With more than 1 million newly diagnosed cases in 2020, gastric cancer (GC) is the fifth most frequent cancer; it was also the third leading cause of cancer-related death worldwide . Gastroesophageal junction (GEJ) cancer concerns a form of gastric cancer developing around the digestive tract where esophagus and stomach connect; in the last years, the prevalence of GEJ constantly increased .
Zanidatamab combined with tislelizumab and chemotherapy
Around 15% to 25% of gastric cancers express the human epidermal growth factor receptor 2 (HER2-positive) [3, 4]. Zanidatamab is a novel bispecific antibody targeting two non-overlapping extracellular domains of HER2; it previously showed an encouraging antitumoral activity and a manageable safety profile, either as monotherapy in HER2-positive biliary tract cancer , with chemotherapy in HER2-positive breast cancer  and in G/GEJ adenocarcinoma .
The ongoing open-label, multicenter Phase 1b/2 study (NCT04276493) evaluates different doses of zanidatamab (Cohort A: 30 mg/kg or Cohort B: 1800 mg/2400 mg) combined with chemotherapy (CAPOX [capecitabine 1000 mg/m2 plus oxaliplatin 130 mg/m2], every third week [Q3W]) and tislelizumab (200 mg, intravenously [IV]; a humanized IgG4 anti–PD-1 monoclonal antibody) as first-line treatment of unresectable, locally advanced, recurrent, or metastatic HER2-positive G/GEJ adenocarcinoma . The treatment is continued until disease progression, intolerable toxicity or in case any other discontinuation criteria are met. Safety and objective response rate (ORR) are the co-primary endpoints; duration of response (DoR), progression-free survival (PFS), disease control rate (DCR) and overall survival (OS) are secondarily analyzed.
So far, 33 eligible patients (Cohort A: 19, Cohort B: 14) have been randomized to this study. At the data cut-off (January 5th, 2022), 20 patients (60.6%) were still on treatment. Figure 1 shows the best percentage change in target lesions. Confirmed ORR was 75.8% (95% CI, 57.7-88.9) with one patient showing a complete response (CR), 24 patients a partial response (PR) and eight patients a stable response (SD). The DCR was 100% (95% CI, 89.4-100), and the median PFS was 10.9 months (95% CI, 8.2-non-estimable), with 36.4% of patients having PFS events.
Concerning the safety, 20 patients (60.6%) experienced at least one grade ≥3 treatment-related adverse event (TRAE), the most common being diarrhea (24.2%) and increased lipase (9.1%). Nine patients (27.3%) had immune-mediated AEs (imAEs), seven of them (21.2%) being grade ≥3 imAEs. Three patients had to discontinue tislelizumab due to imAEs; which included pneumonitis and immune hepatitis.
The authors concluded that zanidatamab combined with tislelizumab and CAPOX chemotherapy showed a tolerable safety profile and efficacy as first-line therapy for patients with HER2-positive G/GEJC. Based on these results, a randomized, global phase 3 study (HERIZON-GEA-01) has been initiated to investigate zanidatamab and chemotherapy with or without tislelizumab for first-line treatment of locally advanced, unresectable, or metastatic HER2-positive gastroesophageal adenocarcinoma.
CT041: CAR T-cell therapy
In solid tumors, chimeric antigen receptor (CAR) T-cell therapy remains limited compared to its success in hematologic malignancies. Nevertheless, CT041, an autologous CAR T-cell product candidate against protein Claudin18.2 (CLDN18.2) previously showed promising antitumoral activity and a tolerable toxicity in a phase 1 study in pre-treated gastrointestinal cancers .
An open-label, multicenter phase 1b/2 study (NCT04581473) investigated in Part 1 (dose-escalation/dose-expansion) the safety, tolerability as well as recommended phase 2 dose of CT041 in adults with pathologically diagnosed advanced G/GEJ adenocarcinoma . Before each CT041 infusion, lymphodepletion treatment with fludarabine, cyclophosphamide and nab-paclitaxel was administered to each patient. Key eligibility criteria included patients who were 18 to 75 years old, were refractory to or intolerant of at least two prior lines of treatment, had a confirmed positive expression of CLDN18.2 by immunohistochemistry (IHC) staining (2+/3+ in ≥40% of tumor cells) and at least one measurable lesion per RECIST v1.1.
