Intrathecal sintilimab for leptomeningeal metastases of non-small cell lung cancer failed from targeted therapy and intrathecal chemotherapy (LMIS study)

Abstract

Background

Leptomeningeal metastases (LMs) are serious complications of non-small cell lung cancer (NSCLC). This study aimed to investigate the safety and efficacy of intrathecal immune checkpoint inhibitors (ICIs) in treating NSCLC-LM.

Methods

We conducted this prospective phase 1 study (ChiCTR2200062245) using a traditional “3+3” design with intrathecal sintilimab (dose escalation 10, 20, 30, and 40 mg) for NSCLC-LM patients who had progressed from targeted therapy and intrathecal pemetrexed. The primary study endpoints were safety and recommended dose, and the secondary endpoints included clinical response rate, progression-free survival (PFS), intracranial progression-free survival (iPFS), and overall survival (OS).

Results

No dose-limiting toxicity was found at 10, 20, 30, and 40 mg for intrathecal sintilimab. Therefore, sintilimab 40 mg was recommended for intrathecal injection. A total of 19 patients were enrolled in this study. The median age at diagnosis of LM was 53 years. The overall incidence of adverse events (AEs) was 68.4%, and rash (n = 4, 21.1%) was the most common AEs, which returned to normal after symptomatic treatment. As 1 patient was lost to follow-up and 18 patients could be evaluated for efficacy, the clinical response rate was 38.9% (7/18). Median PFS was 3.5 months (95% CI: 2.7–4.2 months), median iPFS was 3.5 months (95% CI: 1.3–5.6 months), and median OS was 11.5 months (95% CI: 0.0–25.4 months).

Conclusions

Intrathecal ICIs for NSCLC-LM patients are safe, and the recommended dose of sintilimab is 40 mg. Intrathecal sintilimab for NSCLC-LM failed from multi-line therapies, showed potential effectiveness in some patients, and is worthy of further study.

Key Points.

• Intrathecal sintilimab was safe for NSCLC-LM failed from targeted therapy and intrathecal pemetrexed, and the recommended dose of sintilimab is 40 mg.

• Intrathecal sintilimab for NSCLC-LM showed potential effectiveness in some patients and is worthy of further study.

Importance of the Study.

Recently, the incidence rate of leptomeningeal metastases (LM) increased in non-small cell lung cancer (NSCLC), especially for patients with driver genes mutation, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Due to the presence of a blood-CSF barrier, intrathecal chemotherapy is an effective treatment option for LM. Our previous phase I/II clinical trials showed that intrathecal pemetrexed (IP) was an effective and safe treatment method for NSCLC-LM failed from targeted therapy. This phase I clinical trial showed that intrathecal sintilimab, an immune checkpoint inhibitors (ICIs), was safe for NSCLC-LM patients who failed IP, and the recommended dose of sintilimab is 40 mg. Intrathecal sintilimab for NSCLC-LM showed potential effectiveness in some patients and is worthy of further study.

Leptomeningeal metastases (LMs) are the devastating complications of non-small cell lung cancer (NSCLC), referring to the metastases of tumor cells to the pia meningeal, arachnoid, subarachnoid and cerebrospinal fluid (CSF).^1,2 LMs occur in about 3%–5% of patients with advanced NSCLC; the incidence is increasing yearly due to prolonged survival by target and immune therapies and improving diagnostic methods.^3,4 LM progresses rapidly, the treatment is limited, and the prognosis is very poor. Currently, the main therapeutic methods include molecular targeted therapy, immunotherapy, intrathecal chemotherapy, and radiation therapy.^5,6 The BLOOM study showed that osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), resulted in a median overall survival (OS) of 11 months of treatment of LM patients from EGFR-mutated advanced NSCLC whose disease had progressed on previous TKI therapy.⁴ Delivery through intrathecal injection can bypass the blood-CSF barrier, allowing drugs to directly reach the cerebrospinal membrane.^7–10 Our previous studies showed that intrathecal pemetrexed was a safe and effective method for NSCLC-LM patients who failed from EGFR-TKI therapy, and the median OS was 9–12 months.^11,12 However, drug resistance is inevitable, and further study is needed.

