Johns Reflects on Landmark Studies for Esophageal Cancer Awareness Month

April is Esophageal Cancer Awareness Month. Esophageal cancer is one of the deadliest forms of cancer, and it caused an estimated 16,170 deaths in the United States in 2020 alone.1

Smoking, heavy alcohol consumption, and Barrett’s esophagus are all risk factors for esophageal cancer. The 2 most common types of esophageal cancer are squamous cell carcinoma and adenocarcinoma.

There have been treatment advances across both cancer types in the local, regional, and metastatic settings. Landmark studies have changed the standard of care in both frontline and later line treatment options. This is especially true when it comes to genetic mutations, which are becoming more actionable in many cases. However, challenges remain around targeting HER2 negative disease.

In an interview with Targeted Oncology, Mark E. Johns, MD, a medical oncologist with OHC, a practice in The US Oncology Network, discussed landmark esophageal cancer studies, newly approved treatments, and the future of the space.

TARGETED ONCOLOGY: What has been the evolution of treatments for locoregional esophageal cancer?

JOHNS: With locoregional disease, if you go back, we started with fluorouracil and cisplatin, concurrent with radiation therapy prior to surgery. That was established by the CALGB-9781 trial [NCT00003118].2 It had poor accrual. That having been said, the investigators were still able to show an overall survival [OS] benefit for patients who had trimodality therapy. That effectively remained the standard of care until the CROSS trial [NTR487] that was in the New England Journal of Medicine in 2012.3

The CROSS trial was a randomized, controlled trial comparing preoperative carboplatin, paclitaxel, and radiation therapy, followed by surgery versus surgery alone. That trial demonstrated an improvement in OS for patients who were treated with trimodality therapy. There was a median survival of 49.4 months versus 24 months, favoring trimodality therapy. Patients with either squamous cell carcinoma or adenocarcinoma of the esophagus appeared to benefit from trimodality therapy. That effectively has been the standard of care up until recently.

In the CROSS trial, approximately 29% of all comers had a pathologic complete remission after preoperative chemoradiation. These patients do quite well. The problem has been, what do we do with the other 71% who don't experience a pathologic complete remission? Until recently, the answer has been observation.

Into that setting comes the CheckMate 577 trial [NCT02743494], which was a global, randomized, double-blind, placebo-controlled phase 3 trial that evaluated the checkpoint inhibitor nivolumab [Opdivo] as adjunct therapy.4 In that trial, patients who had resected stage II or III esophageal or gastroesophageal junction [GEJ] cancer and had received prior chemotherapy or radiation therapy, but still had residual cancer in their pathologic specimen, were randomized to nivolumab or matched placebo. Duration of immunotherapy was 1 year. The primary end point was disease-free survival [DFS].

What the authors were able to show was that the DFS was significantly longer for patients who received adjuvant nivolumab than among those who received placebo. There was a sustained separation of DFS curves. The median DFS was 22.4 months among patients who received adjuvant nivolumab compared with 11.0 months for those who received placebo. Post hoc analysis showed that the survival benefit was observed for both adenocarcinoma and squamous cell carcinoma. It also showed DFS was observed in patients who had a combined positive score of at least 5 and in those whose tumor had a score of less than 5. There were no new safety findings. That's not yet FDA approved, but I expect that will occur sometime this year and that's going to be a new standard of care, in my opinion.

TARGETED ONCOLOGY: How has treatment changed in the metastatic setting?

JOHNS: One of the important changes for patients with gastroesophageal cancer came with the REAL-2 trial [ISRCTN51678883], which demonstrated that oxaliplatin and cisplatin were equally efficacious as were fluorouracil and capecitabine in this patient population.5 The trial didn't really improve survival, but it paved the path for a more tolerable regimen like modified FOLFOX6 [folinic acid, fluorouracil, oxaliplatin] being the backbone rather than fluorouracil and cisplatin.

More recently, in 2010, the ToGA trial was published in the Lancet.6 This study showed that for the approximately 15% of tumors that are HER2 positive treatment with trastuzumab [Herceptin] plus chemotherapy improves OS compared with treatment with chemotherapy alone. The median survival was 13.8 months versus 11.1 months. Consequently, trastuzumab plus chemotherapy has become the first line standard of care for patients with HER2-positive gastroesophageal adenocarcinoma.

After that, in 2014, ramucirumab [Cyramza] was approved as a single agent or in combination with paclitaxel for the treatment of gastric or GEJ adenocarcinoma in the second line setting.

Those have primarily been our options until recently. Then, between 2017 and 2020, we have seen the introduction of the checkpoint inhibitors to the second and later lines of therapy based on multiple studies including the KEYNOTE-059, KEYNOTE-181, and the ATTRACTION-3. But now we have the CheckMate-649 trial, and the KEYNOTE-590 trials and those will likely change our first line standard of care.

TARGETED ONCOLOGY: Can you describe the design and efficacy of those 2 trials?

JOHNS: The CheckMate-649 trial [NCT02872116] was a randomized, multicenter, open-label study of nivolumab and ipilimumab [Yervoy] or nivolumab and chemotherapy versus chemotherapy alone.7 It's not published, but it was presented at the 2020 European Society for Medical Oncology [ESMO] Annual Meeting. What was presented at ESMO was the comparison between nivolumab and chemotherapy versus chemotherapy alone. This trial enrolled patients with advanced or metastatic adenocarcinoma of the stomach, GEJ, or esophagus. There were 1581 patients randomized 1:1 between nivolumab plus FOLFOX or XELOX [capecitabine, oxaliplatin], or the same chemotherapy alone. Patients were enrolled regardless of PD-L1 expression and HER2-positive disease was excluded.

