Recent Advances in Esophageal Cancers Go Beyond a One-Size-Fits-All Approach


Nitika Sharma, MD, explores developments in the esophageal cancer landscape for Esophageal Cancer Awareness Month.

Nitika Sharma, MD

Nitika Sharma, MD

Nitika Sharma, MD, is a board-certified and fellowship-trained medical oncologist and hematologist at Cancer Treatment Centers of America, Atlanta.

April is Esophageal Cancer Awareness Month. In the United States, esophageal cancer makes up about 1% of all cancers and it is estimated that about 20,640 new people with esophageal cancer will be diagnosed in 2022. The lifetime risk of esophageal cancer in the United States is about 1 in 125 in men and about 1 in 417 in women. This disease is the sixth most common cause of cancer-related deaths and the eighth most common cancer worldwide with a 5-year survival rate of less than 20%. The 2 most common types of esophageal cancer types are squamous cell carcinoma and adenocarcinoma. The histology can vary by region, for example high rates of esophageal adenocarcinoma are predominately seen in North America compared with squamous cell carcinoma, which is predominantly seen in Asia, Europe, and Africa.1

A better understanding of the disease biology, identification of actionable genetic alterations and use of immunotherapy is heralding an era of precision therapy for treatment of esophageal cancers. There have been significant advances in the treatment landscape for upper gastrointestinal cancers in the past year, with novel approaches available for patients with resectable disease and numerous targeted therapies now approved for advanced disease.

Gastroesophageal (GE) cancers should be tested for HER2 amplification, microsatellite instability (MSI), PD-L1, tumor mutational burden (TMB), and NTRK fusion as these biomarkers can inform use of immune checkpoint inhibitor combinations, targeted agents as well as sequence of therapies. The use of upfront comprehensive next-generation sequencing on tumor tissue is recommended; it is not only associated with shorter time to test results, shorter time to treatment, but is also cost effective and eliminates the risk of missing rare but important oncogenes such as an NTRK fusion.2

Developments for Resectable Esophageal Cancer Treatment

Locally advanced esophageal and gastroesophageal junction (GEJ) cancers are aggressive tumor types that often require multiple approaches to address the disease, including neoadjuvant chemoradiotherapy and surgery. Even after trimodality therapy, there may be a high risk of recurrence for patients who do not achieve a pathologic complete response. There is paucity of data regarding adjuvant treatment options in patients with residual disease post surgery.

The FDA recently approved the use of adjuvant nivolumab (Opdivo) for patients with stage II/III esophageal/GEJ cancer with residual pathologic disease after trimodality treatment regardless of PD-L1 status or histology, based on CheckMate 577 trial (NCT02743494). This study showed a significant improvement in median disease-free survival (DFS) with the use of adjuvant nivolumab vs placebo (22.4 vs 11 months; HR, 0.69; P < .001).3,4

Overexpression and/or amplification of HER2 occurs in 15% to 20% of GE cancers. Since the approval of trastuzumab in advanced metastatic GE cancer, the role of trastuzumab in resectable esophageal cancer has been debated in the absence of phase 3 randomized trial. RTOG-1010 (NCT01196390) is an open-label, randomized phase 3 trial that evaluated the combination trastuzumab with trimodality treatment (chemoradiation followed by surgery) in resectable HER2-positive esophageal adenocarcinoma. Median DFS was 19.6 months with trastuzumab combined with chemoradiotherapy vs 14.2 months for chemoradiotherapy alone (HR, 0.99, P = .97). The addition of trastuzumab to neoadjuvant chemoradiotherapy for HER2-overexpressing esophageal cancer was not effective in improving survival outcomes in this context. There is no role of addition of trastuzumab in resectable HER2-positive GE cancer.5

Enhancements in Treating Metastatic and Advanced Disease

The treatment landscape has evolved in metastatic or advanced unresectable GE cancers. PD-L1 is emerging as a predictive marker for the use of immunotherapy in GE cancer. The combined positive score (CPS) is a measure of PD-L1 positive cells in the tumor microenvironment. It is calculated as percentage of the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells.