The emergence of immune checkpoint inhibitors (ICIs) has improved the survival rate of NSCLC patients.^13,14 Currently, the commonly used ICIs are programmed death receptor-1/ligand-1 (PD-1/PD-L1) inhibitors.¹⁵ Recently, Prakadan et al. reported that there are many kinds of immune cells in the CSF of LM, which could respond to ICIs.¹⁶ The IMpower150 and ORIENT-31 study showed that ICIs combined therapy can produce a certain therapeutic effect on TKI-failed NSCLC.^17,18 However, due to the high molecular weight of ICIs, they cannot readily cross the blood-CSF barrier. If administered intrathecally, ICIs could accumulate to a higher local therapeutic concentration, providing a better therapeutic window. Recently, Huppert et al. reported that intrathecal ICIs were effective in treating LM from melanoma, and the side effects were controllable.¹⁹ Therefore, we designed a prospective phase I clinical trial to study the safety and optimal recommended dose of intrathecal sintilimab (PD-1 antibody) for the treatment of NSCLC-LM.

Methods

Patients

This study was approved by the Ethics Committee of the Second Affiliated Hospital of Harbin Medical University and registered in the Chinese Clinical Trial Registry (ChiCTR2200062245). Inclusion criteria were as follows: (1) age ≥ 18 years; (2) patients diagnosed with confirmed (positive CSF cytology) or probable (with typical clinical signs and positive neuroimaging) NSCLC-LM according to the European Society of Neuro-Oncology—European Society of Medical Oncology (EANO-ESMO) guideline criteria²⁰; modality of LM diagnosis refers specifically to the LM status at the time of study enrollment; (3) LM progressed from targeted therapy and at least once intrathecal chemotherapy assessed by Response Assessment in Neuro-Oncology (RANO) criteria²¹; (4) acceptable organ and bone marrow function; (5) without other serious chronic diseases, and previously treated or stable parenchymal metastases were allowed; (6) without lumbar puncture and ICIs therapy contraindications; (7) able to sign a written informed consent. Exclusion criteria: (1) patients with a history of AIDS, acute or chronic hepatitis B or C infection; (2) pneumonia from previous ICIs treatment, or persistent grade 2 or more adverse events from such treatment; (3) persistent autoimmune disease requiring systemic treatment in the past 2 years; (4) pregnant or lactating patients; (5) patients with serious medical, neurological or mental illness. The general and clinical data of NSCLC-LM patients were collected, including age, gender, Eastern Cooperative Oncology Group (ECOG) score, driver gene variation, time of LM diagnosis, clinical manifestations, brain parenchymal metastasis, extracranial tumor metastasis, and previous treatment methods.

Treatment and Dose Escalation

This trial uses a “3 + 3” design for dose escalation (10, 20, 30, and 40 mg), starting from the initial dose (10 mg), with three patients at each dose level. The dose of sintilimab was made with reference to the clinical trial of intrathecal nivolumab (NCT03025256). Each patient will receive intrathecal sintilimab with a fixed dose and continued systemic therapy. If dose-limiting toxicity (DLT) is absent, intrathecal sintilimab increases to the next dose level. The first dose of sintilimab was observed for 28 days after intrathecal injection as a DLT window. If there is 1 case of DLT at the current dose, 3 subjects are added to the dose level, and then there are 6 subjects at the current dose. If only 1 of the 6 subjects develops DLT, the experiment rolls to the next dose level. If ≥2 cases of DLT occur, the trial is stopped, and the previous dose level of this dose level is defined as the maximum tolerated dose (MTD). If ≥2 out of 3 subjects developed DLT, the trial was discontinued. DLT was evaluated according to Adverse Reaction Evaluation Criteria Version 5.0 (CTCAE 5.0), which is defined as grade 4 or above myelosuppression and grade 3 or above non-hematological toxic adverse events. Intracranial pressure was measured before each intrathecal treatment, and CSF was collected for cytopathological, routine, biochemical, protein, and tumor biomarkers detection. A fixed dose of sintilimab (10, 20, 30, or 40 mg) was dissolved in 0.9% sodium chloride solution (total 5 mL) for intrathecal injection, combined with dexamethasone 1mg for intrathecal injection. After each intrathecal administration, the patient was instructed to lie on the pillow for 4–6 hours. Treatment was given every 3 weeks for a total of 6 cycles, followed by maintenance treatment every 4 weeks until the disease progressed, intolerable toxicity, withdrawal of informed consent, or death, whichever occurs first. All patients were continued on their backbone systemic therapy, and radiation during the course of the study (focal radiation to brain or cauda equina) for symptom control was allowed. Previous therapy directed at LM and/or metastatic cancer is allowed, including IT therapy (washout 7 days), radiation (washout 7 days), and systemic biologic therapy (washout 14 days).

