IMMUNOTHERAPY IN UPPER GI CANCERS

SAN FRANCISCO — Immunotherapy drugs targeting cell programmed death (PD), already marketed for the treatment of melanoma and lung cancer, are making an impact on many other cancer types as well.

Early data now suggest that they hold promise in the treatment of advanced gastric, esophagus, and gastroesophageal junction cancers.

Two studies presented here at the Gastrointestinal Cancers Symposium 2016 showed that the PD-1 inhibitors nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) were well tolerated and demonstrated encouraging antitumor activity in these upper gastrointestinal (GI) cancers.

"Immunotherapy in esophagogastric cancers is an important effort to address an unmet need," said Markus H. Moehler, MD, PhD, from Johannes-Gutenberg University in Mainz, Germany, in a discussion of both studies.

"On one hand, we know that esophagogastric cancers have poor outcomes and we also know that CD4+ and CD8+ T-cell infiltrations correlate with improved survival," he said. "On the other hand, we also know that PD-L1-positive patients have a poorer prognosis than negative patients."

There are — or there will be — up to 10 phase 3 trials in esophagogastric cancer looking at different immunotherapy agents, Dr Moehler pointed out. The checkpoint inhibitors are being increasingly analyzed in the adjuvant setting after chemotherapy or chemoradiation.

"Combination treatment strategies are under investigation, and it is our task as the scientific community to look into interesting combinations, such as with antiangiogenesis agents or maybe with stem cell inhibition," Dr Moehler said. "It is very important that the combination of these agents be studied.

"Checkpoint inhibitors are clearly very promising new agents, and all of these compounds are still in development," he added. "But we have phase 1 data now."

First Findings for Nivolumab Monotherapy

In the first study, Dung T. Le, MD, assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore, and colleagues report results from the phase 1/2 open-label CheckMate-032 study, which is evaluating nivolumab as a single agent and in combination with ipilimumab (Yervoy, Bristol-Myers Squibb). At the meeting, Dr Le presented initial findings for the use of nivolumab monotherapy in advanced and metastatic gastric or gastroesophageal junction cancer.

"The confirmed response rate was 14% in heavily pretreated patients with both PD-L1-positive and -negative tumors," said Dr Le.

"In addition, 49% and 36% of chemotherapy refractory patient were still alive at 6 and 12 months, respectively," she noted

Put in perspective, in the second- and third-line settings, median overall survival in this population for patients receiving chemotherapy is typically 4.0 to 5.3 months, compared with 2.4 to 3.8 months for best supportive care. And the 1-year survival rate is 20% for patients receiving chemotherapy, compared with 8% for best supportive care.

A total of 163 patients with gastric cancer were enrolled in the study, and of those, 59 with locoregionally advanced or metastatic gastric cancer or gastroesophageal junction cancer were assigned to single-agent nivolumab 3 mg/kg administered intravenously every 2 weeks.

Overall, 83% of patients had received at least two previous therapies, and the primary end point of the study was overall response rate. Secondary end points included progression-free survival, overall survival, duration of response, and safety.

The median overall response rate of 14% (n = 8) included one (2%) complete response and seven (12%) partial responses. The rate of stable disease was 19% (n = 11) and of progressive disease was 58% (n = 34).

Four patients (7%) have had ongoing responses and remain on treatment.

Responses were not determined for six (10%) patients.

The disease control rate was 32% (n = 19), and median time to response was 1.6 months, with a median response duration of 7.1 months.

The median overall survival was 5.0 months, whereas 12-month overall survival was 36%. "Forty-nine percent and 36% of chemorefractory patients were still alive at 6 and 12 months, respectively," Dr Le reported.

Even though PD-L1 expression was not an inclusion criterion for the study, PD-L1 levels were available for 40 patients, and they did appear to be "numerically associated" with a higher objective response rate, she pointed out.

Patients with PD-L1 expression above 1% had an overall response rate of 27% versus 12% in those with one below 1%. Using a 5% cutoff, the response rates were 33% in those with expression above 5% and 15% in patients with PD-L1 expression below 5%.

Treatment-related adverse events occurred in 66% of the cohort, and most were grade 1/2. The most common grade 3/4 events, which occurred in 14% of patients, included pneumonitis, fatigue, diarrhea, vomiting, hypothyroidism, and increased aspartate and alanine aminotransferase and alkaline phosphatase levels. There were no treatment-related deaths.

"Nivolumab monotherapy was well tolerated in patients with metastatic gastric, esophageal, or gastroesophageal junction cancer, and the adverse-event profile was similar to that seen with other tumor types," she concluded.

Updated Results for KEYNOTE-028

Results from the second study were presented by lead author Toshihiko Doi, MD, PhD, from the National Cancer Center Hospital East inChiba, Japan. The phase Ib KEYNOTE-028 study is evaluating the safety and efficacy of pembrolizumab in patients with PD-L1-positive advanced solid tumors.

