Clinical Trial Shows Promise in Combination Therapy for Gastric Adenocarcinoma

Dr. Gulam Manji presented results from a phase II clinical trial testing a combination therapy for resectable gastric cancer or gastroesophageal junction (GEJ) cancer at this year’s American Association for Cancer Research Annual Conference held April 8-12, 2022 in New Orleans, LA.

What did this clinical trial evaluate?

This phase II clinical trial tested the hypothesis that combination chemotherapy and pembrolizumab is effective in resectable gastric cancer or gastroesophageal junction (GEJ) cancer. Currently, the standard of care for locally advanced gastric or GEJ cancer is perioperative (before and after surgery) chemotherapy. Unfortunately, not all patients have success with this treatment, so more options are needed. On the other hand, only 3% of patients who receive triple combination chemotherapy (three different chemotherapy drugs at once) have their cancer grow while on therapy. A triple chemotherapy regimen for patients who can tolerate this aggressive treatment is the current standard. We tested a doublet chemotherapy combination (two chemotherapy drugs at once) that would be more tolerable for patients who may not be able to tolerate triple chemotherapy, such as older patients.

What is pembrolizumab and why was it a viable potential option?

We know from previous studies that an immune checkpoint inhibitor (ICI) like pembrolizumab in combination with chemotherapy is effective for metastatic gastric or GEJ cancer whose tumors express PD-L1, a protein that acts as a kind of ‘brake’ on the immune system. We hypothesized that it could be effective for locally advanced (resectable) gastric or GEJ cancer for patients whose tumors do not express PD-L1. ICIs work by taking the brake off the immune system, giving the immune system a ‘boost’ to search and destroy cancer cells. The challenge is that sometimes, ICIs need a little more of a boost to work, which is why this trial tests a combination of pembrolizumab with chemotherapy.

What did the study find?

The results are very encouraging. We found that the combination therapy resulted in a complete pathological response (no viable cancer cells) in 20.6% of patients, and a near-complete response (single or rare small groups off cancer cells) in 17.6% of patients. The study is still following patients, but we can estimate that 60% of patients will have no sign of their cancer at 2 years after treatment, which is a very good result. On top of that, the combination therapy was well-tolerated and most patients had limited side effects. A third of the patients on the study were older than 70 years old, suggesting that older patients can tolerate the combination.

Preliminary results from multiplex immunofluorescence performed on pre-treatment biopsy and on-treatment surgical resections suggest an increase in immune cell infiltration despite of response.

We also collected biopsies from patients before and during treatment, and our preliminary analysis suggest that immune cells increased in patients regardless of how they responded clinically to the therapy. Using machine learning algorithms, we identified a ‘signature’ for response to the therapy, using 39 features from the biopsy samples. A test set from biopsy samples was able to accurately identify pathological complete responses in 82% of the cases, which could be helpful in clinical decision-making.

What are next steps with the study?

Our results of the phase II trial provide an optimistic outlook. There is an ongoing phase 3 study testing triplet and doublet chemotherapy combination with pembrolizumab.

We are planning an additional analysis to validate the predictive signature identified via machine learning algorithms. If validated, our preliminary predictive signature for response will impact patient selection for chemotherapy and pembrolizumab combination in resectable gastric and GE junction adenocarcinoma.