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As part of our coverage of ASCO’s 2017 Gastrointestinal Cancers Symposium held January 19th to the 21st in San Francisco, today we are speaking with Dr. Geoffrey Ku, MD, a medical oncologist with Memorial Sloan Kettering Cancer Center specializing in gastrointestinal malignancies. At this year’s meeting, Dr. Ku will be participating in an education session on advances in systemic therapy for esophageal and gastric cancer.

Dr. Ku, your portion of the session will focus on immunotherapy. Immunotherapy is still somewhat new to the cancer scene, and is most commonly discussed in relation to melanoma, kidney, or lung cancers. How does research into immunotherapy for gastric and esophageal cancers compare with the progress in these other solid tumors? 

 Thanks for the question and I really appreciate the opportunity to discuss this. A part of the excitement is that while immunotherapy is certainly new the recognition is that in many different cancers it really is the most exciting development in last 20 or 30 years.

As you know, the premise is that we are giving drugs that essentially stimulate the immune system so that the immune system is able to recognize and attack cancer cells. These drugs were initially developed in melanoma, but over the space of 5 to 6 years there are now FDA-approved indications in many other common cancers including lung as well as bladder cancer. I would say that in esophageal and gastric cancer development of these drugs lags a little behind lung cancer, but there are certainly phase III studies that are ongoing.

In fact, at the Gastrointestinal Cancers Symposium there will be the results of a phase III study of one of these drugs that will be presented. At this point, we only have little bits of information, but the press release does suggest that it is a positive study that found clear benefit for one of the immune drugs versus placebo. That really is a milestone development in esophageal/gastric cancer.

Do any specific types of gastric or esophageal cancers or subgroup of patients appear to benefit more from immunotherapy approaches?

 That is certainly more than $64,000 question. It is the $640 million question. I think it is clear not only in esophageal/gastric cancer, but in other cancers that do respond to immune treatment that there are subgroups of patients who appear to derive more benefit than others. Certainly we think that one of the most helpful biomarkers, at this point, is a protein called PD-L1. PD-L1 is a target for many of these immune drugs. In esophageal/gastric cancer it is found about 40% of time. When it is present, it significantly increases the chance of shrinkage and response to these immune treatments. That is potentially one way to help select patients. Part of challenge of using PD-L1 is that even when it is not present there still are some patients who can benefit.

That is one important biomarker, but at the same time, we also know that, in general, the immune system is better able to recognize cancer cells that appear very abnormal. The more mutations that a cancer cell has the more likely it is to be recognized by the immune system. This remains an area of active development, but we are all trying to figure out how we can best figure out how abnormal cancer cells looks like, how many mutations they have.

Certainly, the thought is that markers like PD-L1, markers like the amount of mutations that are found in the cancer cells may allow us to fine tune who is and is not likely to benefit from these medications because while they are active, the reality is that they really only do benefit a minority of patients. They can have significant side effects, which involve inflammation of essentially any part of the body. That is what happens when the immune system becomes super activated.

Among the different immunotherapeutic approaches, research of immune checkpoint inhibitors have shown the most promise, what trials have looked into these drugs in gastrointestinal cancers and what have the results shown so far?

 There are a number of drugs that are all relatively similar. They all work by blocking a pathway known as PD-1/PD-L1. This is a pathway that we think helps to lower the immune system. We think that it is one way that cancer cells are able to evade the immune system after the immune system initially recognizes them. There are four or five different drugs that are being looked at and they are all antibodies. They are proteins that block this pathway. Representative drugs include pembrolizumab, nivolumab, and avelumab.

At this point in time, there are probably anywhere from five to seven, potentially even more, complementary phase III studies that are ongoing. As I mentioned, the one study that will be presented in about 10 days at the Gastrointestinal Cancers Symposium involves a drug called nivolumab, which blocks a protein called PD-1. In a study of about 450 patients-it was done mostly in East Asia-nivolumab helped patients live longer than patients who received placebo. Certainly, nivolumab is a leading contender, but pembrolizumab, which is a very similar drug, is also currently being looked at in multiple phase III studies, some of which are complete and potentially for which we will have results over the next 1 or 2 years.

Looking to the future, what areas are yet to be explored and what clinical trials are the most eagerly awaited in this area?

There are really many phase III studies that are ongoing. These are studies all in the advanced setting. Patients who have cancer that has spread in the first place, or cancer that recurred after a combination of surgery, chemotherapy, or radiation. There are studies in the first-line setting, meaning patients who have not received any previous treatment. There are studies in the second-line setting, meaning for patients for whom the cancer has grown on one treatment. They are either looking at these immune drugs on their own or they are comparing them to standard chemotherapy. Any number of these phase III studies have results that are eagerly awaited.

