Three Drugs Beats Two in Advanced Pancreatic Cancer

A small trial in patients with advanced pancreatic cancer found that adding a third chemotherapy to the doublet that is currently the standard of care resulted in substantial tumor shrinkage and significantly extended overall survival (OS).

Cisplatin was added onto standard of care nab-paclitaxel (Abraxane, Celgene) plus gemcitabine (Gemzar, Eli Lilly).

"Both our median progression-free survival and overall survival were almost double what we can achieve with the doublet standard alone, so we believe that we have made real progress in this disease," co-author Gayle Jameson, RN, associate clinical investigator and a nurse practitioner at HonorHealth Research Institute in Scottsdale, Arizona, told Medscape Medical News.

"We know through tumor tissue analysis that one of the hallmarks of pancreatic tumor cells is that they tend to harbor many DNA repair problems and that is a vulnerability when we look at treatment options," she added.

"We also know that cisplatin can target cells that have DNA repair problems and that is why we thought to add it."

The study was published online October 3 in the Journal of the American Medical Association (JAMA) Oncology.

"By adding the drug cisplatin to the current standard of care — nab-paclitaxel plus gemcitabine — we demonstrated substantial clinical activity," said senior author Daniel Von Hoff, MD, director, TGen's molecular medicine division and chief scientific officer at HonorHealth Research Institute, in a statement.

"The results of this triple-drug regimen (dubbed the 'TGen Triple') are very encouraging for these patients," he added.

Details of the Results

The study included 25 previously untreated patients with a median age of 65 years. Slightly over half were male and almost all were white.

Most of these patients (19/25, 76%) had elevated CA19-9 levels at baseline, and 18 patients were subsequently followed up with measurements of this known tumor marker.

All patients received the three drugs, all given intravenously on days 1 and 8 every 21 days until disease progression or unacceptable toxicity, at a dose of 125 mg/m² nab-paclitaxel plus 1000 mg/m² gemcitabine plus cisplatin at one of three doses: 25 mg/m², 37.5 mg/m², or 50 mg/m². The maximum tolerated dose of cisplatin turned out to be 25 mg/m², which was given to 16 patients in the second phase of the study.

Patients also received IV premedication with dexamethasone, palonosetron, and fosaprepitant followed by oral dexamethasone and ondansetron twice a day for 2 days after each chemotherapy session.

Patients were also aggressively hydrated on days 2 and 9 of each cycle, and received pegfilgrastim subcutaneously on day 9 of each cycle.

The median duration of treatment was eight cycles, and almost one third of the group was able to receive treatment for at least 6 months.

"Tumor response was assessed every 9 weeks by spiral computed tomography or magnetic resonance imaging per RECIST 1.1," the investigators note.

The objective response rate in the 24 evaluable patients was 71%, the authors report, with two patients (8%) achieving a complete response (CR) and 15 patients or 62% achieving a partial response. Disease stabilized in another four patients (17%), but three patients (12%) had progressive disease, the researchers observe.

Of these 24 evaluable patients, 16 patients (64%) were still alive at 1 year, and 10 patients (40%) were still alive at 2 years, investigators report.

At 3 years, four patients (16%) were again still alive, and one patient (4%) was still alive at 4-plus years, researchers add.

Improvement on Historical Results

As Jameson noted, without treatment, historically, OS rates in patients with advanced disease ranged between 3 to 6 months.

With gemcitabine alone — the first drug approved to treat advanced pancreatic cancer — this historical rate increased to about 6 months.

Then nab-paclitaxel plus gemcitabine together extended the OS to 8.5 months.

Now, with the triple drug regimen used in the current study, the median OS was 16.4 months.

However, the OS ranged from 36 to 59 months, as investigators report.

Median progression-free survival in the current study was also 10.1 months, yielding a disease control rate of 88% at 9 weeks of follow-up, they add.

Adverse Events

Treatment-related adverse events (AEs) of grade 3 or higher were hematological, with 68% of patients developing thrombocytopenia, 32% developing anemia, and 24% developing neutropenia.

"A total of 16 serious AEs were reported in 12 patients (48%), of which 12 were considered treatment-related," the authors observe.

Fatal events occurred in three patients (12%), of which two were judged to be related to study participation.

Again, however, while hematological toxicity was frequently seen, "most adverse events did not require clinical intervention . . . [and] tolerance of therapy was acceptable, with nearly two-thirds of patients completing full-dose therapy for 3 or more cycles," Jameson and colleagues point out.

The authors also suggest that the aggressive hydration with IV fluids on days 2 and 9 following each chemotherapy session as well as pegfilgrastim support likely minimized the toxicities seen in the study.

Investigators note that their primary endpoint — a 25% CR rate as defined by RECIST 1.1 criteria and by CA19-9 normalization or by CA-125 or CEA normalization in CA19-9 nonexpressers — was not reached.

Even so, "the high objective response rate reported [in this study] is among the highest observed in phase 1b/2 study results," researchers point out.

Investigators also note that most patients with elevated CA19-9 levels at baseline had a rapid decrease in CA19-9 levels — consistent with radiologic findings of a decrease in tumor size, they add.

Further study of the same triple regimen in the metastatic disease setting is now underway.

Jameson reported grants and personal fees from Celgene and Ipsen. Von Hoff has relationships with multiple companies, which he fully discloses in the publication.

JAMA Oncology. Published online October 3, 2019. Abstract

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