Sandra Hanner

Patients with pancreatic adenocarcinoma enrolled on clinical trials have “profoundly improved survival” compared with patients in the general population, according to research presented at the 2016 Gastrointestinal Cancers Symposium. This suggests that oncologists who use trial data to prognosticate may be missing the mark.

In the analysis, there was as much as a 92 percent difference in median overall survival (OS) seen between patients treated in randomized controlled trials and “real world” data from the Surveillance, Epidemiology, and End Results (SEER) database. Additionally, patients treated in clinical trials had a 72.7 percent increase in two-year OS rates compared with the SEER findings.

“We believe that lots of clinicians use trial data to predict their own patients’ survival, but our findings suggest that physicians should use caution when extrapolating survival estimates from clinical trials to the real world,” said senior author James D. Murphy, of University of California, San Diego (UCSD), School of Medicine. “We know that clinical trial patients, in general, are somewhat different from the real-world population.”

For the study, the researchers conducted a literature search of phase 3 trials published between 2005 and 2012 for patients with pancreatic cancer. They excluded secondary or pooled analyses trials with second-line treatments and nonrandomized studies. Findings from the clinical trials were compared with a cohort of patients from the SEER program, matching for diagnosis year, age and stage of disease. The aim was to explore differences in median survival, one-year survival and two-year survival between the SEER registry patients and clinical trial cohorts.

“We know patients have to be fit to enroll, and they tend to live near academic centers (i.e., trial sites), be wealthier, and to have better access to health care,” said Murphy. “If they are on a trial, they are also likely to have closer follow-up. Still, there have not been many studies determining if being on a trial actually translates into a difference in survival.”

The literature search resulted in 27 trials that fit the search criteria, consisting of 55 clinical trial arms involving 8,438 patients. Tumor characteristics were categorized as: (1) patients with mixed metastatic and locally advanced unresectable metastatic pancreatic cancer; (2) those with unresectable locally advanced disease; and (3) patients deemed resectable.

Almost 100 percent of all the randomized trials had survival outcomes that were better than outcomes seen in the SEER registry, and this held true for each of the three populations, reported lead study author Reith R. Sarkar, a medical student at the UCSD, School of Medicine. “Physicians often use clinical trial data to estimate expected survival for their patients; however, clinical trial results may not generalize to a broader population,” he said.

For patients with mixed metastatic/locally advanced unresectable pancreatic cancer, there was a 3.23-month median increase in OS between the clinical trial and the SEER database, representing a 92 percent improvement. In the unresectable locally advanced group, OS was improved by 41 percent in the clinical trial versus SEER, a median improvement of 2.96 months. In the resectable group, median survival was 6.1 months better in the clinical trial arm versus SEER group, a 36 percent improvement.

The average increase in one-year OS, in these respective groups, was 88.8 percent, 45.3 percent and 23.7 percent. Absolute differences in one-year survival were more than 12 percent in each category (ranging from 12 to 14.7). Average increases in two-year OS were 72.7 percent, 49.9 percent and 34.0 percent, which were associated with absolute differences of 2.5 percent, 4.6 percent and 11.9 percent, respectively.

“We saw that for metastatic patients, average survival was almost double for clinical trial patients, versus real-world patients. The differences were greatest for the worst-prognosis cancers,” Sarkar said. “We think this is a pretty profound difference.”

Sarkar acknowledged that he and his team could not assess the SEER database for patient performance status, underlying comorbidities, and differences in treatment-factors that may help explain some of the survival differences. These factors could have impacted the overall outcomes.

Sarkar RR, Matsuno R, Murphy JD. Pancreatic cancer: Survival in clinical trials versus the real world. 

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In the analysis, there was as much as a 92 percent difference in median overall survival (OS) seen between patients treated in randomized controlled trials and "real world" data.

Pancreatic Cancer Survival Rates Lower in Real World Versus Clinical Trials

An analysis of the phase 3 NAPOLI-1 trial supports the benefits of adding MM-398 chemotherapy for the treatment of patients with metastatic pancreatic cancer who were previously treated with Gemzar (gemcitabine).

In the per-protocol assessment, treatment with the nanoliposomal encapsulation of irinotecan (MM-398) plus 5-fluorouracil plus leucovorin (5-FU/LV) improved overall survival by 53 percent compared with 5-FU/LV alone. In the full intent-to-treat population of NAPOLI-1, MM-398 plus chemotherapy improved survival by 43 percent as reported in 2014.

“In the per-protocol population, the MM-398 plus 5-FU/LV combination regimen achieved a median overall survival of 8.9 months,” said Li-Tzong Chen, of the National Institute of Cancer Research in Tainan City, Taiwan, who reported the expanded pre-specified per-protocol and sensitivity analyses of the NAPOLI-1 data at the 2015 Gastrointestinal Cancers Symposium.

MM-398 contains about 80,000 molecules of irinotecan stably encapsulated in a 100-mm liposome.

