Checkpoint Inhibitors Gain Traction in the Frontline Setting for Cancers of the Esophagus

This past year, 2020, will go down as a practice-changing one for the treatment of esophageal cancer, said Yelena Y. Janjigian, MD.

This past year, 2020, will go down as a practice-changing one for the treatment of esophageal cancer, said Yelena Y. Janjigian, MD, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center, in New York, New York, during an interview with Targeted Therapies in Oncology.

Though coronavirus disease 2019 dominated news headlines, oncologists made significant strides that will likely improve survival rates for patients diagnosed with cancer of the esophagus. The PD-1 checkpoint inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) both gained new indications for use in the second-line setting, and additional research suggests they may be beneficial in the first-line setting as well.

“For decades, we had very few options available for the treatment of esophageal cancer, particularly squamous cell cancer,” said Manish A. Shah, MD, chief of the Solid Tumor Service and codirector of the Center for Advanced Digestive Disease at NewYork-Presbyterian, both in New York, New York. “That’s why the advent of PD-1 inhibitors in addition to chemotherapy is so important.”

PD-1 Checkpoint Inhibition in the Frontline Setting

Until recently, treatment options for patients with unresectable/locally advanced or metastatic esophageal cancer have been limited. Five-year survival rates are less than 5%.1 However, adding a checkpoint inhibitor to chemotherapy may bolster the effectiveness of frontline treatment for these malignancies and dramatically improve survival rates, according to results of 2 global, phase 3 clinical trials, KEYNOTE-590 (NCT03189719)2 and CheckMate649 (NCT02872116),3 presented at the European Society for Medical Oncology Virtual Congress 2020.

In the KEYNOTE-590 study, investigators reported a median overall survival (OS) of 12.4 months for patients treated with pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil [5-FU]) compared with 9.8 months for chemotherapy alone (HR, 0.73; 95% CI, 0.62-0.86; P < .0001). Median progression-free survival (PFS) was 6.3 months versus 5.8 months (HR, 0.65; 95% CI, 0.55-0.76; P < .0001) (TABLE).2

The survival benefit of adding pembrolizumab to chemotherapy was also analyzed in terms of combined positive score (CPS), a measure that reflects the proportion of tumor cells positive for PD-L1 protein expression. Patients with CPS of 10 or more seemed to garner the most benefit from the combination therapy, with a median OS of 13.5 months versus 9.4 months for chemotherapy alone (HR, 0.62; 95% CI, 0.49-0.78; P < .0001). Median PFS was 7.5 months versus 5.5 months (HR, 0.51; 95% CI, 0.41-0.65; P < .0001).

Immune-mediated adverse events (AEs) and infusion reactions were more common in patients treated with both pembrolizumab and chemotherapy. Grade 3 or higher immune-mediated AEs occurred in 7.0% of the pembrolizumab/chemotherapy group compared with 2.2% of the chemotherapy-alone group.

Notably, KEYNOTE-590 included patients with squamous cell carcinoma of the esophagus and those with esophageal adenocarcinoma. Both groups experienced benefit from the addition of immunotherapy.2

Shah, one of the investigators for KEYNOTE-590, noted that he hopes the FDA will approve pembrolizumab in combination with chemotherapy for first-line treatment of esophageal cancer later this year.

Nivolumab also shows promise in the first-line setting. CheckMate649, the largest randomized, global, phase 3 study of PD-1 inhibitor–based therapies as frontline treatment for esophageal cancer, randomized patients to receive either chemotherapy or nivolumab plus chemotherapy.3 The trial included patients with advanced unresectable or metastatic esophageal adenocarcinoma, gastroesophageal junction (GEJ) cancer, and advanced gastric cancer, marking the first time patients with esophageal cancer were included in a study of gastric and GEJ cancers. The inclusion of esophageal cancer makes sense, said Janjigian, principal investigator on CheckMate649, because cancer genome research has revealed that adenocarcinoma of the stomach, GEJ, and esophagus is remarkably similar.

“Splitting them up by anatomic location is a bit artificial,” she said, “particularly because when we see adenocarcinoma of the esophagus, it’s almost always in the last third of the esophagus. Higher up, it’s almost always squamous cell cancer.”

