Efforts Continue to Optimize Immunotherapy in Gastric Cancer

David H. Ilson, MD, PhD

The treatment of gastric cancer with immunotherapy continues to be an exciting area of investigation, particularly with the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo).

In the phase III ONO-4538-12 trial, treatment in the third-line or later setting with nivolumab reduced the risk of death by 37% compared with placebo for patients with advanced gastric or gastroesophageal junction (GEJ) cancer. Median overall survival (OS) was 5.32 months with nivolumab versus 4.14 months in the placebo arm (HR, 37%; HR, 0.63; P <.0001).¹

Pembrolizumab was approved by the FDA in September 2017 for the treatment of patients with PD-L1—positive recurrent or advanced gastric or GEJ cancer who have received 2 or more lines of chemotherapy. This includes fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-targeted therapy.

However, exploring checkpoint inhbitors in earlier settings remains a challenge. In the phase III KEYNOTE-061 trial, pembrolizumab did not improve survival for PD-L1—positive patients with advanced gastric or GEJ adenocarcinoma in the second-line setting. The PD-1 inhibitor also failed to demonstrate a statistically significant improvement in progression-free survival (PFS).

OncLive: Please provide an overview of your presentation on gastric cancer.

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Gastrointestinal Cancers, David H. Ilson, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed practice-changing trials, the optimal available therapies, and how immunotherapy fits into the future treatment paradigm for gastric cancer.*Ilson: One of the most important and potentially practice-changing trials [this past year] was determining the optimal adjuvant therapy for resectable gastric cancer.

In gastric cancer, perioperative chemotherapy with the regimen ECF [epirubicin, cisplatin, and 5-flourouracil] or ECX [epirubicin, cisplatin, and capecitabine] either administered intravenously or orally was the standard of care for more than 10 years. There was a trial presented at the 2017 ASCO Annual Meeting, which compared standard perioperative ECF or ECX chemotherapy with a regimen combining FLOT [fluorouracil, leucovorin, oxaliplatin, and docetaxel]. Investigators had pilot data for this regimen because we know that a taxane triplet is more active in metastatic disease than a chemotherapy doublet.

Investigators did a head-to-head comparison of FLOT given every 2 weeks for 4 cycles before surgery and 4 cycles after surgery compared with standard perioperative ECF for 3 pre- and postoperative cycles. The primary endpoint was OS.

We saw preliminary data from the phase II part of the study that indicated that the FLOT regimen had a higher pathologic complete response rate than ECF. This study showed superiority for FLOT at all endpoints. It had a higher curative resection rate by 7% over ECF and it also had a higher complete remission rate of 7% to 8%. The primary endpoint of median OS was improved from 30 months to 50 months. That translated into a survival improvement of about 9% at 5 years. That is a significant benefit over ECF and with improvements in all the other endpoints, which indicates that it probably should be the new standard of care.

The problem is that not all patients can tolerate a 3-drug therapy. The subset analysis indicated that even patients over the age of 65 had benefits, but not all patients are going to be candidates for a taxane triplet regimen. However, this study does displace ECF and should be considered as the new standard of care for perioperative chemotherapy in gastric cancer.

Tumors of the esophagus and GEJ need the addition of radiation concurrently with preoperative therapy to make sure there is a negative margin. There are some other large studies from the United Kingdom that gave chemotherapy alone, primarily esophagus and GEJ, that had curative resection rates of only about 60%. We know from the Dutch CROSS trial that when you give chemotherapy and radiation, the curative resection rate is around 90%. We may need to add concurrent radiation to chemotherapy in tumors of the esophagus and GEJ, but for more dismal gastric cancers, perioperative chemotherapy with FLOT should be considered the standard.

The other advances are in the metastatic setting. A very important study was presented in HER2-positive patients. We know that trastuzumab [Herceptin] added to chemotherapy in HER2-positive disease improves outcomes, but there is a lot of expectation that dual-targeted HER2-therapy would also improve outcomes. Pertuzumab [Perjeta], which targets HER2 and HER3, improves outcomes in HER2-positive breast cancer, so there is hope that pertuzumab added to trastuzumab and chemotherapy would improve survival. Data presented at the 2017 ESMO Congress failed to show a survival improvement; however, it looked like it trended. There was a suggestion of higher PFS and a better response rate but, at the end of the day, the survival endpoint was not met. They were very disappointing results. It is not clear whether pertuzumab is going to move forward in first-line treatment.