In terms of looking to the future, it is a combination of some of the things that we discussed. The one thing I would emphasize is that despite the promise and the excitement of these drugs, it is a relative minority of patients that benefit. Approximately only 15% of all patients benefit from these immune treatments. Part of the goal as we move forward is trying to identify biomarkers or tests that can help us to figure out who falls into the 15% of patients.

Careful patient identification to select patients who are most appropriate for the treatments so that we minimize exposing patients who are not likely to benefit from these treatments is definitely a priority. At the same time, the second generation studies, which are already slowly beginning, are beginning to look at combination strategies with the premise that potentially two drugs are better than one, or two ways of activating the immune system is better than one. This is an approach that is born out in other cancers, including melanoma and lung cancer, but the idea now is to begin to look at two drugs that activate the immune system or a combination of immunotherapy with chemotherapy, or even combining these drugs with radiation. There is some thought that if we treat a tumor with radiation and we are able to kill the tumor cells and the contents of the tumor cells are released, an immune system that is already activated is better able to recognize them.

These are all new strategies that are slowly underway. To the degree that immunotherapy has transformed the treatment of many other cancers, it is on the verge of transforming esophageal and stomach cancer. With the second-generation studies, we will see in the next 5 to10 years an improvement or an increase in the number of patients who will benefit and also an increased ability to better identify patients who will benefit.

I want to thank you again for speaking with us today and providing this update in immunotherapy in esophageal and gastric cancers. 

ASCO Gastrointestinal Cancer Symposium

Ahead of the 2017 ASCO Gastrointestinal Cancer Symposium in San Francisco, we spoke with Dr. Geoffrey Ku on the advances in systemic therapy for esophageal and gastric cancer.

Immunotherapy Treatments Only Just Emerging in Esophageal, Gastric Cancers

Data from the phase 3 SPOTLIGHT trial and the phase 3 GLOW trial supported the approval of zolbetuximab plus chemotherapy in this indication.

FDA Approves Zolbetuximab in Advanced CLDN18.2+ Gastric/GEJ Adenocarcinoma

Data from the GLOW and SPOTLIGHT trials support the European Commission’s approval of zolbetuximab for patients with CLDN18.2-positive gastric cancer.

Zolbetuximab Earns European Approval in Advanced CLDN18.2+ Gastric Cancer

Second-line fruquintinib plus paclitaxel did not sustain sufficient efficacy for patients with advanced gastric or GEJ adenocarcinoma to support approval in China. 

sNDA of Fruquintinib Combo Withdrawn in China for Second-Line Gastric/GEJ Cancer

The addition of neoadjuvant S-1 also reduced the risk of death compared with adjuvant therapy alone in the phase 3 PRODIGY trial.

S-1/Chemo Regimen Improves PFS in Resectable Advanced Gastric Cancer 

Enrollment will soon begin for the dose-expansion portion of the ongoing phase 1 trial assessing EO-3021 in CLDN18.2-positive tumors. 

EO-3021 Elicits Responses in Advanced CLDN18.2+ Gastric/GEJ Cancer

Additional genetic testing measures and targeted therapies may improve outcomes for patients with diverse molecular subgroups of gastric cancers.

Different Treatment Algorithms for Gastric Cancers May Improve Outcomes

An increasing understanding of gastric cancer as multiple disease states will continue to improve outcomes in the field, according to John L. Marshall, MD.

CancerNetwork® spoke with Marshall, physician executive director of the MedStar Washington DC Integrated Hematology-Oncology Division and the Otto J Ruesch Center for the Cure of GI Cancers, and chief medical officer of the Lombardi Comprehensive Cancer Center at Georgetown University, about developments in gastrointestinal (GI) cancers that have the potential to change clinical practice. He discussed possible advancements beyond the

 (Vyloy) plus chemotherapy for patients with locally advanced unresectable or metastatic HER2-negative, Claudin 18.2–positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Marshall began by stressing that the field is garnering a deeper understanding of gastric cancers as multiple disease states as opposed to a singular disease. Despite a need for an even greater understanding of managing GI cancers, he expressed that continuing development of treatment algorithms may improve outcomes for patients in diverse molecular GI cancer subgroups. He stated that increased knowledge pertaining to immunotherapy may help foster more favorable patient outcomes.

Marshall further emphasized a need to incorporate Claudin 18.2 testing in patients with gastric cancers. He concluded by recommending that Claudin 18.2 testing should supplement both microsatellite instability (MSI) testing and HER2 testing in light of developments in the field.