Because patients with esophageal or gastric adenocarcinoma typically receive FOLFOX (folinic acid, 5-FU, and oxaliplatin)chemotherapy, all patients in CheckMate649 received that chemotherapy regimen. The combination arms also received nivolumab at 360 mg every 3 weeks or 240 mg every 2 weeks.

“Nivolumab lends itself well to every-2-week dosing with FOLFOX because that’s administered every 2 weeks as well,” Janjigian noted.

Median OS for patients with PD-L1 CPS of 5 or more who received the nivolumab plus chemotherapy regimen was 14.4 months compared with 11.1 months for similar patients who received chemotherapy alone (HR, 0.71; 98.4% CI, 0.59-0.86; P < .0001). For patients with CPS of 1 or more, median OS was 14.0 months and 11.3 months (HR, 0.77; 99.3% CI, 0.64-0.92; P = .0001). In patients with CPS of 5 or more, nivolumab plus chemotherapy was associated with a 32% reduction in the risk of progression or death versus chemotherapy alone (median PFS, 7.7 months vs 6.0 months; HR, 0.68; 98% CI, 0.56-0.81; P < .0001). The nivolumab combination also produced a PFS benefit in patients with CPS of 1 or more (median PFS, 7.5 months vs 6.9 months; HR, 0.74; 95% CI, 0.65-0.85) and in the overall patient cohort (median PFS, 7.7 months vs 6.9 months; HR, 0.77; 95% CI, 0.68-0.87).

Notably, the objective response rate (ORR) was 60% in the combination treatment group (n = 78) versus 45% for chemotherapy alone (n = 391; P < .0001), with 12 complete responses (CRs) and 48 partial responses (PRs) versus 7 CRs and 38 PRs, respectively.

Serious treatment-related AEs (TRAEs) were more common in the nivolumab/chemotherapy group; 17% of the combination group experienced a grade 3 or 4 AE compared with 10% of the chemotherapy group. However, there were similar rates of TRAEs in patients with CPS of 5 or more and all patients across both treatment arms.3

Janjigian described the results of Check-Mate649 as “very exciting” and anticipated likely FDA approval of nivolumab in combination with chemotherapy for first-line treatment of esophageal adenocarcinoma.

“When, and for which populations? That’s to be determined,” Janjigian said, noting that the regulatory authorities may decide to approve the combination regimen for patients with a minimum CPS of 5 or 1 or for all patients regardless of PD-L1 expression.

Approval of immunotherapy/chemotherapy combination regimens for first-line treatment of esophageal cancer may have a dramatic impact on patients’ clinical outcome.

“I believe that doing immunotherapy as early as possible would be important because that’s when patients are still relatively well and functional. If we want to improve their survival outcomes, this is our chance to do it,” Janjigian said. “We also know that many patients never get treatment beyond the first line, either because they’re very ill or for other reasons. If you look at some trials, only about 30% to 40% of patients ever get immunotherapy at later lines.”

With pembrolizumab and nivolumab both showing efficacy in combination with chemotherapy in the frontline setting, clinicians will have to decide which regimen best suits individual patients. Although the combination regimens have not yet been studied head-to-head, KEYNOTE-590 and CheckMate649 offer some guidance.

“For squamous cell cancer, the only available data are from KEYNOTE-590, which used pembrolizumab, so I certainly think that’s what you would use for squamous cell carcinoma in the first-line setting,” Shah said. “For adenocarcinoma, I think it will depend a bit on the specifics of FDA approval.”

The fact that both pembrolizumab and nivolumab are commonly used drugs will likely accelerate the uptake of the new first-line regimens. “There shouldn’t be much of a learning curve,” Shah said. “Once the FDA approves new indications, clinicians should very quickly integrate these treatments into practice.”

Janjigian said some savvy patients already have requested nivolumab/chemo-therapy. “We’ve been able to get occasional insurance approvals already, based on our presented data,” she said.

