Immunotherapy Hits Its Stride in Esophageal and GEJ Cancers

Targeted Therapies in Oncology, April 2, 2022, Volume 6,
Pages: 24

The recent, significant advances for immunotherapy in esophageal and gastroesophageal junction cancer are promising, and oncologists hope it is just the beginning of further improvements in patient outcomes.

Immunotherapy has garnered significant interest as treatment for esophageal/gastroesophageal junction (GEJ) cancers in recent years, and 2021 saw several approvals that are changing the treatment landscape for this disease.


Esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinoma are the 2 predominant histological subtypes of esophageal cancer, each with a distinct molecular pattern and individual risk factors.1,2 Most esophageal adenocarcinomas are located in the lower esophagus or at the gastroesophageal junction (GEJ), whereas SCC is more often found in the mid thoracic to upper thoracic esophagus.2 Despite increased recognition of differences in epidemiology, localization, and molecular patterns, esophageal cancer has often been treated similarly, regardless of histological subtype, because of a lack of treatment options and 5-year survival rates of approximately 5% for patients in advanced stages.1,2 Following the results of the CROSS and FLOT trials, a shift has occurred over the past decade for operable tumors, favoring neoadjuvant chemoradiotherapy for SCC and adjuvant chemotherapy for adenocarcinoma. However, 30% of patients still experience recurrence within 12 months of surgery, suggesting the unmet need for the patient population.1

Ronan J. Kelly, MD, MBA, director of oncology at the Charles A. Sammons Cancer Center at Baylor University Medical Center and chief of oncology of the North Texas Division of Baylor Scott & White Health in Dallas, discussed advances in immunotherapy in esophageal/GEJ cancers in an interview with Targeted Therapies in OncologyTM and commented on the historical approach in the surgical and nonsurgical setting. “In the operable setting, there’s been a divide between how patients are treated in the United States vs some countries in Europe. For operable patients in stage II to III, [clinicians in] the [United States] prefer to give chemoradiation before surgery, whereas in some European countries, they prefer to give chemotherapy alone. In the metastatic setting, the only real treatment strategy has been chemotherapy until the [past] few years. We have been unable to break through the 12-month median overall survival barrier, which has hindered us for decades.”

Immunotherapy has been proven effective for head and neck and lung cancers, leading to interest across various neoplasias, including esophageal/ GEJ cancer.2 The 2 key immunotherapies to have achieved success in esophageal/GEJ cancer are the PD-1 monoclonal antibodies, pembrolizumab (Keytruda) and nivolumab (Opdivo).1-3 Pembrolizumab first received approval from the FDA in the esophageal/GEJ space in esophagogastric adenocarcinoma in 2017, based on the phase 1b KEYNOTE-012 (NCT01848834) and phase 2 KEYNOTE-590 (NCT03189719) trials.3 Results from the phase 2 KEYNOTE-180 (NCT02559687) and phase 3 KEYNOTE-181 (NCT02564263) trials led to FDA approval in the second-line setting for esophageal SCC in 2019.4 Nivolumab was first approved as second-line therapy for patients with unresectable advanced, recurrent, or metastatic esophageal SCC based on results from the ATTRACTION-3 trial (NCT02569242) in 2020.2,5

“The biggest advance has come in the immunotherapy space, and the [past] 18 to 24 months have been transformative in the esophagogastric cancer setting,” Kelly said. Here, we highlight key trial results and approvals over recent years and evaluate ongoing trials with future potential, according to disease histology.

Squamous Cell Carcinoma and Adenocarcinoma

Pembrolizumab Plus Chemotherapy as First-Line Therapy for Advanced Esophageal/GEJ Cancer Results from the placebo-controlled, double-blind, phase 3 KEYNOTE-590 trial led to the FDA approval of pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or GEJ carcinoma who are not candidates for surgical resection or definitive chemoradiation on March 22, 2021.6 Significant and clinically meaningful improvements in overall survival (OS), progression-free survival (PFS), and objective response rates (ORRs) were observed with pembrolizumab plus chemotherapy compared with placebo plus chemotherapy in patients with unresectable, locally advanced or metastatic esophageal cancer or Siewert type I GEJ cancer in the first-line setting.7

A total of 749 patients were enrolled, with 373 randomly assigned to pembrolizumab plus chemotherapy and 376 randomly assigned to placebo plus chemotherapy.7 At a median follow-up of 22.6 months, OS in patients with esophageal SCC and PD-L1 combined positive score (CPS) of 10 or more was significantly greater for patients receiving pembrolizumab, with a median of 13.9 months vs 8.8 months for those receiving placebo (HR, 0.57; 95% CI, 0.43-0.75; P < .0001). Median OS was also greater for all randomized patients receiving pembrolizumab vs placebo at 12.4 months vs 9.8 months, respectively (HR, 0.73; 95% CI, 0.62-0.86; P < .0001). An OS advantage for pembrolizumab over placebo was seen in terms of OS across subgroups (TABLE 17).

