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