Safety and Efficacy Evaluation

Adverse events (AEs) were evaluated according to CTCAE version 5.0. Follow-up was performed 7 days after each cycle of administration and monthly after the end of treatment. LMs response was evaluated according to the RANO criteria, which consisted of three main aspects: standardized nervous system examination, cytology or flow detection of CSF, and enhanced magnetic resonance imaging (MRI) of the whole brain/spinal cord.²¹ Systemic efficacy was evaluated according to RECIST version 1.1 criteria. Detailed and standardized neurological examination was performed before each intrathecal injection during treatment, CSF was conducted during each cycle, and efficacy evaluation (imaging and systemic disease) was performed every 2 cycles. The primary endpoints were safety and recommended dose, and secondary endpoints included clinical response rate (mean response by RANO criteria), progression-free survival (PFS), intracranial progression-free survival (iPFS), and overall survival (OS). PFS is defined as the time from intrathecal sintilimab to systemic progression or death. iPFS is defined as the time from the start of intrathecal sintilimab to the imaging, cytological, or clinical progression of LM, whichever comes first. OS is defined as the time from initiation of intrathecal sintilimab to endpoint data. The last visit or follow-up time was used as the endpoint data for the lost patients.

Statistical Methods

The Kaplan–Meier method was used to calculate and plot the PFS, iPFS, and OS curves. The median follow-up time was calculated by the reversed Kaplan–Meier method. SPSS 26.0 software (IBM Corporation) was used for statistical analysis and the confidence interval (CI) was calculated at a 95% confidence level. The swimmer diagram was drawn using R software 4.1.3 (Posit).

Results

Baseline Characteristics

A total of 19 NSCLC-LM patients participated in this study from July 2022 to November 2023 (Figure 1, Table 1). The median age at diagnosis of LM was 53 years (range 39–73 years), with 6 men (32%) and 13 women (68%). All patients had driver gene mutations, with 16 (84%) EGFR mutations and 3 (16%) anaplastic lymphoma kinase (ALK) fusion. Ten patients (53%) had brain parenchymal metastases at enrollment. The ECOG score of 18 patients (95%) was ≥ 2, and 1 patient (5%) of ECOG was < 2, and the ECOG median (range) was 3 (1–4). All patients had symptoms of headache, nausea, or vomiting, and most patients (79%) had difficulty walking. Visual, auditory, or facial nerve involvement occurred in 68% of patients, and disturbance of consciousness or epilepsy was present in 42% of patients. There were 16% of patients with meningeal involvement such as neck and back pain or difficulty in defecating. CSF cytology was positive in 89% (17/19) of patients, and enhanced MRI was positive in 58% (11/19) of patients. Six patients (32%) had previously received cerebral radiotherapy (whole brain or local radiotherapy). Combined systematic therapy included osimertinib (5/19, 4 with double dose), almonertinib (4/19, 165 mg), furmonertinib (4/19, double dose), loratinib (3/19), anlotinib (2/19), and PD-1 antibody plus bevacizumab (1/19). Sixteen patients underwent intrathecal sintilimab by lumber puncture, and three patients via Ommaya. The median time (and range) from LM diagnosis to initiation of IT sintilimab was 11 months (3–35 months).

