ESOPEC & TRANSMET Trials Show Promise Across GI Cancers

Mark A. Lewis, MD

In oncology research, 2 studies—ESOPEC (NCT02509286) and TRANSMET (NCT02597348)—have offered significant insights into the treatment of esophageal adenocarcinoma and colorectal liver metastases.^1,2

The ESOPEC trial was a phase 3 study aimed at comparing 2 treatment regimens for esophageal adenocarcinoma: perioperative chemotherapy with 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel (FLOT) vs the established chemoradiation regimen of paclitaxel and carboplatin (CROSS).¹ FLOT, already the standard of care (SOC) for gastric cancer, was tested to see if it could provide similar benefits in esophageal cancer.

The trial’s results showed that FLOT demonstrated superior overall survival and progression-free survival vs the CROSS regimen. Despite these promising findings, experts have concerns surrounding the tolerability of FLOT. While the trial showed that 90% of patients completed the FLOT regimen, only 60% to 65% of patients completed the CROSS regimen. However, the lower completion rate in the CROSS group may reflect the challenges of radiation, according to Mark A. Lewis, MD.

“I do think FLOT is likely superior if patients can tolerate it, but I am not convinced it is necessarily more tolerable than CROSS. It is a study of its time, and it certainly advances the field, but we need to be cautious in interpreting the results,” explained Lewis, in an interview with Targeted Oncology^TM.

The TRANSMET trial (NCT02597348) was a multinational study involving a strict patient selection of those with chemotherapy-induced disease control and no BRAF mutations.2 Patients who met the selection criteria received priority on the transplant list and were transplanted within 2 months after completing chemotherapy.

Results showed there was a 5-year survival rate of 57% in the transplant group, compared with 13% for those who continued chemotherapy alone. While the results are impressive, Lewis, director of gastrointestinal oncology at Intermountain Health, explained that the success of this approach depends heavily on careful patient selection, making it unlikely to become a widespread SOC at this time.

“While this is eye-opening and definitely proof of principle, I do not think we are ready to adopt this approach in the US. The selection process is incredibly critical, and the outcome depends on it,” added Lewis.

In the interview, Lewis further discussed the promise of the ESOPEC and TRANSMET trials and the need for their further investigation.

Targeted Oncology: Can you just discuss the background of the ESOPEC trial?

Lewis: The ESOPEC trial was a study we have been eagerly awaiting for a while. However, I had some initial questions about its design and schema, which I’ll share in a bit. It is difficult to predict how the standard of care will evolve while the trial is still maturing. Let me provide some background first, and then I’ll give my critique.

This was a phase 3 study that sought to answer a key question: For esophageal adenocarcinoma, should we be using perioperative triplet chemotherapy with FLOT (which is arguably now the standard of care in true gastric cancer) for esophageal cancer as well, or should we continue with the CROSS paradigm, which is chemoradiation? From a medical oncology perspective, CROSS might seem more tolerable because the chemotherapy there primarily serves as a sensitizer—using carboplatin and paclitaxel at relatively modest doses. When CROSS was first published, I was finishing my fellowship, and I remember my mentors telling me that it was a huge leap forward. What was interesting about the original CROSS trial was that it included squamous cell carcinoma, which is more radiosensitive.

What did the ESOPEC trial aim to assess?

So, ESOPEC was asking a couple of questions: First, is perioperative chemotherapy with FLOT better than chemoradiation? Second, does chemoradiation provide the same benefits in a population with adenocarcinoma alone? There’s also the background of the Neo-AEGIS study [NCT01726452], which aimed to compare the CROSS regimen to another form of perioperative chemotherapy. However, during the trial, the chemotherapy paradigm shifted away from epirubicin-based triplets to FLOT, so most patients in that study were on epirubicin-based regimens, which are no longer commonly used today.

Regarding ESOPEC, [on the surface], the results seem like a major success for FLOT, showing superior overall survival and progression-free survival as the primary end points. However, I had some concerns about patient tolerance. My initial bias was that I expected CROSS to be at least as tolerable, if not more, than FLOT, but ESOPEC showed that over 90% of patients completed preoperative FLOT, whereas only about 60% to 65% of CROSS patients completed chemoradiation. This surprised me. [Upon further clarification] from the investigators, they explained that with FLOT, there is more flexibility in dose modification or delays, whereas with radiation, the treatment schedule is fixed. So, if patients on the CROSS arm missed even 1 dose of chemotherapy due to cytopenias, that counted as incomplete treatment. This made me question whether the completion rates were truly balanced.

