Cathy Eng, MD, FACP, FASCO

Professor of Medicine

Coleader, Gastrointestinal Cancer Research Program

David H. Johnson Chair in Surgical and Medical Oncology

Codirector, GI Oncology

Vanderbilt-Ingram Cancer Center

Nashville, TN

From CHECKMATE-648 to the HER-Vaxx vaccine, trial data for esophageal and gastroesophageal cancers were highlighted during the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in January, showing significant advances and promise for this patient population, particularly with the use of immunotherapy.

One of the studies that stood out during the meeting was the phase 3 SPOTLIGHT trial (NCT03504397),¹ which explored the possible benefit of a new frontline treatment regimen in patients who have advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma that is claudin 18.2 (CLDN18.2)-positive, defined as moderate to strong claudin 18.2 protein expression on at least 75% of tumor cells, and HER2-negative, defined as absent or very limited HER2 protein expression (immunohistochemistry score of 0 or 1+) on tumor cells.¹

The SPOTLIGHT findings represent much-awaited phase 3 data looking at zolbetuximab plus chemotherapy vs placebo plus chemotherapy. “[The study] did meet [its] end points for overall survival and progression-free survival, and zolbetuximab, in conjunction with chemotherapy, is likely going to be approved in the first-line setting,” said Steve Maron, MD, MSc, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, in an interview with Targeted Therapies in Oncology™. “The phase 2 trial data with this agent were presented almost 7 years ago, so it has taken a very long time to come to this point.”

Steven Maron, MD, MSc

Assistant Attending Physician

Memorial Sloan Kettering Cancer Center

New York, NY

Maron was not the only physician impressed with the SPOTLIGHT data. Cathy Eng, MD, FACP, FASCO, coleader of the gastrointestinal (GI) cancer research program and the David H. Johnson Chair in Surgical and Medical Oncology at Vanderbilt University Medical Center in Nashville, Tennessee, said, “I think the SPOTLIGHT phase 3 trial has [had] the largest impact this year because it has identified a new molecular marker, claudin 18.2, and a new targeted antibody [zolbetuximab] against 18.2.”

Eng added, “Molecular analysis should be completed in all patients with gastric or GEJ cancer at diagnosis. We will need to educate community doctors about the role of claudin 18.2, which is positive in [less than] 20% of patients [with gastric or GEJ cancer].”

SPOTLIGHT Trial

Investigators in the SPOTLIGHT trial examined first-line treatment with zolbetuximab combined with leucovorin calcium, fluorouracil, and oxaliplatin (mFOLFOX6) in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.1 This regimen led to significantly longer progression-free (PFS) and overall survival (OS).¹

The trial screened 2735 patients. Out of those screened, 565 patients were randomly assigned 1:1 to zolbetuximab plus mFOLFOX6 (n=283) or placebo plus mFOLFOX6 (n=282). Median PFS (10.61 vs 8.67 months; HR, 0.751; P=.0066) and OS (18.23 vs 15.54 months; HR, 0.750; P=.0053 with a boundary of <.0135) were significantly improved with zolbetuximab and mFOLFOX6.1 Overall response rates were similar between treatment arms. The most common treatment-emergent adverse effects (TEAEs) with zolbetuximab plus mFOLFOX6 were nausea (82.4% vs 60.8% in zolbetuximab vs placebo arms), vomiting (67.4% vs 35.6%, respectively), and decreased appetite (47.0% vs 33.5%, respectively); the incidence of serious TEAEs was similar in both arms (44.8% vs 43.5%, respectively).¹

Are these potentially practice-changing results? “Absolutely,” Maron said. “To identify patients with claudin-positive tumors, the study used a cutoff of 75% of tumor cells with high claudin 18.2 protein expression. The study findings suggested we should use zolbetuximab in combination with chemotherapy. There is a gray area: tumors that are positive for both PD-L1 and claudin. We do not yet know how to best treat these patients because SPOTLIGHT, which was designed a relatively long time ago, did not account for the interim approval of first-line immune checkpoint blockade.”

Targeted Therapies in Oncology asked Maron if a new study would be beneficial after the completion of the SPOTLIGHT trial.