Figure 1.

Flow diagram.

Table 1.

Baseline Characteristics

Characteristic	n (%)
Median age at LM diagnosis (range)	53 (39–73)
Gender
male	6 (32)
female	13 (68)
ECOG performance status
1	1 (5)
3	12 (63)
4	6 (32)
The modality of LM diagnosis
MRI+/cytology+	9 (47)
MRI-/cytology+	8 (42)
MRI+/cytology-	2 (11)
Gene mutation detection
EGFR	16 (84)
ALK	3 (16)
Clinical manifestation
Headache, nausea or vomiting	19 (100)
Disorders of consciousness or epilepsy	8 (42)
Walking instability	15 (79)
Optic, auditory of facial nerve involvement	13 (68)
Neck and back pain or defecation difficulty	3 (16)
Brain metastasis
With	10 (53)
Without	9 (47)
Brain radiotherapy before LM
Local	4 (21)
Whole	2 (11)
Without	13 (68)
Intrathecal chemotherapy
1L	8 (42)
≥2L	11 (58)
Combined systematic therapy
osimertinib	5 (26.3)
almonertinib	4 (21.1)
vormetinib	4 (21.1)
loratinib	3 (15.8)
anlotinib	2 (15.8)
PD-1 antibody + bevacizumab	1 (5.3)

LM, leptomeningeal metastases; ECOG, Eastern Cooperative Oncology Group; MRI, magnetic resonance imaging; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; ICIs, immune checkpoint inhibitors.

Safety and Recommended Dosage

Twelve patients were enrolled in the phase 1a cohort. Initially, 3 patients were treated with dose level 1 (10 mg), and DLTs were not observed. Next, we moved to dose level 2 (20 mg) and level 3 (30 mg), in which another 3 patients were treated at each level, and DLTs were not observed. Then, we moved to dose level 4 (40 mg), in which no DLT was noted, therefore, the recommended dose is 40 mg (Supplementary Figure 1). Finally, 7 patients were enrolled in phase 1b with level 4.

At the cutoff date of follow-up, 17 patients (89%) stopped treatment, and 2 patients (11%) still in treatment. The median number (range) of intrathecal sintilimab cycles that were received was 2 (1–9). One case (40 mg group) was lost to follow-up. Treatment-related AEs were observed in 13 patients (68.4%), all of whom were grade 1–2 AEs (Table 2). The most common AEs associated with intrathecal sintilimab was rash (n = 4, 21.1%), in which 2 patients developed rash immediately after intrathecal injection and 2 patients developed rash 1–2 weeks after intrathecal injection. The rest of AEs include nausea (n = 3, 15.8%), vomiting (n = 3, 15.8%), fatigue (n = 3, 15.8%), numbness (n = 2, 10.5%), hyperthyroidism (n = 2, 10.5%), itching (n = 2, 10.5%), and neck pain (n = 2, 10.5%). The AEs of intrathecal sintilimab were similar to those of systematic sintilimab, and no unexpected AEs occurred. Overall, the adverse events were mild, no DLT was observed, no treatment-related deaths occurred, and the safety of intrathecal sintilimab was manageable.

Table 2.

Adverse Events

IT sintilimab dose	Patient accession number	Adverse event	Grade 1	Grade 2	Grade 3 or above
10 mg	1	Rash	1
	3	Hyperthyroidism	1
20 mg	4	Hyponatremia		1
	5	Hyperlipidemia		1
		Pruritus	1
		Fatigue	1
	6	Rash	1
		Nausea		1
		Vomiting	1
30 mg	7	Neck pain	1
	8	ALT/AST		1
		Fatigue	1
		Anorexia	1
		Vomiting		1
		Nausea		1
		Dizziness	1
	9	Neck pain	1
40 mg	14	Vomiting		1
		Limb numbness		1
		Diarrhea	1
		Fatigue		1
	16	Herpes		1
		Rash		1
		Hyperthyroidism	1
	17	Rash		1
	18	Limb numbness		1
	19	Nausea	1
		Pruritus	1