"KEYNOTE-028 shows promising antitumor activity in a heavily pretreated population," said Dr Doi. "It showed a manageable toxicity profile."

At the meeting, Dr Doi presented updated results from the esophageal carcinoma cohort of this study.

In this study, 23 patients with PD-L1–positive esophagus or gastroesophageal junction carcinoma received intravenous pembrolizumab 10 mg/kg every 2 weeks for up to 2 years until confirmed progression, intolerable toxicity, or investigator decision. Response was assessed every 8 weeks for the first 6 months, and every 12 weeks thereafter. The primary end point of the study was overall response by investigator review.

Of this group, 73.9% had squamous histology, and 87.0% had received at least two pervious therapies for metastatic disease

At a median follow-up duration of 7.1 months, the objective response rate was 30% (n = 7). All of them were partial responses, with no complete responses.

More than half of the patients (52%) had a reduction in the target lesion burden, Dr Doi pointed out.

In addition, 9% (n = 2) achieved stable disease and 56% (n = 13) had progressive disease. At a data cutoff of November 4, 2015, a statistically significant difference was not observed based on tumor histology.

The time to response was 3.7 months and the duration of response has not yet been reached, but four of seven responses are still ongoing.

Teasing Out a Gene Signature

Dr Doi noted that although some patients had achieved a durable response, others had experienced rapid disease progression in the first cycle. "It was very important to define a biomarker for immune checkpoint treatment," he said.

They selected a six-gene signature that was associated with interferon-gamma-related adaptive immune response within the tumor microenvironment, and a signature score was created based on the normalization of expression values for the six genes (IDO1, CXCL10, CXCL9, HLA-DRA, STAT1, IFN-gamma).

Patients with higher signature scores experienced a more robust response to pembrolizumab and substantial delays in progression.

"The pattern of response with an immune gene-signature score was similar to that found in head and neck cancer and gastric cancer," said Dr Doi, noting that further validation is needed.

A total of nine patients (39.1%) experienced drug-related adverse events, with the most common being decreased appetite (n = 3; 13.%). Four patients (17.4%) had grade 3 events, but there were no pembrolizumab-related deaths or treatment discontinuations.

Immune-mediated adverse events included grade 2 hypothyroidism (n = 2; 8.7%) and adrenal insufficiency (n = 1; 4.3%).

"The molecular and immunological characterization of the patient is key," as was seen with this study with the six-gene signature, noted Dr Moehler, and these are steps in the right direction. "These standardized biomarkers should be able to be broadly used for clinical use in the future," he said.

Dr Doi pointed out that there are several other trials currently ongoing to further evaluate pembrolizumab in esophageal cancer.

One study is the KEYNOTE-180, which is a phase 2 trial evaluating pembrolizumab monotherapy in participants with advanced/metastatic esophagus or gastroesophageal junction cancers who were previously treated with two standard therapies. The other is the KEYNOTE-181, a phase 3 trial in advanced esophageal/esophageal junction carcinoma, including patients whose disease progressed after first-line standard therapy. The cohort will be randomized to receive either single-agent pembrolizumab or the investigator's choice of standard therapy with paclitaxel, docetaxel, or irinotecan.

The study by Dr Le's team was sponsored by BMS and Ono pharmaceuticals. Dr Le reports receiving research funding from Aduro Biotech, Bristol-Myers Squibb, and Merck. Several of the coauthors report relationships with industry, as noted in the abstract. The study by Dr Doi's team was funded by Astellas, Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Eisai, Janssen, Lilly, Serono, MSD, Nanocarrier, Novartis, Pfizer, Taiho, Takeda, Zenyaku Kogyo, Quintiles, and Sanofi. Dr Doi reports relationships with Chugai Pharma, Novartis, Amgen, Lilly Japan, Merck Serono, Otsuka, Astellas Pharma, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Janssen Pharmaceuticals, Lilly Japan Merck Serono, MSD, NanoCarrier, Novartis, Pfizer, Quintiles, Sanofi, Taiho Pharmaceutical, Takeda, and Zenyaku Kog. Study coauthor Jaafar Bennouna, MD, from Institut de Cancérologie de l'Ouest in Nantes, France, reports relationships with Boehringer Ingelheim, Novartis, Pierre Fabre Medicament, and Roche. Dr Moehler reports relationships with Amgen, AstraZeneca/MedImmune, Serono, MSD Oncology, Roche/Genentech Taiho, Bayer, Merck, Lilly/ImClone, Bristol-Myers Squibb, and Nordic Bioscience.

Gastrointestinal Cancers Symposium (GICS) 2016: Abstract 6 and 7. Presented January 21, 2016.