CheckMate 649 (NCT02872116) is a randomized phase 3 trial of nivolumab in combination with chemotherapy for patients with previously untreated, unresectable, advanced, or metastatic GE adenocarcinoma in first-line setting. The patients were randomly assigned to nivolumab plus chemotherapy or chemotherapy alone. The chemotherapy regimen was FOLFOX (folinic acid, fluorouracil, oxaliplatin) or XELOX (capecitabine, oxaliplatin). When stratified according to PD-L1 overexpression, benefits were significant in the subset of patients with CPS greater than or equal to 5 (12-month overall survival [OS] rate, 57% vs 46%; median OS, 14.4 vs 11.1 months; HR, 0.71), and CPS greater than or equal to 1 (12-month survival, 56% vs 47%; median OS; 14 vs 11.3 months, HR, 0.77). However, there was no OS benefit for patients with CPS less than 1 (median OS, 13.1 vs 12.5 months; HR, 0.92) or CPS less than 5 (median OS, 12.4 vs 12.3 months; HR, 0.94). Interaction analysis of OS by PD-L1 CPS cutoffs showed significant interaction by PD-L1 CPS at the cutoff value of CPS 5 (P = .011), but not at the cutoff value of CPS of 1. Although nivolumab is FDA approved irrespective of PD-L1 CPS score, the benefit remains uncertain for patients with low PD-L1 CPS less than 5 unless they are mismatch repair deficient.6

KEYNOTE-590 (NCT03189719) is a randomized phase 3 trial of first line pembrolizumab (Keytruda) in combination with chemotherapy vs chemotherapy alone for previously untreated locally advanced unresectable or metastatic esophageal/GEJ cancer. Patients were randomly assigned to pembrolizumab or placebo, plus 5-fluorouracil and cisplatin. Results indicated that pembrolizumab plus chemotherapy led to a statistically significant improvement in OS (median OS, 12.4 months vs 9.8 months; HR, 0.73; P < .0001). In patients who had a PD-L1 CPS greater than or equal to 10, the median OS with the pembrolizumab regimen was 13.5 months vs 9.4 months with chemotherapy alone (HR, 0.63; P < .0001).7

Additional data presented during the 2020 European Society for Medical Oncology Virtual Congress showed that the objective response rate (ORR) was 45.0% with pembrolizumab/chemotherapy vs 29.3% with chemotherapy alone (P < .0001). In esophageal squamous cell carcinoma (SCC) and PD-L1 CPS greater than or equal to 10, median OS 13.9 months vs8.8 months; hazard ratio 0.57 was noted. Although patients with adenocarcinoma were included in the KEYNOTE-590 trial, the benefits of combined immunotherapy plus chemotherapy were predominantly driven by the subgroup with SCC.

KEYNOTE-062 (NCT02494583) was a phase 3 randomized, controlled trial of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone in first line in patients with locally advanced/unresectable or metastatic GE cancer with positive CPS greater than or equal to 1.Subset analysis in patients with mismatch repair deficient (dMMR)/MSI-high (MSI-H) tumors and CPS greater than or equal to 1 demonstrated significant benefit with pembrolizumab plus chemotherapy compared with chemotherapy (median OS, not reached vs 8.5 months; 24-month OS rate, 65% vs 26%; ORR, 65% vs 37%). Furthermore, pembrolizumab monotherapy compared with chemotherapy was also associated with a higher ORR (57% vs 37%), longer duration of response (21.2 vs 7 months), and longer OS (median, not reached vs 8.5 months).8

Pembrolizumab monotherapy and combination pembrolizumab with chemotherapy are both acceptable alternatives for first-line therapy for patients with PD-L1 overexpressing and dMMR/MSI-H esophagogastric adenocarcinomas. The prevalence of MSI-H signature in esophagogastric cancers is estimated to be between 7% to 15%. In May 2017, based on KEYNOTE-158 (NCT02628067), the FDA approved pembrolizumab as tissue agnostic indication for advanced solid tumors, including gastric cancers, that had MSI-H and had progressed following prior treatment.9

Trastuzumab-Based Therapy for Advanced GE Cancer

In HER2-positive advanced GE cancers, first-line treatment with trastuzumab and chemotherapy has remained the standard of care for last decade based on phase 3 ToGA (Trastuzumab for Gastric Cancer) trial (NCT01041404), in which OS was significantly longer with chemotherapy plus trastuzumab than with chemotherapy alone (median OS, 13.8 months vs. 11.1 months; HR, 0.74).

