Current Treatment of Esophageal Cancer and Promising Clinical Trials Underway

Oncology (Williston Park). 33(3):110-2.

Geoffrey Y. Ku, MD

The treatment of squamous esophageal tumors has not changed much over the last 30 to 40 years and consists primarily of chemotherapy. However, newer options such as targeted therapy, anti–vascular endothelial growth factor (VEGF) receptor antibodies, and immunotherapy may have the potential to alter the standard of care. To discuss current and emerging therapy options for esophageal cancer, ONCOLOGY spoke with Geoffrey Y. Ku, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, who specializes in the treatment of malignancies of the gastrointestinal tract, including esophageal tumors.

Q:First, what are the mainstay adjuvant and neoadjuvant therapy options for patients diagnosed with esophageal cancers?

DR. KU: When it comes to esophageal cancers, there are two things to think about. The first is the location of the tumor, and the second is the histology of the cancer. The National Comprehensive Cancer Network (NCCN) guidelines and Memorial Sloan Kettering’s internal guidelines both split the esophagus and the stomach at the gastroesophageal junction. Therefore, we use the Siewert classification system to describe tumors. A Siewert type I tumor is a lower esophageal tumor extending into the gastroesophageal junction; a type II tumor is a true tumor at the gastroesophageal junction; and a type III tumor is a proximal gastric cancer extending upwards to the gastroesophageal junction.

For the purposes of treatment planning in the localized setting, we consider Siewert type I and type II tumors to be esophageal tumors, and type III tumors and beyond to be gastric tumors. This is the first thing to bear in mind. The second is that there are two histologies in the esophagus. In the United States, by far the more common is adenocarcinoma, but we also see squamous cell carcinoma about 25% of the time. Given the overall rarity of esophageal cancers, this means that squamous esophageal carcinoma is extremely uncommon; its incidence is only about 4,000 to 5,000 patients annually.

With regard to adjuvant and neoadjuvant treatment of esophageal and gastroesophageal adenocarcinomas, we very much continue to administer preoperative chemoradiation. In general, treatment is given preoperatively. It is usually very difficult to give adjuvant treatment, but particularly so after an esophagectomy. The standard of care for esophageal adenocarcinoma remains preoperative chemoradiation. We typically consider surgery to be part of therapy because complete response rates with chemoradiation alone are quite low, between 20% and 25%. For esophageal squamous cell cancer, we consider standard therapy to be definitive chemoradiation with observation. This is due in part to its much higher pathologic complete response rate. The CROSS trial, conducted in the Netherlands, reported a pathologic response rate of almost 50% for patients with squamous cell cancer of the esophagus who received chemoradiation.[1]

In general, most patients who develop squamous cell cancers have comorbidities, since this is a cancer related to smoking and drinking. Many have cardiopulmonary conditions and generally are not good candidates for surgery. Therefore, if we achieve a complete response clinically with chemoradiation, we typically observe these patients without operating.

A potential alternative for adenocarcinoma tumors at the gastroesophageal junction is perioperative chemotherapy. Studies of perioperative chemotherapy for gastric cancer, such as the MAGIC[2] and FLOT4[3] studies, have also included patients with gastroesophageal junction cancers. We still prefer to give chemoradiation to these individuals. This is mainly because, when the tumor is involving the esophagus and the gastroesophageal junction, a complete or R0 resection is achieved only about 70% of the time. The R0 resection rate is up to 90% with chemoradiation. However, in select patients, perioperative chemotherapy for gastroesophageal junction adenocarcinoma can also be considered, but such a decision should be made following a multidisciplinary review.

Q:What therapy options are available for patients with advanced esophageal tumors?

DR. KU: Again, treatment differs for adenocarcinomas vs squamous cell carcinomas. With the exception of the KEYNOTE-181 study (which I will discuss shortly), treatment of squamous esophageal tumors has not really changed over the last 30 to 40 years and primarily consists of chemotherapy. The same chemotherapy drugs are active in both histologies: fluoropyrimidine, platinum agents, taxanes, and irinotecan. The normal sequence, throughout much of the world, is to consider a fluoropyrimidine/platinum doublet in the first-line setting; in the United States, the most widely used regimen is FOLFOX
(folinic acid, fluorouracil, and oxaliplatin). We use this to treat patients with both adenocarcinoma and squamous cell cancer. In the second- or third-line setting, we would consider either a taxane or irinotecan.

For adenocarcinomas, several targeted therapies have been approved by the US Food and Drug Administration (FDA). In 2010, based on the results of the Trastuzumab for Gastric Cancer (ToGA) study,[4] trastuzumab was approved as the first targeted therapy for use in gastroesophageal and gastric cancer. Trastuzumab is used to treat tumors that are human epidermal growth factor receptor 2 (HER2)-positive (about 20% to 25% of tumors). The HER2 positivity rate is even higher in distal esophageal and gastroesophageal junction adenocarcinomas than it is in gastric cancer. So, trastuzumab in combination with FOLFOX is the standard of care for all HER2-positive esophageal or gastric adenocarcinomas.

More recently, in 2014, the anti-VEGF receptor antibody ramucirumab was approved in combination with paclitaxel in the second-line setting. Again, the approval was based on a gastric cancer study that also included patients with gastroesophageal junction adenocarcinomas. Since we now know that adenocarcinomas of the distal esophagus, gastroesophageal junction, and proximal stomach are molecularly the same based on the results of The Cancer Genome Atlas analysis,[5] we extrapolate that same data to distal esophageal adenocarcinomas as well.

