Induction chemotherapy followed by camrelizumab plus apatinib and chemotherapy as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, single-arm trial

Chemo-immunotherapy is the current first-line treatment for patients with extensive-stage small cell lung cancer (ES-SCLC), but survival benefits are modest. We aimed to evaluate the safety,

antitumor activity and biomarkers of first-line camrelizumab and apatinib plus chemotherapy in untreated ES-SCLC patients. In this single-arm trial (ClinicalTrials.gov NCT05001412),

eligible patients received 2 cycles of etoposide and carboplatin (EC) as induction treatment followed by 2–4 cycles of camrelizumab, apatinib plus EC, then maintenance camrelizumab plus

apatinib. Primary endpoint was safety. Secondary endpoints included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Targeted

sequencing and whole transcriptome sequencing were performed to explore biomarkers. All enrolled 40 patients were treated and analyzed for safety. During the entire treatment,

treatment-emergent adverse events (TEAEs) occurred in 40 patients (100%), and 30 (75.0%) were grade ≥3. The most common grade ≥3 TEAEs were neutropenia (35.0%), anemia (15.0%) and increased

alanine aminotransferase (15.0%). No treatment-related deaths occurred. Among 36 evaluable patients, ORR was 88.9% (95% CI: 73.9%–96.9%), median PFS was 7.3 months (95% CI: 6.6–9.2) and

median OS was 17.3 months (11.8-not reached). Mutations in RB1, high levels of tumor mutation burden, natural killer cells, and interferons, and low levels of cancer-associated fibroblasts,

correlated with prolonged PFS. Induction chemotherapy followed by camrelizumab, apatinib plus EC demonstrated acceptable safety and promising antitumor activity in untreated ES-SCLC

patients. The identified biomarkers need further validation.

Trial Registration ClinicalTrials.gov Identifier: NCT05001412.

Small-cell lung cancer (SCLC) is an aggressive and rapidly progressing subtype of lung cancer, comprising about 15% of all lung cancer diagnoses.1 SCLC is associated with a dismal prognosis,

with a median overall survival (OS) limited to just 7 months.2 At diagnosis, approximately 70% of SCLC patients are found to have extensive-stage disease (ES-SCLC).3 In 2019, the FDA

approved a chemo-immunotherapy regimen combining platinum-based chemotherapy and the PD-L1 inhibitor atezolizumab, based on the results from the IMpower133 trial.4 This marked a significant

step forward in the treatment landscape of ES-SCLC and established chemo-immunotherapy as the standard of care for newly diagnosed ES-SCLC patients. Subsequent phase 3 trials also

substantiated the clinical benefits of incorporating PD-L1 inhibitors into first-line regimens, demonstrating improved outcomes in this aggressive disease.5,6,7,8 Despite these advancements,

the survival improvements are modest, with median OS extending by just 2.0 to 4.7 months.5,6,7,8 Hence, novel therapies are urgently needed to further improve outcomes for patients with

ES-SCLC.

Recent studies have revealed the highly heterogeneous and immunosuppressive microenvironment of SCLC, and insufficient CD8 + T cell infiltration is a key reason for limited response to

immune checkpoint inhibitors (ICIs) in SCLC.9 The aggressive growth and invasiveness of SCLC are driven by angiogenesis, and vascular endothelial growth factor (VEGF) overexpression

correlates with poor prognosis in patients with SCLC.10,11 The overexpressed VEGF downregulates endothelial adhesion molecules, like ICAM-1 and VCAM-1, thereby reducing immune cell adhesion

and migration.12 Thus, targeting the VEGF pathway might increase CD8 + T cells infiltration and reduce neovascularization, potentially enhancing the antitumor response in ES-SCLC. Combining

ICIs with anti-VEGFR agents has synergistic effects via increasing T-cell infiltration in the tumor microenvironment.13 Preclinical data have shown that apatinib, a VEGFR inhibitor, can

modulate the tumor microenvironment by decreasing tumor hypoxia, enhancing CD8 + T cell infiltration, and decreasing the accumulation of tumor-associated macrophages in lung cancer

tissues.14 In lung cancer mouse models, the combination of apatinib with anti-PD-L1 antibodies led to significant suppression of tumor growth and metastasis while prolonging mouse

survival.14

The combination strategy of ICIs, anti-VEGFR agents, and chemotherapy has shown promising efficacy in patients with lung cancer. Specifically, in the IMpower 150 trial, first-line therapy

with atezolizumab plus bevacizumab and platinum-based chemotherapy notably improved OS (median OS: 19.2 months versus 14.7 months; hazard ratio [HR] = 0.78) and objective response rate (ORR;

