Research Efforts Abound in HER2-Positive Gastric and GEJ Cancers

Rutika J. Mehta, MD, MPH

Biomarkers play an essential role in the diagnosis and management of patients with gastric and gastroesophageal junction (GEJ) cancers, according to Rutika J. Mehta, MD, MPH, who added that many ongoing trials are working to identify the optimal treatment of subgroups whose tumors harbor different genomic alterations, such as HER2 mutations.

For patients with HER2-expressing disease, fam-trastuzumab deruxtecan-nxki (Enhertu) was granted a breakthrough therapy designation from the FDA in May 2020; the decision partially based on data from the phase 2 DESTINY-Gastric01 trial, which showed that the antibody-drug conjugate (ADC) improved overall survival versus chemotherapy in heavily pretreated patients with unresectable or metastatic HER2-positive gastric or GEJ cancer.¹

Results from the phase 2/3 PETRARCA trial showed that the addition of trastuzumab (Herceptin) and pertuzumab (Perjeta) to 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel (FLOT) perioperatively led to a significant improvement in pathologic complete response and nodal negativity rates compared with FLOT alone in patients with HER2-positive resectable esophagogastric adenocarcinoma.²

Other research efforts, such as the phase 2/3 MAHOGANY trial (NCT04082364) examining margetuximab in patients with HER2-positive gastric and GEJ cancer,³ and the phase 2 trial (NCT03929666)⁴ evaluating the investigational agent ZW25 in combination with chemotherapy in the first-line treatment of patients with HER2-positive metastatic gastric, gastroesophageal junction, and esophageal adenocarcinomas are also underway, according to Mehta.

“Anyone who is treating patients with gastric cancer, especially in the metastatic setting, needs to be mindful of ordering molecular tests. The mismatch repair status or microsatellite instability (MSI) status is becoming more important these days,” said Mehta. “[Although] very few patients [with these genomic alterations are seen] in practice, it could mean a whole world of difference to give them immunotherapy versus chemotherapy.”

In an interview with OncLive during the 2020 International Perspectives in Cancer webinar on Gastrointestinal Malignancies, Mehta, a medical oncologist specializing in gastrointestinal cancers at Moffitt Cancer Center, discussed key updates in gastric and GEJ management, trials of interest, and the importance of testing for biomarkers.

OncLive: What are some of the key updates to read out in gastric and GEJ cancers?

Mehta: When considering the entire gamut of gastric cancer, we need to consider the locally advanced and metastatic settings. We have a few trials to talk about in the locally advanced setting, and although results from these trials have not necessarily been practice changing, they still offer important insight into how we can advance or develop better clinical trial designs in this setting.

In the metastatic setting, again, we don't have any [trials] that we consider to be rapidly practice changing, but [these efforts do] offer some insight into the MSI-high (MSI-H) subgroup of [patients with] gastric cancer how to uniquely manage them. [This is] in contrast with our prior beliefs from several years ago that all patients with gastric cancer [should be] treated equally. We have important molecular subtypes that are emerging in the field that deserve special attention.

How do treatment approaches differ between locally advanced and metastatic disease?

GEJ cancers, depending on which cancer center a patient goes to, can be treated like esophageal cancer or gastric cancer. Most commonly, we do combine GEJ cancers with gastric cancers for clinical trial purposes. In the locally advanced setting, the standard has always been perioperative chemotherapy and, until a few years ago, our standard treatment approach was epirubicin-based treatment with 3 cycles preoperatively and 3 cycles postoperatively; we commonly refer to this as “sandwich” therapy. Following a trial that was published a couple of years ago, we now know that FLOT has become the new standard of care, surpassing the median overall survival (OS) benefit [that we had previously seen] with impressive pathologic complete response rates, as well. Thus, epirubicin-based therapy should now be reserved for patients with gastric cancer in the locally advanced setting who are otherwise candidates for surgery.

Is FLOT being examined in patients with HER2-expressing gastric or GEJ cancers?

Investigators have looked at this in the PETRARCA trial, which was recently presented at the 2020 ASCO Virtual Scientific Meeting. The trial design was to use FLOT for perioperative chemotherapy in combination with trastuzumab and pertuzumab, which are anti-HER2 treatments that are commonly used in patients with HER2-positive breast cancer.

Unfortunately, the trial did close because of some results that were obtained from the previously ongoing JACOB trial in the metastatic setting. Therefore, that question still remains unanswered. [We don’t know] whether targeting HER2 in the locally advanced setting would be useful or not. The authors did point out that the combination therapy did carry some adverse effects that were out of proportion to what we would expect with FLOT by itself.