An OS advantage was demonstrated with chemoimmunotherapy versus chemotherapy alone in patients who had a combined positive score greater than or equal to 5. The median OS was 14.4 months versus 11.1 months, with a hazard ratio of 0.71, and a P value of less than .0001. A survival benefit was seen in patients with a combined positive score greater than or equal to 1 and in all randomized patients. A forest plot analysis of subgroups showed an OS benefit consistently favoring chemoimmunotherapy in all prespecified subgroups including a comparison of PD-L1 greater than or equal to 1% versus less than 1%. There were no new safety signals. Nivolumab was approved by the FDA on April 16, 2021 in combination with a fluoropyrimidine and platinum-containing chemotherapy for patients with advanced or metastatic gastric cancer, GEJ, and esophageal adenocarcinoma. This sets a new standard of care for patients with an adenocarcinoma of the esophagus or GEJ.

The KEYNOTE-590 trial [NCT03189719] was also presented at 2020 ESMO.8 This was a randomized, double-blind, placebo-controlled study of pembrolizumab [Keytruda] plus chemotherapy versus placebo plus chemotherapy in patients with previously untreated carcinoma of the esophagus or GEJ with an epicenter 1 to 5 cm above the GEJ. There were 749 patients with either a squamous cell carcinoma or adenocarcinoma were enrolled. Of those, 73% had a squamous cell carcinoma and 27% had an adenocarcinoma. Patients were randomized 1:1 between pembrolizumab and chemotherapy or placebo and chemotherapy. The cytotoxic chemotherapy consisted of fluorouracil and cisplatin and was given up for up to 6 cycles. The immunotherapy was given for up to 35 cycles.

Chemoimmunotherapy showed a statistically significant improvement in OS compared with chemotherapy alone in patients that have a squamous cell carcinoma with a combined positive score greater than or equal to 10. Median survival was 13.9 months versus 8.8 months, with a hazard ratio of 0.57 and a P value of less than .0001. A survival benefit was seen in all patients, [including those] with squamous cell carcinoma and patients with a combined positive score greater than equal to 10. A forest plot analysis of subgroups showed an OS benefit that favored pembrolizumab plus chemotherapy in all prespecified subgroups including combined positive score greater than or equal to 10 and combined positive score less than 10. There were no new safety signals. On March 22, 2021 the FDA approved pembrolizumab in combination with a platinum and fluoropyrimidine-based chemotherapy for advanced or metastatic esophageal or gastroesophageal carcinoma with an epicenter 1 to 5 cm above the GEJ. This also sets a new standard of care for the treatment of esophageal or GEJ carcinoma in the first line setting.

TARGETED ONCOLOGY: What do you think the future of care is as a result of these trials?

JOHNS: What I think will happen is that patients with an adenocarcinoma are going to be treated pursuant to the CheckMate-649 trial because that trial included only patients with adenocarcinoma. I think that patients with squamous cell carcinoma are likely to be treated pursuant to the KEYNOTE-590 trial. I don't think it would be wrong [to treat] adenocarcinoma pursuant to KEYNOTE-590. I just think that will be a path a little less traveled.

Recently, a randomized phase 2 trial of trastuzumab deruxtecan [DS-8201] called the DESTINY-Gastric01 trial was published in the New England Journal of Medicine in June 2020.9 This was a trial of trastuzumab deruxtecan versus physician’s choice of chemotherapy. The trastuzumab deruxtecan was given 6.4 mg/kg every 3 weeks. The physician’s choice of chemotherapy was either irinotecan every 2 weeks or weekly paclitaxel.

The study drug is an antibody drug conjugate. It's a HER2-directed antibody with a cleavable linker and a cytotoxic topoisomerase-1 inhibitor. One of the features of the drug is that the cytotoxic payload is membrane permeable, which allows it to enter neighboring tumor cells. We think that's important because HER2-positive gastric and gastroesophageal adenocarcinomas can have heterogeneous HER2 expression.

In that trial, 187 patients are randomized 2:1 to trastuzumab deruxtecan versus chemotherapy of the physician’s choice. The primary end point was objective response. There was a 51% objective response rate in patients treated with the antibody drug conjugate compared with 14% of those treated with chemotherapy. The P value was less than .001, and median duration of response was 11.3 months versus 3.9 months favoring trastuzumab deruxtecan. There was an improvement in OS seen as well—median OS was 12.5 months versus 8.4 months favoring the antibody drug conjugate. This represents a new treatment option in the second line setting for HER2-positive gastroesophageal adenocarcinomas, and this was FDA approved on January 15, 2021 for the treatment of patients with locally advanced, metastatic, HER2-positive gastric or GEJ adenocarcinoma.


1. Eosphageal cancer awareness month. AACR. Accessed April 29, 2021.

2. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008;26(7):1086-92. doi:10.1200/JCO.2007.12.9593

3. 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(22):2074-84. doi:10.1056/NEJMoa1112088

4. Kelly RJ, Ajani JA, Kuzdzal J, et al; CheckMate 577 Investigators. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384(13):1191-1203. doi:10.1056/NEJMoa2032125

5. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46. doi:10.1056/NEJMoa073149

6. 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-esophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-97. doi:10.1016/S0140-6736(10)61121-X

7. Moehler M, Shitara K, Garrido M, et al. LBA6_PR - Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325

8. Kato K, Shah MA, Enzinger PC, et al. LBA8_PR - Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase 3 KEYNOTE-590 study. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325

9. Shitara K, Bang YJ, Iwasa S, et al; DESTINY-Gastric01 Investigators. Trastuzumab deruxtecan in previously treated her2-positive gastric cancer. N Engl J Med. 2020;382(25):2419-2430. doi:10.1056/NEJMoa2004413