Immunotherapy Reaches New Heights in Upper GI Cancer Trials


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Immunotherapy has demonstrated significant benefits in recent large trials, reaching new survival benchmarks for upper gastrointestinal cancers across various settings of disease, according to Jaffer A. Ajani, MD.

Jaffer A. Ajani, MD

Immunotherapy has demonstrated significant benefits in recent large trials, reaching new survival benchmarks for upper gastrointestinal (GI) cancers across various settings of disease, according to Jaffer A. Ajani, MD.

“This is very unusual for upper GI tumors to all of a sudden have practice-changing outcomes like this,” said Ajani, professor in the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, during a presentation at the virtual 17th Annual Meeting of the International Society of Gastrointestinal Oncology.1 “It’s really great for our patients, but it’s going to create a lot of challenges for investigators because the landscape is going to get very complicated.”

Ajani presented on recent data released from large immunotherapy trials in gastroesophageal cancers that could potentially lead to FDA approvals in the near future.

Esophageal Cancer

For patients with advanced esophageal cancer, the use of pembrolizumab (Keytruda) is already FDA approved in the second-line setting, largely based off of the results of the phase 3 KEYNOTE-181 trial (NCT02564263). In the study, patients with recurrent locally advanced or metastatic esophageal cancer or Siewert type I adenocarcinoma of the esophagogastric junction who had progressed on or after 1 prior line of systemic therapy and had positive PD-L1 expression on their tumor cells (combined positive score [CPS] ≥10) showed significant overall survival (OS) benefit from treatment with pembrolizumab in comparison with investigator’s choice of chemotherapy.2

The median OS with pembrolizumab was 9.3 months compared with 6.7 months with chemotherapy (HR, 0.69; 95% CI, 0.52-0.93; P = .0074).

Ajani also pointed to the progression-free survival (PFS) curves in the PD-L1 positive population, which he said were similar to the curves in other studies of immunotherapy in gastric cancers. “Fifty percent of the patients don’t seem to benefit, it’s a rapid drop off. And then there is a group that truly benefits that I think we need to learn to recognize as we go forward,” he commented.

Nivolumab (Opdivo) is also approved for the treatment of patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) in the second-line setting after prior fluoropyrimidine- and platinum-based chemotherapy. The approval was based off of findings from the phase 3 ATTRACTION-3 trial (NCT02569242), which explored the use of nivolumab versus chemotherapy of paclitaxel or docetaxel in patients with unresectable advanced or recurrent ESCC.3

The median OS with nivolumab was 10.9 months versus 8.4 months with chemotherapy (HR, 0.77; 95% CI, 0.62-0.96; P = .019). Ajani noted that the objective response rates (ORRs) were similar between the 2 arms at 19% with nivolumab and 22% with chemotherapy, but the duration of response (DOR) was much better in the immunotherapy arm at 6.9 months versus 3.9 months.

Following these results, investigators sought to move up immunotherapy to the frontline. The use of phase 3 KEYNOTE-590 trial (NCT03189719) explored the use of pembrolizumab in the frontline setting in patients with locally advanced, unresectable, or metastatic esophageal cancer, patients in the trial were randomized 1:1 to either pembrolizumab plus chemotherapy or chemotherapy alone.

According to findings recently presented at the 2020 ESMO (European Society of Medical Oncology) Virtual Congress, the median OS among all patients treated with the immunotherapy combination was 12.4 months versus 9.8 months with chemotherapy alone (HR, 0.73; 95% CI, 0.62-0.86; P <.0001). In those with PD-L1 expression of CPS ≥10, the median OS was 13.5 months with immunotherapy versus 9.4 months without (HR, 0.62; 95% CI, 0.49-0.78; P <.0001). Further, for those specifically with ESCC and CPS ≥10, the median OS was 13.9 months versus 8.8 months with pembrolizumab/chemotherapy and chemotherapy/placebo, respectively (HR, 0.57; 95% CI, 0.43-0.75; P <.0001).4

Ajani said that this trial will change the treatment landscape for esophageal cancer and he expects that this regimen will soon be approved for use in the frontline setting for advanced ESCC.

Ajani noted that additional ongoing trials that are exploring the use of immunotherapy in the frontline setting for esophageal cancer that could also change the treatment landscape include: the phase 3 CheckMate 648 trial (NCT03143153), which is studying the use of nivolumab (Opdivo) and chemotherapy with or without added ipilimumab (Yervoy) versus fluorouracil and cisplatin chemotherapy alone for the treatment of previously untreated patients with unresectable, advanced, or metastatic ESCC, and the phase 3 Rational-306 study (NCT03783442) of the novel PD-1 inhibitor tislelizumab (BGB-A317) with or without chemotherapy for the first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic ESCC. Neither study has released any findings yet.

Gastroesophageal Adenocarcinoma

The largest study to date looking at the use of immunotherapy in the metastatic gastroesophageal adenocarcinoma space, Ajani said, was the CheckMate 649 trial (NCT02872116). The study was designed to explore the use of immunotherapy with or without chemotherapy versus standard-of-care chemotherapy in patients with previously untreated unresectable, advanced or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma.