63.5% versus 48.0%) compared with bevacizumab combined with platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC).15 Additionally, the incorporation of an

anti-VEGFR agent, bevacizumab, into cisplatin and etoposide also enhanced progression-free survival (PFS; median PFS: 6.7 months versus 5.7 months; HR = 0.72) and ORR (55.3% versus 58.4%;

odds ratio=1.13) compared with cisplatin and etoposide alone in newly diagnosed ES-SCLC patients.16 Recently, the ETER 701 trial demonstrated the efficacy of combining ICIs, anti-VEGFR

agents, and platinum-based chemotherapy in ES-SCLC patients in the first-line setting.17 This combination regimen, comprising benmelstobart, anlotinib, carboplatin, and etoposide

significantly prolonged OS (median OS: 19.3 months versus 11.9 months; HR = 0.61) and increased ORR (81.3% versus 66.8%) compared with carboplatin and etoposide alone in patients with

ES-SCLC.17 However, in the clinical setting, most SCLC cases are centrally located near the hilum and large blood vessels,2 which carry a high risk of bleeding. Previous trials of anti-VEGFR

agent combinations for SCLC typically excluded patients with large vessel invasion or high bleeding risk.17,18 This exclusion poses a challenge to the clinical application or optimization

of anti-angiogenic combination strategies in this subset of ES-SCLC patients. Addressing this gap is essential, as these patients represent a considerable proportion of the ES-SCLC

population.

Apatinib, a VEGFR2-targeting tyrosine kinase inhibitor, and camrelizumab, a PD-1 inhibitor, has each shown notable antitumor activity in ES-SCLC patients beyond the first-line

treatment.19,20 The PASSION study reported that camrelizumab plus apatinib yielded promising antitumor activity and was well-tolerable in ES-SCLC patients, including those with responsive

and resistant to chemotherapy, in the second-line setting.21 A retrospective study showed that first-line camrelizumab plus chemotherapy, then maintenance camrelizumab plus apatinib,

provided better survival benefits compared with PD-L1 inhibitors plus chemotherapy and exhibited strong antitumor activity.22 At the ASCO 2024 meeting, this combination also showed efficacy

(ORR: 82.14%; median PFS: 7.56 months) and tolerable safety in untreated ES-SCLC patients.18 In this study, we aimed to evaluate the safety and antitumor activity of first-line induction

etoposide and carboplatin (EC), followed by a combination of camrelizumab, apatinib, and EC in ES-SCLC patients, including those with large vessel invasion. The choice of induction

chemotherapy was based on its high ORR of 97% after 2 treatment cycles in limited-disease SCLC.23 This suggests that for most patients, this approach could promote tumor shrinkage and

separation from surrounding vasculature, thereby reducing the bleeding risk associated with anti-VEGFR agents. Moreover, this approach could induce immunogenic cell death, thereby enhancing

the efficacy of subsequent immunotherapy.24 When we designed this study, chemotherapy alone was also the standard recommended first-line regimen for patients with ES-SCLC.25 Concurrently, we

identify potential biomarkers that could predict clinical response.

Between 21 January 2021 and 20 August 2022, 40 patients were included and received induction EC (Fig. 1). After one cycle of induction EC, 4 patients withdrew informed consent and were

unevaluable for tumor response. Thus, 40 patients were evaluable for safety, and 36 patients were evaluable for tumor response. Of 40 patients, the median age was 60 years (range: 40-73),

and 36 (90.0%) were male. All 40 patients (100%) presented with stage IV disease. Most patients had central SCLC (33/40, 82.5%) and had an Eastern Cooperative Oncology Group (ECOG)

performance status (PS) of 1 (31/40, 77.5%). Table 1 presents the baseline characteristics. Vascular invasion was assessable in 35 patients, and all of them had large vessel invasion (Table

1, Supplementary Table 1).

In total, 36 patients completed initial 2 cycles of induction EC. Subsequently, one patient discontinued treatment due to disease progression. Thus, 35 patients received camrelizumab plus

apatinib plus EC. During this phase, additional 5 patients discontinued treatment due to progressive disease (n = 4) and withdrawal of informed consent (n = 1). Finally, 30 patients entered

the maintenance treatment phase with camrelizumab plus apatinib. The reasons for treatment discontinuation during maintenance treatment were progressive disease (n = 24) and adverse events

(n = 2).

