Study protocol: A single-arm, multicenter, phase II trial of camrelizumab plus apatinib for advanced nonsquamous NSCLC previously treated with first-line immunotherapy.

BACKGROUND: For advanced nonsquamous non-small cell lung cancer (NSCLC), the mechanisms of resistance to first-line immunotherapy are not clear. Immune checkpoint inhibitors (ICIs) in combination with agents targeting other pathways may serve as second-line therapy options. Apatinib (a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) could increase the efficacy of camrelizumab (an ICI agent). The efficacy and safety of this combination regimen as a second-line therapy for NSCLC patients after failure on first-line immunotherapy has not previously been evaluated.
METHODS: In this single-arm, multicenter, phase II trial, metastatic nonsquamous NSCLC patients previously treated with single-agent ICI or ICI plus chemotherapy will be enrolled. Participants will receive intravenous camrelizumab 200 mg D1 and oral apatinib 250 mg D1-21 for a 21-day cycle. The study treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is progression-free survival by investigator. Secondary endpoints are overall survival, objective response rate, disease control rate, duration of response by investigator, quality of life, safety, and toxicity.
CONCLUSIONS: This trial will provide evidence of the benefit of treatment with camrelizumab combined with apatinib in advanced nonsquamous NSCLC patients who were previously treated with first-line immunotherapy.

INTRODUCTION

Lung cancer is considered the most common cause of cancer death. Non‐small cell lung cancer (NSCLC) accounts for nearly 85% of lung cancer cases. About 70% of patients with NSCLC are diagnosed at an advanced stage. For advanced or metastatic disease with negative driver gene and programmed death‐ligand 1 (PD‐L1) expression ≥1%, the standard first‐line treatment is immune checkpoint inhibitors (ICIs), with or without chemotherapy, and second‐line therapy is chemotherapy.

For advanced NSCLC, although the mechanisms of resistance to first‐line immunotherapy are not clear, studies have shown the efficacy of ICI rechallenge on patients with progression during first‐line ICIs. A retrospective analysis of the phase III OAK study indicated that patients who received atezolizumab treatment beyond progression (TBP) had a numerically longer median overall survival (OS). The OS in the atezolizumab TBP arm (n = 168; 19.6% had received second‐line therapy), other anticancer treatment arm (n = 94), and no anticancer treatment arm (n = 70) were 12.7 months versus 8.8 months versus 2.2 months, respectively. A case series shared the experience of pembrolizumab on 12 patients previously treated with nivolumab. Eight (66.7%) received second‐line chemotherapy before pembrolizumab treatment. Median progression‐free survival (PFS) was 3.1 months. Another retrospective real‐world study also demonstrated the OS benefit of ICI TBP. The median OS were 26.6 versus 9.5 months (TBP group vs. non‐TBP group; hazard ratio, 0.40; 95% confidence interval [CI]: 0.23–0.69). In the KEYNOTE‐146/study 111, 21 patients were enrolled in the NSCLC cohort, in which 11 (52.4%) had received prior ICIs and 11 (52.4%) had received ≥2 prior lines of therapy. All participants received pembrolizumab plus lenvatinib (a multitargeted tyrosine kinase inhibitor [TKI]). As a result, seven (33.3%) achieved objective response and the median PFS was 5.9 months. Each anti‐programmed death 1 (PD‐1)/PD‐L1 antibody targeted different sites of PD‐1/PD‐L1. Thus, patients who previously treated with immunotherapy may benefit from the same or different kind of ICIs with or without antiangiogenic agents.

Camrelizumab (SHR‐1210) is an anti‐PD‐1 antibody, whose binding sites (CC' and FG loop of PD‐1) is distinct from pembrolizumab (C'D loop) and nivolumab (BC loop). CameL, a phase III trial, has confirmed the efficacy of camrelizumab plus chemotherapy as first‐line treatment for advanced or metastatic nonsquamous NSCLC. The hazard ratio for PFS (camrelizumab plus chemotherapy [n = 205] vs. chemotherapy [n = 207]) was 0.60 (95% CI: 0.45–0.79).

