Second-Line Motixafortide Plus Pembrolizumab/Chemo Substantially Improves Survival in Stage IV PDAC

Manuel Hidalgo, MD, PhD

The combination of motixafortide (BL-8040) plus pembrolizumab (Keytruda) and chemotherapy was found to result in a substantial improvement in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) when used as a second-line treatment in patients with stage IV pancreatic ductal adenocarcinoma (PDAC), according to final data from the phase 2a COMBAT/KEYNOTE-202 trial (NCT02826486).¹

The data with the novel triplet regimen demonstrated a substantial improvement across all study end points vs historical results.

Specifically, the median OS with the triplet was 6.5 months vs 4.7 months seen with liposomal irinotecan (Onivyde) plus 5-fluorouracil (5-FU)/leucovorin in the phase 3 NAPOLI-1 trial (NCT01494506).² Moreover, the median PFS reported with the triplet was 4.0 months vs 2.7-3.1 months, as was observed in a systematic review of oxaliplatin- or irinotecan-based chemotherapy.^3,4

Additionally, motixafortide plus pembrolizumab/chemotherapy elicited a confirmed ORR of 13.2% vs just 7.7% with liposomal irinotecan.⁴ The ORR was 21.2% with the triplet regimen vs 16% with liposomal irinotecan plus 5-FU/leucovorin.² Also, the disease control rate (DCR) with the triplet was 63.2% vs 29% to 52%, as was seen with oxaliplatin- or irinotecan-based chemotherapy3 and liposomal irinotecan plus 5-FU/leucovorin.⁵

“These results are highly encouraging in light of the extremely challenging population, even among [patients with] PDAC, in this study cohort,” principal study investigator Manuel Hidalgo, MD, PhD, who is also chief of the division of Hematology and Medical Oncology, a senior member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork–Presbyterian/Weill Cornell Medical Center, stated in a press release.¹ “All patients were initially diagnosed at stage IV, and greater than 70% had liver metastases, key contributing factors to very poor prognoses. I believe the results from this study strongly support further development.”

In the phase 2 trial, investigators examined the safety and efficacy of motixafortide in combination with pembrolizumab as well as the combination of motixafortide, pembrolizumab, and liposomal irinotecan/5-FU/leucovorin in patients with metastatic PDAC.

A total of 43 patients diagnosed with unresectable stage IV metastatic PDAC who had experienced disease progression after frontline gemcitabine-based treatment were enrolled to the triplet arm of the trial.

To be eligible for enrollment, patients had to have histologically or cytologically confirmed adenocarcinoma of the exocrine pancreas, have metastatic disease, have documented progressive disease following previous gemcitabine-based treatment, and have a Karnofsky performance status of at least 70.⁶ Patients also had to have acceptable bone marrow, hepatic, and renal function. If they had active central nervous system metastases, clinically significant gastrointestinal disorders, or experienced severe arterial thromboembolic events less than 6 months before inclusion, they were excluded.

Study participants were given single-agent motixafortide as a priming treatment for the duration of 5 days; this was followed by combination cycles of motixafortide, pembrolizumab, and chemotherapy. Treatment was given until disease progression.

The primary end point of the trial was ORR, while key secondary end points included confirmed ORR, OS, PFS, and DCR.

Additional results revealed that the triplet had favorable tolerability, with a toxicity profile that proved to be consistent with the individual profiles of each of the agents alone. The severe toxicities reported with the regimen were determined to be as expected with chemotherapy-based combinations.

Moreover, the triplet regimen also proved to have safety advantages vs historical data pertaining to the specific chemotherapy agents utilized in the trial. For example, a lower incidence of grade 3 neutropenia was observed with the triplet vs historical data, at 7% vs 20%, respectively; this was also true with regard to the incidence of grade 3 infections, at 7% vs 17%, respectively.

“We are extremely pleased with these results, which demonstrate a meaningful improvement vs historical data across all study end points,” Philip Serlin, chief executive officer of BioLineRx, added in the release. “The consistent improvement across all study end points represents a key differentiating factor relative to other compounds that showed improvement in only 1 end point in their initial studies and eventually failed in advanced studies. These positive results are further supported by a long-lasting median durability of clinical benefit of 5.6 months that we observed in this trial.”

BioLineRx, the developer of motixafortide, announced plans to meet with regulatory authorities as it examines next developmental steps. The pharmaceutical company also shared that they anticipate presenting the full study dataset at an upcoming medical meeting.

References

1. BioLineRx announces final results from phase 2a COMBAT/KEYNOTE-202 triple combination study of motixafortide in second line metastatic pancreatic cancer (PDAC). News release. BioLineRx Ltd. December 16, 2020. Accessed December 16, 2020. http://bit.ly/2WnkV3C.
2. Mercadé TM, Chen L-T, Li C-P, et al. Liposomal irinotecan + 5-FU/LV in metastatic pancreatic cancer: subgroup analyses of patient, tumor, and previous treatment characteristics in the pivotal NAPOLI-1 trial. Pancreas. 2020;49(1):62-75. doi:10.1097/MPA.0000000000001455
3. Petrelli F, Inno A, Ghidini A, et al. Second line with oxaliplatin- or irinotecan-based chemotherapy for gemcitabine-pretreated pancreatic cancer: a systemic review. Eur J Cancer. 2017;81:174-182. doi:10.1016/j.ejca.2017.05.025
4. Onivyde. Prescribing information. Merrimack Pharmaceuticals, Inc; 2015. Accessed December 16, 2020. https://www.pfizermedicalinformation.com/en-us/zithromax
5. Wang-Gillam A, Hubner RA, Siveke JT, et al. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019;108:78-87. doi:10.1016/j.ejca.2018.12.007
6. Study assessing safety and efficacy of combination of BL-8040 and pembrolizumab in metastatic pancreatic cancer patients (COMBAT-KEYNOTE-202) (COMBAT). Clinicaltrials.gov. Updated June 9, 2020. Accessed December 16, 2020. https://clinicaltrials.gov/ct2/show/NCT02826486