Grade 3 or greater treatment-related adverse events (TRAEs) were observed in 72% (n = 266) of patients receiving pembrolizumab with chemotherapy and 68% (n = 250) of patients receiving placebo with chemotherapy.7 Twenty-four percent of patients in the pembrolizumab and chemotherapy arm discontinued because of AEs compared with 20% in the chemotherapy and placebo arm.

KEYNOTE-590 was the first trial to show significant survival benefit with the combination of immunotherapy plus chemotherapy in the first-line setting for esophageal cancer.7 Pembrolizumab plus chemotherapy has the potential to become the new standard of therapy for these patient populations and has already been added as a preferred treatment option in the most recent National Comprehensive Cancer Network (NCCN) guidelines.8

Adjuvant Nivolumab for Locally Advanced Esophageal/GEJ Cancer
The FDA approved nivolumab on May 20, 2021, for patients with completely resected esophageal or GEJ cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy, based on results from the placebo-controlled, double-blind, phase 3 CheckMate 577 trial (NCT02743494).9 Results from the study indicate a significantly longer disease-free survival (DFS) with adjuvant nivolumab compared with placebo among patients with resected esophageal or GEJ cancer who had received neoadjuvant chemoradiotherapy.10

Updated results from CheckMate 577 with extended follow-up were recently presented at the European Society for Medical Oncology (ESMO) Congress 2021.10 Patients with resected stage II or III esophageal or GEJ cancer and residual pathologic disease who received neoadjuvant chemoradiotherapy were randomized 2:1 to receive nivolumab (n = 532) or placebo (n = 262). Patients receiving nivolumab achieved a median DFS of 22.4 months (95% CI, 16.9-33.6) compared with 10.4 months (95% CI, 8.3-13.9) in those receiving placebo (HR for disease recurrence or death, 0.67; 95% CI, 0.55-0.81). Median distant metastasis–free survival was also significantly greater for patients receiving nivolumab (29.4 months; 95% CI, 23.7-36.6) vs placebo (16.6 months; 95% CI, 11.4-24.9), with a hazard ratio of 0.71 (95% CI, 0.58-0.87). Hazard ratios for disease recurrence or death indicated an advantage for nivolumab across prespecified subgroups, based on demographic and baseline disease characteristics.

Grade 3 or higher TRAEs were observed in 14% (74/532) of the nivolumab group and 6% (16/260) of the placebo group, with treatment discontinuation because of TRAEs occurring in 9% and 3% of patients, respectively.11 Overall, the safety profile of nivolumab was consistent with previous studies.10,11

The primary end point of the study was originally OS, but because of enrollment issues and evidence supporting DFS as a surrogate for OS, there was a protocol shift.10 The study is ongoing and OS analysis is planned. “We showed a doubling in the median DFS and found we can delay the onset of metastasis for over a year, which is a big advancement,” Kelly said. “This is the only recent positive trial in the operable space and is already listed as category 1 evidence in the NCCN guidelines.”8


First-Line Nivolumab/Chemotherapy for Gastric, GEJ and Esophageal Adenocarcinoma
Nivolumab with fluoropyrimidine- and platinum-containing chemotherapy was approved by the FDA on April 16, 2021, for advanced metastatic gastric, GEJ, and esophageal adenocarcinoma, based on results from the open-label, randomized phase 3 CheckMate 649 trial (NCT02872116).12 Nivolumab with chemotherapy produced significantly improved OS and PFS in the first-line setting for patients with advanced gastric, GEJ, or esophageal adenocarcinoma compared with chemotherapy alone.13

