Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: final analysis of the randomized phase 2 FIGHT trial

Background We report the final results of the randomized phase 2 FIGHT trial that evaluated bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 in patients with FGFR2b-positive (2 + /3 + membranous staining by immunohistochemistry), HER-2–negative gastric or gastroesophageal junction cancer (GC). Methods Patients received bemarituzumab (15 mg/kg) or placebo once every 2 weeks with an additional bemarituzumab (7.5 mg/kg) or placebo dose on cycle 1 day 8. All patients received mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months. Results In the bemarituzumab-mFOLFOX6 (N = 77) and placebo-mFOLFOX6 (N = 78) arms, respectively, 59.7% and 66.7% of patients were FGFR2b-positive in ≥ 10% of tumor cells. The median PFS (95% confidence interval [CI]) was 9.5 months (7.3–13.7) with bemarituzumab-mFOLFOX6 and 7.4 months (5.7–8.4) with placebo-mFOLFOX6 (hazard ratio [HR], 0.72; 95% CI 0.49–1.08); median OS (95% CI) was 19.2 (13.6–24.2) and 13.5 (9.3–15.9) months, respectively (HR 0.77; 95% CI 0.52–1.14). Observed efficacy in FGFR2b-positive GC in ≥ 10% of tumor cells was: PFS: HR 0.43 (95% CI 0.26–0.73); OS: HR 0.52 (95% CI 0.31–0.85). No new safety findings were reported. Conclusions In FGFR2b-positive advanced GC, the combination of bemarituzumab-mFOLFOX6 led to numerically longer median PFS and OS compared with mFOLFOX6 alone. Efficacy was more pronounced with FGFR2b overexpression in ≥ 10% of tumor cells. Confirmatory phase 3 trials are ongoing (NCT05052801, NCT05111626). Clinical trial registration NCT03694522. Supplementary Information The online version contains supplementary material available at 10.1007/s10120-024-01466-w.


Introduction
Gastric cancer (GC), including gastroesophageal junction (GEJ) cancer, is often diagnosed at an advanced stage and is associated with poor prognosis [1].Systemic chemotherapy has been the standard first-line treatment for advanced GC, although the clinical benefits have been limited [2,3].Recent therapeutic approaches including immune checkpoint inhibitors or targeted therapies that are directed towards different mechanistic pathways of GC have demonstrated promising outcomes, especially in biomarker-enriched patient populations [4,5].Human epidermal growth factor receptor 2 (HER-2)-directed therapies such as trastuzumab and trastuzumab deruxtecan have improved overall survival (OS) outcomes in HER-2-positive GC [6,7].However, most targeted therapies, such as bevacizumab, everolimus, or panitumumab and cetuximab, have not demonstrated OS benefits in unselected patients with GC, which has been attributed, Previous presentation: Presented at the WCGIC congress as a short oral and poster presentation, 28 June-1 July 2023; Barcelona, Spain.#SO-11 .
Extended author information available on the last page of the article in part, to intratumoral heterogeneity or a lack of selective biomarkers [4,5].Treatment decisions are therefore best guided by biomarker expression and histological classifications to preselect patients most likely to benefit from targeted therapies and adapt treatments to help improve outcomes for GC.New and effective biomarker-targeted treatment options remain an unmet clinical need for advanced GC.
The fibroblast growth factor/FGF receptor (FGF/FGFR) pathway plays a crucial role in the growth and development of cancer cells, and overexpression of proteins in this pathway could lead to disease progression [8].The IIIb splice isoform of FGFR2 (FGFR2b) was observed to be overexpressed in approximately 30% of HER-2-negative GC [9][10][11][12].FGFR2b overexpression in GC may be associated with poorly differentiated diffuse-type histology and poor outcomes, including lower OS, and warrants further investigation [10,11,13].
Bemarituzumab is a first-in-class, humanized monoclonal antibody specific to human FGFR2b that blocks FGF binding to the receptor.Bemarituzumab acts through a two-pronged approach [14].First, it selectively inhibits FGFR2b signaling with downstream effects on cancer cell proliferation [14,15].Second, the afucosylated structure of bemarituzumab leads to activation of FcγRIIIa/CD16a, which increases the affinity of bemarituzumab for natural killer cells, thereby enhancing its antibody-dependent cellular cytotoxicity against FGFR2b-expressing tumor cells [14,16].
The first-in-human (FIH) study of bemarituzumab monotherapy showed that it was well tolerated and demonstrated activity as later-line therapy in patients with advanced GC, with a confirmed objective response rate (ORR) of 17.9% (95% confidence interval [CI], 6.1-36.9) in 28 patients with FGFR2b-positive tumors and a median duration of response of 12.6 weeks (range, 9.1-19.1)[17].The phase 1/2 FIGHT trial (NCT03694522) evaluated the efficacy and safety of bemarituzumab in combination with modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy as first-line treatment for HER-2 non-positive advanced GC with FGFR2b overexpression and/or FGFR2 gene amplification [18].The phase 1 safety run-in was an open-label, doseescalation study of bemarituzumab-mFOLFOX6 in patients with gastrointestinal tumors.The randomized phase 2 study further assessed the efficacy and safety of the combination versus placebo-mFOLFOX6 in HER-2 non-positive FGFR2selected advanced GC [9].The primary analysis (median follow-up, 10.9 months) showed that the median progression-free survival (PFS) was 9.5 months (95% CI 7.3-12.9)with bemarituzumab-mFOLFOX6 versus 7.4 months (95% CI 5.8-8.4) with placebo-mFOLFOX6 (hazard ratio [HR], 0.68; 95% CI 0.44-1.04;P = 0.07) [9].Here, we report the final analysis and updated safety results after a minimum follow-up of 24 months.

