Shah Discusses KEYNOTE-180 and BRIGHTER Results in GI Cancers

Manish A. Shah, MD

Manish A. Shah, MD

At the 2018 ASCO Annual Meeting, 2 clinical trials addressed the unmet needs for select patients with gastrointestinal (GI) cancers. However, according to Manish A. Shah, MD, a number of challenges still remain in the field.

The KEYNOTE-180 trial, an open-label phase II study, investigated the use of pembrolizumab (Keytruda) in patients with metastatic squamous cell carcinoma or adenocarcinoma of the esophagus who had previously received at least 2 lines of therapy. Pembrolizumab was given to patients at 200 mg every 3 weeks for up to 2 years or until disease progression or unacceptable toxicity.

Data suggested modest efficacy with an objective response rate (ORR) of 10% for the overall patient population, ORR being the primary endpoint of this study.¹Subgroups were also determined based on PD-L1 expression, with PD-L1—high tumors demonstrating a slightly better response (14%).

Shah said patients who responded to immunotherapy showed significant durability. KEYNOTE-181, a phase III trial, is now evaluating pembrolizumab against standard therapy for patients with advanced esophageal/esophagogastric junction carcinoma who progressed after frontline treatment (NCT02564263).

The BRIGHTER study, presented at the 2018 ASCO Annual Meeting as well, investigated the stem cell inhibitor napabucasin (BBI-608) in patients with gastric and gastroesophageal junction adenocarcinoma. By targeting STAT3, napabucasin is intended to block cancer stem cell self-renewal.

Patients on napabucasin received the oral inhibitor at 480 mg twice daily; paclitaxel was administered in the standard dose of 80 mg/mg²on days 1, 8, and 15 in a 4-week cycle. However, trial investigators did not report an improvement in survival for patients on napabucasin compared with paclitaxel.²Subset analyses will determine whether patients who have high expression of STAT3 benefited from the agent, Shah said.

In an interview withTargeted Oncology, Shah, director of Gastrointestinal Oncology and chief of Solid Tumor Service at Weill Cornell Medicine/NewYork-Presbyterian Hospital, discussed key details of the KEYNOTE-180 trial, as well as results from the BRIGHTER study. He also shared his insights on the unanswered questions that still need to be addressed in the field.

TARGETED ONCOLOGY:Please provide some background to the KEYNOTE-180 trial.

Shah:Esophageal cancer is a deadly disease. Unfortunately, most patients with metastatic disease die within 1 year. There are very few targeted therapies in esophageal cancer and most patients don't get treatment after the second line of therapy. The active cytotoxic drugs have modest activity, but we are really in search for more. It's certainly an unmet need.

Pembrolizumab is a PD-1 inhibitor as we all know, and we examined that in esophageal cancer—both squamous cell and adenocarcinoma—in the third-line setting. We looked at patients who were both PD-L1 positive and PD-L1 negative, and we looked at the efficacy. We saw there was modest efficacy at about 10% ORR. It was 14% in the PD-L1—positive population and 6% in the PD-L1–negative population. Squamous cell cancers seemed to respond more than adenocarcinomas, but even that was modest.

The most compelling thing about the data is that the responses are durable. Patients who did respond to immunotherapy were alive at 8, 10, 12 months, or even longer. That is really life-changing. It contributes to the literature of the use of immunotherapy in gastrointestinal cancers. There seems to be modest activity across the board for most tumors, and we hope that we can learn more about which cancers specifically will respond better.

TARGETED ONCOLOGY:What were some of the safety data you observed?

Shah:Overall, pembrolizumab was quite safe. One of the concerns in esophageal cancer—and this may be unique to this kind of cancer—is that most patients have received chemotherapy and radiation therapy. After that, is pembrolizumab safe? Of course, the risk of pneumonitis is there. However, we did not see a significant rate of pneumonitis in these patients. It was a typical safety spectrum of immunotherapy drugs. Some patients had diarrhea, thyroid problems, fatigue, and rash, but it was generally manageable. Very few patients required steroids.

TARGETED ONCOLOGY:What are some next steps following KEYNOTE-180?

Shah:Based on the modest activity, the drug is being tested in the second-line setting against chemotherapy. That study is completed. It's also being tested in the frontline setting. There are efforts to see if we can even use it in the neoadjuvant or adjuvant space.

TARGETED ONCOLOGY:What is your vision for immunotherapy in esophageal cancer?

Shah:We have a clear understanding that there is modest activity with immunotherapy in esophageal cancer. What we don't know is what the mechanism of resistance is. Is it increased regulatory T cells that are inhibitory? Is it a lack of antigen-presenting cells? Is it not enough cytotoxic T cells? We don't know these things. We need to actually do more studies, get the tissue, and understand what the mechanism of resistance is to either augment the immunotherapy with another drug or be better selective.

TARGETED ONCOLOGY:Moving on to gastric cancer, please provide some background to the BRIGHTER trial.

Shah:The BRIGHTER trial is a phase III clinical trial examining the role of napabucasin, which is a stem cell inhibitor in gastric cancer. This was a randomized placebo-controlled study of paclitaxel with or without napabucasin. Unfortunately, it was a negative study. Patients who received napabucasin did not have an improvement in survival.

We are still doing the biomarker analysis in a subset of patients with overexpression of STAT3 target to see if they benefited. There are data in colon cancer where the phosphorylated STAT3 group did benefit from napabucasin. There is an ongoing second-line study of chemotherapy with or without napabucasin in colon cancer and we're hoping to get some data in gastric cancer that will be a parallel of that.

TARGETED ONCOLOGY:What were some of the more surprising data from this trial?

Shah:Some key features of the study that may not be so obvious is that there was a slight increase in toxicity with napabucasin, specifically diarrhea. Even though the survival and progression-free survival was the same in both arms, patients who received napabucasin did receive 1 less month of chemotherapy. How much this played a role in the negative results, we don't know. This definitely highlights the importance of making sure that your targeted drug can be administered safely and without any added toxicity. This does potentially affect the chemotherapy dose. We have seen that before in other phase III studies, where the effect of chemotherapy—specifically the dose—is significant.

TARGETED ONCOLOGY:From a general standpoint, how much progression has the field of GI cancer treatment seen in the last few years?

Shah:It's clear that we are trying to dice up the different diseases into different subtypes that will benefit from specific targeted agents. There are these 4 different subtypes of colon cancer, probably more. We've already talked about the microsatellite instability—high subtype. We are also talking about theBRAF-positive subtype. The left-sided tumors seem to have significant activity with EGFR inhibition. Not only do they tend to be a wild-type, but they have increased ligand signaling. Over the next 5 years, we're going to be a lot smarter with tailoring therapy to specific targeted agents.

References:

1. Shah M, Kojima T, Enzinger P, et all. Pembrolizumab for patients with previously treated metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: phase 2 KEYNOTE-180 study.J Clin Oncol.2018;36 (suppl; abstr 4049).
2. Shah M, Muro K, Shitara K. The BRIGHTER trial: a phase III randomized double-blind study of BBI-608 + weekly paclitaxel versus placebo (PBO) + weekly paclitaxel in patients (pts) with pretreated advanced gastric and gastro-esophageal junction (GEJ) adenocarcinoma.J Clin Oncol.2018;36 (suppl; abstr 4010).