We are increasingly understanding that gastric cancer is more than 1 disease. It is molecularly broken out into different subgroups, and depending on the molecular subgroups, we have different treatment algorithms. We are beginning to gain knowledge that I believe, over time, is going to continue to improve outcomes. As with many of the GI cancers, we still have a long road [ahead] to understand how to better manage this cancer [type]. I am hopeful that with improvements in our understanding of immunotherapy approaches, [and with] more precision medicine targets and therapies, that we will see the kind of robust improvements that we need.

The biggest thing that we need to do as clinicians is begin to incorporate Claudin 18.2 testing for our patients. We are not learning fast enough––incorporating fast enough––the molecular testing that is required based on the speed of development. Make sure, if you have a [patient with] gastric cancer [for whom] you do HER2 testing and MSI [testing], you also now have to do Claudin 18.2 [testing].

Astellas’ VYLOY™ (zolbetuximab-clzb) approved by U.S. FDA for treatment of advanced gastric and GEJ cancer. News release. Astellas Pharmaceuticals. October 18, 2024. Accessed October 23, 2024. https://tinyurl.com/5745k9a8

Videos

Data from the SPOTLIGHT and GLOW trials reveal that zolbetuximab increased survival in patients with CLDN18.2-positive gastric or GEJ adenocarcinoma.

Zolbetuximab/Chemo Displays PFS, OS Benefits in Gastric Cancer Trials

CancerNetwork® spoke with John L. Marshall, MD, physician executive director of the MedStar Washington DC Integrated Hematology-Oncology Division and the Otto J Ruesch Center for the Cure of GI Cancers, and chief medical officer of the Lombardi Comprehensive Cancer Center at Georgetown University, ahead of the 

 about his impression of findings from 2 clinical trials that ultimately supported the agent’s approval.

Specifically, he discussed the phase 3 SPOTLIGHT trial (NCT03504397), which evaluated traditional chemotherapy with or without zolbetuximab, and the phase 3 GLOW trial (NCT03653507), which evaluated capecitabine (Xeloda)-based chemotherapy with or without zolbetuximab in patients with Claudin 18.2–positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Marshall began by stating that both trials measured Claudin 18.2 expression, in which about 40% of patients exhibited high enough levels to be included for evaluation. He then expressed that there was an improvement in progression-free survival (PFS) and overall survival (OS) when zolbetuximab was added to either chemotherapy regimen across both trials. He followed up by stating that the delta was small in terms of response rates before describing how the therapy may have impacted the biology of the patient population.

Marshall then discussed a quandary in treating patients with both positive Claudin 18.2 expression and PD-L1–positive disease. He posed a question as to whether immunotherapy could be used in this population before explaining that expression of PD-L1 is typically lower in patients with Claudin 18.2–positive disease. Based on these factors, he concluded by stating the biggest decision to make when treating patients with gastrointestinal cancers is which targeted therapy to use.

The 2 big phase 3 studies that were done that demonstrate [support for the approval] took patients with gastric and GEJ cancers [and] measured their Claudin 18.2 expression. [Approximately] 40% had high enough levels to be involved [in the studies]. It was a big chunk of the overall percentage that had the expression of this marker. One of the studies was using traditional chemotherapy, the other [used] capecitabine-based therapy; [these were] essentially the same trial, [with] 2 different backbones of the fluoropyrimidine. Both of them demonstrate an improved progression-free and overall survival [with zolbetuximab]. Based on [the findings], we are hoping to get this approval.

It is important to note that there was not a big delta in response rate, which surprised [us]; there was some delta, but not a big delta. It is doing something to the biology of this patient population. The one thing that will be confusing to us as clinicians is what to do in a patient [whose disease] is PD-L1–positive and Claudin 18.2–positive. Do you bring an immunotherapy in? Right now, the preliminary data suggest that most of the patients who [have Claudin 18.2–positive disease] also have low PD-L1 [expression]. That might help our decision-making as to what targeted therapy to bring to the table, but that will be the biggest decision tree we will have going forward.

Shitara K, Lordick F, Bang Y-J, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. 

. 2023;401(10389):1655-1668. doi:10.1016/S0140-6736(23)00620-7

Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. 

. 2023;29:2133-2141. doi:10.1038/s41591-023-02465-7

The incorporation of zolbetuximab in addition to chemotherapy has shown benefit in patients with Claudin 18.2–positive gastric cancers in clinical trials.

Zolbetuximab Has Benefit in Targeting CLDN18.2 in Gastrointestinal Cancers

After assessment of Claudin 18.2–targeting therapies for gastrointestinal (GI) cancers for some time, 2 clinical trials have displayed benefit among patients with Claudin 18.2-positive disease, according to John L. Marshall, MD.