Study design
The study design and protocol have been described previously [9].Briefly, the phase 2 portion was a randomized, double-blind, placebo-controlled study conducted at 164 sites across 18 countries and was designed to evaluate the efficacy and safety of bemarituzumab-mFOLFOX6 in patients with advanced HER-2 non-positive GC prescreened for FGFR2b overexpression (via immunohistochemistry [IHC]) and/or FGFR2 gene amplification (via circulating tumor DNA [ctDNA] assay).Positive FGFR2b overexpression status by IHC was defined as exhibiting any moderate (2 +) to strong (3 +) membranous staining in more than 0% of tumor cells.Patients were randomized (1:1) to receive either bemarituzumab-mFOLFOX6 or placebo-mFOLFOX6.Treatment continued until disease progression, as determined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), or unacceptable toxicity.During the long-term follow-up period, patients were contacted every 3 (± 1) months for 24 months after the last patient was enrolled, or until death, loss to followup, consent withdrawal, or study termination, whichever occurred first.Data cutoff for this final analysis was May 13, 2022.
All patients provided written and informed consent; study protocols (online only) received institutional approval.Complete procedural details are available in the protocol (online only).

Patients
Eligible patients were ≥ 18 years and had histologically confirmed GC or GEJ adenocarcinoma; unresectable, locally advanced/metastatic disease not amenable to curative therapy; FGFR2b overexpression as determined by a centrally performed IHC tissue test and/or FGFR2 gene amplification via a centrally performed ctDNA bloodbased assay; measurable or non-measurable, but evaluable disease using RECIST v1.1; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; adequate organ function; and no prior chemotherapy for metastatic or unresectable disease.Patients were permitted, at the discretion of the investigator, to receive a single dose of mFOLFOX6 while awaiting results of centralized FGFR2 testing.Key exclusion criteria included untreated or symptomatic central nervous system metastases; ≥ grade 2 Common Terminology Criteria for Adverse Events (CTCAE) peripheral sensory neuropathy; corneal abnormalities that may increase the risk of developing a corneal ulcer; and known tumor positivity for HER-2 (as identified by a positive IHC test of 3 + or IHC of 2 + with positive fluorescent in situ hybridization).Complete eligibility criteria are available in the online protocol.

Treatment and randomization
Bemarituzumab or an equivalent placebo was administered at a dose of 15 mg/kg body weight intravenously every 2 weeks (Q2W); an additional dose of 7.5 mg/kg bemarituzumab was administered on cycle 1 day 8.The standard mFOLFOX6 regimen, comprising oxaliplatin (85 mg/m 2 ), leucovorin (400 mg/m 2 ), and 5-fluorouracil (400 mg/m 2 bolus followed by 2400 mg/m 2 over approximately 48 h), was administered Q2W in both arms.Eligible patients were stratified by geographic region, prior treatment status (de novo versus adjuvant/neoadjuvant), and administration of a single dose of mFOLFOX6 before enrollment (yes or no).A permuted block scheme with a block size of four was used for randomization to ensure an equal sample size and a similar distribution of stratification factors.

Endpoints and assessments
The primary endpoint was PFS, defined as the time from randomization until disease progression based on investigator assessment (using RECIST v1.1) or death, whichever occurred first.Secondary endpoints included OS, defined as the time from randomization until death from any cause; ORR, defined as the proportion of patients with partial response (PR) or complete response (CR) according to investigator assessment of tumor lesions per RECIST v1.1; and incidence of adverse events (AEs).An exploratory endpoint was duration of response (DOR) limited to patients who were responders to treatment, as determined by the investigator per RECIST v1.1, and defined as the time of first response to progression or death from any cause, whichever occurred first.AEs were coded using Medical Dictionary for Regulatory Activities version 25.0 and were graded using CTCAE version 5.0.