At the data cut-off on May 30, 2023, the median duration of follow-up was 20.6 months (range: 4.1–27.5). 3 (8.3%) of 36 patients were still on the study treatment. 30 patients (83.3%)

received 6 cycles of EC (Supplementary Table 2). The median treatment cycles of camrelizumab were 7.0 (range: 2.0–35.0). The median treatment duration of apatinib was 5.23 months (range:

0–24.2). The reasons for not completing 4 cycles of camrelizumab plus apatinib plus EC are provided in Supplementary Table 3.

During the entire treatment phase, any grade treatment-emergent adverse events (TEAEs) occurred in 40 patients (100%), with the most common being leukopenia (31 [77.5%]), anemia (28

[70.0%]), and neutropenia (25 [62.5%]) (Table 2). Grade 3/4 TEAEs occurred in 30 patients (75.0%), with the most common being neutropenia (14 [35.0%]), anemia (6 [15.0%]), and increased

alanine aminotransferase (6 [15.0%]). No deaths were considered related to study drug by the investigator. Serious adverse events occurred in 6 (15.0%) patients.

Any grade immune-related adverse events (irAEs) occurred in 30 patients (85.7%) and grade 3/4 irAEs occurred in 9 patients (25.7%). The most common irAEs were hyperthyroidism (13 [37.1%]),

increased alanine aminotransferase (8 [22.9%]), and increased thyroid stimulating hormone (7 [20.0%]) (Supplementary Table 4). Adverse events (AEs) related to apatinib are presented in

Supplementary Table 5. No grade ≥ 3 bleeding events related to apatinib were observed.

AEs led to treatment discontinuation of camrelizumab in 4 patients (11.4%) and apatinib in 2 patient (5.7%), including grade 3 pneumonitis, grade 3 hyponatremia, grade 2 muscle spasm, and

grade 2 pulmonary tuberculosis (n = 1 each). No AEs led to treatment discontinuation of chemotherapy. AEs led to treatment delay of camrelizumab in 12 patients (34.3%) and treatment

interruption of apatinib in 7 patients (20.0%). AEs led to dose reduction of apatinib in 2 patients (5.7%) and chemotherapy in 3 patients (7.5%).

After 2 cycles of induction EC, 24 of 36 patients had an objective response (66.7%, 95% CI: 49.0–81.4); 35 of 36 patients had disease control (97.2%, 95% CI: 85.5–100) (Table 3). Among them,

24 (66.7%) patients had partial response (PR), and 11 (30.6%) had stable disease (SD). Notably, 72.7% (8/11) of those with initial SD then achieved PR after combination treatment with

camrelizumab, apatinib plus EC, followed by maintenance camrelizumab plus apatinib.

After the entire treatment, 32 of 36 patients had an objective response (88.9%, 95% CI: 73.9–96.9); 35 of 36 patients had disease control (97.2%, 95% CI: 85.5–100) (Table 3). Among them, 32

(88.9%) had PR, and 3 (8.3%) had SD. In total, 34 patients (94.4%) had a decrease in tumor size of target lesions from the baseline. Median best change from baseline was −63.3% (Fig. 2a).

Median duration of response (DoR) was 5.4 months (95% CI: 4.2–7.7; Fig. 2b–d). Median time to response (TTR) was 1.5 months. The overall ORR in all 40 patients was provided in the

Supplementary Table 6.

Clinical outcomes. a Maximum reduction from baseline in target lesion. b Treatment response and duration. c Spider plot showing the percentage change in the sum of target lesion diameters

during treatment. d Duration of response. e Kaplan-Meier curve for progression-free survival. f Kaplan-Meier curve for overall survival. NR not reached

At the data cut-off on May 30, 2023, the median duration of follow-up was 20.6 months (range: 4.1–27.5). Of the 36 evaluable patients, 30 (83.3%) had disease progression or deaths (n = 21).

The median PFS was 7.3 months (95% CI: 6.6–9.2, Fig. 2e). The median OS was 17.3 months (95% CI: 11.8-NR). The 12-month OS rate was 63.4% (95% CI: 45.4%–76.9%) (Fig. 2f).

We evaluated the association between genomic alteration and clinical outcomes. Baseline tissue samples were available from 30 patients for targeted gene sequencing and from 21 patients for

whole transcriptome sequencing (WTS). TP53 (97%) and RB1 (90%) were the most frequently mutated genes (Fig. 3a). No significant correlation between genomic mutations and response (complete

response/PR) during the induction treatment and the entire treatment was observed. Mutations in RB1 were associated with longer PFS (P