Second-Line Options Allow for Treatment Sequencing in Pancreatic Cancer

Evolving ParadigmsPancreatic Cancer

First-line therapies with improved efficacy might encourage use of second-line treatment in a larger proportion of patients with advanced pancreatic cancer.

Gemcitabine has an established role in first-line treatment of patients with metastatic pancreatic cancer. More recently, nab-paclitaxel has been integrated as an addition to gemcitabine in the first-line setting along with FOLFIRINOX. These agents can effectively be sequenced along with newer options.

5-FU, Leucovorin, and Oxaliplatin

The combination of 5-FU, leucovorin, and oxaliplatin (OFF regimen) demonstrated efficacy as a second-line option for patients with advanced pancreatic cancer following a gemcitabine-based regimen.11In an open-label phase III study, the OFF regimen was compared with best support care; however, the study was stopped early due to poor accrual.

The OFF regimen consisted of leucovorin at 200 mg/m2 followed by 5-FU at 2,000 mg/m2 on days 1, 8, 15, and 22 plus oxaliplatin at 85 mg/m2 on days 8 and 22. After a rest of 3 weeks, the next cycle was started on day 43. Overall, 46 patients were enrolled in the trial.

Median OS with the OFF regimen was 4.8 months compared with 2.3 months with best supportive care (HR, 0.45; 95% CI, 0.24-0.83;P= .008); however, thisPvalue was misleading because the study was stopped early. Those who received gemcitabine in the frontline setting followed by the OFF regimen had a total median OS of 9.1 versus 7.9 months for those who took gemcitabine followed by best supportive care (HR, 0.50; 95% CI, 0.27-0.95;P= .031).

Irinotecan Liposome Injection

In October 2015, the FDA approved irinotecan liposome injection (MM-398; Onivyde) in combination with 5-FU and leucovorin as a treatment for patients with metastatic pancreatic cancer following prior administration of a gemcitabine-based regimen. The approval was based on data from the phase III NAPOLI-1 trial, which enrolled 417 patients with gemcitabine-refractory metastatic pancreatic cancer.12

In the trial, patients were randomized to irinotecan liposome injection monotherapy, 5-FU with leucovorin (control), or irinotecan liposome injection plus 5-FU and leucovorin. Per standard irinotecan protocols, dexamethasone and a 5-HT3 antagonist could be administered in the combination arms.

In the irinotecan liposome injection combination arm, the median OS was 6.1 months compared with 4.2 months with 5-FU and leucovorin alone (HR, 0.57; 95% CI, 0.41-0.80;P= .0009). The median PFS was 3.1 months for the combination compared with 1.5 months with the control (HR, 0.56; 95% CI, 0.41-0.75;P= .0001). At 12 weeks, 57% of patients treated with the combination were alive and progression-free compared with 26% with 5-FU and leucovorin alone.

Irinotecan liposome injection monotherapy did not demonstrate superior efficacy compared with 5-FU and leucovorin. The median OS with monotherapy was 4.9 months versus 4.2 months with 5-FU and leucovorin (HR, 0.93;P= .5545). Moreover, irinotecan liposome injection alone was associated with more AEs compared with the combination, suggesting that the drug should only be used in combination.

TABLE 1. Grade 3/4 Adverse Events in NAPOLI-1

MM-398 Plus5-FU/LV

5-FU Plus LV



















Abdominal Pain






Abbreviations: ESA, erythropoiesis-stimulating agents; G-CSF, granulocyte-colony stimulating factor

Adverse events were higher with the combination versus the control arm (TABLE 1). For the combination versus single-agent irinotecan liposome injection, grade 3/4 diarrhea occurred in 12.8% versus 21.1% and the rates of vomiting were 11.1% versus 13.6%, respectively. Additionally, febrile neutropenia occurred in 1.7% of patients in the combination arm compared with 4.1% with irinotecan liposome injection monotherapy and not at all with 5-FU/leucovorin alone. Given the differences in efficacy and AEs, irinotecan liposome injection was specifically not approved for use as a single agent, the FDA emphasized in a statement.

Clinical Trial Data Provides Sequencing Clues

With second-line options now available, optimal treatment sequences have become a focus of research. According to findings presented at the 2016 GI Cancers Symposium,13second-line therapy is feasible, particularly following frontline nab-paclitaxel plus gemcitabine, yet it is often underutilized.

Patients who received any second-line therapy after progression on nab-paclitaxel/gemcitabine had a median OS of 12.8 months compared with 9.9 months for those who received gemcitabine alone in the first-line setting. Patients who received second-line FOLFIRINOX after frontline nab-paclitaxel and gemcitabine had the longest total survival (median OS of 15.7 months).

The analysis of second-line therapy was conducted on data from the MPACT trial. When the randomized treatment ended in 2013, an extension study was initiated to accumulate additional information about survival and clinical management, including second-line treatment for metastatic pancreatic cancer.

