As soon as Merrimack Pharmaceuticals Inc. unveiled strongly positive data from the NAPOLI-1 phase III trial with MM-398 in metastatic pancreatic cancer patients previously treated with gemcitabine, investors began to mull the chances for the drug – a nanoliposomal encapsulation of the chemotherapy agent irinotecan – in first-line disease.

"Of course it's on our mind," too, said Peter Laivins, who heads late-stage development for Cambridge, Mass.-based Merrimack, responding to J.P. Morgan analyst Geoff Meacham during a conference call regarding the data. But Laivins said it was premature to speculate. "Right now we're just processing this initial data here and getting a full understanding of it," he said.

Wall Street understood it well enough, taking Merrimack shares (NASDAQ:MACK) on a ride that left the shares 59 percent higher at the end of Thursday, closing at $6.99, up $2.60, after selling for as much as $7.65.

NAPOLI-1 tested MM-398 with 5-fluorouracil (5-FU) and leucovorin and garnered an overall survival of 6.1 months, a 1.9 month improvement over the 4.2 month survival demonstrated by the control arm of 5-FU and leucovorin alone. The primary log-rank analysis of overall survival was statistically significant (p = 0.012) with a corresponding hazard ratio of 0.67. Researchers also noted a statistically significant advantage for progression-free survival was also observed in the combination arm.

As for adverse events, the most common grade 3 or higher ones in the combination arm were neutropenia (14.5 percent), fatigue (13.7 percent), diarrhea (12.8 percent) and vomiting (11.1 percent). Sepsis (3.4 percent) was the only serious life-threatening event that occurred with a more than 2 percent difference between the combination arm and the control arm.

NAPOLI-1, which enrolled 417 patients, was "designed really to catch two different regimens, both the monotherapy and the combination," Laivins noted. "Either one or both could be successful. If you think about treating pancreatic cancer patients, you really have to try to strike a balance between efficacy and toxicity of different regimens, and the combination arm achieved that with a very exciting 6.1 month survival, so we're head over heels about that result."

Specifically, the monotherapy gained a 4.9 month median overall survival, but did not achieve a statistically significant advantage compared to the 4.2 months in the control arm. The hazard ratio for overall survival was 0.99 with a corresponding "p" value of 0.942. In general, patients experienced a higher level of adverse events with the MM-398 monotherapy dose and treatment schedule compared to patients who received the combination therapy, Merrimack said.

"The monotherapy arm performed to our expectations," Laivins said, calling the 4.9 months "very similar to what we observed in the phase II trial, and better than what we expected in the survival estimates for the study itself. What was unexpected was the performance of the control arm at about 4.2 months. That was a level of activity that we hadn't seen in previous literature. The net [result] from the monotherapy vs. control is that both of those arms showed considerable activity."

In a research report, Cowen and Co. analyst Eric Schmidt called the results "impressive. We look forward to full data at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer, where we will look for any imbalances in basal patient population or subsequent therapy that could color the results, as well as secondary endpoints such as progression-free survival and response rate. Barring any such surprises, we believe MM-398 is likely to be approved and adopted."

Since gemcitabine-based regimens take up nearly 60 percent of front-line unresectable pancreatic patients, "the number of U.S. patients eligible for MM-398 and healthy enough to receive the drug might number more than 10,000 annually," Schmidt estimated. "This should translate into a multi-hundred million dollar revenue opportunity."

Merrimack plans to file a new drug application this year and will probably commercialize MM-398 itself in the U.S., as discussions with potential partners in the rest of the world continue.

"Merrimack's earlier pipeline, driven by its Network Biology approach to oncology, has the potential to yield a unique insight into therapy," in Schmidt's view, but the promise "remains to be clinically validated" by Merrimack and partner Sanofi SA, of Paris.

In late October, Merrimack reported a phase II failure but said two of five biomarkers turned out predictive of benefit from MM-121, a fully human monoclonal antibody that targets ErbB3, in 34 percent of ovarian cancer patients. The global, open-label, randomized study tested MM-121 in combination with paclitaxel vs. paclitaxel alone in patients with platinum-resistant or platinum-refractory advanced ovarian cancers. (See BioWorld Today, Oct. 31, 2013.)

Despite efficacy signals in biomarker-defined subsets of patients, MM-121 "has yet to produce convincing evidence" that it works, Schmidt wrote.