Zhen Explores the Role of Immunotherapy in Upper GI Cancers

Peers & Perspectives in OncologyAugust 2023
Volume 1
Issue 4
Pages: 59

During a Targeted Oncology™ Case-Based Roundtable™ event, David Zhen, MD, explored treatment options for patients with advanced HER2-negative upper gastrointestinal cancers.

Zhen headshot

David Zhen, MD

Assistant Professor, Clinical Research Division

Fred Hutchinson Cancer Center

Seattle, WA


  • A 60-year-old man with abrupt 10-lb weight loss, dyspepsia, bloating after meals, and loss of appetite; all symptoms have worsened over the past 3 months
  • Family history: father had gastric cancer, died at age 50
  • Medical history: overweight, Barrett esophagus
  • Esophagogastroduodenoscopy showed 2-cm protruding mass in the body of the stomach, without ulceration
  • Biopsy revealed poorly differentiated adenocarcinoma
  • Molecular testing: HER2/neu (–); mismatch repair proficient/microsatellite stable; PD-L1 combined positive score of 5%, NTRK alteration negative
  • CT scan of abdomen and chest revealed a gastric polypoid mass and thickening; no ascites; 2 lesions in left lung lower lobe
  • Lung biopsy confirmed metastatic adenocarcinoma consistent with gastric primary tumor
  • PET/CT scan confirmed metastatic disease
  • Diagnosis: stage IV gastric adenocarcinoma

What are the FDA-approved indications for immunotherapy for HER2-negative upper gastrointestinal (GI) cancers?

ZHEN: The FDA-approved indications are not necessarily things that we may do in clinic. The foundation is chemotherapy and some type of immune checkpoint inhibitor [ICI] for esophageal cancer, GEJ [gastroesophageal junction] cancer, and gastric cancer.

In esophageal squamous cell carcinoma, we are focusing on chemoimmunotherapy combinations. In the first-line setting, there is an FDA approval for ICIs alone: nivolumab [Opdivo] and ipilimumab [Yervoy].1,2 [However], technically nivolumab is approved for esophageal cancer, GEJ cancer, and gastric cancer [right now].1 The first-line approval for pembrolizumab [Keytruda] is currently in esophageal squamous cell carcinoma, esophageal adenocarcinoma, and Siewert type I GEJ cancer, which is…tumors located within 1 to 5 cm proximal to the GEJ.3 It is not approved for Siewert type II and III GEJ cancer or gastric cancer [right now].

However, I know we can often get these approved [in clinic], and I think there are updated data that were presented at ESMO [European Society for Medical Oncology Annual Congress]. The KEYNOTE-062 [NCT02494583] study was the very first one that [investigated] pembrolizumab with chemotherapy in the first line, [and it] ended up being a negative study.4 Interestingly, it was repeated and presented at ESMO as KEYNOTE-859 [NCT03675737].5 They found a survival benefit. I think the first study potentially showed that, but it was just a statistical [issue]. The take-home is that you can use any ICI agent, but there are FDA-approved indications with these diseases.

In advanced disease, chemotherapy is typically combined with ICIs. In HER2-positive disease, trastuzumab [Herceptin] is added. We also have approvals for the use of adjuvant nivolumab for patients who receive trimodal therapy for localized esophageal cancer.1 Thereafter, they get neoadjuvant chemoradiotherapy. In unresectable disease, chemoimmunotherapy or combined immunotherapy is approved. Basically, this is the treatment landscape we currently have.

What are the recommended therapies for HER2-negative upper GI cancers?

In the current NCCN [National Comprehensive Cancer Network] guidelines, the use of combined chemotherapy [and platinum]— specifically fluoropyrimidine, and typically oxaliplatin—plus nivolumab is a category 1 recommendation, meaning there is very high-level evidence and complete agreement among the NCCN panel to use it in patients who have a PD-L1 CPS [combined positive score] of greater than or equal to 5.

