Immunotherapy With Checkpoint Inhibitors: Evolving Therapeutic Options for Esophageal Cancer

Jaffer A. Ajani, MD, is a professor of medicine at The University of Texas MD Anderson Cancer Center in Houston. His primary interest is upper gastrointestinal cancer with a focus on combined modality trials for gastric and esophageal cancers. He has led numerous phase 2 and 3 randomized trials, has participated in cooperative groups, and currently chairs the National Comprehensive Cancer Network (NCCN) panels for gastric and esophageal cancer.

Esophageal cancer remains a challenging disease to treat and has a poor prognosis. What is the traditional standard of care for locoregional and locally advanced disease?

Therapeutic strategies and protocols have significantly improved the treatment of esophageal cancer; however, because most patients continue to be diagnosed with late-stage disease, overall 5-year survival for esophageal cancer remains less than 20%.¹ Treatment usually requires a multidisciplinary approach, including surgery, endoscopic procedures for premalignant and early tumors, and neoadjuvant therapy with chemotherapy or chemoradiotherapy. Current guidelines recommend combination therapy with fluoropyrimidine and platinum drugs as first-line chemotherapy but after that, there is no accepted standard of care.² Therapeutic options have been limited regardless of epidemiology, localization, or histologic subtypes, and new treatment strategies are urgently needed to improve outcomes.Because immunotherapy has proved to be effective in the treatment of various cancer entities, including lung and head and neck tumors, it was evaluated as a viable treatment option for esophageal cancer.

How did the results from the KEYNOTE-181 (ClinicalTrials.gov Identifier: NCT02564263) and ATTRACTION-3 (ClinicalTrials.gov Identifier: NCT02569242) studies change the treatment paradigm for esophageal cancer?

Until about 2 years ago, no drugs were approved for patients with squamous cell carcinoma of the esophagus, and patients did very poorly. The case was similar for adenocarcinoma. Then the KEYNOTE-181 study, which was done in the second-line setting, compared pembrolizumab with the standard of care in patients with advanced or metastatic esophageal cancer.³ The study findings were positive, leading to the approval of pembrolizumab in that setting. That was the start of immunotherapy being used for esophageal cancer, but the approval was tied to programmed death-ligand 1 (PD-L1) expression.

The study randomly assigned 628 patients with advanced or metastatic squamous cell carcinoma or adenocarcinoma of the esophagus to pembrolizumab or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or irinotecan. The primary endpoints were overall survival in patients with a PD-L1 combined positive score (CPS) of at least 10, in patients with squamous cell carcinoma, and in all patients. In the final analysis conducted 16 months after the last patient was randomly assigned, overall survival was longer for patients treated with pembrolizumab compared with patients treated with chemotherapy. In patients with a CPS of at least 10, median overall survival was 9.3 months for patients treated with pembrolizumab compared with 6.7 months for patients treated with chemotherapy (hazard ratio [HR], 0.69; P =.0074). The estimated 12-month overall survival rate was 43% in patients treated with pembrolizumab and 20% in patients treated with chemotherapy. Median overall survival in all patients with squamous cell carcinoma was 8.2 months in the pembrolizumab cohort vs 7.1 months in the chemotherapy cohort (HR, 0.78; P =.0095). In all patients, median overall survival was 7.1 months in the pembrolizumab cohort vs 7.1 months in the chemotherapy cohort (HR, 0.89; P =.0560). The US Food and Drug Administration (FDA) approved pembrolizumab in this setting for patients with a PD-L1 CPS of at least 10.

The ATTRACTION-3 trial compared nivolumab with chemotherapy in patients with previously treated advanced esophageal squamous cell carcinoma.⁴ This study was unique because it was not tied to PD-L1 expression, and the FDA approved nivolumab in this setting without regard to PD-L1 expression. This was very beneficial in the clinic because we no longer had to wait for PD-L1 expression testing to prescribe nivolumab for our patients.

In this study, 419 patients with unresectable, advanced, recurrent, or metastatic esophageal squamous cell carcinoma were randomly assigned to either nivolumab or the investigator’s choice of taxane chemotherapy. Median overall survival was 10.9 months with nivolumab vs 8.4 months with taxane chemotherapy (HR, 0.77; P =.019). Median overall survival in the pembrolizumab and chemotherapy groups was 10.9 months vs 8.1 months (HR, 0.69), respectively, in patients with tumor PD-L1 expression of at least 1% and 10.9 months vs 9.3 months (HR, 0.84), respectively, in patients with tumor PD-L1 expression of less than 1%.

Both pembrolizumab and nivolumab have now been approved for use in the second-line setting. Is immunotherapy being explored in the first-line setting?

Immunotherapy is moving into the first-line setting, as we have seen with the KEYNOTE-590 study (ClinicalTrials.gov Identifier: NCT03189719).⁵ That study showed that if pembrolizumab were added to chemotherapy, there was an advantage, especially if there were high PD-L1 expression. The addition of first-line pembrolizumab to chemotherapy resulted in improved overall and progression-free survival in patients with advanced esophageal and Siewert type 1 gastroesophageal junction cancers. These benefits were observed among all patients with esophageal squamous cell carcinoma and a PD-L1 CPS of at least 10, all patients with esophageal squamous cell carcinoma, and all patients with a CPS of at least 10. The trial supported FDA approval of pembrolizumab in the first-line setting when used in combination with platinum- and fluoropyrimidine-based chemotherapy.

The CheckMate 648 study (ClinicalTrials.gov Identifier: NCT03143153) had a unique feature in that one of the study arms was immunotherapy only.⁶ We have always given chemotherapy in the first-line setting, but now there is an opportunity to avoid chemotherapy completely. Almost 1000 patients, irrespective of PD-L1 expression status, were randomly assigned to 1 of 3 treatment arms: nivolumab plus chemotherapy with fluorouracil and cisplatin, nivolumab plus ipilimumab, or chemotherapy alone.