KEYNOTE-811 (NCT03615326) is a randomized, double-blind, placebo-controlled phase 3 study evaluating the use of first-line pembrolizumab in combination with trastuzumab and chemotherapy as compared with placebo, trastuzumab, and chemotherapy in metastatic HER2-positive gastric/GEJ adenocarcinoma. An interim analysis showed ORR of 74% with addition of pembrolizumab vs 52% with placebo. The final response rates were improved and more durable with ORR difference of 22.7% (P = .00006). The progression-free survival and OS results are pending. This led to an accelerated approval by the FDA based on tumor response rate and durability of response.10

The use of trastuzumab leads to an inevitable development of resistance to this drug. Several treatment strategies with anti-HER2 drugs have failed to show clinical benefit in advanced GE cancers. Regardless of HER2 expression, paclitaxel plus ramucirumab (Cyramza), an anti–VEGFR-2 antibody, is recommended as second-line therapy and is associated with a median OS of 9.6 months vs. 7.4 months with paclitaxel alone as per RAINBOW trial (NCT01170663).11

The DESTINY–Gastric01 study (NCT03329690) evaluated the use of antibody-drug conjugate trastuzumab deruxtecan (Enhertu) vs physician’s choice chemotherapy in previously treated, HER-2 positive, gastric/GEJ adenocarcinoma. This open-label, randomized phase 2 trial was conducted in Japan and Korea and reported improvement in response rate of 51% with T-DXd as compared with 14% with physicians’ choice chemotherapy (P < .001). Median OS was 12.5 vs 8.4 months (P = .01). Based on this trial, the FDA approved trastuzumab deruxtecan in second-line or beyond metastatic HER-2 positive gastric/GE adenocarcinoma.12

DESTINY–Gastric02 (NCT04014075) is a single arm, phase 2 trial that evaluated trastuzumab deruxtecan in HER-positive advanced gastric/GEJ cancer who progressed on or after trastuzumab-containing first-line therapy in Western population. This study showed efficacy with a response rate of about 30%.13

Several other studies are ongoing comparing other HER2 agents with trastuzumab, including margetuximab (Margenza) and zanidatamab.

Other Relevant Targeted Therapies

Larotrectinib has FDA approval as tissue agnostic indication for patients with metastatic unresectable solid tumors that have NTRK gene fusion. Pembrolizumab is also approved for tumor mutational burden-high unresectable or metastatic (≥10 mut/Mb), that have progressed following prior treatment without satisfactory alternative treatment options.

Newer targeted agents such as anti-FGFR2b antibody, bemarituzumab, are being studied in combination with chemotherapy in FIGHT study (NCT03694522). Zolbetuximab (IMAB362) in combination with chemotherapy is being studied in CLDN18.2+ GE adenocarcinoma.

Biomarker assessment has become critically important for selecting treatment approach to systemic therapy. Personalization and individualization of treatment based on biomarkers for gastroesophageal cancers leads to better outcomes with more durable responses and improved survival.


1. Key statistics for esophageal cancer. American Cancer Society. Accessed April 15, 2022.

2. Pennell NA, Mutebi A, Zhou ZY, et al. Economic impact of next-generation sequencing versus single-gene testing to detect genomic alterations in metastatic non-small-cell lung cancer using a decision analytic model. JCO Precis Oncol. 2019;3:1-9. doi:10.1200/PO.18.00356

3. FDA approves nivolumab for resected esophageal or GEJ cancer. FDA. May 20, 2021. Accessed April 15, 2022.

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

5. Safran HP, Winter K, Ilson DH, et al. Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2022;23(2):259-269. doi:10.1016/S1470-2045(21)00718-X

6. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27-40. doi:10.1016/S0140-6736(21)00797-2

7. 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

8. Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6(10):1571-1580. doi:10.1001/jamaoncol.2020.3370

9. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1-10. doi:10.1200/JCO.19.02105

10. Janjigian YY, Kawazoe A, Yanez PE, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: Initial findings of the global phase 3 KEYNOTE-811 study. J Clin Oncol. 2021;39(suppl 15):4013. doi:10.1200/JCO.2021.39.15_suppl.4013

11. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. doi:10.1016/S1470-2045(14)70420-6

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

13. Van Cutsem E, Di Bartolomeo M, Smyth E, et al. Primary analysis of a phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741

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