLC): A Multicentric Case-Control Study, Cancers. 15 (18) (2023 Jan) 4593.

[20] M. Porte, A. Vaudron, P. Crequit, L. Vaugier, T. Chatellier, C. Fronteau, et al., A Multicenter Study Assessing the Real-World Use and Effectiveness of First-Line Chemotherapy Plus Immunotherapy in Advanced Small-Cell Lung Cancer (SCLC) Patients, Clin Lung Cancer. S1525-7304 (23) (2023 Nov 23) 00252-00258.

[21] C.J. Tsai, J.T. Yang, N. Shaverdian, J. Patel, A.F. Shepherd, J. Eng, et al., Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogenic breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogenesis): an open-label, randomised, controlled, phase 2 study, Lancet Lond Engl. 403 (10422) (2024 Jan 13) 171-182.

[22] A.J. Schoenfeld, H.A. Rizvi, D. Memon, N. Shaverdian, M.J. Bott, J.L. Sauter, et al., Systemic and Oligo-Acquired Resistance to PD-(L)1 Blockade in Lung Cancer, Clin Cancer Res off J Am Assoc Cancer Res. 28 (17) (2022 Sep 1) 3797-3803.

[23] W. Xie, S. Forveille, K. Iribarren, A. Sauvat, L. Senovilla, Y. Wang, et al., Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity, Oncoimmunology. 8 (11) (2019 Sep 5) e1656502.

[24] A. Calles, A. Navarro, B. Doger, M.J. de Miguel, R.M. Alvarez Alvarez, V. Moreno, et al., A phase 1/2 trial of lurbinectedin (L) in combination with pembrolizumab (P) in relapsed small cell lung cancer (SCLC): The LUPER study, J Clin Oncol. 40 (16_suppl):8581-8581 (2022 Jun).

[25] G. Genestreti, M. Tiseo, H. Kenmotsu, W. Kazushige, M. Di Battista, G. Cavallo, et al., Outcomes of Platinum-Sensitive Small-Cell Lung Cancer Patients Treated With Platinum/Etoposide Rechallenge: A Multi-Institutional Retrospective Analysis, Clin Lung Cancer. 16 (6) (2015 Nov 1) e223.

[26] K. Kushiro, S. Watanabe, Y. Goto, T. Fujisaki, N. Yanagimura, A. Ohtsubo, et al., Efficacy and safety of amrubicin therapy after chemoimmunotherapy in small cell lung cancer patients, Transl Lung Cancer Res. 11 (9) (2022 Sep) 1858-1865.

[27] H. Imai, Y. Nagai, H. Minemura, T. Tsuda, Y. Yamada, S. Wasamoto, et al., Efficacy and safety of amrubicin monotherapy after atezolizumab plus carboplatin and etoposide in patients with relapsed small-cell lung cancer, Invest New Drugs. 40 (5) (2022 Oct) 1066-1079.