PD-1 inhibitor combined with albumin paclitaxel and apatinib as second-line treatment for patients with metastatic gastric cancer: a single-center, single-arm, phase II study

According to Global Cancer Statistics 2020, over 1 million new cases of gastric cancer (GC) occurred in 2020, which is the 5th most common malignancy and the 4th leading cause of cancer death [1]. Of these, 60% of new cases occurred in East Asia [2]. About 40–50% of patients present with unresectable disease at diagnosis due to a locally advanced or metastatic condition [3]. Among them, about 40% of patients receiving first-line therapy may be candidates for second-line therapy. Oxaliplatin plus with capecitabine (Xelox) or S1 (SOX) were most commonly used in the first-line and subequal taxane agents in the second settings in China. Recently, the management of metastatic GC (mGC) has improved with the advent of novel drugs and the establishment of a continuum of care for this aggressive disease. Immunotherapy has become the mainstay of treatment for mGC according to data from several clinical trials [4, 5]; however, the standard second-line or subsequent therapy is dependent on prior therapy and patient performance status (PS), with survival being limited and frustrating. The National Comprehensive Cancer Network (NCCN) recommended second-line preferred regimens including ramucirumab and paclitaxel, docetaxel, paclitaxel, irinotecan, fluorouracil, irinotecan, and so on. The randomized phase 3 studies RAINBOW [6], REGARD [7], WJOG 4007 [8], and COUGAR-02 [9] showed that median progression-free survival (PFS) in patients with advanced gastric or gastro-esophageal junction (G/GEJ) adenocarcinoma who progressed on first-line chemotherapy with platinum and fluoropyrimidine was less than 6 months and median overall survival (OS) was less than 9 months, representing an unmet need for clinician and patients. Compared to paclitaxel, pembrolizumab, a programmed cell death 1 (PD-1) inhibitor as a kind of immunotherapy, did not significantly improve OS as second-line therapy for advanced GC with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher, although pembrolizumab had a better safety profile [10]. Therefore, more effective treatment regimens are required.

In recent years, combination therapy of antiangiogenic agents with anti-PD-1 antibodies has shown a favorable outcome and exhibited a synergistic effect. The anti-PD-1 antibody nivolumab plus regorafenib (a VEGFR1-3 inhibitor) achieved an ORR of 44% (5/9) in patients with pretreated GC in REGNIVO study [11], which provides a rationale for the application of immunotherapy combined with antiangiogenic agents in gastric or esophagogastric junction cancer (GC/EGJC). Combination therapy with a PD-1 inhibitor and apatinib (a domestic highly selective VEGFR1-3 inhibitor) further showed encouraging clinical activity and tolerable toxicity in the second-line setting [12].

As far, there have been no studies on the addition of antiangiogenic agents and anti-PD-1 antibodies to chemotherapy for mGC. In the ABSOLUTE trial [13], weekly nanoparticle albumin-bound paclitaxel (w-nab-PTX) showed non-inferiority to weekly solvent-based paclitaxel (w-sb-PTX) for OS and PFS. Therefore, based on the results of previously developed innovative strategies, we carried out a prospective phase II clinical study to assess the efficacy and safety of a PD-1 inhibitor combined with apatinib and albumin paclitaxel (a surrogate of paclitaxel) as second-line therapy for patients with mGC.

This single arm, single-center, phase II trial evaluated the efficacy and safety of a combination therapy of a PD-1 inhibitor with albumin paclitaxel and apatinib as second-line treatment in patients with mGC, providing an option for patients who were previously treated with first-line platinum- or oxaliplatin-based chemotherapy.

This was the first time that the PD-1 inhibitor and small molecule anti-angiogenic agents were combined with chemotherapy in an attempt to improve the current dilemma of second-line therapy. Nivolumab and sintilimab have been approved as immune checkpoint inhibitors for the first-line treatment of advanced GC/EGJC [4]. But till now, there has been no evidence that PD-1 inhibitor monotherapy is comparable to single-agent chemotherapy [10]. Apatinib was approved as third-line therapy for advanced GC in 2014 [14]. The combination of PD-1 inhibitor and anti-angiogenesis has a coordinated function, which has been demonstrated in several works [12]. However, the efficacy of the addition of chemotherapy to the above combination in the second-line therapy is still questionable.

In our study, it was observed that the median PFS was 6.2 months (95% CI, 3.9–9.3), and OS was 10.1 months (95% CI, 7.5–14.1). Compared with the results of previous studies, a significantly increased survival benefit was shown. These results suggested that the outcomes of the three-drug combination were more favorable than those of double drugs in previous studies. In the RAINBOW study [6], the median PFS with ramucirumab plus paclitaxel was 4.4 months (95% CI, 4.2–5.3) and the median OS was 9.6 months (95% CI, 8.5–10.8). The outcomes were even worse in the REGARD study, with the median OS of 5.2 months and the median PFS of 2.1 months [7]. In the similar population-based study of nivolumab combined with paclitaxel plus ramucirumab as second-line treatment for advanced GC [15], the 6-month PFS rate was 46.5% (80% CI, 36.4%–55.8%), and median survival time was 13.1 months (95% CI, 8.0–16.6) as 60.5% of patients had PD-L1 CPS ≥ 1. These outcomes were better than those of the present study, possibly due to a higher proportion of patient with PD-L1 positive status than that of our study. Overall, the addition of a PD-1 inhibitor to chemotherapy and anti-angiogenic agents in the second-line therapy showed significant superiority over chemotherapy alone or combined with anti-angiogenic agents [16].

With regard to tumor response, the ORR and DCR of a PD-1 inhibitor plus apatinib were 20.9% and 88.3%, which were better than chemotherapy alone [8, 9] or combined with anti-angiogenic agents [17]. The ORR and DCR of apatinib combined with chemotherapy were 18.52% and 92.59%, respectively [18]. By contrast, an objective response was observed in 20 (69%, 95% CI, 49–85) of 29 patients, including one patient with MMR-deficient tumor in the EPOC study [19].

The safety profile in this study was generally consistent with that of monotherapy with a PD1 inhibitor, apatinib or albumin paclitaxel, or any combination of two or three drugs for mGC (e.g., nivolumab plus paclitaxel and ramucirumab [15] or lenvatinib plus pembrolizumab [19]), with the notable exception of proteinuria, a frequent toxic effect of apatinib. The addition of a PD-1 inhibitor to apatinib did not increase the known toxic effects associated with apatinib. Common toxicities reported in this study, such as bone marrow suppression, hypertension, hand-foot reaction, and hypothyroidism, were mild to moderate and were manageable with appropriate dose modifications and supportive care. And the incidence of these AEs was similar to that reported in the EPOC1706 trial [19] and in trials involving patients with mGC [12, 15, 18]. No rare serious toxic effects occurred and no patients reported treatment-related deaths.