A total of 1581 patients were randomized regardless of PD-L1 expression to nivolumab plus chemotherapy (n = 789) or chemotherapy alone (n = 792).13 Median OS for nivolumab plus chemotherapy was 14.4 months (95% CI, 13.1-16.2) vs 11.1 months with chemotherapy alone (95% CI, 10.0-12.1) at a minimum folow-up of 12 months for patients with PD-L1 CPS of5 or more. The addition of nivolumab resulted in a 29% reduction in the risk of death compared with chemotherapy alone (HR, 0.71; 98.4% CI, 0.59-0.86; P <.0001). Nivolumab plus chemotherapy also resulted in significantly improved PFS for patients with PD-L1 CPS of 5 or more, with a median PFS of 7.7 months (95% CI, 7.0-9.2) compared with 6.0 months (95% CI, 5.5-6.9) for chetherapy alone (HR, 0.68; 98% CI, 0.56-0.81; P <.0001). Patients with PD-L1 of 1 or more and all randomly assigned patients also saw significant improvement in OS and PFS. TRAEs of grade 3 or higher occurred in 59% (n = 462/782) of patients treated with nivolumab and 44% (n = 341/767) of patients on chemotherapy alone, and no new safety signals were identified.

Nivolumab became the first PD-1 inhibitor to result in improved OS, PFS, and an acceptable safety profile in combination with chemotherapy vs chemotherapy alone in patients with advanced gastric, GEJ, or esophageal adenocarcinoma in the first-line setting.13 Results from another cohort in this study receiving nivolumab plus ipilimumab (Yervoy) vs chemotherapy alone remain blinded and will be reported at a later date. “CheckMate649 has been transformative,” Kelly said. “This has become the go-to regimen, and we were able to break through the 12-month median overall survival barrier that’s been hindering us for so long.”

Trastuzumab Deruxtecan in HER2-Positive Advanced GEJ
On January 15, 2021, the FDA approved the antibody-drug conjugate, fam-trastuzumab deruxtecan-nxki (Enhertu), for the treatment of adults with locally advanced or metastatic HER2-positve gastric or gas- troesophageal adenocarcinoma, who had previously received a trastuzumab-based (Herceptin) regimen, based on results from the open-label, randomized, phase 2 DESTINY- Gastric01 trial (NCT03329690).14 Results indicated patients with HER2-positive gastric adenocarcinoma receiving trastuzumab deruxtecan achieved significant improvements in response and OS compared with standard-of-care chemotherapy.15

A total of 125 patients with HER2-positive locally advanced metastatic gastric or GEJ adenocarcinoma who had progressed on at least 2 prior regimens, including trastuzumab and a fluoropyrimidine- or a platinum-containing chemotherapy, received trastuzumab deruxtecan, and a total of 62 patients received chemotherapy (n = 55, irinotecan; n=7, paclitaxel).15 Median OS was 12.5 months (95% CI, 9.6-14.3) with trastuzumab deruxtecan compared with 8.4 months (95% CI, 6.9-10.7) with chemotherapy (HR for death, 0.59; 95% CI, 0.39- 0.88; P =.01). Median PFS with trastuzumab deruxtecan was 5.6 months (95% CI, 4.3-6.9) vs 3.5 months (95% CI, 2.0-4.3) with chemotherapy (HR for disease progression or death, 0.47; 95% CI, 0.31-0.71). Trastuzumab deruxtecan–related pneumonitis or interstitial lung disease was observed in 12 patients (10%), with 3 patients experiencing grade 3 or 4 disease. As of the published analysis, 8 of the cases had resolved.

DESTINY-Gastric01 was carried out with patients from Japan and South Korea, and the follow-up phase 2 DESTINY-Gastric02 study (NCT04014075) was prepared for patients from Western countries.15,16 Primary analysis findings were presented at the ESMO Congress 2021.16 A total of 79 patients rom the United States and European Union with unresectable or metastatic gastric or GEJ cancer and a median of 1 prior therapy were treated with trastuzumab deruxtecan. The confirmed ORR by independent central review was 38% (n = 30/79; 95% CI, 27.3%-49.6%) and the disease control rate was 81.0% (95% CI, 70.6%-89.0%). Median PFS was 5.5 months (95% CI, 4.2-7.3) and the median duration of response was 8.1 months (95% CI, 4.1–not evaluable). Drug-related interstitial lung disease occurred in 6 patients, with 5 experiencing grade 1 to 2 disease and 1 patient experiencing grade 5 disease.

