Phase 3 Trial Data Inform Advancements in Targeted Therapy for Gastric/GEJ Cancers

Cindy M. Pabon, MD, sat down for an interview with OncLive®, where she provided an overview of updated efficacy and safety findings, as well as clinical implications from 3 recent trials in gastric and gastroesophageal (GEJ) cancer. These investigations address critical questions within the treatment paradigm and include the phase 3 TOPGEAR trial (NCT01924819) evaluating the addition of preoperative radiotherapy to perioperative chemotherapy; the phase 3 KEYNOTE-811 trial (NCT03615326) of pembrolizumab (Keytruda) plus trastuzumab (Herceptin) and chemotherapy in HER2-positive gastroesophageal cancers; and the phase 1b/2 DESTINY-Gastric03 trial (NCT04379596) assessing fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) combinations in HER2-positive gastric cancer.

Findings from these studies collectively inform treatment strategies, emphasizing a shift toward targeted and systemic treatment, highlighting the importance of balancing efficacy with toxicity, according to Pabon. All 3 trials were highlighted in her presentation at the 2024 Sylvester Cancer Survivorship Symposium.

In a concurrent interview, Pabon expanded on the ongoing development of effective biomarker–targeted therapies in gastric/GEJ cancer.

Pabon is an assistant professor at Sylvester Cancer Center, University of Miami, and assistant lead of GI Cancer Clinical Research in the Department of Gastrointestinal Medical Oncology at the University of Miami Health Systems, in Florida.

OncLive: What is the significance of data from the TOPGEAR trial, and why was it important to clarify the role of preoperative chemoradiation in gastric cancer?

Pabon: TOPGEAR is exciting, because it helps answer a debate that's been ongoing in upper gastrointestinal [GI] cancers as to whether there is a role for preoperative or perioperative radiation. TOPGEAR was a randomized phase 3 study that looked at whether there was a benefit in adding chemoradiation to our standard of care [SOC] perioperative approach for gastric cancers.¹ This was a multicenter study, but it was predominantly conducted in Australia. Findings were presented at the 2024 ESMO Congress.

What was different [about the study] was that there was a subset of patients who were randomly assigned to also receive some chemoradiation right before they went to surgery. This has been highly debated for some time, because we see that when we add more treatment options, whether it's immunotherapies or radiation, we can cause things to regress. In other words, when we go to the operating table, we see that the cancer is smaller or that fewer lymph nodes are involved, and that translates to a pathologic complete response [pCR], or reduction of tumor burden. Usually that's quite exciting in cancer treatment. [However,] in these cancers that tend to come back very fast, we haven't really been sure if it translates automatically to a survival benefit, or if it's sort of fooling us into thinking that the cancer responded and that we're going to have a good outcome in the long run. Chemoradiation is an example of [an approach] where we see that [the disease will] regress nicely.

What did this study reveal about the safety and long-term efficacy of preoperative chemoradiation in gastric cancer?

In TOPGEAR…the data showed that the pCR [rate] almost doubled. Basically, if [we only administered] SOC treatment with chemotherapy, [followed by] surgery and then chemotherapy, only approximately 8% of patients [achieved] a pCR, where their tumor completely went away; when we added chemoradiation, approximately 16% had their tumor go away completely. That sounds amazing.

We're doubling the likelihood of that tumor going away with treatment before surgery. Nevertheless, after following these patients in the long term, investigators saw that progression-free survival and overall survival [outcomes] were not improved for patients who received chemoradiation.

[The regimen’s toxicity profile] was quite manageable. The chemoradiation was 5-fluorouracil–based, which is something that a lot of centers have experience with. [Accordingly,] there [weren’t any toxicities] substantially leading to dropout rates or treatment discontinuation. Generally, fatigue and some mild myelosuppression were noted.

How may findings from TOPGEAR and similar studies influence future therapeutic strategies in GI cancer?

It's a very important reminder that this gastric cancer acts a bit differently than other cancers, and we can't be so trusting of a pCR. We have to wait studies like TOPGEAR out to see whether [a pCR] translates to a benefit in long-term survival outcomes.

This was a good deciding factor [regarding] the necessity or [utility] of chemoradiation in this setting. It is also timely, because earlier this year, during the 2024 ASCO Annual Meeting, we had a presentation of [data from] a study looking at chemoradiation in upper esophageal cancers. We saw that radiation didn't play a role [in this setting] either. We're starting to learn that these upper GI cancers may not be as responsive to radiation as we would have hoped for. It will be good for us moving forward to refocus our interests in developing treatments, not necessarily focused on radiation but on systemic therapies instead.

What data were initially reported from the KEYNOTE-811 trial?

KEYNOTE-811 is a study that all of us are familiar with because we were introduced to it a couple years ago. It's a phase 3, placebo-controlled study evaluating first-line pembrolizumab plus chemotherapy and trastuzumab vs placebo in HER2-positive metastatic [GEJ cancers.]² Trastuzumab is the agent that's being tested here. This study was designed to see whether there was benefit [with the addition of] trastuzumab with pembrolizumab to SOC chemotherapy. We know that targeting HER2 improves outcomes in HER2-positive breast cancer, for instance. Once we started noticing that some stomach cancers also express HER2, we [thought that] there may be benefit in targeting that component. KEYNOTE-811 [went a bit father] in that they also have this immunotherapy component. [Data from this study were] presented in the past and led to the FDA approval of this treatment regimen [in 2021.]³ It was [originally] a blanket-accepted treatment for HER2-positive metastatic [gastric cancer].

