Shah Highlights Shift Toward Earlier Use of IO and Targeted Therapy in Gastric/GEJ Cancer

Manish A. Shah, MD

Despite multiple negative trials, the treatment paradigm of gastric/gastroesophageal junction (GEJ) cancer has shifted to include immunotherapy and targeted therapy, according to Manish A. Shah, MD. Moreover, these treatments, which may elicit significant responses for select patients, are moving from later lines of treatment to the first- and second-line settings.

"Similar to the evolution of treatment in colon cancer, where we went from specific lines of treatment to a continuum of care with more treatment options, we are now in an era of [immunotherapy] and targeted therapy in gastric/GEJ cancer," said Shah. "We have more treatments available wherein it is important to consider the lines of therapy and the options for care to maximize the benefit for our patients."

Though additional biomarkers are needed to establish which patients are most likely to benefit from immunotherapy, patients with mismatch repair deficiencies (dMMR) should be considered for upfront immunotherapy, explained Shah.

In an interview with OncLive, Shah, the Bartlett Family Associate Professor of Gastrointestinal Oncology, associate professor of medicine at Weill Cornell Medical College, and associate attending physician at NewYork-Presbyterian Hospital, discussed how the management of patients with gastric/GEJ cancer has evolved over the last several years.

OncLive: Could you discuss the treatment landscape of gastric/GEJ cancer?

Shah: Not too long ago, we were giving patients 1 or 2 lines of therapy. Now there are approvals in the third-line setting. Additionally, immunotherapy has demonstrated some activity, and there has been a lot of data evaluating immunotherapy in the first- and second-line settings.

Could you discuss the evolution of immunotherapy in this space? What is its current role?

Initially, immunotherapy was developed in the advanced setting for patients in third- or later-line settings. It demonstrated activity in some patients.

Those patients who benefit from immunotherapy derive tremendous benefit. Immunotherapy was then evaluated in the second-line setting, the first-line setting, and now [it is being looked at] in the locally advanced setting.

We have some data in the second-line setting that suggest immunotherapy is not superior to chemotherapy. In the first-line setting, the addition of immunotherapy to chemotherapy is not superior to chemotherapy alone. We have learned that some patients benefit significantly from immunotherapy, but we haven't been able to identify who those patients are.

In gastric cancer, patients with a large burden of disease are typically symptomatic. For those patients, we believe that starting with chemotherapy is probably optimal unless there is a specific target such as a dMMR. In those cases, we may consider giving upfront immunotherapy.

Are there currently any biomarkers or characteristics you look for when recommending a patient for immunotherapy versus chemotherapy?

We look at dMMR status because patients who have dMMR have a high chance of significantly benefitting from immunotherapy with durable responses.

That is the main biomarker we use at the beginning. However, we also use the combined positive score (CPS) as a marker for those patients who may benefit from immunotherapy in the third-line setting.

What data have we seen regarding trastuzumab (Herceptin) in patients with HER2-positive gastric/GEJ cancer?

There have been several studies evaluating [therapy for] patients with HER2-positive gastric/GEJ cancer. The first study that is worth reviewing [is the phase III HELOISE trial which] evaluated the combination of cisplatin and capecitabine plus or minus trastuzumab as frontline therapy in patients with metastatic HER2-positive gastric/GEJ cancer. In this large multinational study, the addition of trastuzumab was associated with a significant survival benefit.

Based on that, trastuzumab was approved in the first-line setting. However, multiple studies since have failed to move the bar.

Lapatinib (Tykerb) was examined in the first- and second-line settings. However, those studies were negative and lapatinib is not approved in gastric/GEJ cancer.

We also examined ado-trastuzumab emtansine (TDM-1; Kadcyla), an antibody—drug conjugate approved in breast cancer, in gastric cancer in the second-line setting. That study was also negative.

Pertuzumab (Perjeta) was examined in the first-line setting in the phase III JACOB trial, which was also negative.

Based on those negative trials, we can confirm that trastuzumab has activity and should be given in the first-line setting to patients who are HER2-positive.

The dose and schedule of trastuzumab were examined in the phase IIIb HELOISE study. The study results confirmed that the dose and schedule used in the phase III ToGA study is appropriate. That schedule consisted of an 8-mg loading dose, followed by 6 mg/kg every 3 weeks. Some clinicians have modified that and give a 6 mg loading dose, followed by 4 mg/kg every 2 weeks.

HER2-positive gastric cancer is not like HER2-positive breast cancer. Drugs like lapatinib, pertuzumab, and TDM-1 that are approved in breast cancer, are not approved in gastric cancer.

Additionally, we should limit HER2-targeted therapy to the first-line setting. Beyond the first line, there is no evidence that adding HER2-targeted therapy has any benefit.

Are there any challenges sequencing these drugs?

In the ways these studies have been performed and their results, I don't think there is much of a sequencing issue right now. If a patient is HER2-positive, they would get chemotherapy with trastuzumab.

There is some suggestion that upfront trastuzumab plus chemotherapy plus immunotherapy might be superior, but that is being tested in a phase III clinical trial.

In the second-line setting, the most common approach is paclitaxel and ramucirumab (Cyramza). For that combination, patients don't have to have a specific target. In the third-line setting, patients who are PD-L1—positive with a CPS of ≥1 are considered for immunotherapy.

Certainly, if a patient has dMMR, we would move immunotherapy earlier to the second- or first-line settings.

Could you discuss findings from the GATSBY trial? What conclusions can be drawn from the biomarker analysis?

GATSBY was a phase II/III study comparing TDM-1 versus taxane chemotherapy. It was a superiority study that showed there was no improvement in patient outcomes with TDM-1 versus chemotherapy.

The biomarker analysis looked at the level of HER2-expression to see if that made a difference. Certainly, tumors that have high HER2-expression have a significant benefit with TDM-1. [The analysis] did not show the superiority of T-DM1 [in this setting], but that was a subgroup analysis.

The tumors that had low HER2 expression that were still HER2-positive by immunohistochemistry had inferior survival compared with chemotherapy.

For that reason, we are confident that targeting HER2 in the second-line setting is unlikely to be a smart strategy to pursue.

Have there been any other advances in gastric/GEJ cancer?

There is a lot of research being done evaluating the gastric microbiome and its impact on cancer development and treatment. Like many things in oncology, the better we get at treating something, the more questions arise.

One of the key questions in GEJ cancer is how to integrate immunotherapy in HER2-positive disease. Currently that is being asked in a large registrational study.

For squamous cell cancer of the esophagus, pembrolizumab (Keytruda) was recently approved in the second-line setting for patients with PD-L1 CPS ≥10. That is quite exciting.

We do know that squamous cell cancer is more sensitive to immunotherapy than adenocarcinoma. That has led to a large study of definitive chemotherapy and radiation with or without pembrolizumab in patients with locally advanced esophageal cancer who are not candidates for surgery.