Andrea Wang-Gillam, MD, PhD, associate professor, Department of Medicine, Oncology Division of Molecular Oncology, Washington University School of Medicine in St. Louis, discusses potential next steps with a novel combination regimen in pancreatic ductal adenocarcinoma (PDAC).

A recent phase 1 study (NCT02546531) evaluated the investigational FAK inhibitor in combination with pembrolizumab (Keytruda) and gemcitabine. The findings demonstrated signs of efficacy in the maintenance and relapsed/refractory settings in patients with metastatic PDAC.

As such, expanding this study in the maintenance setting appears to be a rational next step, says Wang-Gillam. Specifically, as the triplet was well tolerated, the regimen could have utility for patients who received a chemotherapy doublet in the frontline setting, or in combination with other agents in the frontline setting, concludes Wang-Gillam.

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Andrea Wang-Gillam, MD, PhD, discusses potential next steps with a novel combination regimen in pancreatic ductal adenocarcinoma.

Dr. Wang-Gillam on Next Steps With Defactinib Combo in Pancreatic Ductal Adenocarcinoma

Andrea Wang-Gillam, MD, PhD, associate professor, Department of Medicine, Oncology Division of Molecular Oncology, Washington University School of Medicine in St. Louis, discusses the results of a phase 1 study with defactinib in patients with pancreatic ductal adenocarcinoma (PDAC).

In a phase I study (NCT02546531), investigators evaluated the investigational FAK inhibitor defactinib in combination with pembrolizumab (Keytruda) and gemcitabine. The findings, which were presented as part of the virtual platform for the 2020 AACR Annual Meeting, demonstrated efficacy signals in both the maintenance and relapsed/refractory settings in patients with metastatic PDAC.

As part of the dose-expansion portion of the trial, patients enrolled in the maintenance cohort were required to have stable disease following frontline therapy with gemcitabine/nab-paclitaxel (Abraxane), says Wang-Gillam. Patients who progressed on 1 or more lines of systemic therapy were enrolled in the refractory cohort. This regimen could also be beneficial as a second-line option for these patients, adds Wang-Gillam.

In the dose-expansion cohort, patients received 400 mg of defactinib twice daily, 1000 mg/m

 of gemcitabine on days 1 and 8, and 200 mg of pembrolizumab on day 1 of a 21-day cycle. The regimen was well-tolerated in both cohorts. Updated outcomes and correlative analyses are to be presented in the future.

Andrea Wang-Gillam, MD, PhD, discusses the results of a phase 1 study with defactinib in patients with pancreatic ductal adenocarcinoma.



Dr. Wang-Gillam on Results of a Phase 1 Study With Defactinib in Pancreatic Ductal Adenocarcinoma

Andrea Wang-Gillam, MD, PhD, assistant professor, Department of Medicine, Oncology Division, Washington University School of Medicine in St. Louis, discusses the combination of the CCR2 antagonist PF-04136309 with FOLFIRINOX for the treatment of patients with borderline resectable and locally advanced pancreatic adenocarcinoma.

A phase Ib study investigating the combination found that the toxicity was very comparable with the FOLFIRINOX regimen alone. Efficacy findings were promising, notes Wang-Gilliam. The study found that 48% of patients taking the combination had a partial response and 48% had stable disease.

View more from the 2015 GI Cancer Symposium

Andrea Wang-Gillam, MD, PhD, assistant professor, Department of Medicine, Oncology Division, Washington University School of Medicine in St. Louis, discusses a combination treatment of PF-04136309 with FOLFIRINOX for borderline resectable and locally advanced pancreatic adenocarcinoma (PC).

Dr. Wang-Gillam on PF-04136309 Plus FOLFIRINOX in Pancreatic Adenocarcinoma

Andrea Wang-Gillam, MD, PhD, assistant professor, Department of Medicine, Oncology Division, Washington University School of Medicine in St. Louis, discusses the mechanism of action of MM-398, a novel encapsulation of irinotecan in a long-circulating nanoliposome.

Wang-Gillam says the agent consists of approximately 80,000 irinotecan molecules packed into a stable, liposomal-based nanopartical. This special delivery system allows the drug to stay in the circulation longer and results in a much higher AUC — 70-times higher AUC than conventional irinotecan.

Another feature of MM-398, Wang-Gillam says, is that it allows higher uptake of the drug at the tumor site. When patients who received MM-398 had their tumor biopsied, a 5-times higher active metabolite SM38 was seen compared to what they find in the patients’ blood at baseline.

These two key features make this delivery system much more attractive than conventional irinotecan, Wang-Gillam says.

Dr. Wang-Gillam Discusses the Mechanism of Action of MM-398

Andrea Wang-Gillam, MD, PhD, assistant professor, Department of Medicine, Oncology Division, Washington University School of Medicine and Siteman Cancer Center in St. Louis, discusses the trial design and results of the phase III NAPOLI-1 trial that examined MM-398 with 5-fluorouracil (5-FU) and leucovorin in patients with metastatic pancreatic cancer following progression on gemcitabine-based therapy.

Wang-Gillam says the primary endpoint of the study was overall survival (OS) and secondary endpoints included progression-free survival and response rate. The study was done globally and recruited patients from over 100 sites. The study had 3 arms, one examining MM-398 monotherapy, the second looking at 5-FU with leucovorin (control), and the third examined the combination of MM-398, 5-FU, and leucovorin.

Results of the study showed that the combination arm of MM-398 plus 5-FU/leucovorin had a superior OS compared with 5-FU/leucovorin alone (OS = 6.1 months vs 4.2 months). The combination of MM-398 plus 5-FU/leucovorin also showed superior progression-free survival (PFS), overall response rare (ORR), and CA19-9 response. 

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; 

 <.001) and CA19-9 levels were decreased by ≥50% in 36% versus 12% of patients in the combination and control arms, respectively.

View more from the 2014 World GI Congress

Andrea Wang-Gillam, MD, PhD, from the Siteman Cancer Center, discusses the trial design and results of the phase III NAPOLI-1 trial that examined MM-398 with 5-fluorouracil and leucovorin in patients with metastatic pancreatic cancer following progression on gemcitabine-based therapy.

Andrea Wang-Gillam, MD, PhD

Articles

Dr. Wang-Gillam on Next Steps With Defactinib Combo in Pancreatic Ductal Adenocarcinoma

Dr. Wang-Gillam on Results of a Phase 1 Study With Defactinib in Pancreatic Ductal Adenocarcinoma

Dr. Wang-Gillam on PF-04136309 Plus FOLFIRINOX in Pancreatic Adenocarcinoma

Dr. Wang-Gillam Discusses the Mechanism of Action of MM-398

Dr. Wang-Gillam Discusses the NAPOLI-1 Trial in Pancreatic Cancer