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Efficacy Valuation

Secondary endpoints included clinical response rate, PFS, iPFS, and OS. Follow-up ended on November 20, 2023, with a median follow-up of 9 months. At the end of follow-up, 1 patient was lost to follow-up (40 mg group), 8 patients died, and 10 patients survived. Two patients under treatment interruptions due to brain parenchymal metastasis and one patient under treatment interruption due to hydrothorax and thoracic chemotherapy. Of the surviving patients, 4 stopped the treatment due to disease progression, 1 stopped the treatment due to personal preference, 3 stopped treatments due to AEs, and 2 continued to receive intrathecal sintilimab (Figure 2). Temporary dexamethasone and mannitol were taken for 5 patients for intracranial hypertension, and no patient underwent radiation or ventriculoabdominal shunt placement. A total of 18 patients were evaluated for efficacy based on RANO criteria, 38.9% (7/18) were clinical response, 33.3% (6/18) were stable, and 27.8% (5/18) were progressed (Table S1). Clinical examination, CSF cytologic, and radiographic evaluation for each patient were shown in Table S2. Seven patients with response included 2 patients in sintilimab 20 mg group (2/3), 1 patient in sintilimab 30 mg group (1/3), and 4 patients in sintilimab 40 mg group (4/10; Table S2). Seven patients with response cleared CSF cytology and the median time to response was 3 months (range 1.5–5 months). Five of them were radiological improvements while the other 2 were cytological improvements without any radiological finding before enrollment. The median PFS was 3.5 months (95%CI: 2.7–4.2 months), the median iPFS was 3.5 months (95%CI: 1.3–5.6 months), and the median OS was 11.5 months (95%CI: 0.0–25.4 months; Figure 3). One patient in this trial who received intrathecal sintilimab of 20 mg was still alive 60 weeks after the first treatment. The patient was diagnosed with lung adenocarcinoma 6 years before enrollment. Genetic testing indicated EGFR 21 exon L858R mutation, and the patient was treated with chemotherapy and EGFR-TKI. The patient developed headache, nausea, vomiting, disturbance of consciousness, inability to walk, and abnormity of auditory and visual by 43 months after diagnosis of lung cancer. Finally, the patient developed LM confirmed by CSF pathology. The disease progressed after intrathecal pemetrexed and thiotepa, and the patients received intrathecal sintilimab. After 1 cycle of intrathecal sintilimab without changing the background systemic treatment regimen, the neurological symptoms were relieved, the CSF cytology turned negative for 21 weeks, and the MRI showed improvement (Supplementary Figure 2).

Figure 2.

Duration on intrathecal treatment for all treated patients (n = 19).

Swimmer plot for all treated patients. No, No intrathecal treatment.

Figure 3.

Survival of patients. (A) Progression-free survival (PFS); (B) Intracranial progression-free survival (iPFS); (C) Overall survival (OS).

Another patient treated with intrathecal sintilimab of 40 mg has already received 4 cycles of treatment. The patient was diagnosed with lung adenocarcinoma and treated with chemotherapy, immunotherapy, and targeted therapy before admission. After 9 months of treatment, headache, nausea, and vomiting appeared, and LM was confirmed by CSF cytopathology. After diagnosis of LM, the patient was treated with intrathecal pemetrexed and oral volmetinib. As the disease progressed, intrathecal sintilimab was given. After the first cycle of sintilimab treatment, the CEA of the CSF decreased from 954.82 ng/mL to 342.83 ng/mL. At the third cycle of treatment, the patient developed grade 2 limb numbness and CSF CEA continued to decrease to 5.03 ng/mL. After 4 cycles of treatment, the patient’s clinical symptoms improved with a CSF CEA of 0.99 ng/mL. The patient is currently in treatment.