In the primary PD-L1-positive population, the 12-month overall survival rates were 58% in the nivolumab-plus-chemotherapy arm, 57% in the nivolumab-plus-ipilimumab arm, and 37% in the chemotherapy arm. In the full cohort, 12-month survival rates were 54%, 54%, and 44%, respectively.⁷ Toxicity was similar, although it was higher when chemotherapy was added to nivolumab and when chemotherapy was used alone. These results are promising, but the FDA has not approved the combination yet. We are hesitant to offer the combination therapy to patients as there may be reimbursement issues; payers look at the National Comprehensive Cancer Network guidelines and may hesitate to cover the cost because the combination is not yet in the guidelines or has not yet been specifically approved.

What other immunotherapies have been approved for esophageal cancer or for additional indications?

These are only 2 therapies approved for esophageal cancer. Earlier this year, the FDA approved nivolumab as an adjuvant treatment for completely resected esophageal or gastroesophageal junction cancer in patients who have residual pathologic disease and who have received neoadjuvant chemoradiotherapy.⁸ The data supporting approval came from the phase 3 CheckMate 577 trial (ClinicalTrials.gov Identifier: NCT02743494) that demonstrated a doubling of the median disease-free survival compared with placebo (22.4 months vs 11.0 months). This translated to a 31% reduction in the risk for disease recurrence or death compared with placebo (HR, 0.69; P =.001).

Another option, but only for a limited subset of patients, is dostarlimab. It is a checkpoint inhibitor that targets the PD-1/PD-L1 pathway and was granted accelerated approval in August 2021 for patients with DNA mismatch-repair-deficient (dMMR) recurrent or advanced solid tumors as determined by an FDA-approved test.⁹ This includes subsets of patients with advanced esophageal or gastroesophageal dMMR tumors. The efficacy of dostarlimab was evaluated in the GARNET trial (ClinicalTrials.gov Identifier: NCT02715284), which included 144 patients with dMMR recurrent or advanced solid tumors that progressed after systemic therapy.¹⁰ The confirmed overall response rate in patients with dMMR was 38.7%, with a complete response rate of 7.5%. The overall response rate was consistent across tumor types and included esophageal cancer.

Immunotherapy appears to be a promising option in esophageal cancer. Are additional therapeutic options being investigated in this setting? What do you see as unmet needs in this space?

A number of ongoing trials are looking at immunotherapy for patients with resectable or unresectable disease and metastatic esophageal cancer. Combination therapy is being evaluated in many of the studies, including the SKYSCRAPER-07 trial (ClinicalTrials.gov Identifier: NCT04543617), which is investigating the efficacy and safety of tiragolumab plus atezolizumab compared with placebo in participants with localized but unresectable esophageal squamous cell carcinoma.

We are seeing a growing number of products being developed in China that are trying to penetrate the Western market. They do not bring anything new or unique and have not been found to be more advantageous than products currently approved. There is no compelling reason to choose one of them except for a lower price, but many hospitals will jump on that. Clinical trial results on 2 of these drugs, which are both humanized anti-PD-1 monoclonal antibodies, were presented at the 2021 American Society of Clinical Oncology® (ASCO®) annual meeting. Camrelizumab was investigated in the ESCORT-1st trial (ClinicalTrials.gov Identifier: NCT03691090) in combination with chemotherapy in a first-line setting for the treatment of metastatic esophageal squamous cell carcinoma and led to improved overall survival compared with chemotherapy plus placebo (15.3 vs 12.0 months, respectively; HR, 0.70; one-sided P =.0010).¹¹ This response was irrespective of PD-L1 expression.

The RATIONALE 302 trial (ClinicalTrials.gov Identifier: NCT03430843) investigated tislelizumab vs chemotherapy in the second-line setting and found that tislelizumab clinically and significantly improves overall survival (median: 8.6 months vs 6.3 months, respectively; HR, 0.70; P =.0001).¹²

The first approvals for immunotherapy were in the second-line setting, but immunotherapy is now approved in the first-line setting. This creates a problem because once we use an agent for first-line treatment, we can no longer use it in the second-line setting. We have chemotherapy agents that have been around for 40 years or so but not much else to offer patients once these options are exhausted. This is an unmet need.

We do not have a clear answer as to whether switching agents will work, such as if a patient who received pembrolizumab as a first-line treatment would respond to nivolumab after cancer progression. The targets are the same, and the 2 drugs are very similar, so it is not likely this switch would be effective. This question has not been formally studied, although it would be interesting to look at. Researchers are investigating other options for second-line treatment, such as vaccines and chimeric antigen receptor (CAR) T-cell therapy. Targeted therapies, unfortunately, are moving very slowly in this space.

We have made advances with liquid biopsy, which will help with early detection. Within 10 years, liquid biopsy may change the landscape of this disease. Technology is moving rapidly. I am using it on and off but for therapeutic purposes and not early detection.

Do you feel that immunotherapy has been a game changer in esophageal cancer?

We are seeing increased survival and better outcomes. The results from large clinical trials have demonstrated significant benefits in reaching new survival benchmarks for upper gastrointestinal cancers. Squamous cell cancer is more responsive to immunotherapy than adenocarcinoma, but immunotherapy is still used and there is a subpopulation of patients for whom it works well. Before immunotherapy, we never imagined that metastatic esophageal squamous cell carcinoma could be cured. I have some patients who have completed 2 years of treatment and we cannot find any trace of cancer. We do need longer follow-up, for at least 5 years, but this is extremely promising.