Statistical analysis
The planned enrollment for phase 1 was up to 21 patients, and up to 155 patients were to be enrolled in phase 2, with a total enrollment of approximately 167 patients in the study.Efficacy was assessed in the intention-to-treat (ITT) population, which included all randomized patients, while safety was assessed in the safety analysis set, which included patients who had received at least one dose of the assigned treatment.The Kaplan-Meier method was used to estimate the median PFS and OS and the associated 95% CIs in each treatment arm.HRs and 95% CIs were calculated using a stratified Cox regression model.Formal hypothesis testing was not performed at this final analysis.In a prespecified exploratory analysis, PFS and OS were assessed for subgroups of patients who were FGFR2b-positive in ≥ 10% of tumor cells with moderate to strong staining intensity (2 + /3 +) as assessed by IHC.Data on AEs are presented descriptively by number of patients and frequency.Statistical analyses are detailed in the protocol (online only).

Discussion
This randomized, double-blind, placebo-controlled phase 2 trial was designed to evaluate the bemarituzumab-mFOL-FOX6 combination in patients with HER-2 non-positive, FGFR2b-selected, treatment-naïve advanced GC.Because the study design was changed from a confirmatory phase 3 to a phase 2 study, it was not powered to assess statistically significant improvements in PFS and OS [9].The primary analysis showed a clinically meaningful improvement in PFS with bemarituzumab-mFOLFOX6 treatment compared with placebo-mFOLFOX6 (HR 0.68; 95% CI 0.44-1.04;P = 0.07) [9].At this final analysis conducted after a minimum follow-up of 24  In the ITT population, the HR for OS at the primary analysis was 0.58 (95% CI 0.35-0•95), and was 0.77 (95% CI 0.52-1.14)at this final analysis [9].This final analysis HR for OS is similar to point estimates recently reported in successful phase 3 trials involving similar control arms, such as the KEYNOTE-859 (HR 0.78; 95% CI 0.70-0.87),CheckMate 649 (HR 0.79; 95% CI 0.71-0.88),SPOT-LIGHT (HR 0.75; 95% CI 0.60-0.94),GLOW (HR 0.76; 95% CI 0.35-1.64),and RATIONALE 305 (HR 0.74; 95% CI 0.59-0.94)trials [19][20][21][22][23]. Compared with the primary analysis, the treatment benefit with bemarituzumab-mFOL-FOX6 at this final analysis could have been weakened due to a potential impact of subsequent anticancer therapies on OS reflected in the additional follow-up.In the FGFR2b ≥ 10% subgroup, the HR for OS at the primary analysis increased from 0.41 to 0.52 at this final analysis-a finding that still supports promising activity for bemarituzumab in this subset, with a noteworthy 2-year OS rate in bemarituzumab-mFOLFOX6 more than twice that of placebo-mFOLFOX6 (51.3% versus 21.3%).Collectively, together with the FIH dose-escalation/dose-expansion study showing bemarituzumab single-agent activity in an FGFR2b selected gastroesophageal adenocarcinoma population, these data support FGFR2b as a potentially important predictor of response to treatment with bemarituzumab [17].
The safety results were generally similar to those reported at the primary analysis.No new safety findings were observed with longer follow-up.Treatment discontinuation due to TEAEs was higher in the bemarituzumab-mFOLFOX6 arm compared with the placebo-mFOLFOX6 arm.Corneal TEAEs were the primary reason for treatment discontinuation in the bemarituzumab-mFOLFOX6 arm, which may not necessarily be due to the severity of the AE, but could be an unintended outcome of the protocol design wherein no prophylaxis was mandated and treatment was discontinued for any corneal TEAE that was not resolved or improved to grade 1 within 28 days of treatment initiation [9].In addition, the median time to onset of grade ≥ 2 corneal events was longer than that for any-grade corneal events (23.7 weeks versus 16.9 weeks), suggesting a possible opportunity for early recognition and active management of AEs by prophylactic measures in future studies.Accordingly, the use of ocular lubricants and eyelid hygiene are being assessed in the ongoing phase 3 studies, which also exclude the 28-day requirement for corneal AE resolution in their study designs [24,25].
This final analysis should be interpreted considering its strengths and limitations.One limitation of this study is the relatively small sample size.In addition, no prophylaxis or mitigation for corneal toxicity was included as a part of the study design.However, this study has several strengths.First, the trial prospectively enrolled a biomarker-selected population, with evaluation of biomarkerenriched subgroups such as those with ≥ 10% of tumor cells expressing FGFR2b.Second, the use of one optional cycle of "induction" FOLFOX is a novel aspect of this trial that facilitates the inclusion of an upfront biomarkerdriven cohort of patients and may be used as a template for other upfront biomarker-driven studies in the future.Third, a long minimum follow-up duration of 24 months permitted sufficient follow-up of PFS and OS endpoint outcomes.Lastly, the consistent treatment benefits with respect to all efficacy endpoints in the FGFR2b ≥ 10% subgroup further support the hypothesis that increased scrutinization of FGFR2b as a biomarker may lead to increased efficacy.This analysis is similar to the subset analysis of the ToGA trial which identified that patients with higher HER-2 expression (3 + by IHC) received enhanced benefit from the trastuzumab-chemotherapy combination, reinforcing the concept that increased protein expression of an IHC biomarker can predict greater efficacy [7].
At this final analysis, bemarituzumab-mFOLFOX6 treatment continued to demonstrate promising clinical efficacy and manageable safety in FGFR2-selected, HER-2 nonpositive advanced GC, with more pronounced treatment benefit in the patient subset with FGFR2b overexpression (2 + /3 + staining) in ≥ 10% of tumor cells than in those with FGFR2b overexpression in any tumor cell.These data are encouraging and support further evaluation of the bemarituzumab-mFOLFOX6 combination in patients with FGFR2b overexpressed gastric and GEJ cancer in the frontline setting.Phase 3 trials are ongoing to confirm this observed clinical benefit, with a focus on enhanced biomarker selection (NCT05052801, NCT05111626) [24,25].

