In a major evaluation of the part 3 SPOTLIGHT trial (NCT03504397), frontline remedy with zolbetuximab plus mFOLFOX6 garnered superior progression-free and general survival (OS) in sufferers with CLDN18.2-positive, HER2-negative domestically superior unresectable or metastatic gastric/ gastroesophageal junction (GEJ) adenocarcinoma, in contrast with placebo plus mFOLFOX6.one
Outcomes introduced through the 2023 Gastrointestinal Cancers Symposium confirmed that the median progression-free survival (PFS) by impartial assessment committee was 10.61 months (95% CI, 8.90-12.48) with zolbetuximab/mFOLFOX6 vs 8.67 months (95% CI, 8.21-10.28 ) with placebo/mFOLFOX6, resulting in a 25% discount within the danger of illness development or demise (HR, 0.751; 95% CI, 0.589-0.942; P = .0066).
“Zolbetuximab plus mFOLFOX6 is a brand new potential standard-of-care remedy for a biomarker-based subgroup of sufferers with CLDN18.2-positive/HER2-negative domestically superior unresectable or metastatic gastric/GEJ adenocarcinoma,” Kohei Shitara, MD, the lead examine creator of the trial and a medical oncologist at Nationwide Most cancers Heart Hospital East in Kashiwa, Japan, stated in a presentation through the assembly.
Normal remedy for sufferers with HER2-negative, metastatic gastric/GEJ adenocarcinoma is chemotherapy with mFOLFOX6, however there may be nonetheless an unmet want when it comes to focused therapies for this inhabitants.2 Presently, the median OS is roughly 1 12 months previous.
CLDN18.2 is a decent junction protein that’s expressed in regular gastric mucosa cells and is retained in superior gastric/GEJ tumor cells. As CLDN18.2 could turn out to be uncovered on the floor of gastric/GEJ cells, Shitara famous that it makes a promising goal.
Zolbetuximab, which is a first-in-class CLDN18.2-targeting chimeric IgG1 monoclonal antibody that induces antibody-dependent mobile cytotoxicity/complement dependent cytotoxicity, resulted in a prolongation of survival in sufferers with larger expression of CLDN18.2 in part 2b FAST trial (NCT01630083).3 Right here, the median PFS was 9.0 months with zolbetuximab and epirubicin, oxaliplatin, and capecitabine (EOX) vs 5.7 months with EOX alone; the median OS was 16.5 months and eight.9 months, respectively.
The worldwide, double-blind, placebo-controlled SPOTLIGHT trial enrolled sufferers with beforehand untreated domestically superior unresectable or metastatic gastric/GEJ adenocarcinoma and CLDN18.2 positivity. To be eligible for enrollment, sufferers will need to have had moderate-to-strong CLDN18 staining in no less than 75% of tumor cells, have HER2-negative illness, and an ECOG efficiency standing of 0 or 1.
Research members have been randomly assigned 1:1 to obtain the mixture of zolbetuximab and mFOLFOX6 (n = 283) or placebo and mFOLFOX6 (n = 282).
Zolbetuximab was given intravenously (IV), at 800 mg/m2 on day 1 of cycle 1 adopted by 600 mg/m2 on day 22 of cycle 1 and days 1 and 22 of subsequent cycles, each 3 weeks and mFOLFOX6 was given IV each 2 weeks in cycles 1 to 4 of 42-day cycles. For cycles 5 and past, zolbetuximab was given on the similar dosing schedule together with 5-fluorouracil (5-FU) and folinic acid IV each 2 weeks. Sufferers within the placebo arm got placebo on the every-3-week schedule and chemotherapy was administered on the similar dosing schedule.
Sufferers have been stratified by area (Asian vs non-Asian), variety of organs with metastases (0-2 vs ≥ 3), and prior gastrectomy (sure vs no).
The first finish level was PFS. Key secondary finish factors have been OS, time to confirmed deterioration in world well being standing/high quality of life, bodily functioning, and OG25-Ache. Further final result measures included goal response charge (ORR), period of response (DOR), security, and patient-reported outcomes (PROs).
As a part of the examine design, OS was solely examined if the PFS profit with zolbetuximab was discovered to be important. Shitara famous that the interim OS evaluation was deliberate on the major PFS evaluation, with a cutoff date of September 9, 2022, for each analyses. Within the interim OS evaluation, the 1-sided P worth threshold for significance was .0135.
Relating to baseline traits, the median age was 61.0 years (vary, 20-86), 62.2% of sufferers have been male, and 31.4% of sufferers have been from Asia. Most sufferers had 2 or much less organs with metastases (77.6%), and 29.4% of sufferers had prior gastrectomy. The first illness website was abdomen in 76.0% of sufferers and was GEJ in 24.1%.