From November 2020 to May 2021, 14 eligible patients with G/GEJC were enrolled and received one cycle of bridging chemotherapy, of whom 13 received FOLFIRI and one patient received 5-FU plus intraperitoneal nab-paclitaxel. All patients had at least one infusion of CT041 (11 patients received 2.5 x 108 and 3 patients received 3.75 x 108 cells, respectively) whereas seven patients received two infusions (6 in the low dose and 1 in the high dose group), with a median interval between the two infusion of 132 days.
The median persistence time of these CAR T-Cells after the first/second CT041 infusion was 27 days (range, 14-189) and 26 days (range, 5-68), respectively. Most frequently observed grade ≥3 TREAs were lymphopenia related to the lymphodepletion. Otherwise, three serious TRAEs were reported in two patients, while no patients had dose-limiting toxicities (DLTs) or AE leading to death. All patients experienced light or moderate (grade 1 or 2) cytokine release syndrome after the first infusion and six out of seven patients (85.7%) after the second infusion (median onset time of 2 days and 1 day, respectively). The median recovery time was seven days (range, 1-22). After a median follow-up of 8.8 months (range, 3.0-13.6), eight out of 14 patients (57.1%) had a PR and three patients (21.4%) showed stable disease after the first CT041 infusion. The ORR reached 57.1% (95% CI, 28.9-82.3), the DCR was 78.6% (95% CI, 49.2-95.3), the median PFS (Figure 2A) was 5.6 months (95% CI, 1.9-7.4) and the median OS 10.8 months (95% CI, 5.1-non reached) (Figure 2B).
This preliminary data of CT041 suggests a manageable safety and tolerability profile, as well as a promising efficacy in previously treated patients with advanced G/GEJ adenocarcinoma. A phase 2 study is currently ongoing.
IBI110 in combination with sintilimab
Efficacy and safety of the anti-PD-1 inhibitor sintilimab have been demonstrated in several malignant entities , both in advanced disease like recently shown in esophageal squamous cell carcinoma , and in the neoadjuvant setting . In gastric cancer, sintilimab plus XELOX (capecitabine plus oxaliplatin) has demonstrated efficacy after neoadjuvant chemotherapy , while lymphocyte-activation gene 3 (LAG-3) – an immune checkpoint receptor protein – controls T-cell response, activation, and growth . Thus, a dual inhibition with anti-PD-1 and anti-LAG-3 might act synergistically against tumoral cells . Indeed, IBI110 – an anti-LAG-3 monoclonal antibody – plus sintilimab has previously shown preliminary efficacy in advanced solid tumors .
At this year ASCO meeting, a phase 1b study (NCT04085185) investigated the safety and efficacy of IBI101 (200 mg, IV, Q3W) plus sintilimab (200 mg, IV, Q3W) plus XELOX as first-line treatment in patients with unresectable, locally advanced, or recurrent/metastatic HER2-negative G/GEJ adenocarcinoma . The primary endpoints included safety, tolerability, and efficacy of the combined therapy.
At the data cut-off date (January 22, 2022), 18 eligible patients have already been enrolled in this study. With a median follow-up of four weeks (range, 0-20) and a median exposure of combination therapy of 9.4 weeks (range, 3-24), the most common grade ≥3 TRAEs included decreased neutrophil count, decreased platelet count, abnormal hepatic function (n = 2; 11.1% each). ImAEs occurred in seven patients (38.9%), the most frequent one being increased amylase (n = 2, 11.1%).
Among the 15 evaluable patients, the ORR reached 60%, including nine patients with a PR, and the DCR was 100%. The median DoR and the median PFS were not mature at the data cut-off date, as 17 patients were still on treatment.
The authors concluded that, although this triple combination seemed to be well tolerated, longer follow-up is needed to analyze the clinical benefit.
Camrelizumab plus FLOT as neoadjuvant therapy
In patients with locally advanced G/GEJC, both docetaxel-based neoadjuvant chemotherapy and immunotherapy have already shown promising efficacy in gastric cancer [19, 20]. A randomized study (ChiCTR2000030610) evaluated the safety and efficacy of camrelizumab – an anti-PD-1 immune checkpoint inhibitor – plus chemotherapy versus chemotherapy alone as neoadjuvant therapy for patients with resectable locally advanced GC/GEJC .
Eligible patients who underwent gastrectomy with D2 lymph node dissection received fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in Arm A and FLOT plus camrelizumab (200 mg, IV, Q3W) in Arm B. The primary endpoint was pathologic complete response (pCR) and R0 resection rate, while the secondary endpoints comprised the ORR, PFS, OS and safety.
