ODAC Votes on PD-1 Inhibitors Underscore Importance of Biomarker Testing in Gastric/GEJ and Esophageal Cancers

The evolving treatment landscape for patients with unresectable or metastatic gastric, gastroesophageal junction (GEJ), and esophageal cancers has been largely credited to the use of anti–PD-1 antibodies and emerging therapies, according to Nataliya Uboha, MD, PhD, who added that biomarker testing has been critical in this armamentarium shift.

Immune checkpoint inhibitors have been approved in the frontline setting for the treatment of patients with these malignancies; however, on September 26, 2024, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted against both the risk:benefit profile of PD-1 inhibitors in the first-line treatment of patients with advanced HER2-negative, microsatellite stable (MSS) gastric/GEJ adenocarcinoma with a PD-L1 expression of less than 1 and the risk:benefit profile of anti–PD-1 antibodies in the first-line treatment of patients with metastatic or unresectable esophageal squamous cell carcinoma (ESCC) with a PD-L1 expression of less than 1.

Although the ODAC votes did not change the currently approved indications for PD-1 inhibitors in patients, it underscored the importance of biomarker testing to determine optimal treatment decision-making in these patient populations.

“I’m hoping that testing for biomarkers will be done reflexively in community and academic settings,” Uboha said in an interview with OncLive®. “Treatment recommendations based on biomarker results are critical to improve outcomes in these patients, and we need to educate our pathologists, community partners, [and] the partners in academic institutions [about] how important it is for all patients to get their biomarker test results so that we can offer the best treatment.”

In the interview, she expanded on the current indications for checkpoint inhibitor therapy in these patient populations, how she uses PD-L1 expression to determine if an immune checkpoint inhibitor could be applicable for a given patient, and the current state of PD-L1 testing in clinical practice.

Uboha is a medical oncologist, associate professor, and researcher in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health in Madison.

OncLive: What are the current indications for checkpoint inhibitors in unresectable/metastatic gastric/GEJ cancer and esophageal cancer?

Uboha: Anti–PD-1 antibodies are approved for the treatment of patients with advanced esophageal, GEJ junction, and gastric adenocarcinomas, as well as esophageal squamous cell carcinomas. At this time, we primarily use these agents in the first-line setting, although in squamous cell cancer, anti–PD-1 agents can also be used in the second-line setting in patients who have not had prior exposure to these agents earlier during treatment.

What have the cumulative data shown regarding the relationship between PD-L1 expression and treatment efficacy in these patient populations?

A growing number of data show that PD-L1 expression is a predictive marker for response to anti–PD-1 agents in [patients with these malignancies]. We know that patients whose tumors have some level of expression of PD-L1 respond better to these agents, and we also see a trend across studies that patients whose tumors have higher expression of PD-L1 have a higher chance of response. We also see that those with tumors that have no PD-L1 expression, [meaning a] PD-L1 combined positive score [CPS] of less than 1%, do not [derive the same] benefit from the addition of these agents to chemotherapy or from the use of these agents alone, as in the case of squamous cell cancers.

How much variation is there in assessing for PD-L1 expression level, and what is the threshold to define positivity?

This is a very important question, and it’s a complicated question. There are many ways to answer. There are many different aspects to testing for PD-1 expression. First, there are different antibodies, and there have been different clones for PD-1 expression we [have] used across different studies.

The second issue is that there are different ways to look for expression of PD-L1 in tumors. CPS is probably the most widely accepted score right now, and it looks at the expression of PD-L1 on both the tumor cells as well as immune cells present in the tumor microenvironment. However, there are other ways to look at PD-L1 expression. One of them is TAP [tumor area positivity] score. This is the way that PD-L1 was assessed in the studies that used tislelizumab-jsgr [Tevimbra] most recently.

The good news is that we’ve seen a good correlation between different scoring methods. For example, tumors that have a PD-L1 CPS of 10 or higher are also likely to have a TAP score of 10 of higher. They technically could be used interchangeably; we’re not missing patients or identifying additional patients with a different scoring method.

What do you do if you are treating a patient with a PD-L1 CPS score between 1 and 10 in your practice?

In my practice, I offer immunotherapy to those with a PD-L1 CPS of 1 or greater. I have become less dogmatic about this—when the initial data with nivolumab [Opdivo] came out, my cutoff was [a PD-L1 CPS of] 5. However, I am seeing variability between PD-L1 expression between the primary and metastatic sites—just yesterday, I saw a PD-L1 CPS of 2.3, even with a decimal point. These patients have very serious illnesses, and they need better treatments. In the era of uncertainty, the benefits of the addition of immunotherapy outweigh the risks, especially when the testing for the biomarker is not always reliable.

With the heterogeneity between primary and metastatic tissue, is there a preference on which to biopsy?

A lot of our patients would have both primary and metastatic sites biopsied. I don’t think there is a preference, but all patients will come to see us in the clinic with a tissue diagnosis of their malignancy. In my practice, all patients have testing [done] for mismatch repair protein expression to look for microsatellite instability. All my patients [also] have HER2 immunohistochemistry [performed] and PD-L1 CPS determined.

Over the next couple of months, we are also anticipating that the anti-Claudin antibody zolbetuximab-clzb [Vyloy] will get approved for patients with adenocarcinomas. Therefore, I am planning to incorporate reflexive Claudin 18.2 [CLDN18.2] testing into our treatment paradigms as well, but this will be applicable only to adenocarcinomas in the advanced setting.

Editor's note: This interview took place prior to the October 18, 2024, FDA approval of zolbetuximab in combination with chemotherapy for the treatment of adult patients with locally advanced unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN18.2-positive, as detected by an FDA-approved test.

Reference

September 26, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/live/ELA3JDqtcFw