Mitazalimab/mFOLFIRINOX Is Tolerable, Generates Responses in Treatment-Naive mPDAC

The CD40 agonist mitazalimab in combination with modified FOLFIRINOX (mFOLFIRINOX) yielded early efficacy signals and a manageable safety profile in the frontline setting in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), meeting the primary end point of the phase 1b/2 OPTIMIZE-1 trial (NCT04888312), according to findings that were presented at the 2024 ESMO World Congress on Gastrointestinal Cancer.¹

Findings from the latest data update showed that, at a median follow-up of 18 months and a data cutoff of June 26, 2024, 17 patients who received the combination remained on treatment or in follow-up, and the confirmed objective response rate (cORR) was 42.1%.

A prior data update showed that the unconfirmed ORR with the combination was 50.9% (n = 29; 90% CI, 39.3%-62.4%). The cORR was 40.4% (n = 23; 90% CI, 29.4%-52.1%), which was compared with the 30% ORR seen with FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) as a historical control. Best overall responses of complete response, partial response, stable disease, and progressive disease were observed in 1.8%, 38.6%, 38.6%, and 26.3% of patients, respectively. The disease control rate (DCR) was 78.9%.

Furthermore, lead study author Teresa Macarulla Mercade, MD, PhD, noted in the presentation that, “an unprecedented duration of response [DOR] was observed over a long treatment and follow-up period. This provides an extended survival benefit for these patients.” Macarulla Mercade is the group leader of the Gastrointestinal and Endocrine Tumors Group and the Noncolorectal GI Cancer Translational Research Group at the Vall d’Hebron Institute of Oncology in Barcelona, Spain.

Part 1 of OPTIMIZE-1 was a dose-escalation portion where doses of mitazalimab were escalated from 450 µg/kg to 900 µg/kg, which was determined to be the recommended phase 2 dose (RP2D). This modified version of FOLFIRINOX included no 5-fluorouracil bolus and an irinotecan dose that was reduced from 180 mg/m2 to 150 mg/m2. Part 2 of the trial included a futility analysis (n = 23) followed by an interim analysis (n = 57) and the primary analysis (n = 57).

Patients could receive a CT scan until day –21 of treatment, at which point their tumors were biopsied. Patients began treatment by receiving a priming dose mitazalimab on days 1 and 10 and mFOLFIRINOX on day 8 of a 21-day cycle, during which dose-limiting toxicities were assessed. All subsequent cycles lasted 14 days, during which patients received mFOLFIRINOX on day 1 of each cycle and mitazalimab on day 3 of each cycle. Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. An end-of-study visit was conducted 28 to 56 days after patients’ end-of-treatment CT scan was conducted.

The objective of part 1 was to determine the RP2D of mitazalimab. The primary end point of part 2 was ORR. Secondary end points in part 2 included DOR, progression-free survival (PFS), overall survival (OS), DCR, safety, and pharmacokinetics. Exploratory end points in part 2 included pharmacodynamic biomarkers.

In the efficacy-evaluable population (n = 57), patients had a median age of 62 years (range, 43-77). Most patients were female (57.9%), had an ECOG performance status (PS) of 0 (54.4%), and had not received prior surgery for their disease (96.5%). The median time from diagnosis to the start of study treatment was 29.5 days (IQR, 21.8-35).

Among patients with CA19-9 data available at baseline (n = 48), 16.7%, 27.1%, and 56.3% of patients had levels below 100 U/mL, between 100 U/mL and 1000 U/mL, and over 1000 U/mL, respectively. Among 56 patients with available neutrophil:lymphocyte ratio data, 82.1% had a ratio below 5, and 17.9% had a ratio above 5. Among 55 patients with available primary tumor data, 45.5%, 38.2%, and 16.4% had primary tumors located in the head, body, and tail of the pancreas, respectively. Metastases were present in the liver (73.7%), lung (15.8%), peritoneal region (15.8%), lymph node (17.5%), and other sites (28.1%).

In the safety-evaluable population (n = 70), patients had a median age of 62 years (range, 43-77). Most patients were female (57.1%), had an ECOG PS of 0 (54.3%), and had not received prior surgery for their disease (95.7%). The median time from diagnosis to the start of study treatment was 29 days (IQR, 21-35).

Among the 61 patients with CA19-9 data available at baseline, 14.8%, 21.3%, and 63.9% of patients had levels below 100 U/mL, between 100 U/mL and 1000 U/mL, and over 1000 U/mL, respectively. Among 69 patients with available neutrophil:lymphocyte ratio data, 82.6% had ratios below 5, and 17.4% had ratios above 5. Among 67 patients with available primary tumor data, 43.3%, 34.3%, and 22.4% had primary tumors located in the head, body, and tail of the pancreas, respectively. Metastases were present in the liver (78.6%), lung (17.1%), peritoneal region (14.3%), lymph node (20.0%), and other sites (28.6%).

Findings from the latest data update showed that the median DOR was 12.6 months and the median PFS was 7.7 months, with a 12-month PFS rate of 35.1%. The median OS was 14.9 months, and the 12- and 18-month OS rates were 57.8% and 36.2%, respectively.

Previously, investigators reported that, at a median follow-up of 12 months, the median OS was 14.3 months (95% CI, 10.0-21.6), and the 12-month OS rate was 59.3% (95% CI, 44.2%-71.7%). The median DOR was 12.5 months (95% CI, 7.5-not evaluable [NE]). The median PFS was 7.7 months (95% CI, 5.8-11.3), and the 6- and 12-month PFS rates were 62.4% (95% CI, 48.3%-73.6%) and 34.0% (95% CI, 20.8%-47.7%), respectively.

Among patients who received mitazalimab 450 µg/kg (n = 5), any grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 60.0%, the most common of which were hypokalemia, peripheral neuropathy, nausea, and asthenia, which occurred in 1 patient each. Among patients who received mitazalimab at 900 µg/kg (n = 65), any-grade TEAEs occurred in 80.0% of patients, the most common of which were neutropenia (27.7%), hypokalemia (15.4%), anemia (12.3%), thrombocytopenia (12.3%), fatigue (10.8%), diarrhea (9.2%), peripheral neuropathy (7.7%), nausea (4.6%), and asthenia (4.6%).

Investigators observed that the expansion of CD4, natural killer T, and CD8 cell subsets that occurred on cycle 1 day 8 correlated with OS and depth of response outcomes. Patients with high CD4 effector T-cell expansion on cycle 1 day 8 had a median OS of 14 months (95% CI, 12-NE), whereas those with low CD4 effector T-cell expansion on cycle 1 day 8 had a median OS of 8.8 months (95% CI, 7.4-NE; P = .019).

“Overall, mitazalimab in combination with mFOLFIRINOX represents a promising regimen for patients with metastatic pancreatic cancer and will be developed as a frontline therapy in a randomized phase 3 trial,” Macarulla Mercade concluded.

Disclosures: Dr Macarulla reports performing consultant or advisory roles with Amgen, Servier, Incyte, Sanofi, AstraZeneca, Taiho, Celgene, and Boehringer; receiving research funding from Celgene, AstraZeneca, BeiGene, Incyte, and Servier; and performing speaking roles with AstraZeneca, Incyte, Servier, and Roche.

References

Macarulla Mercade TM, Borbath I, Geboes K, et al. CD40 agonist mitazalimab combined with mFOLFIRINOX (mFFX) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): primary analysis of the OPTIMIZE-1 phase Ib/II study. Ann Oncol. 2024;35(suppl_1):S119-S161. doi:10.1016/annonc/annonc1481