The Lauren classification of illness was diffuse (35.6%), intestinal (24.3%), or blended/others (39.8%). Greater than half of sufferers had an ECOG efficiency standing of 1 (56.7%). A complete 13.2% of sufferers had tumors with a PD-L1 mixed constructive rating of no less than 5, which was a part of an ad-hoc evaluation.
Forty-eight p.c of sufferers within the zolbetuximab arm acquired subsequent anticancer therapies vs 53% within the placebo arm.
Further information confirmed that the 12- and 24-month PFS charges have been 49% and 24%, respectively, within the zolbetuximab arm and 35% and 15%, respectively, within the placebo arm. The PFS profit with zolbetuximab/mFOLFOX6 was noticed throughout most prespecified subgroups, aside from these whose major website of illness was GEJ (HR, 1.015; 95% CI, 0.649-1.586) and with blended/different classification (HR, 0.929; 95% CI, 0.601-1.434).
The median OS was 18.23 months (95% CI, 16.43-22.90) with zolbetuximab/mFOLFOX6 and 15.54 months (95% CI, 13.47-16.53) with placebo/mFOLFOX6 (HR, 0.750; 95% CI, 0.601-0.936; P = .0053).
At 12, 24, and 36 months, the OS charges within the zolbetuximab and placebo arms, respectively, have been 68% vs 60%, 39% vs 28%, and 21% vs 9%, respectively. Much like the PFS evaluation, the OS profit was seen in most affected person subgroups, aside from these with GEJ as the first website of illness (HR, 1,072; 95% CI, 0.690-1,666) and others with blended/different classification (HR, 0.992; 95% CI, 0.638-1.543).
The ORR with zolbetuximab was 60.7% (95% CI, 53.72%-67.30%) and 62.1% (95% CI, 55.17%-68.66%). The most effective general response was a whole response in 5.7% and three.3% of zolbetuximab- and placebo-treated sufferers, respectively; a partial response in 55.0% and 58.8% of sufferers, steady illness in 21.3% and 24.6% of sufferers, and progressive illness in 6.6% of sufferers on each arms. The median DOR was 8.51 months (95% CI, 6.80-10.25) on the zolbetuximab arm and eight.11 months (95% CI, 6.47-11.37) on the placebo arm.
Shitara famous that the formal PROs evaluation is pending, however an preliminary descriptive evaluation didn’t point out variations between remedy arms.
Relating to security, the incidence of treatment-emergent adversarial results (TEAEs) was related between arms, at 99.6% in each remedy teams. Grade 3 or larger TEAEs have been reported in 86.7% and 77.7% of these on the zolbetuximab and placebo arms, respectively; critical TEAEs occurred in 44.8% and 43.5%. Remedy-related adversarial results (TRAEs) that led to remedy discontinuation of zolbetuximab or placebo occurred in 13.6% and a pair of.2% of sufferers, respectively. Moreover, 1.8% and 1.4% of TRAEs, respectively, led to demise.
The most typical TEAEs related to zolbetuximab/mFOLFOX6 have been nausea (all-grade, 81.0%; grade ≥ 3, 16.1%), vomiting (all-grade, 64.5%; grade ≥ 3, 16.1%), and decreased urge for food (all- grade, 47.0%; grade ≥ 3, 5.7%). Shitara added that the primary incidence of nausea and vomiting occurred within the first or second remedy cycles.
Editor’s Be aware: Dr. Shitara has acquired an honoraria from Bristol-Myers Squibb; Jansen; taken; consulting or advisory roles with Abbvie, Amgen, Astellas Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Guardant Well being Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda; and analysis funding from Amgen (Inst); Astellas Pharma (Inst); Chugai Pharma (Inst); Daiichi Sankyō (Inst); Eisai (Inst); MSD(Inst); Ono Pharmaceutical (Inst); Taiho Pharmaceutical (Inst).
- Shitara Ok, Lordick F, Bang YJ, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) remedy for sufferers (pts) with claudin-18.2+ (CLDN18.2+) / HER2− domestically superior (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: major outcomes from part 3 SPOTLIGHT examine. J Clin Oncol. 2023;41(suppl;abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292
- Van Cutsem, Sagaert X, Topal B, et al. Gastric most cancers. lancet. 2016;388(10060):2654-2664. doi:10.1016/S0140-6736(16)30354-3
- Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomized part II examine of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line remedy of superior CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32:609-619. doi:10.1016/j.annonc.2021.02.005