PD-1 Checkpoint Inhibition in the Second Line and Beyond

Second-line use of PD-1 inhibitors is quickly becoming the standard of care, thanks to FDA approval of pembrolizumab4 and nivolumab to treat advanced esophageal cancer refractory or intolerant to previous chemotherapy based on KEYNOTE-181 (NCT02564263)1 and ATTRACTION-3 (NCT02569242).5 KEYNOTE-181 compared pembrolizumab versus chemotherapy in patients with advanced or metastatic esophageal squamous cell carcinoma or adenocarcinoma. Patients received either pembrolizumab 200 mg every 3 weeks or chemo-therapy (paclitaxel, docetaxel, or irinotecan). Results were stratified by PD-L1 CPS.1

“We found that in squamous cell cancers, particularly if the CPS is 10 or higher, pembrolizumab demonstrates significant activity over chemotherapy,” said Shah, an investigator on the study.

For patients with CPS of 10 or more, median OS with pembrolizumab was 9.3 months versus 6.7 months for the chemotherapy group (HR, 0.69; 95% CI, 0.52-0.93; P = .0074), and the estimated 12-month OS rates were 43% (95% CI, 33.5%-52.1%) and 20% (95% CI, 13.5%-28.3%), respectively. The addition of pembrolizumab did not improve efficacy outcomes for patients with adenocarcinoma and/or CPS of less than 10.

Notably, patients treated with pembroli-zumab also experienced fewer AEs. TRAEs occurred in 86% of patients treated with chemotherapy versus 64% of patients treated with pembrolizumab. Grade 3 or higher TRAEs occurred in 40.9% of patients in the pembrolizumab group and 18% of patients in the chemotherapy group.

Durable responses were more common in the pembrolizumab group, in which 53.5% of patients experienced a response lasting at least 9 months versus 38.1% of the chemotherapy group.1

On July 30, 2019, the FDA approved second-line use of pembrolizumab to treat patients with recurrent, locally advanced, or metastatic squamous cell carcinoma of the esophagus with CPS of 10 or higher.4

ATTRACTION-3 investigated the effectiveness of nivolumab compared with chemotherapy (paclitaxel or docetaxel) in the second-line setting. ATTRACTION-3 focused exclusively on squamous cell carcinoma, and patients were enrolled regardless of PD-L1 expression.5

At a minimum follow-up of 17.6 months, OS was significantly improved in the nivolumabgroup (median OS, 10.9 vs 8.4 months for the chemotherapy group; HR, 0.77; 95% CI, 0.62-0.96; P = .019). Just 18% of the patients treated with nivolumab experienced grade 3 or 4 TRAEs, compared with 63% of patients treated with chemotherapy.5

On June 10, 2020, the FDA approved nivolumab for the treatment of patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma who, like the participants in ATTRACTION-3, had previously received fluoropyrimidine- and platinum-based chemotherapy.6

Janjigian hailed the approvals of pembrolizumab and nivolumab in the second-line setting but said that “clinically, it may not be enough,” given that most cases of esophagealcancer in the United States are adenocarcinoma, not squamous cell carcinoma. “I think that’s the place where we may need to explore chemotherapy plus immune checkpoint inhibitors,” she said.

Currently recommended third-line therapy for both squamous cell cancer of the esopha-gus and esophageal adenocarcinoma is pembrolizumab, on the basis of KEYNOTE-180 (NCT02559687), a phase 2, single-arm study that produced an ORR of 9.9% (95% CI, 5.2%-16.7%) in the overall patient population.7,8

As this KEYNOTE-180 outcome illustrates, there is room for improvement. “As of 2020, for adenocarcinoma, we use pembrolizumab monotherapy in the third line,” Janjigian said. “However, most [patients] with relatively low PD-L1 expression have very minimal, if any, response.”

PD-1 Checkpoint Inhibition as Adjuvant Therapy

Administering nivolumab after trimodality therapy (chemotherapy, radiation, and surgery) may improve outcomes for patients with resectable locally advanced esophageal cancer or GEJ cancer.

At present, neoadjuvant chemoradiotherapy, followed by surgery, is the standard of care for this patient population. However, the risk of recurrence after treatment is high. CheckMate 577 (NCT02743494), a global, phase 3 study, investigated the effectiveness of administering adjuvant nivolumab after trimodality therapy.9

Results were promising. Compared with placebo, nivolumab provided superior disease-free survival (DFS), with a 31% reduction in the risk of recurrence or death. Median DFS in the nivolumab group (22.4 months) was double that in the placebo group (11.0 months; HR, 0.69; 96.4% CI, 0.56-0.86; P = .0003). DFS results also favored nivolumab across multiple patient subgroups (TABLE 2).9

“CheckMate 577 is practice changing,” Janjigian said. “In my mind, there’s very little downside to doing additional adjuvant therapy if the patient is motivated.”