“Yes. So that’s really the question: How is claudin-directed therapy for gastroesophageal cancers going to be studied next in the first-line checkpoint blockade–containing setting? Zolbetuximab combined with FOLFOX and nivolumab [Opdivo] is undergoing phase 2 evaluation [ILUSTRO; NCT03505320]. And there’s a publication²…[with results that were presented] at the European Society of Medical Oncology by Dr Kohei Shitara, [a lead SPOTLIGHT investigator]. The study assessed claudin expression in 408 patients with advanced gastroesophageal adenocarcinoma—including overlap with subsets of patients with MSI [microsatellite instability]-high, HER2-positive, and PD-L1–positive tumors. Until demonstrated otherwise, once approved, I would reserve zolbetuximab for patients with tumors that are MSI, HER2-negative, and PD-L1 CPS [combined positive score] less than 5, [approximately 25% of the population]. This is a population that, although it has an approval for nivolumab and pembrolizumab with first-line chemotherapy, guidelines indicate category 2B evidence,” Maron said.

CheckMate 648

With its FDA approval on May 27, 2022, nivolumab in combination with ipilimumab (Yervoy) can be used as a first-line treatment for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC).³ Nivolumab plus chemotherapy is also approved in this population.

In an updated analysis of data from the phase 3 CheckMate 648 trial (NCT03143153), first-line treatment with nivolumab, in combination with either chemotherapy or ipilimumab, led to a clinically meaningful OS benefit compared with chemotherapy alone in patients with treatment-naïve advanced ESCC.^4,5

At a median follow-up of 28.8 months, the median OS in the nivolumab/chemotherapy group (n=321) was 12.8 months (95% CI, 11.1-15.7) compared with 10.7 months (95% CI, 9.4-12.1) for chemotherapy alone (n=324) in the intent-to-treat population (HR, 0.78; 95% CI, 0.65-0.93). The 24-month OS rate was 29% vs 19% in favor of the experimental arm. For patients with PD-L1 expression of 1% or higher, the median OS again favored the nivolumab arm (n=158) at 15.0 vs 9.1 months in the chemotherapy arm (n=157; HR, 0.59; 95% CI, 0.46-0.76). The 24-month OS rate was 31% compared with 12%, respectively.^4,5

CheckMate 649

The main purpose of the CheckMate 649 study (NCT02872116) was to compare how long patients with gastric, GEJ, or esophageal cancer with a PD-L1 CPS of 5 or more live, with or without disease progression, after receiving nivolumab and chemotherapy compared with patients receiving chemotherapy alone.⁶

This multicenter, randomized, open-label phase 3 trial enrolled patients from 175 hospitals across 29 countries. Eligible patients had non–HER2-positive gastric, GEJ, or esophageal carcinoma and were treatment naïve.⁶

Patients were randomly assigned 1:1:1 to receive 360 mg of nivolumab every 3 weeks or 240 mg every 2 weeks and chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone. The primary end points for the nivolumab and chemotherapy vs chemotherapy arm were OS or PFS in patients whose tumors had a PD-L1 CPS of 5 or more.⁶

HERIZON—HER-Vaxx vaccine

It is hypothesized that administration of IMU-131, an HER2/neu peptide vaccine, in addition to chemotherapy will prolong survival and may delay tumor progression and/or reduce tumor burden in patients with HER2-overexpressing gastric or GEJ adenocarcinoma.

HERIZON, a phase 1b study (NCT02795988), aims to determine the safety and tolerability of IMU-131 and identify the recommended phase 2 dose of IMU-131 in combination with chemotherapy in HER2/neu overexpressing gastroesophageal adenocarcinoma to carry into the phase 2 dose-expansion study.⁷ The phase 2 component will be submitted as an amendment and will be initiated following completion of phase 1b. Phase 2 will further characterize the safety and explore clinical activity of IMU-131 in combination with chemotherapy in HER2/neu overexpressing ACS. The phase 2 study is a randomized, open-label comparison of IMU-131 plus standard-of-care chemotherapy vs standard-of-care chemotherapy alone.7

“I think it is too early to determine the role of vaccines at this time. Of course, we are hopeful. The HERIZON study was a small, randomized phase 2 trial and we [need further study],” Eng said.

INFINITY

In patients with MSI-high gastric or GEJ cancer who are eligible for radical surgery, the INFINITY trial (NCT04817826) examines the safety of tremelimumab and durvalumab in the neoadjuvant setting (cohort 1) or definitive treatment (cohort 2).⁸

“A smaller study of interest is the INFINITY trial, [which] evaluated neoadjuvant durvalumab [Imfinzi]/tremelimumab [Imjudo] for locally advanced esophageal [cancer]. [It] was interesting, but it was a single-arm phase 2 pilot study of only 18 [patients]. Similar to the NEONIPIGA (NCT04006262) single-arm phase 2 study, there is interest in the use of immune-oncology therapy in MSI-H UGI [MSI-high upper gastrointestinal] tumors,” Eng said.