However, for patients who have a CPS of less than 5, it is a category 2B. [In the NCCN], the definition for category 2B is essentially that the data are not as strong, but some data suggest that maybe there is benefit. [However], there is also some mild disagreement among the panel about whether to use it.6


The patient was started on FOLFOX (folinic acid, fluorouracil, and oxaliplatin) plus nivolumab.

What data support nivolumab combined with chemotherapy as first-line therapy in the HER2-negative upper GI cancer setting?

The study that led to the approval of nivolumab in the first-line setting with chemotherapy was CheckMate 649 [NCT02872116]. This was a very straightforward study of patients with previously untreated, unresectable, advanced HER2-negative gastric, GEJ cancer, or esophageal adenocarcinoma. Patients had to have good ECOG performance status [PS] of 0 to 1. They were randomly assigned 1:1 to chemotherapy alone or combined with nivolumab. They were flexible in terms of the chemotherapy, so it was either CapeOx [capecitabine (Xeloda) and oxaliplatin] or FOLFOX vs the same chemotherapy regimens in combination with nivolumab. They had different strategies for the dosing of nivolumab, either every 2 weeks with FOLFOX or every 3 weeks with CapeOx. Patients were treated until progressive disease or unacceptable toxicity. The stratification factors were tumor PD-L1 expression, region, ECOG PS, and chemotherapy. The overall survival [OS] and progression-free survival [PFS] were coprimary end points in the [population with a] PD-L1 CPS of 5 or above. The secondary end point was OS in [patients with a] PD-L1 CPS of above 1 and in all randomly assigned patients, plus overall response rate [ORR] in all randomly assigned patients.7

For baseline characteristics…70% of patients were White compared with [approximately] 24% who were Asian. That is important, because many of the gastric cancer studies are done in Asia, and we know patients from East Asia do have some different biological characteristics, and their responses and prognoses are often different from a White population. The take-home is that this was representative of a more Western patient population. Most patients had a good ECOG PS of 0 to 1.7

In terms of primary tumor location, most were truly gastric cancers—70% in both arms—with a smaller proportion of GEJ cancer or esophageal adenocarcinoma. This was [mostly a] gastric cancer study, and most patients had metastatic disease—more than 95%. Chemotherapy choice, whether it was FOLFOX or CapeOx, was just a little bit more toward FOLFOX, but it was pretty much even. Most patients were [microsatellite stable].7

A statistically significant improvement was seen in the nivolumab plus chemotherapy arm, with a median OS of 14.4 months vs 11.1 months with chemotherapy alone [HR, 0.71; 98.4% CI, 0.59-0.86; P < .0001]. Historically, this was a big movement, because this was the first study in HER2-negative [advanced] disease that reached a median OS beyond 1 year. [Approximately] 30% of patients received more long-term and durable benefit. These are meaningful data that led to the approval of nivolumab.

[In patients with a PD-L1 CPS of at least 5], nivolumab plus chemotherapy increased the ORR to 60% from 45%, [which] we historically see with chemotherapy alone [Figure8]. The PFS was also better with nivolumab, at 8.3 months vs 6.1 months with chemotherapy alone.

Figure. Objective Response Rate in the CheckMate 649 trial8

Overall, toxicity rates aren’t that much different, but there were [slightly] more grades 3 and 4 toxicities and some treatment-related deaths: 16 patients in the nivolumab arm vs 4 in the chemotherapy alone arm.7 Particularly in the immunotherapy arm, 3 of those deaths were related to pneumonitis. Generally, nivolumab is well tolerated, with no significant increases in toxicities. There was a bit of immune-related hepatotoxicity from nivolumab.

Which trial combined nivolumab with chemotherapy as first-line therapy for esophageal squamous cell carcinoma?

The CheckMate 649 study was designated for gastric, GEJ cancer, and esophageal adenocarcinoma, but it was [primarily] a gastric cancer study. CheckMate 648 [NCT03143153] investigated nivolumab for [only] esophageal squamous cell carcinoma. The third arm was a chemotherapy-free regimen of nivolumab plus ipilimumab, which is interesting, but [that’s] for another discussion.