“Not surprisingly, the combination achieved a highly significant improvement in overall survival in the per-protocol analysis. But more surprisingly, it also significantly improved overall survival in the non-per-protocol population versus the control arm,” Chen said. “Analysis of the subgroups consistently favored overall survival for the MM-398 plus 5-FU/LV arm over 5-FU/LV alone.”

No benefit was observed for MM-398 as a single agent, with median OS of 4.9 months, compared to 4.2 months with 5-FU/LV.

Dose reductions were necessary for 33 percent of the MM-398 arm versus 3 percent of the control arm, and dose delays occurred in 61 percent versus 21 percent, respectively. In spite of this, the average duration of exposure was 21 weeks for the combination versus 13 weeks for 5-FU/LV alone, Chen indicated.

The safety profile of the combination regimen was considered manageable. In the per-protocol population, the most frequent moderate to severe adverse events were neutropenia, fatigue, diarrhea and vomiting.

Laura Goff, MD, of Vanderbilt University Medical Center, Nashville, commented as the study discussant that the partial response rate of 16 percent in a second-line population was “provocative,” and the median survival times were similar to those previously reported for FOLFIRI (fluorouracil, leucovorin, irinotecan) in second-line pancreatic cancer.

“MM-398 appears to have activity in combination with 5-FU/leucovorin in previously treated pancreas cancer, and it has received fast track status from the FDA,” Goff indicated.

In November 2014, the FDA granted MM-398 plus 5-FU and leucovorin a fast track designation as a second-line treatment for patients with metastatic pancreatic cancer, based on data from the NAPOLI-1 study. 

An analysis of the phase 3 NAPOLI-1 trial supports the benefits of adding MM-398 chemotherapy for the treatment of patients with metastatic pancreatic cancer who were previously treated with Gemzar.

Analysis of NAPOLI-1 Study Shows MM-398 Benefit in Metastatic Pancreatic Cancer

Among patients with metastatic gastric cancer treated with the PD-1 inhibitor Keytruda (pembrolizumab), the agent showed promising antitumor activity and manageable side effects, according to updated findings from the KEYNOTE-012 study presented at the 2015 Gastrointestinal Cancers Symposium.

The gastric cancer cohort of the KEYNOTE-012 trial involved 39 patients whose tumors expressed PD-L1.  Cancer cells that express PD-L1 bind to a protein called PD-1 found on the surface of T cells, immune cells that would ideally attack cancer cells. By binding to PD-1, the malignant cell switches off the T cell and renders cancer cells invisible to the immune cell.

Patients received Keytruda every two weeks for up to 24 months or until complete response, disease progression or if the side effects became too severe.

In an update of the initial analysis presented in September at the European Society for Medical Oncology, Kei Muro, of the Aichi Cancer Center Hospital in Nagoya, Japan, reported that at 8.8 months’ follow-up, there was strong evidence of anticancer activity. Eight patients experienced partial responses; stable disease was observed in another five. Responses were similar for Asian and non-Asian populations.

For four patients, response was not assessed or able to be determined. Approximately 53 percent of patients had some degree of tumor shrinkage.

“Six of the eight responders were still responding at the time of this analysis,” Muro noted. The median time to response was eight weeks, he said, and median response duration was 24 weeks. Median progression-free survival was 1.9 months. At 6 months, the overall survival (OS) rate was 69 percent. Median OS had not been reached, he reported. “We found a trend toward improved outcomes with higher levels of PD-L1 expression,” Muro added.

Four patients had a treatment-related adverse event of grade 3-5. One death was reported from hypoxia.

The phase 2 KEYNOTE-059 study of Keytruda monotherapy or in combination with cisplatin plus 5-fluorouracil for advanced gastric cancer will be initiated early in 2015.

Ronald Levy, professor and chief of the Division of Oncology at Stanford University School of Medicine, presented a keynote lecture on anti-PD-1 monoclonal antibodies at the meeting, showing enthusiasm for immune therapies in cancer in general. “We have found out that we can use the immune system to kill cancer, and this includes gastrointestinal cancers,” he said.

Commenting on the KEYNOTE-012 findings, in particular, he noted, “Not many of the tumor cells need to express this ligand for this drug to work,” however, he acknowledged that only 40 percent of patients had that 1 percent necessary for eligibility, and the majority did not respond.

“Why do some patients respond and not others?” Levy asked. “Is it PD-L1 expression by the tumor cells or stromal cells in the environment? They can talk to the incoming T cells and shut them off, but they are not perfect as predictors.”

Efforts are underway to try to boost these response rates through combinatorial therapy, he said, and potentially by increasing the expression of the target, the PD-1 ligand.

Among patients with metastatic gastric cancer treated with the PD-1 inhibitor Keytruda, the agent showed promising activity, according to updated findings from the KEYNOTE-012 study presented at the Gastrointestinal Cancers Symposium.

Sandra Hanner

Pancreatic Cancer Survival Rates Lower in Real World Versus Clinical Trials

Analysis of NAPOLI-1 Study Shows MM-398 Benefit in Metastatic Pancreatic Cancer

Updated Study Results Shows Activity for Keytruda in Gastric Cancer

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