Leveraging Limited Data in Metastatic Pancreatic Cancer

Damian Laber, MD

Although both regimens carry added toxicities, FOLFIRINOX and the combination of gemcitabine and nab-paclitaxel (Abraxane) have each been shown to improve survival over gemcitabine alone for patients with metastatic pancreatic cancer, said Damian Laber, MD.

Results of the phase III MPACT study showed that the combination of gemcitabine and nab-paclitaxel improved progression-free and overall survival (OS) over gemcitabine alone (HR, 0.69; 95% CI, 0.58-0.82; P <.001) in patients with metastatic disease with a Karnofsky performance status score ≥70.¹ However, common grade 3/4 toxicities included fatigue, neutropenia, and sensory neuropathy.

The PRODIGE 4 ACCORD 11 trial compared FOLFIRINOX with gemcitabine in patients with chemotherapy-naïve metastatic disease and an ECOG performance status ≤1. The trial indicated a 4.3-month extension in median OS with FOLFIRINOX compared with gemcitabine alone (HR, 0.57; 95% CI, 0.45-0.73; P <.001). Moreover, the median PFS was improved by 3.1 months with FOLFIRINOX versus gemcitabine monotherapy (HR, 0.47; 95% CI, 0.37-0.59; P <.001). Similarly, FOLFIRINOX resulted in a higher rate of grade 3/4 fatigue, neutropenia, and sensory neuropathy.

Then, the PRODIGE-35/PANOPTIMOX study was designed to see if an oxaliplatin stop-and-go strategy could offset some of the toxicities seen in the initial trial. Patients were randomized to receive standard FOLFIRINOX (arm A); FOLFIRINOX followed by 5-fluorouracil (5-FU)/leucovorin until progression, after which FOLFIRINOX was reintroduced (arm B); or sequential therapy with FOLFIRI.3 and gemcitabine (arm C).

Results showed indicated similar rates of median OS and PFS between arms A and B, demonstrating the feasibility and efficacy of a stop-and-go approach for patients who are unable to tolerate the full FOLFIRINOX regimen.

However, besides modifications to existing regimens, physicians have not been as successful in developing novel therapies for patients, explained Laber.

“Since 1997, when gemcitabine showed an improvement in survival, pain, performance status, and clinical benefit versus 5-FU, it took 14 years for a combination to make a significant difference. During those years, a lot of combinations with gemcitabine were negative. There was only one positive study with erlotinib (Tarceva), but the benefit was so small that most physicians do not use it,” said Laber.

In an effort to improve survival outcomes, several studies are examining the use of vaccines in combination with PD-L1 inhibition as a way to enhance the body’s immune response against tumor growth.

“There are several new agents trying to attack the matrix of pancreatic cancer,” added Laber. “By doing that, we may be better able to deliver drugs to patients.”

OncLive: Could you discuss the trials that led to current frontline approaches?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Laber, hematologist/oncologist and senior member of Moffitt Cancer Center, provided a brief history of the trials that led to current frontline and second-line standards for patients with metastatic pancreatic cancer and shared his hope for the future of the treatment paradigm.Laber: It took many years [to establish FOLFIRINOX as a frontline treatment for patients with metastatic pancreatic cancer]. In 2011, a study was published comparing gemcitabine with FOLFIRINOX; patients in that study had not received prior chemotherapy. They had to have locally advanced or metastatic disease and were not candidates for curative therapy; the randomization was done fairly well.

The results showed that patients who received FOLFIRINOX had an improvement in OS compared with patients who received gemcitabine. There is more toxicity with the combination, but the quality of life was improved with the combination. As a caveat, not everyone can tolerate this regimen. Patients have to have good organ function and a good performance status.

Could any of these chemotherapy agents be dropped to increase the tolerability of FOLFIRINOX?

What therapies are available in the second-line setting?

The second study published in 2013 compared gemcitabine with the combination of nab-paclitaxel and gemcitabine. In that study, the patients who received the combination had an improvement in OS and PFS. Patients also experienced a little bit more toxicity, but overall it was quite manageable. This is a combination treatment, so patients have to have good organ function and a good performance status to tolerate it.That's what was looked at in the PRODIGE-35/PANOPTIMOX study. The study randomized patients to 6 months of FOLFIRINOX, 4 months of FOLFIRINOX followed by 5-FU/leucovorin, or single-agent gemcitabine alternating with FOLFIRI.3. In Arm B, FOLFIRINOX was reintroduced if patients progressed; the third arm was the worst arm. Arms A and B showed the same PFS. The response rates between those arms were very similar as well. This is a phase II study, so we don't have survival data yet. However, in the clinic we're seeing that a lot of patients cannot tolerate the full FOLFIRINOX regimen for a long time. This study gives us options.We don't have data on FOLFIRINOX in the second-line setting. The question is whether it will work as well or whether patients will be in good enough shape to tolerate that regimen.

For patients who progress after some combination with gemcitabine, we have data from the NAPOLI study, which randomized patients to nanoliposomal irinotecan plus 5-FU, single-agent 5-FU, or 5-FU/leucovorin. That trial didn’t show much improvement with single-agent 5-FU. However, the combination of nanoliposomal irinotecan plus 5-FU indicated the best improvement in PFS and OS. That combination has since been approved and is available as second-line treatment in patients who have progressed after gemcitabine-based therapy.

What are some emerging regimens?

Were you surprised by the negative results of the combination of PEGPH20 and FOLFIRINOX?

Moving forward, what can clinicians anticipate?

We don't have a true second-line treatment for patients who progress after FOLFIRINOX. Most of us use gemcitabine or a combination with gemcitabine because of the older data showing clinical improvement. Beyond that, we really don't know.Some phase III studies have completed. We also have data on the patients who have microsatellite instability-high tumors. Unfortunately, in pancreatic cancer, it's about 1% of patients. We are hoping some of the vaccines might prove helpful, but so far, they have not. There are even some experimental treatments with chimeric antigen receptor T cells, though these are very early in development.The negative results were disappointing because we want these medicines to help our patients. We have to accept that delivering more of a drug may not be what we need because the cancer cells may already be resistant to those agents. I'm sure there will be more [explanations] when we see the final results of the study.We're going to get smarter in how we treat these patients, and when I say get smarter, I mean with the limited data we have. We may use combinations with rapid de-escalation or with some of the maintenance therapies. I hope we can start profiling our patients better because personalized medicine in pancreatic cancer hasn't been that exciting so far; I hope it will get better.

References

1. Von Hoff DD, Ervin T, Arena FF, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Eng J Med. 2013;369(18):1691-1703. doi: 10.1056/NEJMoa1304369
2. Conroy T, Desseigne F, Ychou M, et al, for the Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. doi: 10.1056/NEJMoa1011923.
3. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-1703.
4. Dahan L, Phelip JM, Le Malicot K, et al. FOLFIRINOX until progression, FOLFIRINOX with maintenance treatment, or sequential treatment with gemcitabine and FOLFIRI.3 for first-line treatment of metastatic pancreatic cancer: a randomized phase II trial (PRODIGE 35-PANOPTIMOX). Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 4000. meetinglibrary.asco.org/record/159166/abstract.