“We tried for many years to discover how to properly target HER2, attempting numerous drugs previously approved in HER2-positive breast cancer, with no real success. We now have trastuzumab deruxtecan providing a targeted delivery system as an antibody-drug conjugate and the first big step forward in [patients with] gastric and GEJ [cancer] in over a decade. We showed that if you received chemotherapy plus trastuzumab in the first-line setting, then you should receive trastuzumab deruxtecan in the second-line setting, because it appears more effective than any chemotherapy,” Kelly said.

Pembrolizumab in HER2-Positive Gastric/GEJ Cancer
Accelerated approval was granted to pembrolizumab in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for first-line treatment of locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma on May 5, 2021, based on interim results from the double-blind, placebo-controlled phase 3 KEYNOTE-811 trial (NCT03615326).17

Interim analysis of 264 patients with previously untreated, unresectable, or metastatic gastric or GEJ cancer revealed a confirmed ORR of 74.4% (95% CI, 66.2%-81.6%) for pembrolizumab plus standard-of-care chemotherapy vs 51.9% (95% CI, 43.0%- 60.7%) for placebo plus standard-of-care chemotherapy (P = .00006) and a complete response rate of 11.3% vs 3.1%, respectively.18 The median duration of response was 10.6 months with pembrolizumab vs 9.5 months without. Rates of grade 3 or higher AEs were similar, with 57.1% of patients receiving pembrolizumab and 57.4% of patients receiving placebo affected.

The initial data are promising for the use of pembrolizumab plus chemotherapy as a potential new treatment option for this population, but the study is ongoing, with OS data still to come.18 “This study is encouraging for the 15% to 20% of patients that overexpress the HER2 gene. Historically, we gave chemotherapy plus trastuzumab, and now we can also give pembrolizumab. The response rates look very promising, but we are still waiting for long-term efficacy data,” Kelly said.

Squamous Cell Carcinoma

Nivolumab Plus Ipilimumab or Chemotherapy
The FDA accepted supplemental biologics license applications for the combination of nivolumab plus ipilimumab and the combination of nivolumab plus fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment options for patients with unresectable advanced, recurrent, or metastatic esophageal SCC in September 2021.19 The acceptance was based on results from the open-label phase 3 CheckMate 648 trial (NCT03143153), in which both first-line treatment with nivolumab and chemo- therapy and first-line treatment with nivolumab and ipilimumab significantly increased OS vs chemotherapy alone.19,20

A total of 970 patients with previously untreated, unresectable advanced, recurent, or metastatic esophageal SCC were randomized 1:1:1 to receive nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone.20 OS was significantly greater for patients with PD-L1 expression of 1% or greater, receiving nivolumab plus chemotherapy vs chemotherapy alone (median, 15.4 vs 9.1 months, respectively; HR, 0.54; 99.5% CI, 0.3-0.8; P < .0001) and receiving nivolumab plus ipilimumab vs chemotherapy alone (median, 13.7 vs 9.1 months, respectively; HR, 0.64; 98.6% CI, 0.46-0.90; P = .002) (TABLE 220 on page 27).

Significant improvement was also observed in the overall patient population for patients receiving nivolumab plus chemotherapy vs chemotherapy alone (median OS, 13.2 vs 10.7 months, respectively; HR, 0.74; 99.1% CI, 0.58-0.96; P = .002) and for patients receiving nivolumab plus ipilimumab vs chemotherapy alone (median, 12.7 vs 10.7 months, respectively; HR, 0.78; 98.2% CI, 0.62-0.98; P = .01). Significant PFS benefit was observed with nivolumab plus chemotherapy vs chemotherapy alone in patients with PD-L1 expression of 1% or greater (median, 6.9 vs 4.4 months, respectively; HR for disease progression or death, 0.65; 98.5% CI, 0.46-0.92; P = .002) but not with nivolumab plus ipilimumab vs chemotherapy (median, 4.0 vs 4.4 months, respectively; HR, 1.02; 98.5% CI, 0.73-1.43; P = .90). TRAEs of grade 3 or higher occurred in 47% of patients receiving nivolumab plus chemotherapy, 32% of patients receiving nivolumab with ipilimumab, and 36% of patients with chemotherapy alone.

The assigned target action date for the FDA approval of nivolumab and chemotherapy and nivolumab and ipilimumab is May 28, 2022.19 “We’ve seen a huge number of trials in squamous cell, many coming from Asia, where it is the predominant histology,” Kelly said. “Several PD-1 inhibitors have been evaluated, and they all show improvements with administration with chemotherapy in the first-line setting for squamous cell carcinoma. Whether they all receive FDA approval remains to be seen.”