Although nivolumab is not yet approved for use as adjuvant therapy for esophageal cancer, change is on the horizon. On January 20, the FDA accepted a supplemental biologics license application for this indication and granted it priority review status, based on the results of CheckMate 577.10 “I believe the regulatory authorities will be able to take action based on disease-free survival, but we will see. We may need to wait until we have overall survival data [from Check-Mate 577],” Shah said.

However, Janjigian is not sure nivolumab will have a long-term role as an adjuvant treatment. “There are several other studies right now exploring the use of immunotherapy in the neoadjuvant setting,” she said. “Certainly, in lung cancer and other diseases, preoperative immunotherapy has been shown to be very promising.”

Lingering Research Questions and Unmet Needs

Although investigators and clinicians are thrilled to have additional treatment options, the fact remains that “most patients with metastatic esophageal cancer will still, unfortunately, die of their disease,” Shah said.

Investigators continue to evaluate possible treatment regimens. KEYNOTE-811 (NCT03615326) is currently examining the effectiveness of adding pembrolizumab to trastuzumab (Herceptin) and chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine) for frontline treatment of HER2-positive, unresectable, metastatic gastric, or GEJ cancer. KEYNOTE-811 initiation was based on results of an earlier phase 2 study (NCT02954536), in which a similar regimen in a similar patient population produced an ORR of 87% and a disease control rate of 100%.11,12

Other checkpoint inhibitors may eventually be added to clinicians’ tool kit. Pembrolizumab and nivolumab were the first 2 FDA-approved PD-1–targeting checkpoint inhibitors, but many others have since been developed. Investigators continue to evaluate their effectiveness in treating many types of cancer, both alone and in combination with other therapies. “The future treatment of esophageal and gastric cancers will likely include the combination of checkpoint inhibitors with other drugs,” Shah said.


1. Noone AM, Cronin KA, Altekruse SF, et al. Cancer incidence and survival trends by subtype using data from the Surveillance Epidemiology and End Results Program, 1992-2013. Cancer Epidemiol Biomarkers Prev. 2017;26(4):632-641. doi:10.1158/1055-9965.EPI-16-0520

2. Kato K, Sun JM, Shah MA, et al. 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):S1192-S1193. doi:10.1016/j.annonc.2020.08.2298

3. Moehler M, Shitara K, Garrido M, et al. 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):S1191. doi:10.1016/j.annonc.2020.08.2296

4. FDA approves pembrolizumab for advanced esophageal squamous cell cancer. FDA. Updated July 31, 2019. Accessed January 4, 2021.

5. Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(11):1506-1517. doi:10.1016/S1470-2045(19)30626-6

6. FDA approves nivolumab for esophageal squamous cell carcinoma. FDA. Updated June 11, 2020. Accessed January 4, 2021.

7. Shah MA, Kojima T, Hochhauser D, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol. 2019;5(4):546-550. doi:10.1001/jamaoncol.2018.5441

8. Kato K, Shah MA, Enzinger P, et al. KEYNOTE-590: phase III study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. Future Oncol. 2019;15(10):1057-1066. doi:10.2217/fon-2018-0609

9. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiation therapy (CRT): first results of the CheckMate 577 study. Ann Oncol. 2020;31(suppl 4):S1193-S1194. doi:10.1016/j.annonc.2020.08.2299

10. US Food and Drug Administration accepts for priority review application for Opdivo (nivolumab) as adjuvant therapy for patients with resected esophageal or gastroesophageal junction cancer. News release. Bristol Myers Squibb. January 20, 2021. Accessed January 25, 2021.

11. Chung H, Bang Y, Fuchs C, et al. KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer: a double-blind, randomized, placebo-controlled phase 3 study. Ann Oncol. 2019;30(suppl 4):IV25. doi:10.1093/annonc/mdz155.093

12. Janjigian YY, Chou JF, Simmons M, et al. First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA). Presented at: 2019 Gastrointestinal Cancers Symposium; January 16-19, 2019; San Francisco, CA. Accessed January 26, 2021.