In Pancreatic Cancer, a 'Step' Means a New Standard of Care

Nick Mulcahy

June 04, 2016

CORRECTED June 7, 2016 // CHICAGO — For some cancers, overall survival is now improving by leaps and bounds. But in pancreatic cancer, progress occurs on a more humble pace — by steps — according to experts here at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.

The latest step — and there are not many — comes from the phase 3 clinical trial known as the European Study Group for Pancreatic Cancer (ESPAC)-4.

In ESPAC-4, patients underwent surgery and were subsequently treated with chemotherapy. The estimated 5-year survival rate was better in those treated with the combination of gemcitabine plus capecitabine than in those treated with gemcitabine alone (28.8% vs 16.3%).

And, as a bonus, the combination was not significantly more toxic than the monotherapy.

The 15% improvement in the estimated 5-year overall survival is impressive and promising.

The standard of care worldwide for adjuvant treatment has been gemcitabine alone, said investigator John P. Neoptolemos, MD, a surgeon at the University of Liverpool in the United Kingdom.

That has now changed.

"This [combination chemotherapy] is now the standard of care," he told reporters during a meeting press conference. The results represent a "step change."

Other experts agreed.

"It's a small step forward for a group of patients who desperately need better treatment options," Richard Schilsky, MD, chief medical officer of ASCO, told Medscape Medical News.

Dr Don Dizon

With "such a difficult disease, we are going to see steps and incremental benefits [such as this result]," said Don Dizon, MD, from the Massachusetts General Hospital Cancer Center in Boston, who assessed the ESPAC-4 results while moderating the press conference.

Nonetheless, it also represents a practice change, said others, echoing principal investigator Dr Neoptolemos.

Dr Smitha Krishnamurthi

"I do believe this represents the new standard of care," said Smitha Krishnamurthi, MD, a medical oncologist at Case Western Reserve University in Cleveland, who attended the press conference as an ASCO expert.

Another clinician was leaning toward a practice change.

"Given the positive data on the combination, I would start to think about using gemcitabine plus capecitabine in the adjuvant setting," said Andrea Wang-Gillam, MD, PhD, a medical oncologist at Washington University in St. Louis, Missouri, who specializes in the treatment of pancreatic cancer and is involved with another clinical trial.

"The 15% improvement in the estimated 5-year overall survival is impressive and promising," she told Medscape Medical News.

The study cohort was an "atypical pancreatic cancer population," Dr Wang-Gillam pointed out. But there was something unusual about the success of their surgeries. "I am bit surprised about its high R1 resection rate — 60%," she said.

An R1 resection is considered a good surgical outcome, and the ESPAC-4 data far outstrip other major clinical trials of resected pancreatic cancer, she said.

For example, the CONKO-001 study, which compared gemcitabine with observation, had a rate of R1 resection below 20%, and the ESPAC-3 study, which compared gemcitabine with 5-FU, had an R1 resection rate of about 35%.

I am bit surprised about its high R1 resection rate — 60%.

Is the impressive 5-year survival rate in ESPAC-4 largely the result of expert surgeons? No, said Dr Neoptolemos, who is exclusively a pancreatic cancer surgeon. For the surgical skill required, "we're not talking about a Maserati; we are talking about a decent, well-maintained Chevrolet," he said.

Dr John Neoptolemos

In terms of the history of treatment advances for pancreatic cancer, ESPAC-3 was actually the last "step change," Dr Neoptolemos explained. That trial established adjuvant single-agent gemcitabine as a standard of care (over 5-FU). The estimated 5-year survival rate was a more modest 18%, he reported.

A study that examined gemcitabine in combination with another drug — erlotinib (Tarceva, Genentech) — showed that there was no difference between the combination and gemcitabine alone, he noted.

Nonetheless, this new survival benefit is available to a minority of patients. Only about 10% of all pancreatic cancers qualify for surgery because the disease is already too advanced at diagnosis, he said.

"The advancements of therapeutic intervention in pancreatic cancer are truly lagging behind other solid cancers," said Dr Wang-Gilliam. "Pancreatic cancer not only has a dominant KRAS mutation that is difficult to target, it also has a complex tumor microenvironment, consisting of dense fibrosis and immunosuppressive cells."

Pancreatic cancer is one of the world's most difficult cancers to treat. "If cancer is the emperor of all maladies, then pancreatic adenocarcinoma is the ruthless dictator of all cancers," Deborah Schrag, MD, MPH, from the Dana-Farber Cancer Institute in Boston, wrote in a recent editorial (JAMA. 2016;315:1837-1838).

Study Details

In ESPAC-4, 725 patients with pancreatic ductal adenocarcinoma were randomly assigned in the 12 weeks after surgery, conducted from 2008 to 2014, to six 4-week cycles of intravenous gemcitabine or to the combination of gemcitabine plus oral capecitabine.

The primary end point was overall survival; however, the Independent Trial Steering Committee requested that the trial proceed to full analysis before the target number of deaths was reached, said Dr Neoptolemos.

Median age was 65 years, which is older than the ESPAC-3 study population (60 years). This suggests that the ESPAC-4 findings are not the result of an enhanced patient population, Dr Neoptolemos explained. In addition, WHO performance status was 0 in 42% of the cohort, 1 in 55%, and 2 in 3%.

Median maximum tumor size was 30 mm, 80% were node-positive, and 40% were poorly differentiated.

Median survival with the combination of gemcitabine plus capecitabine was 28.0 months (95% confidence interval [CI], 23.5 - 31.5), and with gemcitabine alone was 25.5 months (95% CI, 22.7 - 27.9). This translates into a hazard ratio of 0.82 (95% CI, 0.68 - 0.98).

In terms of adverse events, 196 of the 366 (53.6%) patients in the monotherapy group reported 481 grade 3/4 adverse events, and 226 of the 359 (62.9%) patients in the combination group reported 608 grade 3/4 adverse events (= .242).

Dr Neoptolemos reports financial ties with multiple pharmaceutical companies, including Boehringer Ingelheim, Novartis, Kael-Gemvax, Taiho Pharmaceutical, and AstraZeneca. Dr Schilsky has disclosed no relevant financial relationships. Dr Dixon reports ties with Aeterna Zentaris and UpToDate. Dr Krishnamurthi reports ties with Nektar and Taiho Pharmaceutical. Dr Wang-Gillam reports relationships with Merrimack, Pfizer, Aduro Biotech, AstraZeneca, EMD Serono, Halozyme, Merrimack, Newlink Genetics, OncoMed, Pfizer, Precision Therapeutics, and Prometheus.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract LBA4006. To be presented June 6, 2016.

Editor's note: An earlier version of this story misidentified Dr Don Dizon, who was the moderator of the press conference.

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