CancerNetwork® spoke with Marshall, physician executive director of the MedStar Washington DC Integrated Hematology-Oncology Division and the Otto J Ruesch Center for the Cure of GI Cancers, and chief medical officer of the Lombardi Comprehensive Cancer Center at Georgetown University, about what the 

 (Vyloy) plus fluoropyrimidine- and platinum-based chemotherapy will mean for patients with locally advanced or unresectable Claudine 18.2–positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Marshall emphasized a desire within the GI cancer field to develop therapies that treat new targets. He expressed a belief that the approval of zolbetuximab combination therapy in this patient population may benefit outcomes based on 2 clinical trials: the phase 3 SPOTLIGHT (NCT03504397) and phase 3 GLOW (NCT03653507) trials.

 He additionally highlighted an excitement to incorporate the therapy into practice in light of delays to the approval process.

Data from the phase 3 SPOTLIGHT trial published in 

showed a median progression-free survival (PFS) benefit with zolbetuximab plus modified folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6) vs FOLFOX6 alone; 10.61 months (95% CI, 8.90-12.48) and 8.67 months (95% CI, 8.21-10.28), respectively (HR, 0.75; 95% CI, 0.60-0.94; 

.0066). Additionally, 12-month PFS rates were 49% (95% CI, 42%-55%) vs 35% (95% CI, 28%-42%) in the respective arms; 24-month PFS rates were 24% (95% CI, 17%-32%) vs 15% (95% CI, 9%-22%).

Results from the phase 3 GLOW trial published in 

 showed a median PFS benefit with zolbetuximab plus capecitabine (Xeloda) and oxaliplatin (CAPOX) vs CAPOX alone; 8.21 months and 6.80 months, respectively (HR, 0.687; 95% CI, 0.544-0.866; 

 = .0007). In each respective arm, the 12-month PFS rates were 35% vs 19%, and the 24-month PFS rates were 14% vs 7%.

In GI cancers, we have been longing for new targets. We have been longing for new therapies. Finally, we are getting one. Claudin 18.2 has been out there for a while, and drug development targeting this has been going on for a while. Two big, randomized studies now support benefit [of zolbetuximab] in this patient population. Now, we are going to get the drug [approval]. We have been delayed a while by some other issues that have slowed the approvals, but we are excited, and we are all looking forward to incorporating [zolbetuximab] into our treatment paradigm.

2022 International Gastric Cancer Conference

, Kohei Shitara, MD, chief in the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kahiwa, Japan, sat down with CancerNetwork® and discussed using checkpoint inhibitors in front-line gastric cancer. He also spoke about the CheckMate649 study (NCT02872116) and the survival benefit seen in patients with advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma who were treated with nivolumab (Opdivo) plus chemotherapy vs chemotherapy alone.

We have an immune checkpoint inhibitor anti–PD-1 therapy nivolumab plus chemotherapy in front-line for gastric cancer. This is especially recommended for patients with PD-L1, or CPS [combined positive score] of 5 or higher globally based on CheckMate649 and its subgroup analysis. Meanwhile, there is controversy with its use for PD-L1 CPS of less than 5, according to the subgroup; there was a lesser [survival] benefit in this population. 

Importantly MSI [microsatellite instability]–high patients achieved remarkable survival benefit with the checkpoint inhibitor in the CheckMate649 study and other previous studies of checkpoint inhibitors in gastric cancer. This is a very important biomarker, so it’s better to test all patients for it in the front-line. About 20% to 30% of MSI-high patients showed PD-L1 with a CPS as low as 5, so a CPS test alone may miss MSI-high populations. Recently, in pembrolizumab [Keytruda] plus trastuzumab and chemotherapy was approved the United States for HER2-positive gastric cancer with accelerated approval from the FDA.

 Overall, MSI [status], PD-L1 CPS, and HER2 are always important [to determine] before we start immunotherapy.

1. 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

2. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News Release. FDA. May 5, 2021. Accessed March 8, 2022. https://bit.ly/3pMQYcC

Kohie Shitara, MD, spoke about the use of immunotherapy in the first-line setting for metastatic gastric cancer.

Kohei Shitara, MD, Discusses Immunotherapy in Gastric Cancer at 2022 IGCC

 spoke with Dr. Shaila Merchant about the difficulty in determining and linking the many disparities in gastric cancer and how genetic research can help.

Cancer Network spoke with Dr. Shaila Merchant about the difficulty in determining and linking the many disparities in gastric cancer and how genetic research can help.

Gastric Cancer

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