The dual primary objectives of the extension phase analysis were total OS from initial randomization and OS-2, defined as survival from the end of first-line therapy. About 40% of patients in the MPACT trial received second-line therapy, which included 5-FU or capecitabine in more than 75% of cases.

Patients who received second-line therapy had better baseline performance status, and those who received FOLFIRINOX in the second-line setting had better performance status at the end of first-line treatment.

During the randomized phase of the trial, 431 patients received nab-paclitaxel plus gemcitabine and 430 received gemcitabine alone. In the extension study, 170 patients in the nab-paclitaxel arm received second-line therapy, as did 177 patients randomized to the gemcitabine alone arm.

Among patients who received second-line therapy, 59% and 74% discontinued first-line therapy because of progression in the nab-paclitaxel/gemcitabine and gemcitabine monotherapy arms, respectively. Adverse events led to discontinuation for 26% of those in the combination arm versus 14% with single-agent gemcitabine.

Initial treatment with nab-paclitaxel was associated with significantly longer total survival among patients who received second-line therapy (P= .015). Additionally, in those who did not receive second-line treatment, OS was still significantly improved with the addition of nab-paclitaxel (6.2 vs 4.7 months;P<.001).

OS-2 was similar in the nab-paclitaxel combination and gemcitabine groups among patients who received second-line therapy (6.7 vs 6.4 months;P= .273), suggesting that second-line therapies were not the cause for the extension in OS in the MPACT trial. In those who did not receive second-line treatment, the OS-2 was significantly longer with nab-paclitaxel versus gemcitabine alone (2.5 vs 1.6 months;P<.001).

TABLE 2. Overall Survival With Second-Line Therapy


5-FU orCapecitabineContaining

5-FU orCapecitabineCombo





Plus Gemcitabine












Abbreviations: ESA, erythropoiesis-stimulating agents; G-CSF, granulocyte-colony stimulating factor

Patients treated with 5-FU plus capecitabine following frontline nab-paclitaxel/gemcitabine also experienced an extension in OS compared with gemcitabine alone. In this group, the median OS was 13.5 months compared with 9.5 months with monotherapy (TABLE 2).

In the absence of data, many strategies evolved for the second-line setting. In an interview, Philip A. Philip, MD, PhD, from Wayne State University, discussed his strategies for sequencing therapies for patients with pancreatic cancer, including novel chemotherapy combinations.

Q:What is your treatment strategy?

Philip: We use a lot of FOLFOX second-line, and also it&rsquo;s used in the community, FOLFOX with XELOX (capecitabine plus oxaliplatin). If you look at the data with FOLFOX, really it&rsquo;s not consistent. In fact, the OFF study, which was the initial trial that we interpreted as FOLFOX, was positive. But if you look at it, the curves are really very close. And then the Canadians presented a study in 2014 at ASCO where they showed, in fact, FOLFOX itself was worse than 5-FU/leucovorin in the control arm.

We had also experience in SWOG, with a study in the second-line, and I can tell you that the performance of FOLFOX wasn&rsquo;t really that good. So, we have a study that shows benefit, although, again, it&rsquo;s a modest benefit. So, we have to think of that as being, for the time being, the best evidence we have and to use that, and the best sequence will be to use gemcitabine/nab-paclitaxel in the frontline and then move on to a regimen, such as the one using NAPOLI-1 study, which makes sense. And also, you&rsquo;re removing that risk of exacerbation of neuropathy, because you&rsquo;re not going to use a drug that will affect that.

I think it&rsquo;s a nice way of sequencing that makes sense, based on evidence. The key thing is based on evidence. And, in fact, in the NAPOLI-1 trial, there were some patients who had received irinotecan in the frontline as a combination with gemcitabine. Look at the breakdown of the prior therapies.

Q:Would you ever then use FOLFOX third-line?

Philip: That opens up the discussion of, what&rsquo;s the philosophy of using second-, third-line treatments? I sit with academic oncologists, GI oncologists, from Dana-Farber, MD Anderson, Sarah Cannon. I always hear about, in advisory boards, when people say more than 70% of my patients go on a second-line. Well, wait a second, 70% of patients who come to MD Anderson or my institution get second-line. That&rsquo;s not the real world.

If you look at the clinical trials, even like MPACT, even in those trials, which were patients who went on first-line clinical trials—so, they&rsquo;re different than the average patient&mdash;50% is the maximum you see going on second-line treatment. If you go to the real world, community patients, it will be less than 20% or 30% that can go on second-line treatments.

It tells you something. The majority of those patients are still very compromised by the disease. But, the fact is that in the second-line treatment and third-line, probably, the chance of cytoreduction and getting a good response in those patients and a good PFS is really very small. So what becomes important? Quality of life. So, do I want to use FOLFOX in the third-line? Yeah, I can use it maybe in an outpatient who&rsquo;s doing very well because of biology, but it will not be my recommendation.

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