The last issue that I discussed in my talk was about immunotherapy drugs. There are positive data from both nivolumab and pembrolizumab. The nivolumab trial was in third-line gastric cancer versus best supportive care. They did not use PD-L1 selection in those patients and they reported a response rate of around 11% and an improvement in 1-year survival from 11% to almost 27%, indicating a modest benefit. If you look at the PFS in most patients, they progress on the treatment very quickly but there is a tail on the curve of the patients who do benefit.

The other data come from pembrolizumab where they received an FDA indication from their large phase II expansion cohort trial, in which they treated over 250 patients with chemotherapy-refractory esophagus and GEJ cancer. There was no PD-L1 selection but they did prospectively test PD-L1 in 60% of patients most having had 2 or more previous chemotherapy regimens.

The data were very similar to nivolumab. The response rate in all patients was 10% and the 1-year survival was around 25%, which is comparable to the phase III results for nivolumab. However, on this trial they did look at PD-L1 testing and the response rate was higher in the PD-L1—positive patients with 15% compared with 5% for PD-L1–negative patients. Based on the phase II data, they received an FDA indication for gastric cancer to use pembrolizumab in PD-L1–positive chemotherapy-refractory patients.

Are immunotherapy agents going to be used in combination next?

Earlier this year, pembrolizumab was approved for microsatellite instability-high (MSI-H) tumors. In colon cancer, anti—PD-1 drugs are active in MSI-H tumors with response rates to 30% or 50%. Also, there are provocative data in other MSI-H tumors that you get responses in 50% or more patients. Even in this large phase II expansion trial, they did treat 7 MSI-H patients where 4 out of the 7 responded. We now have an FDA approval of pembrolizumab for MSI-H tumors and chemotherapy-refractory GEJ and gastric cancers that are PD-L1–positive.We are awaiting the results in first-line trials. There are 2 major first-line trials in esophageal and gastric adenocarcinoma. One is looking at pembrolizumab alone versus chemotherapy alone versus the combination of chemotherapy plus pembrolizumab. That is an important study that is nearly accrued. Nivolumab also has a first-line trial of FOLFOX chemotherapy versus FOLFOX plus nivolumab versus the combination of nivolumab and ipilimumab (Yervoy) without chemotherapy. That is an ongoing trial.

We will see whether adding an anti—PD-1 drug to chemotherapy offers a benefit and whether upfront combination immunotherapy or single-agent chemotherapy offers any kind of benefits to patients. The problem is that immunotherapy still has a relatively low response rate and may not be the optimal initial therapy.

Looking ahead to the future of this treatment landscape, is there an approach that does not include chemotherapy?

When looking at immunotherapy combination strategies, ipilimumab adds a lot of toxicity and often these patients are ill to begin with, so that might not be the optimal combination strategy. We will have to see what the first-line data show. There are many other modulatory drugs, such as the IDO inhibitors and other pathway stimulators like LAG3 drugs combined with immunotherapy. It is an exciting time, and we will have to see whether combination strategies will be effective and if they will augment the modest signal of benefit that we see for single-agent immunotherapy.Not right now. The drugs have a small signal of activity that I am not convinced should move up in earlier lines, except for MSI-H patients even though that only includes 5% of the population. We need to determine whether moving immunotherapy up earlier with chemotherapy offers an advantage. Upfront single-agent therapy does not have enough activity unless you have an MSI-H tumor.

A maintenance strategy is being looked at with avelumab (Bavencio) after chemotherapy. Later-line use is already being validated and there are many second-line trials that determine how these drugs fair against second-line chemotherapy, as well.

The future is going to be combination strategies, new modulators, and identifying biomarkers and new targets because we have hit a plateau with these drugs. We are anxiously awaiting the first- and second-line trial data and combination data with chemotherapy.

*Editor’s Note: This interview was conducted prior to the results of the KEYNOTE-061 trial.

Reference

1. Kang Y-K, Satoh T, Ryu M-H, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial. J Clin Oncol. 2017;35(suppl 4S; abstract 2).