Pembrolizumab Plus Chemotherapy Elicits Continued Survival Benefit in Advanced Esophageal Cancer

Manish A. Shah, MD

Combined treatment with pembrolizumab (Keytruda) and chemotherapy has been shown to promote longevity in patients with advanced esophageal cancer as evidenced by results from the phase 3 KEYNOTE-590 study (NCT03189719), which continue to show persistent and proven benefits with the regimen vs chemotherapy alone.

At the 2024 Gastrointestinal Cancers Symposium in San Francisco, California Manish A. Shah, MD, presented data from the KEYNOTE-590 trial which investigated the efficacy and safety of the combination in patients with locally advanced or metastatic esophageal cancer. Updated results from the trial, which were presented with a median follow-up of 58.8 months (range, 49.2-70.6), showed that patients who received pembrolizumab plus chemotherapy achieved a median overall survival (OS) of 12.3 months (95% CI, 10.5-14.0) versus 9.8 months (95% CI, 8.8-11.0) with placebo plus chemotherapy (HR, 0.72; 95% CI, 0.62-0.84).^1,2

Discussing the study’s impact, Shah explained, “Immunotherapy has been transformative in many cancers, and it is transformative in esophageal cancer. We need to test [for] biomarkers to [see whether] tumors express PD-L1. If they do, we should consider adding pembrolizumab to chemotherapy to maximize the benefit. The real message is that some patients may live quite a long time [on this regimen], even 5 years, which was previously unheard of.”

In an interview with OncLive^®, Shah elaborated on the 5-year outcomes from the phase 3 KEYNOTE-590 study. Shah is the director of the GI Oncology Program at Weill Cornell Medicine and chief of the Solid Tumor Service Program as well as the codirector of the Center for Advanced Digestive Disease at NewYork-Presbyterian in New York.

OncLive: What have earlier results shown about the efficacy of this regimen?

Shah: KEYNOTE-590 was a practice-changing study of chemotherapy plus immunotherapy in esophageal cancer. We heard the initial results after about 2 years of follow-up where they suggested pembrolizumab plus chemotherapy was significantly better in terms of survival compared with chemotherapy alone for patients with esophageal cancer. The update from this poster was the five-year results.

This was a large study; about 700 patients were randomized to either receive chemotherapy plus placebo, or chemotherapy with pembrolizumab. The study [enrolled patients with] esophageal cancer, which included both squamous cancer and adenocarcinoma. The investigators looked at different subgroups of patients that had a high PD-L1 combined positive score (CPS) score of 10 or higher or 1 or higher and then in all-comers.

The upshot is that even throughout five years there was a significant benefit with the addition of pembrolizumab to chemotherapy compared with no pembrolizumab. The five-year survival rate with pembrolizumab was somewhere between 10% to 15%, depending on what subgroup you’re looking at, compared with about 3% with chemotherapy alone. Tripling to quadrupling the five-year survival rate was remarkable.

How has the addition of pembrolizumab to chemotherapy affected the immune response in patients with varying levels of PD-L1 expression?

Pembrolizumab is a PD-1 inhibitor. By finding PD-1 on the cancer cells and on the T cells, you can activate the immune response against the cancer. Squamous cell cancer as well as esophageal adenocarcinoma can overexpress PD-1, so by blocking that pathway, you’re effectively turning off the brake for the immune system to become activated. Tumors that have a higher PD-1 status are more sensitive to the addition of pembrolizumab. We measure that by something called the hazard ratio. [The hazard ratio equates the relative benefit of adding pembrolizumab versus not].

In the CPS 10 or higher group, which is the group that should benefit the most with pembrolizumab, the hazard ratio [for OS] was around 0.64. So, there was about a 36% improvement in survival with the addition of pembrolizumab to chemotherapy. Then, as the CPS score went lower and lower, the benefit was still there, but it wasn’t as striking.

How might these factors influence the interpretation of the study, and the application of it in real-world scenarios for patients?

With the long-term survival benefit, it’s well established now that pembrolizumab should be given to patients with esophageal cancer, along with chemotherapy. One of the key things that we found is that the people who had the longest survival had typical evidence of metastatic disease, including patients with liver metastases. The consistent, sustained benefit in both progression-free survival and OS, along with minimal increase in toxicity suggest that pembrolizumab should now be a standard with chemotherapy for esophageal cancer.

References

1. Shah MA, Sun JM, Shen L, et al. First-line pembrolizumab plus chemotherapy for advanced esophageal cancer: 5-year outcomes from the phase 3 KEYNOTE-590 study. J Clin Oncol. 2024;42(suppl 3):250. doi:10.1200/JCO.2024.42.3_suppl.250
2. First-line esophageal carcinoma study with chemo vs. chemo plus pembrolizumab (MK-3475-590/​KEYNOTE-590). ClinicalTrials.gov. Updated July 27, 2023. Accessed February 21, 2024. https://clinicaltrials.gov/study/NCT03189719?tab=results