Additionally, with perioperative FLOT, only half of patients heal enough for surgery after completing the preoperative therapy, so most of the benefit happens upfront. Another consideration is the era of adjuvant immunotherapy. [Karyn A. Goodman, MD, MS, FASCO], a radiation oncologist, pointed out that there could be a synergy between preoperative radiation and adjuvant nivolumab after surgery, as seen in the CheckMate 577 trial [NCT02743494]. I thought that was a very insightful observation.

Ultimately, I do not think we can conclude that FLOT is the new standard for everyone just based on ESOPEC. I do think FLOT is likely superior if patients can tolerate it, but I am not convinced it is necessarily more tolerable than CROSS. It is a study of its time, and it certainly advances the field, but we need to be cautious in interpreting the results.

Do you see any potential for further tailoring therapy based on patient characteristics or tumor biology?

Dr. Goodman has long advocated for PET-informed treatment decisions, and I think she raised a valid point regarding the potential for tailoring therapy. For some patients, induction chemotherapy followed by a PET scan might help determine whether to switch to chemo-radiation or proceed directly to surgery. After surgery, patients could even receive adjuvant therapy. This approach would involve multiple treatment phases—induction, PET reassessment, chemoradiation, surgery, and possibly immunotherapy—which is a lot, but for a disease with high morbidity and mortality, it may be necessary.

I think there is a strong potential for biomarker-driven treatment in upper GI cancers. Many of our successes in oncology now come from refining treatments based on biomarkers, and we’re seeing that with rectal cancer as well. However, the ESOPEC study is interesting because it was not biomarker-driven, which is somewhat unusual for current oncology trials. While ESOPEC is not as focused on biomarkers, it still represents a significant step forward for the field.

How does TRANSMET compare to that trial?

TRANSMET is another fascinating study, and it is the kind of trial that could only be done in Europe. This multinational collaboration between France, Germany, and Italy asked whether there’s a role for liver transplant in patients with unresectable colorectal liver metastasis. The study focused heavily on patient selection—each case was reviewed by a tumor board, and they rejected about 40% of the patients, despite strict inclusion criteria.

The selected patients were given priority on the transplant list and received their new liver within about 2 months after their final chemotherapy. The results were remarkable: The 5-year survival rate in the transplant group was 57%, compared with just 13% for those who continued chemotherapy alone. While this is eye-opening and definitely proof of principle, I do not think we are ready to adopt this approach in the US. The selection process is incredibly critical, and the outcome depends on it.

What are the most promising future directions for research in this patient population?

One area that hasn’t been discussed much yet is circulating tumor DNA [ctDNA]. This could play an important role in managing these patients. For instance, in rectal cancer, patients with positive ctDNA after definitive treatment tend to have worse outcomes. This makes sense biologically, as the rectum has unique blood flow patterns, and those with positive ctDNA may be at higher risk for lung metastasis.

With respect to transplant, it would be interesting to explore ctDNA in these patients as well. If a patient clears ctDNA after chemotherapy, it could indicate they are a better candidate for liver transplant. The idea would be to prioritize transplants for patients who have cleared ctDNA or remain negative for it throughout treatment. While this was not part of the TRANSMET trial, ctDNA could be a useful tool to further refine who benefits most from transplant and who might be at risk for recurrence.

In summary, the integration of ctDNA into these treatment paradigms could help identify patients who are more likely to benefit from therapies and help guide decision-making in cases like transplant, where patient selection is critical.

REFERENCES:

1. Hoeppner J, Lordick F, Brunner T, et al. ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286). BMC Cancer. 2016;16:503. Published 2016 Jul 19. doi:10.1186/s12885-016-2564-y

2. Chemotherapy and liver transplantation versus chemotherapy alone in patients with definitively unresectable colorectal liver metastases: A prospective multicentric randomized trial (TRANSMET). J Clin Oncol.2024;42:3500. Published 2024 May 29. doi:10.1200/JCO.2024.42.16_suppl.3500