The other arms were cisplatin and fluorouracil, which were the chemotherapy backbone, with or without nivolumab. This had a very similar design compared with CheckMate 649. The coprimary end points were OS and PFS in the population with a PD-L1 CPS of 1 and above.9 For patients with an elevated PD-L1 expression of greater than or equal to 1%, the nivolumab and chemotherapy arm showed a median OS of 15 months, and it was 9.1 months [with chemotherapy alone].

That is statistically significant. In all randomly assigned patients, there was still a statistical significance with the median OS in the nivolumab arm at 12.8 months vs 10.7 months with chemotherapy alone, although just not as drastic of a degree of benefit as with the higher PD-L1 [expression].9 Unlike what we see in adenocarcinoma, squamous cell histology is a different biology of disease, so we do often see a bit more response with ICIs. With squamous cell [histology], we don’t care as much about the PD-L1 in terms of selecting patients. However, we do still check it, because there does seem to be a prognostic indicator in terms of the role of the PD-L1 score.

How do you choose between ipilimumab plus nivolumab vs chemotherapy plus nivolumab?

I wasn’t going to focus too much on the third arm [of CheckMate 648]. However, in terms of choosing both regimens, nivolumab plus chemotherapy was compared with chemotherapy and nivolumab plus ipilimumab was compared with chemotherapy, so we do not have a head-to-head study at all yet of nivolumab with either chemotherapy or ipilimumab. That has not been answered. It is hard to do cross-number comparisons here in terms of survival and what is better, and…there is probably not that much difference in terms of survival. When you look at the Kaplan-Meier survival curves, it is the same thing that we see over and over. When we give single or dual ICI without chemotherapy, [approximately] 20% to 30% of patients progress very rapidly. One is taking a risk when they give immunotherapy alone because there’s a group of patients who are going to rapidly progress. For most of us, we still prefer that if patients can get chemotherapy, we give it to them.

We might consider nivolumab plus ipilimumab [ for] somebody with a lower burden of disease who is not progressing rapidly. We also have cases where patients had, for example, locally advanced esophageal squamous cell carcinoma, then we treated them with chemoradiation, and then suddenly they got a local recurrence. What do you do? Should you give them chemotherapy? We feel bad giving an older patient chemotherapy, so sometimes we might give them immunotherapy alone. Those are some of the considerations. But in terms of data on how we choose or which is going to be better, there is going to be more research forthcoming.


1. Opdivo. Prescribing information. Bristol Myers Squibb; 2018. Accessed May 23, 2023. https://tinyurl.com/2kxcpcsv

2. Yervoy. Prescribing information. Bristol Myers Squibb; 2023. Accessed June 29, 2023. https://tinyurl.com/2cd4d7nx

3. Keytruda. Prescribing information. Merck Sharp & Dohme Corp; 2021. Accessed May 23, 2023. https://tinyurl.com/4uxzxzaz

4. Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6(10):1571-1580. doi:10.1001/jamaoncol.2020.3370

5. Rha SY, Wyrwicz LS, Yañez-Weber PE, et al. Pembrolizumab (pembro) plus chemotherapy (chemo) as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: phase III KEYNOTE-859 study. Presented at: ESMO Virtual Plenary; February 16-17, 2023.

6. NCCN. Clinical Practice Guidelines in Oncology. Gastric cancer, version 2.2022. Accessed May 23, 2023. https://tinyurl.com/5n7utrn3

7. 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

8. Janjigian YV, Shitara K, Moehler MH, et al. Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 3-year follow-up from CheckMate 649. J Clin Oncol. 2023;41(suppl 4):291. doi:10.1200/JCO.2023.41.4_suppl.291

9. Kato K, Ajani JA, Doki Y, et al. Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 29-month (mo) follow-up from CheckMate 648. J Clin Oncol. 2023;41(suppl 4):290. 10.1200/JCO.2023.41.4_suppl.290

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