Furthermore, an in vivo and clinical study suggested low‐dose apatinib, a vascular endothelial growth factor receptor 2 (VEGFR2) TKI, combined with an ICI significantly inhibited tumor growth and metastases, and prolonged survival in lung cancer mouse models. Promising anticancer activity has also been observed in pretreated advanced NSCLC patients. Another phase II trial has also shown the efficacy of camrelizumab in combination with apatinib on NSCLC after failure of first‐line chemotherapy, with an objective response rate (ORR) of 30.9%, median PFS of 5.7 months, and median OS of 15.5 months.

However, the efficacy of camrelizumab plus apatinib as a second‐line therapy for NSCLC patients who were previously treated with immunotherapy has not been explored. Therefore, we hypothesized that camrelizumab plus apatinib can bring benefit to advanced nonsquamous NSCLC patients after failure on first‐line immunotherapy. This phase II trial was designed to assess the efficacy and safety of the combination regimen.

METHODS

Study design

This nonrandomized, open‐label, single‐arm, multicenter, phase II trial (NCT04670913) aimed to evaluate the efficacy and safety of camrelizumab combined with apatinib in patients with metastatic nonsquamous NSCLC previously treated with first‐line immunotherapy. Table 1 is the SPIRIT flow diagram.

TABLE 1

SPIRIT flow diagram

	Enrolment	Cycle 1 a	Cycle 2	Etc.	End of treatment	Safety follow‐up	Survival follow‐up
Enrolment:
Eligibility screen	X
Informed consent	X
Medical history, physical and laboratory examination	X
Interventions:
Camrelizumab 200 mg D1
Apatinib 250 mg D1‐21
Assessments:
Tumor	X	X (every 6 weeks)
Quality of life		X	X	X	X	X b
Survival						X	X c
Adverse events		X	X	X	X	X d
Serum and plasma samples e		X			X

One cycle is 21 days.

Last assessment of quality of life is at 30 days after the end of treatment.

Survival was assessed every 3 months.

Last assessment of adverse events is at 90 days after the end of camrelizumab treatment or 30 days after the end of apatinib treatment (whichever is later).

Samples will be obtained before study drug administration at cycle 1 and when progression occurs.

The protocol was approved by the ethics committees of all participating centers, and the trial will be conducted in compliance with the Good Clinical Practice principles and the Declaration of Helsinki. All patients will provide written informed consent before participation.

Eligibility criteria

Patients aged 18–75 years, with stage IIIB/IV nonsquamous NSCLC, previously treated with single‐agent ICI (including camrelizumab) or ICIs in combination with chemotherapy as first‐line treatment, whose best objective response was stable disease or better, and PFS was longer than 3 months with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, life expectancy ≥12 weeks, measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and adequate organ function are eligible for inclusion in the study. Key exclusion criteria are previous treatment with anticancer virus therapy, T cell costimulation therapy (e.g., cytotoxic T lymphocyte‐associated protein 4 [CTLA‐4] inhibitors), or antiangiogenic drugs, intolerance to the ICI during first‐line treatment, autoimmune disease, pulmonary tuberculosis, active brain metastasis or pneumonitis, radiotherapy within 4 weeks, antiplatelet or anticoagulation treatment within 10 days after study treatment initiation, and the presence of tumor invasion of local major blood vessels.

Treatment

Participants will receive intravenous camrelizumab 200 mg D1 and oral apatinib 250 mg D1–D21 for a 21‐day cycle. Combination therapy will continue until disease progression, unacceptable toxicity, or withdrawal of consent. After progression, study treatment can continue at the discretion of the investigators.

When adverse events (AEs) prespecified according to the protocol occur, camrelizumab will be suspended until AEs revert to grade 1 or less, or be discontinued. Dose reduction of camrelizumab is not permitted. Additionally, if camrelizumab suspension lasts for more than 9 weeks, camrelizumab will also be discontinued.

When AEs caused by apatinib occur, treatment will be suspended or administered every other day until AEs revert to grade 1 or less, or discontinued according to the protocol.

Study assessment and endpoints

Tumors will be assessed using CT or MRI per RECIST version 1.1 within 28 days before treatment initiation and then every 6 weeks after the start of the study until disease progression or study treatment discontinuation. Quality of life (QoL) will be determined by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ‐C30; version 3, Chinese version) and QLQ Lung Cancer 13 (QLQ‐LC13; Chinese version) D1 of every cycle, at the end of study treatment, and 30 days after treatment discontinuation. Follow‐up for survival outcome will be performed by clinical or telephone follow‐up every 3 months.

