Immunotherapy Potential Continues to Grow in Gastric Cancers

Hendrik-Tobias Arkenau, MD, PhD

The PD-L1 antibody avelumab demonstrated promise in previously treated patients with gastric/gastroesophageal junction cancers (GC/GEJ), according to results from the phase Ib JAVELIN trial presented at the 2016 ASCO Annual Meeting.¹

The study is investigating avelumab in patients across multiple solid tumor types who progressed on more than 2 lines of prior therapy or had received 1 line of chemotherapy but had not yet progressed.

As of February 13, 2015, 75 patients with GC/GEJ were treated with avelumab. Of those patients, responses were observed in 7. PD-L1 expression was evaluable in 55 patients, including in 3 patients with a response. Median progression-free survival (PFS) in patients who had received 2 or more prior lines of therapy was 36 weeks (95% CI, 6.0-36.0) for PD-L1—positive patients and 11.6 weeks for PD-L1−negative patients. Among patients who had received 1 prior line of chemotherapy, the median PFS was 17.6 weeks for PD-L1–positive patients and 11.6 weeks for PD-L1–negative patients.¹

OncLive: Can you discuss the significance of the GC/GEJ cohort in the JAVELIN trial?

In an interview with OncLive, Hendrik-Tobias Arkenau, MD, PhD, founding medical director, executive medical director, Sarah Cannon Research Institute UK, discusses the significance of the JAVELIN results for gastrointestinal (GI) cancer. He also explains the potential for CTLA-4 and PD-1/PD-L1 combinations, the promise of pembrolizumab (Keytruda) in colorectal cancer, and the overall challenges of treating patients with GI cancers.Arkenau: The JAVELIN trial with avelumab is the largest phase I trial going on right now with a PD-L1 inhibitor. Right now, there are 1600 patients enrolled on the trial. At the 2016 ASCO Annual Meeting, we presented the safety and efficacy data. In terms of efficacy, we see that several patients in selected tumors types have an increased benefit. Regarding safety, this large trial confirms that adverse events are in line with previously reported side effects with immunotherapies.

What immunotherapy advancements are on the horizon in GC?

What are the biggest challenges remaining in the treatment of patients with GI cancers?

Of particular interest is a subgroup of patients in an expanded cohort of GEJ. These are patients who progressed on first-line standard therapy. Again in this cohort, there were no significant side effects. At ASCO, we reported that some of these patients have an increased benefit with avelumab in terms of progression-free survival. Overall, these are really interesting data to bring forward into randomized trials in the later stage.Immune combinations are really exciting—particularly the idea of enhancing both CTLA-4 or PD-1/PD-L1 inhibitors by giving them together. The OX40/PD-1 combination has some potential as well, but there were added toxicities. I will be very interested in seeing data from phase II and expanded cohorts examining these combinations—especially from a safety viewpoint—but from an efficacy point of view, as well.Patients with GI cancers are obviously very heterogeneous. In upper GI and pancreatic cancer, where we have not seen the benefit of immunotherapies, there is certainly a challenge for us. In liver, gallbladder, and biliary tract cancers, we have seen very early data, but it is too early to say that the standard of care will be immunotherapy there right now.

It is likely that at the 2017 ASCO Annual Meeting, we will see some interesting data regarding this. In GEJ and GC, the biggest challenge for us is getting the window of opportunity right. Once patients have progressed on the standard of care chemotherapies, they need to get on a clinical trial quickly and efficiently and get relevant biopsied biomarker data.

At this year’s ASCO Annual Meeting, were there any findings in GI cancers that you found particularly exciting?

These patients are often a challenge to treat because they progress very quickly, which can cause weight loss and other issues. It would be great if we could see these tumor types flourishing with immunotherapy.There were data presented on mismatch repair-deficient GI cancers, particularly in colorectal cancer (CRC). Here, we see really exciting and promising data. These patients with CRC do not usually respond to standard chemotherapies, and they progress very quickly.

The data we saw presented at ASCO (NCT01876511) showed that patients with mismatched repair-deficient CRC have response rates in the range of 60%, a disease-control rate of about 40%, and a 2-year PFS rate and overall survival rate of 61% and 66%, respectively, with pembrolizumab. This was one of the most exciting things to come out of the meeting in GI cancers.

Outside of immunotherapy, there was also a very interesting meta-analysis of more than 13,000 patients on phase I studies. Out of these 13,000 patients, there were 54 treatment arms of targeted therapies. We have talked at the last few ASCO meetings about how the more targeted patients are treated with small molecules, the better the outcomes are. In terms of an unselected approach, the response rate was in the range of 5% versus a 35% response with a targeted approach. This really confirms that the strategy of personalized medicine—matching the genetic alteration to a drug—can result in very successful data, even in a phase I study.

1. Le D, Uram J, Wang H, et al. Programmed death-1 blockade in mismatch repair deficient colorectal cancer. J Clin Oncol 2016;34 (suppl; abstr 103).