The primary end point of cohort 1 is rate of pathologic complete response (pCR) and negative circulating tumor (ct) DNA after neoadjuvant immunotherapy. The primary end point of cohort 2 is 2-year complete response rate. This is defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy during nonoperative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in patients with localized/locally advanced gastric (GC)/GEJ cancer selected for deficient mismatch repair (dMMR)/MSI-high status eligible for radical resection.⁸

NEONIPIGA

In patients with resectable esophagogastric adenocarcinoma, radical surgery is the only curative option. Despite the evolution in treatment with multimodality treatment strategies, eso-gastric cancer remains one of the most lethal malignancies, with 5-year survival rates reaching only 22%. When the disease is localized, perioperative chemotherapy with cytotoxic agents is the preferred strategy because it increases the OS rate. However, in eso-gastric cancers with MSI, which is a favorable prognostic factor, the recommended cytotoxic chemotherapy combination seems inefficient and even deleterious.

It is now well established that dMMR/MSI-high phenotypes are surrogate markers of response to immunotherapy. The combination of nivolumab and ipilimumab had shown promising efficacy in multiple tumor types, including dMMR/MSI. Based on these data, the phase 2 NEONIPIGA study was designed to evaluate the complete pathological response rate in patients with nonmetastatic dMMR/MSI eso-gastric adenocarcinoma who are treated with neoadjuvant nivolumab and ipilimumab.⁹

Final Thoughts

“I think you are seeing [that] we are continuing to find new treatment options for patients, and research in GI malignancies is hopeful,” Eng said. “We need patients to remain hopeful and [to] enroll [in] a clinical trial whenever possible. We cannot make any treatment advances [without] patients participating. Do not settle for an initial opinion and the available standard of care. Every single chemotherapy agent/targeted therapy needs to proceed through 3 phases of development before FDA approval, unless it is for a rare cancer, which may only need 2 phases of drug development. Regardless, we need patients to enroll [in] clinical trials. We need advocacy groups to push for more NCI [National Cancer Institute] funding for clinical trial research, and we need more individuals who [have the means] to consider philanthropic [donations] to cancer research.”

References

1. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary results from phase 3 SPOTLIGHT study. J Clin Oncol. 2023;41(suppl 3):LBA292. doi:10.1200/JCO.2023.41.3_suppl.LBA292

2. Kubota Y, Kawazoe A, Mishima S, et al. Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer. ESMO Open. 2023;8(1):100762. doi:10.1016/j.esmoop.2022.100762

3. FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications. FDA. Updated May 31, 2022. Accessed February 15, 2023. http://bit.ly/3ktmWei

4. Chau I, Ajani JA, Doki Y, et al. Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): expanded efficacy and safety analyses from CheckMate 648. J Clin Oncol. 2022;40(suppl 16):4035. doi:10.1200/JCO.2022.40.16_suppl.4035

5. Chau I, Doki Y, Ajani JA, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): first results of the CheckMate 648 study. J Clin Oncol. 2021;39(suppl 15):LBA4001. doi:10.1200/JCO.2021.39.15_suppl.LBA4001

6. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27-40. doi:10.1016/S0140-6736(21)00797-2

7. Maglakelidze M, Ryspayeva D, Bulat I, et al. A phase 1b/2 open-label study with randomization in phase 2 of imu-131 HER2/neu peptide vaccine plus standard of care chemotherapy in patients with HER2/neu overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction. Cancer Res. 2021;81(suppl 13):CT107. doi:10.1158/1538-7445.AM2021-CT107

8. Raimondi A, Palermo F, Prisciandaro M, et al. Tremelimumab and durvalumab combination for the non-operative management (NOM) of microsatellite instability (MSI)-high resectable gastric or gastroesophageal junction cancer: the multicentre, single-arm, multi-cohort, phase II INFINITY study. Cancers. 2021;13(11):2839. doi:10.3390/cancers13112839

9. André T, Tougeron D, Piessen G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability–high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase II study. J Clin Oncol. 2023;41(2):255-256. doi:10.1200/JCO.22.00686