In the study, 1581 patients with HER2-negative status were randomized to one of 3 arms: nivolumab plus ipilimumab followed by nivolumab monotherapy, nivolumab plus capecitabine and oxaliplatin (XELOX) chemotherapy or nivolumab plus folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy, and XELOX or FOLFOX alone.

First results from the trial were presented for the immunotherapy/chemotherapy and chemotherapy-alone arms at the 2020 ESMO Congress.5 Among patients with a CPS ≥5, the median OS was 14.4 months with nivolumab and chemotherapy versus 11.1 months with chemotherapy alone (HR, 0.71; 98.4% CI, 0.59-0.86; P <.0001). At 1 year, the OS rate was 57% with immunotherapy/chemotherapy and 46% with chemotherapy alone.

“This is highly significant. This is one of the first global trials where the experimental arm has crossed 12 months of overall survival. So, I think this is a really big achievement if it can persist like that,” Ajani said.

In the overall population of all randomized patients, the median OS was 13.8 months with nivolumab and chemotherapy versus 11.6 months with chemotherapy (HR, 0.80; 99.3% CI, 0.68-0.94; P = .0002). The OS rate at 12 months was 55% with immunotherapy/chemotherapy and 48% with chemotherapy alone.

The other co-primary end point of PFS showed significant benefit in the CPS ≥5 population with a median PFS of 7.7 months with nivolumab and XELOX or FOLFOX compared with 6.0 months with XELOX or FOLFOX alone (HR, 0.68; 98% CI, 0.56-0.81; P <.0001). In the overall population, the median PFS was 7.7 and 6.9 months in the immunotherapy/chemotherapy and chemotherapy-alone arms, respectively (HR, 0.77; 95% CI, 0.68-0.87).

The ORR in the CPS ≥5 group was 60% with nivolumab and chemotherapy versus 45% with chemotherapy alone. The median DOR was 9.5 months with immunotherapy/chemotherapy and 7.0 months with chemotherapy, which Ajani said was also something that has not been seen before.

Ajani said that he expects an approval is imminent for frontline nivolumab plus chemotherapy for the treatment of patients with advanced gastroesophageal adenocarcinoma based off of the results of this study.

He next pointed to impressive elements of the ATTRACTION-4 trial (NCT02746796). The study enrolled 724 patients with unresectable advanced or recurrent HER2-negative gastric or GEJ cancer and randomized them equally to nivolumab and chemotherapy or chemotherapy alone. Chemotherapy included S-1 and oxaliplatin or XELOX.

The median PFS was 10.45 months with nivolumab and chemotherapy compared with 8.34 months with chemotherapy/placebo (HR, 0.68; 98.51% CI, 0.51-0.90; P = .0007).6 “The curves separate very early and they remain separated with a very big tail. I think we haven't seen such a high tail in any of the trials,” Ajani said.

ORR with nivolumab/chemotherapy was 57.5% compared with 47.8% with chemotherapy alone. The median DOR was 12.91 months in the nivolumab and chemotherapy arm, which Ajani said was also a new landmark, versus 8.67 months in the chemotherapy-alone arm.

However, a significant benefit was not seen in OS in the ATTRACTION-4 trial with no clear reason as to why the effect seen in PFS did not carry through. The median OS was 17.45 months with nivolumab/chemotherapy and 17.15 months with chemotherapy/placebo (HR, 0.90; 95% CI, 0.75-1.08; P = .257).

The CheckMate 577 trial (NCT00743494) also looked at the potential of nivolumab in the gastroesophageal space, however, unlike in the other trials, the study enrolled higher risk patients with stage II or III esophageal or GEJ adenocarcinoma or squamous cell carcinoma who had been treated with neoadjuvant chemoradiation therapy and surgical resection but had residual pathologic disease. Also, patients were randomized 2:1 to nivolumab or placebo alone and the primary end point was disease-free survival (DFS) compared with OS or PFS as seen in the other trials.

In results from the study, which were also presented at ESMO, the median DFS with nivolumab was 22.4 months versus 11.0 months with placebo (HR, 0.69; 96.4% CI, 0.56-0.86; P = .0003).7 Ajani pointed out that all subgroups trended toward improvement with nivolumab over placebo. “Overall, this is a very positive study throughout,” he said, and surmised that this study would also lead to an approval for patients with high-risk resected esophageal cancer after chemoradiation therapy.


1. Ajani J. What, What, When, Where and How of Immunotherapy in Esophageal/Gastric Cancer. Presented at: 2020 International Society of Gastrointestinal Oncology Annual Meeting; October 2-3, 2020; Virtual.

2. Kojima T, Muro K, Francois E, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. J Clin Oncol. 2019;37(suppl 4):2. doi:10.1200/JCO.2019.37.4_suppl.2

3. 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

4. Kato K, Sun J, Shah MA, 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):S1192-S1193. doi:10.1016/j.annonc.2020.08.2298

5. 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):S1191. doi:10.1016/j.annonc.2020.08.2296

6. Boku N, Ryu MH, Oh D, et al. LBA7_PR Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. Ann Oncol. 2020;31(suppl 4):S1192. doi:10.1016/j.annonc.2020.08.2297

7. Kelly RJ, Ajani JA, Kuzdzal J, et al. LBA9_PR 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

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