Fig. 1
Fig. 1 Patient disposition.a Patient chose to discontinue treatment but continued in follow-up.b Radiographic disease progression was assessed as per RECIST version 1.1.AE, adverse event; mFOLFOX6,

Fig. 2
Fig. 2 PFS and OS in the ITT population.a PFS in the ITT population.b OS in the ITT population.The intention-to-treat population included all patients who underwent randomization.HRs and 95% CIs were calculated using the Cox proportional hazards model, adjusted for randomization stratification factors, including administra-

Fig. 3
Fig. 3 PFS and OS in the FGFR2b ≥ 10% subgroup.a PFS in the FGFR2b ≥ 10% subgroup.b OS in the FGFR2b ≥ 10% subgroup.The FGFR2b ≥ 10% subgroup included patients with FGFR2b tumor staining score of 2 + or 3 + in at least 10% of tumor cells by immunohistochemistry. HRs and 95% CIs were calculated using the unstrati-

Table 1
Demographics and disease characteristics at baseline (ITT analysis set) Data are number (%) of patients unless indicated otherwise.The ITT analysis set included all randomized patients ctDNA circulating tumor DNA; ECOG Eastern Cooperative Oncology Group; FGFR2b IIIb splice isoform of fibroblast growth factor receptor 2; IHC immunohistochemistry; ITT intention-to-treat; mFOLFOX6 modified FOLFOX (infusional 5-fluorouracil, leucovorin, and oxaliplatin)

Table 2
Tumor response Data are number (%) of patients unless indicated otherwise.The ITT set included all randomized patients.The FGFR2b ≥ 10% subgroup comprised patients with FGFR2b 2 + /3 + IHC staining in ≥ 10% of tumor cells.Overall response is based on RECIST version 1.1 CI confidence interval; CR complete response; FGFR2b IIIb splice isoform of fibroblast growth factor receptor 2; IHC immunohistochemistry; ITT, intention-to-treat; mFOLFOX6 modified FOLFOX (infusional 5-fluorouracil, leucovorin, and oxaliplatin); PR partial response; RECIST Response Evaluation Criteria in Solid Tumors a ORR is computed as the sum of CR and PR b Two-sided CI based on Clopper-Pearson method c Median duration of response for the FGFR2b ≥ 10% subgroup is not reported because of low patient numbers in each arm for this analysis 3-13.8) First-line bemarituzumab for G/GEJ cancer

Table 3
Summary of TEAEs (safety analysis set) Data are number (%) of patients.AEs were coded according to MedDRA version 25.0.TEAEs began on or after the study drug start date up to 28 days after the last dose of any study drug.Multiple AEs were counted only once per patient for each PT.PTs were presented by descending order of the total frequencies AE adverse event; MedDRA Medical Dictionary for Regulatory Activities; mFOLFOX6 modified FOLFOX (infusional 5-fluorouracil, leucovorin, and oxaliplatin); PT preferred term; TEAE treatment-emergent adverse event

Table 4
Summary of corneal TEAEs (safety analysis set) Data are number (%) of patients unless indicated otherwise.AEs were coded according to MedDRA version 25.0.Severity grades were defined per CTCAE version 5.0.Time to resolution was calculated among patients with AE onset AE adverse event; CTCAE Common Terminology Criteria for Adverse Events; IQR interquartile range; MedDRA Medical Dictionary for Regulatory Activities; mFOLFOX6 modified FOLFOX (infusional 5-fluorouracil, leucovorin, and oxaliplatin); TEAE treatment-emergent adverse event