Although 61 patients had been recruited in this study between mid-January 2020 and mid-January 2022, the data presented at ASCO 2022 were related to 47 analyzed patients only (Arm A, n = 26; Arm B, n = 21). The median age was 63 years in both arms. The patients in Arm B showed a higher R0 resection rate than in Arm A (100.0% in Arm B vs 90.5% in Arm A); a similar outcome was reflected in the pCR (11.5% vs 4.8%, respectively) and the proportion of postoperative stage ypN0 (46% vs 24%, respectively).
No serious intraoperative complications, or immune-related adverse events (irAEs) were observed during perioperation. TRAEs – mostly neutropenia and leucopenia – were manageable and no treatment-related death occurred.
In the neoadjuvant setting, camrelizumab plus FLOT showed a promising efficacy, low complications, and manageable safety profile in patients with locally advanced resectable G/GEJ adenocarcinoma.
FORTITUDE-101: bemarituzumab plus mFOLFOX6
Overall, 80% to 85% of patients with advanced GEJ cancer do not express HER2; in those HER2-negative GEJC patients, prior clinical trials reached a limited median OS of 12 to 14 months [22-24]. Around 30% of HER2-negative
G/GEJ adenocarcinoma express the fibroblast growth factor receptor 2b (FGFR2b) . Bemarituzumab is a first-in-class monoclonal antibody that is binding specifically FGFR2b to inhibit tumor proliferation and it has the potential to enhance the antibody-dependent cellular cytotoxicity (ADCC) [26-27]. In the phase 2 FIGHT study, bemarituzumab plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) already demonstrated a median PFS (9.5 vs 7.4 months; HR: 0.68; 95% CI, 0.44-10.4) and OS (19.2 vs 13.5 months; HR: 0.6; 95% CI, 0.38-0.94) benefit in this patient group , see Figure 3.
Moreover, a phase 3 study will investigate the combination of bemarituzumab plus mFOLFOX6 versus mFOLFOX6 in patients with FGFR2b overexpressing advanced gastric or GEJ cancer . The FORTITUDE-101 study (NCT05052801) is currently enrolling patients according to the following inclusion criteria: adults, histologically confirmed G/GEJ adenocarcinoma, FGFR2b overexpression as determined by centrally performed IHC testing, unresectable, locally advanced, or metastatic disease, evaluable disease per RECIST v1.1 and no contraindication to receive mFOLFOX6 chemotherapy. The 516 patients will be randomized 1:1 and patients will receive either bemarituzumab (15 mg/kg, Q2W + additional 7.5 mg/kg on Cycle 1 Day 8) and mFOLFOX6 (Q2W) or mFOLFOX6 alone. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent or death (whichever occurs first). The stratification will occur according to the geographic region (US/European Union vs Asia vs rest of world), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1), as well as tumor cell and PD-1 status (Combined Positive Score [CPS] ≥5 vs <5 or indeterminate).
The primary endpoint is OS, while the secondary endpoints enclose PFS assessed locally per RECIST v1.1, ORR, DoR, DCR, TEAEs, clinically significant changes, pharmacokinetics, QoL and anti-bemarituzumab antibody formation.
Figure 3: Improvement in progression-free survival (data cut-off, September 2020) (A) and overall survival (data cut-off, February 2021) (B).
FORTITUDE-102: bemarituzumab plus mFOLFOX6 plus nivolumab
Preclinical studies previously showed that bemarituzumab can change the tumor microenvironment to sensitize tumors to PD-1 inhibitors [26, 29]. A phase 1b/3 study currently evaluates the efficacy and safety of bemarituzumab plus mFOLFOX6 plus nivolumab versus mFOLFOX6 plus nivolumab in patients with previously untreated FGFR2b overexpressing advanced G/GEJ cancer . The FORTITUDE-102 trial (NCT05111626) presents a similar design than the previously described FORTITUDE-101 study, except that it is a 2-part study, that in Part 1 elucidates the recommended dose to be used in the Part 2. Eligible patients should not present any contraindication to receive nivolumab. The co-primary endpoints of Part 1 are overall safety, tolerability, and pharmacokinetics; in Part 2 of this trial, the primary endpoint is OS. In this study, the stratification occurs according to FGFR2b IHC 2+/3+ staining in ≥10% of tumor cells vs FGFR2b IHC 2+/3+ in <10%.
In Part 2, FORTITUDE-102 aims to enroll approximately 682 patients. An overview of all currently ongoing bemarituzumab studies is presented in Table 1.