Advancements Continue to Shape the Landscape of Esophageal and Gastric Cancers

According to Ronan Kelly, MD, MBA, the esophageal and gastric cancer spaces have seen many advances over the past 2 years. Among the advances in the space, there have been numerous FDA approvals.

In April 2021, the FDA approved nivolumab (Opdivo) in combination with certain chemotherapies for the initial treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer (GEJ), and esophageal adenocarcinoma. This was based on data from the phase 3 CheckMate-649 study (NCT02872116), which showed nivolumab added to chemotherapy improved overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone. Patients given the addition of nivolumab lived on average 2.2 months longer than patients who received chemotherapy alone.

Then in May 2021, the FDA granted approval to adjuvant nivolumab for patients with completely resected esophageal or GEJ cancer with residual pathologic disease. The agent was approved based on data from the phase 3 CheckMate-577 trial (NCT02743494), which showed a statistically significant disease-free survival benefit with nivolumab vs placebo.¹

Most recently in May 2022, the combination of nivolumab and fluoropyrimidine- and platinum-containing chemotherapy and nivolumab plus ipilimumab (Yervoy) was granted approval by the FDA for first-line treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma, regardless of PD-L1 status based on the phase 3 CheckMate-648 study (NCT03143153).

Other approvals have also paved the way in this space, including the phase 3 KEYNOTE-590 trial (NCT03189719) which led to the approval of pembrolizumab (Keytruda) in combination with platinum and fluoropyrimidine-based chemotherapy for the treatment of patients with metastatic or locally advanced esophageal or GEJ carcinoma who are not eligible for surgical resection or definitive chemoradiation and the phase 3 KEYNOTE-811 trial (NCT03615326) which served as the basis for the FDA approval of pembrolizumab plus trastuzumab (Herceptin), fluoropyrimidine-and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma.^2,3

“We have improved treatment options for gastric and esophageal cancer. Although they are difficult tumor types to treat given their nature and their impact, there have been big steps forward. We should be treating our patients in the first-, second-, and even third-line setting in the metastatic setting because patients are deriving benefits from some of these treatments,” stated Ronan Kelly, MD, MBA, in an interview with Targeted Oncology^TM.

In the interview, Kelly, director of the Charles A. Sammons Cancer Center Baylor University Medical Center, chief of oncology at Baylor Scott & White Health System, clinical professor at Texas A&M University College of Medicine, adjunct associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center Johns Hopkins, and professor of the clinical sciences division at the Translational Genomics Research Institute further discussed the most recent updates seen in these patient populations and what research aims to further examine.

Targeted Oncology: Can you discuss the current management strategies for esophageal and gastric cancers?

Kelly: In the last 2 or 3 years, we've seen numerous FDA approvals in the metastatic setting that have changed the treatment landscape for the management of esophageal squamous cell carcinoma but also esophageal adenocarcinoma, GEJ junction, and gastric cancers. If we look at the trials that have received FDA approval and changed the landscape, the first would be CheckMate-649 which was a combination study looking at nivolumab plus chemotherapy. This was a landmark study because for the first time the investigators were able to demonstrate median overall survival for all comers of more than 1 year. That 1-year overall survival ceiling in a non HER2 positive patient population has proven difficult to break through over the last few decades...In this particular study, the median overall survival for all randomized patients was 13.8 months vs 11.6 months, so that was an exciting advance.

Then we saw a similar study in KEYNOTE-590, which investigated the efficacy of pembrolizumab plus chemotherapy. This didn't include gastric cancer. The study population in KeyNote 590 included esophageal squamous cell carcinoma, esophageal adenocarcinoma, andthe first part of the GEJ junction Siewert 1 tumors. CheckMate-649 on the other hand included no squamous cell esophageal cancers, butdenocarcinomas across those 3 anatomical regions of the esophagus to the entire GEJ junction and the stomach. KEYNOTE-590 also was a positive phase 3 trial with median overall survival for all randomized patients of 12.4 months vs 9.8 months. Those 2 studies came out around the same time and they changed the standardof care for how we treat patients in the first line metastatic setting.

A little bit after that, we saw KEYNOTE-811, which was a trial in the HER2-positive population, where historically we've given chemotherapy plus trastuzumab. We haven't seen any advances over 10 years in that space, but KEYNOTE-811 asked the question, could we add pembrolizumab to a chemotherapy plus trastuzumab backbone? We have seen so far, and this received FDA approval, an overall response rate of74%-75% in that group vs 51%-52%. We are waiting on more data to be published, but I think this trial is widely regarded as another practice changing trial in those patients.

CheckMate 649, KEYNOTE-590 and KEYNOTE-811 have completely changed the first-line metastatic setting for esophageal adenocarcinoma, GEJ junction, gastric cancer, and in a HER2-positive population. There were some questions about the optimal management of esophageal squamous cell carcinoma. KEYNOTE-590 did include some esophageal squamous cell carcinomas, but then this year, we saw the publication of the CheckMate-648 study [NCT03143153], which was in a purely squamous cell population. Patients were randomized to eithernivolumab plus chemotherapy, chemotherapy [alone] or a chemotherapy-free option of nivolumab plus ipilimumab. Ag,ain the data was very compelling and we saw that both of the IO options were better than chemotherapy alone. I think CheckMate-648 has been a practice changing study

Can you discuss the role of immune-based approaches in this space?