How have updated survival data from KEYNOTE-811 helped clarify the long-term efficacy of this regimen within select patient subgroups?

The final OS analysis [was presented at] this year’s ESMO Congress.2 Similar to long-term outcomes in TOPGEAR, when [results from] KEYNOTE-811 were initially presented a couple years ago, we were all so excited to see good responses in a HER2-positive population. [However,] it was a test of time to see whether these good outcomes were going to be durable. This year, when they presented the OS data, we were happy to see that the [addition of] trastuzumab and pembrolizumab improves OS. However, if you split [the patient population] into 2 groups and look at the combined positive score [CPS], which is an indication of whether somebody will be responding to immunotherapy, you see what one would suspect: those who had a higher CPS did experience OS benefit [with the regimen. The other group that had a low CPS didn't really benefit as much. For this group, it's reasonable to just give them the SOC and omit pembrolizumab [based on these data].

What is important to know about the safety profile of pembrolizumab plus trastuzumab and chemotherapy in GI cancer?

These medications are ones we're comfortable with when we treat patients with other tumor types. There wasn't any surprise with the toxicity when we combined pembrolizumab and trastuzumab, though we have to be thoughtful about cardiopulmonary adverse effects [AEs]. For instance, we know that with pembrolizumab and immunotherapy there is a risk of [developing] pneumonitis, or inflammation in the lungs. With trastuzumab, there have been reported AEs of heart failure and reduced ejection fraction. Both pneumonitis and heart failure, can have similar symptoms, [including] shortness of breath or getting tired with exertion.

It's important to assess patients as a whole, follow up on echocardiograms, and image the lungs if there are any questions at all. That way, we're able to discern which of the AEs we're really witnessing when a patient comes in with some shortness of breath.

What were the objectives of the DESTINY-Gastric03 trial? How might this study inform the potential use of T-DXd in earlier lines of treatment for HER2-positive gastric cancer?

DESTINY-Gastric03 [comprises] multiple groups undergoing treatment with different doses.4 It's a phase 1b/2 trial [evaluating] patients who have unresectable, locally advanced or metastatic esophageal adenocarcinoma, as well as gastric or GEJ adenocarcinoma. These patients all have HER2-positive, treatment-naive disease and were receiving different combinations of T-DXd. T-DXd has been [FDA approved] in the second line for patients with HER2-positive metastatic disease. [However], we've seen such great outcomes with T-DXd in other tumor types like breast cancer that we are now wondering if maybe the agent deserves a place in the first-line setting or earlier on in locally advanced gastric cancer if [a patient is HER2 positive].

What efficacy results were reported from this study?

In DESTINY-Gastric03 we evaluated T-DXd in patients in the front line and at different dose levels either [alone] or combined with chemotherapy [with or without] immunotherapy, to see if there's a cumulative benefit combining these agents. Similar to KEYNOTE-811, we targeted HER2 with a HER2-specific agent but kept the SOC chemotherapy backbone, and then added some immunotherapy in several arms to see if, together, [they produce an] overall benefit in this group. There were 6 groups in DESINTY-Gastric03 all with different dose levels. Overall, all groups showed that [the addition of T-DXd] generated good overall response rates for these patients. This is a phase 1b/2 study, so it's not necessarily looking at survival outcomes. [Instead, it asks:] is this a treatment that's working? Is this something we should investigate in phase 3 trials and beyond?

What kind of safety profile can patients with gastric/GEJ cancers anticipate to come with their treatment plan?

We're seeing good responses throughout these individuals, but we're also noting that there is quite a bit of toxicity. T-DXd does have more notable AEs than trastuzumab. [A notable AE associated with] T-DXd is interstitial lung disease or pneumonitis. That's quite severe and is not neceasily reversible as some AEs that other agents produce. ILD was noted in some patients receiving T-DXd.

[Data] in the group that received T-DXd at the full dose [alongside] chemotherapy and immunotherapy, [particularly providing] a warning that although this combination can produce a good response, it may not be a safe one. At the ESMO Congress, [the study investigators] did suggest that they were exploring the same regimen at a lower dose level to see if benefit [could be generated] from treatment without as much harm in this patient population.

References

1. Leong T, Smithers BM, Michael M, et al. A randomized phase III trial of perioperative chemotherapy (periop CT) with or without preoperative chemoradiotherapy (preop CRT) for resectable gastric cancer (AGITG TOPGEAR): Final results from an intergroup trial of AGITG, TROG, EORTC and CCTG. Ann Oncol. 2024;35(suppl 2):S1249. doi:10.1016/j.annonc.2024.08.2300
2. Janjigian YY, https://www.annalsofoncology.org/article/S0923-7534(24)02985-5/fulltextKawazoe A, Bai Y, et al. Final Overall Survival for the Phase III, KEYNOTE-811 Study of Pembrolizumab plus Trastuzumab and Chemotherapy for HER2+ Advanced, Unresectable or Metastatic G/GEJ Adenocarcinoma. Ann Oncol. 2024;35(suppl 2):S877-S878. doi:10.1016/j.annonc.2024.08.1466
3. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. FDA. May 5, 2021. Accessed November 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer?utm_medium=email&utm_source=govdelivery
4. Janjigian YY, van Laarhoven HWM, Rha SY, et al. Trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2-positive (HER2+) esophageal, gastric or gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03 (DG-03). Ann Oncol. 2024;35(suppl 2):S878-S912. doi:10.1016/annonc/annonc1603