Immunotherapy may now also be an option for the treatment of squamous cell esophageal carcinomas. The recent phase III KEYNOTE-181 study,[6] presented at the 2019 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, evaluated the anti–programmed death 1 (PD-1) antibody pembrolizumab. Specifically, researchers studied pembrolizumab vs paclitaxel in the second-line setting for both esophageal adenocarcinomas and squamous cell carcinomas. Patients, particularly those with squamous cell carcinoma, appeared to benefit more from pembrolizumab than from paclitaxel. However, the survival benefits did not meet statistical significance, and that in large part is because of the statistical plan for the study, which comprised three co-primary endpoints. The takeaway point is that pembrolizumab appears to be effective for an unselected population of patients with esophageal squamous cell carcinoma, irrespective of programmed death ligand 1 (PD-L1) status. It remains to be seen whether this agent will ultimately receive FDA approval, or perhaps an NCCN compendium listing, which will allow us to obtain it as a standard-of-care option.

Q:Last year, pembrolizumab also received accelerated FDA approval for patients with gastric and gastroesophageal junction adenocarcinoma. Which patients are most likely to benefit from this therapy?

DR. KU: That particular approval first opened the door to immunotherapy in esophagogastric cancer. In September 2017, the FDA approved pembrolizumab based on the results of the KEYNOTE-059 trial. This single-arm study evaluated almost 260 patients who received pembrolizumab as third-line or greater therapy. In patients with PD-L1–positive tumors, there did appear to be modest benefits; specifically, the response rate in this treatment-refractory patient population was about 12%. There was also durable survival: the 12-month survival rate was approximately 25% in a treatment-refractory population.[7]

I would add that, again, the FDA approval of pembrolizumab is contingent on the tumor cells being PD-L1–positive. This is determined using a specific assay with the 22C3 antibody. PD-L1 positivity is defined as a combined positive score of at least 1, which indicates that there is some staining in either the tumor cells or the peritumoral mononuclear cells. As noted earlier, the KEYNOTE-181 study is one that looked at pembrolizumab as a second-line treatment for esophageal squamous cell cancer.[6] There are now other trials that are studying anti–PD-1 antibodies in the first-line setting.

Q: Are there any other esophageal cancer clinical trials underway that could be practice-changing in the short term?

DR. KU: As I touched on earlier, the KEYNOTE-181 trial, which was just presented, may have implications for treatment in the second-line setting for esophageal squamous cell cancer.[6] The results of another second-line study, KEYNOTE-061, were also reported last year. This was a randomized study of pembrolizumab vs paclitaxel in patients with gastroesophageal junction and gastric adenocarcinomas. Although it was a negative study overall, researchers did find that patients whose tumors have higher PD-L1 positivity (a combined positive score of ≥10), derived more benefit from pembrolizumab vs paclitaxel chemotherapy.[8]

Of course, the study results that I think we are all waiting for are those of KEYNOTE-062, and they may be reported as soon as the 2019 ASCO Annual Meeting in June. The KEYNOTE-062 study is a first-line study with three arms: standard 5-FU/cisplatin chemotherapy, pembrolizumab alone, and pembrolizumab plus 5-FU/cisplatin.[9] The hope is that combination immunotherapy and chemotherapy will be more effective than chemotherapy alone, and we did get a hint of that based on results from an arm of the KEYNOTE-059 trial.[7] Specifically, a small cohort of 25 patients received first-line therapy with a combination of pembrolizumab and 5-FU/cisplatin; although the arm was very small, the outcomes seemed to be slightly improved with the addition of pembrolizumab compared with chemotherapy alone, particularly among patients with PD-L1–positive tumors.[9]

KEYNOTE-062 completed accrual about 2 years ago, so the results will hopefully mature soon. It would certainly be practice-changing if it is a positive study, as it would move pembrolizumab and immunotherapy all the way up from the third-line setting to the first-line setting. If that’s the case, it would represent a significant improvement over everything that’s come before.

Financial Disclosure:Dr. Ku provides research support to Arog, AstraZeneca, Bristol-Myers Squibb, Merck, Pieris, and Zymeworks. He is also a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, and Pieris.

References:

1. van Hagen P, Hulshof MC, van Lanschot JJ, et al; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074-84.

2. Cunningham D, Allum WH, Stenning SP, et al; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11-20.

3. Al-Batran SE, Homann N, Schmalenberg H, et al. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. J Clin Oncol. 2017;15(suppl):abstr 4004.

4. Bang YJ, Van Cutsem E, Feyereislova A, et al; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-97.

5. Cancer Genome Atlas Research Network, Analysis Working Group: Asan University, BC Cancer Agency, et al. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017;541:169-75.

6. Doi T, Bennouna J, Shen L, et al. KEYNOTE-181: Phase 3, open-label study of second-line pembrolizumab vs single-agent chemotherapy in patients with advanced/metastatic esophageal adenocarcinoma. J Clin Oncol. 2017;34:suppl 15:abstr TPS4140.

7. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018 May 10. [Epub ahead of print]

8. Shitara K, Ozguroglu M, Bang YJ, et al; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018;392:123-33.

9. Tabernero J, Bang YJ, Fuchs CS, et al. KEYNOTE-062: Phase III study of pembrolizumab (MK-3475) alone or in combination with chemotherapy versus chemotherapy alone as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol. 2017;34:suppl 4:abstr TPS185.