Discussion

This study is a single-arm, prospective, open-label, phase 1 clinical trial of intrathecal sintilimab for treating patients with LM from NSCLC. We designed this phase 1 study for NSCLC-LM using the traditional “3+3” design for dose escalation. As NSCLC-LM usually underwent multilines of therapy, we did not restrict the previous treatment methods, including ICIs therapy. There were 3 patients treated with ICIs previously in our study. Moreover, due to the poor physical status of NSCLC-LM, patients with poor physical status were allowed to enter the group. There were 95% (18/19) patients with poor ECOG score (≥2). Even so, no DLT was found by dose escalation, and we demonstrated that intrathecal sintilimab is safe and the recommended dose for sintilimab was 40 mg (highest planned dose). In these heavily pretreated patients, intrathecal sintilimab showed potential effectiveness in some patients, and is worthy of further study.

The incidence of adverse reactions in this study was similar to previous IV sintilimab, with no new or unexpected toxicities.^18,22 All the adverse reactions in this study were grade 1 to grade 2 and were relieved after symptomatic treatment. We found that rash (n = 4, 21.1%) was the most common AEs with intrathecal sintilimab, appearing immediately or 1–2 weeks after intrathecal injection, and relieved after timely administration of desensitization therapy. In particular, we found that the most common neurological AEs was limb numbness (n = 2, 10.5%), which occurred immediately after intrathecal sintilimab, mainly in the lower extremities, and relieved in 30 minutes.

For the secondary endpoints, the median OS (11.5 months) in this study was higher than previously retrospective studies with systemic (IV) ICIs for NSCLC-LM (4.0 and 3.7 months),^23,24 which might be attributed to the fact that intrathecal ICIs achieving dose intensification in the CSF. This was consistent with intrathecal ICIs for LM from melanoma, which demonstrated good efficacy in patients with previously ICIs-refactory patients.²⁵ Intrathecal ICIs is similar to the concept for intratumoral immunotherapy which uses the tumor as the remedy.²⁶ Upon direct injections into the tumor, a high concentration of immunostimulatory products can be achieved in situ, while using small amounts of drugs. Local delivery of immunotherapies allows multiple combination therapies, while preventing significant systemic exposure and off-target toxicities. We acknowledge that definitive conclusions about efficacy are not possible from a phase 1 study, but these results from our study are promising and support the rationale to continue to explore intrathecal ICIs in NSCLC-LM.

There are some limitations in this study. First, this trial did not restrict the previous treatment regimen of enrolled patients and allowed patients to continue background systemic treatment. Therefore, it was difficult to determine whether there were drug interactions, but it was inevitable for this type of disease as LM was the late manifestation of NSCLC. Second, lack of standardization for LM response due to the defects of the RANO assessment criteria adopted in this study.²⁷ The assessment of LM response is a challenging topic in neuro-oncology. Third, due to the small number of patients and only NSCLC-LM with driver mutation included in this study makes drawing conclusions challenging, further study with the large number of patients and NSCLC-LM without driver mutation is needed to prove the efficacy.

In conclusion, the adverse effects of intrathecal sintilimab for NSCLC-LM patients were controllable, and 40 mg of sintilimab was recommended for intrathecal injection. Intrathecal ICIs are worthy of further study to verify the efficacy of NSCLC-LM.

Funding

This study was funded by Wu Jieping Medical Foundation (320.6750.2022-16-3) and Beijing Association for Cancer Control and Prevention (CAPTRALung2021008).

Conflict of interest statement

All authors declare no potential conflicts of interest.

Authorship statement

Conceptualization, C.F., L.L., and T.X.; Funding acquisition, C.F. and T.X.; Data curation, C.F., Y.H., C.T., Y.L., X.S., L.L., D.H., L.D., G.W., Y.D., S.M., Z.Z, and J.Z.; Methodology, C.F., Y.H., C.T., Y.L., X.S., L.L., T.X., D.H., and Y.D.; Software, Y.H., C.T., X.S., D.H., and Y.D.; Supervision, W.S., Q.J., D.H., L.D., G.W., and T.X.; Writing & editing, C.F., Y.H., C.T., X.S., W.S., Q.J., Y.D., L.L., and T.X..

Data availability

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