This is the new standard of care for patients in terms of whether they should be getting immunotherapy or not. There's not that many patients that would be excluded. In fact, the FDA did give, broad approval across all patients regardless of PD-L1 expression. They did that in KEYNOTE-590, CheckMate-649, and KEYNOTE-811. However, the European authorities and the NCCN have commented on the fact that patients should have a PD-L1 CPS greater than 5.

What patient cohorts do you believe may gain the most benefit from these immune-based approaches?

PD-L1 is our main predictive biomarker at the moment. We've seen time and time again that those patients’ tumors with a high PD-L1 combined positive score have a better response. When a tumor or its immune microenvironment is documented as being PD-L1-negative or CPS low, the efficacy of the PD-1/PD-L1 inhibitors doesn't seem to be as impressive. In 2022, the main predictive biomarker we have is PD-L1 expression and CPS is better than TPS.

We also know that microsatellite instability [MSI-H] and mismatch repair deficiency [dMMR] can indicate whether a person will have a good response to the immune checkpoint inhibitors.We do have some data on the predictive nature of tumor mutation burden high and tumors that are Epstein Barr Virus positive, but they're not as strong and we don't have as much data as we do in the PD-L1 CPS and the MSI-H or dMMR subgroups.

Can you discuss the advances which have been seen in the operable setting?

If you look at the adjuvant space, we have a study called CheckMate-577, which resulted in a doubling in the median disease-free survival in patients in the post-operative setting. The primary end point was disease free survival. Who would have thought that esophageal cancer would be the second tumor type that received FDA approval for the use of an adjuvant PD-1 inhibitor after melanoma? That was amazing to see. Since then, we've seen numerous other tumor types receive adjuvant checkpoint inhibitor approvals.

CheckMate-577 showed a doubling in the median disease-free survival from 22.4 months to 11 months. We're also looking at other trial designs investigating the efficacy of giving immune checkpoint inhibitors in early-stage gastric cancer. One of those was the NEONIPIGA study [NCT04006262] which was recently published. That raised the question of what is the impact of giving perioperative nivolumab plus ipilimumab before surgery in patients with documented mismatch repair deficiency or microsatellite instability, high tumors?

What we saw was an amazing response with approximately 59% of the patients having a pathologic complete response, which we haven't really seen before. Now we're seeing even more impressive results in a similar patient population but in other GI tumors such as in rectal cancer and colon cancer.

What are the takeaways for your research in this space?

We're moving the immune checkpoint inhibitors from the metastatic setting into early-stage operable tumors. We're beginning to see very exciting results, like with CheckMate-577 and the NEONPIGA study. We are waiting on a number of other studies to see if they can continue to change the treatment landscape. It is very exciting that the immune checkpoint inhibitors are now not just being used in the metastatic setting. It looks like they're going to have a firm role in the operable stage II and III setting to prevent disease from occurring, and hopefully improving overall survival. But we have to wait an additional few years to see that data.

What unmet needs still exist in this space?

Hopefully this is just the start. We are not where we need to be which is to be able to cure everyone with these diseases. A lot more work needs to happen and we need to understand a lot more about the immune microenvironment. We need to understand why some patients have good responses while others don't. We need to move beyond just PD-L1 expression as a predictive biomarker. We need to understand what other signatures are available. I think that's where the next couple of years needs to go.

Can we identify patients who will have a response based on personalized IO combination strategies? I think the basket studies where we look at different combinations maybe haven't been as successful as we would have hoped for with different immunotherapy strategies. However, I think if we can personalize care and understand how we may engage the patient's immune system, I think we'll be in a better spot. We also need to utilize newer technologies such as minimal residual disease detection post operatively and throughout a patients journey with cancer to understand how we may be able to maximize the benefits of the treatments we can prescribe.

We're also looking at some of the emerging breakthroughs with cellular therapeutics. Certainly, the chimeric antigen receptor T program targeting Claudin 18.2 and others are looking exciting. What we need to figure out there is how do we maintain that T-cell response so that it's not short lived, but a durable T-cell response over many years. I think the future looks bright, but I think a lot more understanding of the immune microenvironment and tailoring the correct treatment strategies to the correct patients, rather than a 1 size fits all approach, is where we need to get to.

What advice would you give to community oncologists who want to learn and more about this space?

Community oncologists may not see that many gastric and esophageal cancers. The good news is that many advances are happening in esophagogastric tumors after years of minor incremental benefits. It's not a huge amount of additional learning as our community oncology colleagues are already very familiar with administering PD-1 inhibitors with chemotherapy for other tumor types.

REFERENCES:

1. FDA approves nivolumab for resected esophageal or GEJ cancer. News release. FDA. May 21, 2021. Accessed October 7, 2022. https://bit.ly/3EqyQgs

2. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759-771. doi: 10.1016/S0140-6736(21)01234-4

3. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. FDA. May 5, 2021. Accessed October 7, 2022. https://bit.ly/3RMpb6W