Could you provide some background on the DESTINY-Gastric01 study in the HER2-positive space? How has trastuzumab deruxtecan impacted the paradigm?

The treatment of patients with HER2-positive gastric cancers is a bit challenging. Unlike patients with HER2-positive breast cancer, we really did not have many treatment options to offer these patients. There also are no data to support continuing trastuzumab beyond progression. Many researchers around the world are trying to understand the mechanism of resistance, either innate resistance that is present in tumors at the start of receiving trastuzumab treatment or that is acquired resistance that is developed after receiving trastuzumab.

Certain theories are behind this. As opposed to HER2-positive breast cancer, HER2-positive gastric cancers are more heterogeneous, which means if I take a cross-section of the tumor, there could be islands of HER2-positive cells versus islands of HER2-negative cells. This begs the question: If I take a biopsy sample of a certain lesion, is that representative of the entire cancer in the patient? Therefore, we do not know if trastuzumab or any anti–HER2-based treatments would be useful in these patients or not.

Liquid biopsies are emerging in the field, as well, to overcome the barrier of identifying HER2-positive versus -negative cells in the same cancer. Trastuzumab deruxtecan has been a very promising drug. It's an ADC that has shown impressive results, even in the refractory setting when patients have already received 2 or more lines of prior treatment, including trastuzumab. In fact, data show that this drug bypasses all the resistance pathways that we consider to be challenging when patients receive trastuzumab-based treatment.

Could you expand on the role of biomarkers?

Biomarkers have a very important role to play in gastric cancer. I believe every patient walking in the door with metastatic gastric cancer deserves to be profiled for various molecular biomarkers. I typically check mismatch repair deficient, MSI, HER2 status, PD-L1, and now tumor mutational burden, for all my patients.

The easiest thing to do would be to order next-generation sequencing if tissue is available because that will offer a gamut of results, which will not only help identify what potential standard treatment options are available, but also some clinical trials that are being designed to specifically target certain molecular subtypes.

Were there any other important trials that have recently read out that you wanted to highlight?

The exciting news has been about the KEYNOTE-062 trial; many thought leaders and researchers across the world were waiting for these results to come out. While these data did not change any paradigm in current treatment practice, it did leave us with some important insights to think about. When pembrolizumab (Keytruda) was compared with chemotherapy in patients with PD-L1–positive HER2-negative gastric cancer in the first-line metastatic setting, pembrolizumab was not inferior to chemotherapy.

Investigators looked at a specific subgroup population of those with MSI-H tumors; we see less than 5% of these patients in practice. Being a subgroup analysis, more data are needed, but [there] was compelling evidence to say that [this approach] did significantly improve median OS. The median progression-free survival was 11.2 months versus 6.6 months as opposed to chemotherapy.

Therefore, that suggests a very strong rationale to support the use of immunotherapy for the MSI-H subgroup of patients. My expectation would be, now that we have pembrolizumab approved for patients with MSI-H tumors after they have received chemotherapy, these data would push more and more clinicians to use immunotherapy up front for this subgroup.

What other agents are coming down the pike?

Some HER2-positive trials are ongoing. For example, we do have the MAHOGANY study in the HER2-positive setting. The ZW25 drug is also being tested in the first-line setting. In the HER2-negative, first-line space, we do have a [study examining] a drug that targets claudin 18.2; that trial is currently ongoing, and we're awaiting the results. Several ongoing trials are examining combinations with immunotherapy and trying to see how trastuzumab deruxtecan could make its way to an earlier-line setting; that would also be important to see.

References

1. ENHERTU granted breakthrough therapy designation in the U.S. for HER2 positive metastatic gastric cancer. News release. Daiichi-Sankyo. May 11, 2020. Accessed August 19, 2020. https://bit.ly/2AjGb2D.
2. Hofheinz RD, Haag GM, Ettrich TJ, et al. Perioperative trastuzumab and pertuzumab in combination with FLOT versus FLOT alone in HER2-positive resectable esophagogastric adenocarcinoma: final results of the PETRARCA multicenter randomized phase II trial of the AIO. J Clin Oncol. 2020;38(suppl 15):4502. doi:10.1200/JCO.2020.38.15_suppl.4502
3. MacroGenics announces initiation of phase 2/3 MAHOGANY study of margetuximab in gastric or gastroesophageal junction cancer. News release. MacroGenics, Inc. October 25, 2019. Accessed August 19, 2020. https://bit.ly/3iTRq2I.
4. Zymeworks opens phase 2 clinical trial for ZW25 in first-line HER2-expressing metastatic gastroesophageal cancers. News release. Zymeworks Inc. April 15, 2019. Accessed August 19, 2020. https://bit.ly/3ge9Jhp.