Looking Ahead

“As a result of CheckMate 648, KEYNOTE-590, and KEYNOTE-811, everything has moved from the second-line setting to the first-line setting,” Kelly said. “We also have an adjuvant approval in CheckMate 577. It’s been an amazing 18 to 24 months, and I’m not sure [whether] there’s been another tumor type to see this many approvals or trials in this short [of] a period.”

Although the approvals are promising and provide more options for patients and providers, Kelly admits there is still much more work to be done. “Median survival is still [approximately] 13 to 14 months in the metastatic setting. We need to be aiming for long-term survival for our patients. I think we do that by improving our understanding of the immune micro-environment. We need to determine why some people respond, why others don’t, [and] why some stop responding. There are many studies ongoing, so hopefully we see continued improvement.”

Kelly mentioned that new targets for future therapeutics that are being evaluated include FGFR and claudin 18.2.21,22 Additionally, new therapeutics continue to be developed and studied, including the first-in-class chimeric monoclonal immunoglobulin G1 antibody, zolbetuximab, that binds to claudin 18.2.23 The recent, significant advances for immunotherapy in esophageal/GEJ cancer are promising, and oncologists hope it is just the beginning of further improvements in patient outcomes.


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3. Turgeman I, Ben-Aharon I. Evolving treatment paradigms in esophageal cancer. Ann Transl Med. 2021;9(10):903. doi:10.21037/atm.2020.03.110

4. FDA approvespembrolizumabfor advancedesophagealsquamouscellcancer. FDA. Updated July 31, 2019. Accessed March 28, 2022.

5. FDA approvesnivolumabfor esophagealsquamous cell carcinoma. FDA. Updated June 11, 2020. Accessed March 28, 2022.

6. FDA approvespembrolizumabfor esophagealor GEJ carcinoma. FDA. Updated March 22, 2021. Accessed March 28, 2022.

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. Ajani JA, D'Amico TA, Bentrem DJ, et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(2):167-192. doi:10.6004/jnccn.2022.0008

9. FDA approvesnivolumabfor resected esophagealor GEJ cancer. FDA. Updated May 20, 2021. Accessed March 28, 2022.

10. 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

11. Moehler M, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): 14-month follow-up of CheckMate 577. Ann Oncol. 2021;32(suppl 5):S1045-S1046. doi:10.1016/j.annonc.2021.08.1490

12. FDA approves nivolumabin combination with chemotherapyfor metastatic gastric cancerand esophageal adenocarcinoma. FDA. Updated April 16, 2021. Accessed March 28, 2022.

13. 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 3trial. Lancet. 2021;398(10294):27-40. doi:10.1016/S0140-6736(21)00797-2

14. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA. Updated January 15, 2021. Accessed March 28, 2022.

15. ShitaraK, 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

16. 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 westernpatients (Pts) with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer who progressed on or after a trastuzumab-containing regimen. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741

17. FDA grants accelerated approvalto pembrolizumabfor HER2-positive gastric cancer. FDA. Updated May 05, 2021. Accessed March 28, 2022.

18. Janjigian YY, Kawazoe A, Yanez PE, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: initialfindings of the global phase 3 KEYNOTE-811 study. J Clin Oncol. 2021;39(suppl15):4013. doi:10.1200/JCO.2021.39.15_suppl.4013

19. US Food and Drug Administration acceptsBristol Myers Squibb’s applicationsfor Opdivo (nivolumab) + Yervoy (ipilimumab) and Opdivo + chemotherapyfor unresectable advanced, recurrentor metastaticesophagealsquamouscellcarcinoma. News release. Bristol Myers Squibb; September 27, 2021. Accessed March 28, 2022.

20. Doki Y, Ajani JA, Kato K, et al; CheckMate 648 Trial Investigators. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386(5):449-462. doi:10.1056/NEJMoa2111380

21. Zhang W, Zhou Y, Li C, et al. The expression and prognostic value of FGF2, FGFR3, and FGFBP1 in esophageal squamous cell carcinoma. Anal Cell Pathol (Amst). 2020;2020:2872479. doi:10.1155/2020/2872479

22. Moentenich V, Gebauer F, Comut E, et al. Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies. Oncol Lett. 2020;19(6):3665-3670. doi:10.3892/ol.2020.11520

23. Sahin U, Türeci Ö, Manikhas G, et al. FAST:a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32(5):609-619. doi:10.1016/j.annonc.2021.02.005