Treatment‐emergent adverse events (TEAEs) will be assessed from the first therapeutic dose throughout the treatment period and for 90 days after the end of camrelizumab treatment or 30 days after the end of apatinib treatment (whichever is later) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Serum and plasma samples will be obtained before study drug administration at cycle 1 and when progression occurs. Tumor samples at diagnosis and after progression will also be collected when it is possible. All these samples will be analyzed using next‐generation sequencing or other technique to explore efficacy predictors and resistance biomarkers.

The primary endpoint is PFS (defined as the time from the start of study treatment to the first time of disease progression or death from any cause, whichever is earlier) assessed by the investigator. Secondary endpoints are OS (defined as the time from the start of study treatment to death from any cause), ORR (the proportion of patients with complete response [CR] or partial response [PR]), disease control rate (DCR; the proportion of patients with CR, PR or stable disease [SD]), duration of response (DoR; defined as the time from the first documented response to the first time of disease progression or death, whichever is earlier) by the investigator, QoL, safety, and toxicity. Biomarker analysis for efficacy predictors and resistance mechanisms is the exploratory endpoint.

Statistical considerations

The median PFS has previously been reported to be 2.8 months for docetaxel. The expected median PFS is 5.1 months for the study treatment. Assuming an enrolment period of 12 months and a follow‐up period of 6 months, 24 patients were calculated with a power of 80% and a one‐sided α of 5%. Considering the 20% dropout rate, 30 patients are required for the study.

All patients, who have received at least one dose of study, will be considered in the efficacy analysis. Safety will be assessed in all patients who received at least one dose of the treatment and safety evaluation.

The curves of PFS, OS and DoR will be plotted using Kaplan–Meier method, and the median and 95% CIs of these endpoints will be estimated by log–log method.

For ORR and DCR, the rates and corresponding 95% CIs will be calculated using the Clopper‐Pearson method.

Descriptive statistics will be applied for EORTC QLQ‐C30/LC13 of each timepoint and the changes from baseline, and safety analysis.

DISCUSSION

ICIs are the standard first‐line treatment for advanced or metastatic NSCLC patients with negative driver gene and PD‐L1 expression level ≥1%. A previous study has indicated the efficacy of atezolizumab TBP. ICI rechallenge after first‐line immunotherapy failure has also demonstrated potential benefit. , ,

A phase III trial has shown that camrelizumab plus chemotherapy as first‐line treatment can bring benefit to advanced or metastatic nonsquamous NSCLC. Pilot studies have demonstrated that the combination treatment enhanced the anticancer capability as higher‐line therapy in advanced NSCLC patients previously treated with chemotherapy. , Additionally, for advanced hepatocellular carcinoma and cervical cancer, camrelizumab plus apatinib is also a potential option. Thus, the regimen has promising anticancer activity in solid tumors and is worthy of further investigation.

However, there is a lack of assessment of combined treatment for NSCLC patients previously treated with immunotherapy. The present single‐arm, multicenter, phase II trial aims to evaluate the efficacy and safety of camrelizumab combined with apatinib.

In addition, as an antiangiogenic agent, apatinib could also inhibit reactive cutaneous capillary endothelial proliferation (an immune‐related adverse event arising from camrelizumab), which is an immune response of skin capillary endothelial cells. Thus, for camrelizumab, we postulate that additional apatinib could increase efficacy and reduce the certain toxicity on advanced nonsquamous NSCLC patients previously treated with first‐line immunotherapy.

The present study has several limitations. First, because the present trial is an exploratory study, the sample size has not been calculated and is set at 30. Second, it is a single‐arm, phase II trial, and if the regimen demonstrates potent anticancer activity, the efficacy should be confirmed in a randomized, controlled phase III study.

There are three similar trials. All of them are still ongoing, and no results have so far been revealed. A single‐arm, phase II trial (NCT03689855) was designed to assess atezolizumab in combination with ramucirumab (an anti‐VEGFR2 antibody). In the other two randomized, controlled phase III trials, the efficacy and safety of atezolizumab plus cabozantinib (a multitargeted TKI) versus docetaxel (NCT04471428), and pembrolizumab plus lenvatinib versus docetaxel plus lenvatinib (NCT03976375) will be compared. The present trial and these three studies will provide evidence of the benefit of ICIs combined with antiangiogenic agents/multitargeted TKI for advanced nonsquamous NSCLC patients previously treated with first‐line immunotherapy.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.