KEY TAKEAWAYS
- The NUMANTIA phase 1 & 2 trial aimed to investigate the efficacy of NLM-001, a Hh pathway inhibitor, in enhancing chemotherapy outcomes in pts with aPC.
- Researchers noticed promising efficacy and comparable safety with NLM-001 + G+nP+Z.
FOLFIRINOX and gemcitabine (G) in combination with nab-paclitaxel (nP) are the standard first-line (1L) treatment for patients (pts) with advanced pancreatic cancer (aPC) but the impact on outcomes is limited. The hedgehog (Hh) pathway plays an important role in developmental biology. In preclinical cancer models, Hh inhibitors disrupt the tumor microenvironment, increasing the delivery and efficacy of chemotherapy and immunotherapy. NLM-001 is an oral investigational small molecule inhibitor of the Hh pathway.
Roberto A. Pazo Cid and the team aimed to investigate the efficacy of NLM-001, a Hh pathway inhibitor, in enhancing chemotherapy outcomes in aPC.
They performed an inclusive analysis through a phase Ib/IIa, open-label, single-arm study in adults with aPC previously untreated and ECOG PS 0-1. Patients received standard treatment with G+nP. NLM-001 was administered at a dose of 800 mg/day p.o. on days -4 to -1 and 10-13 before G+nP treatment in cycles 1-3, 6-8, 11-13, and so on (3 cycles followed by 2 rest cycles). The anti-CTLA-4 inhibitor, zalifrelimab (Z), was administered on day 15 of cycle 1 and every 6 weeks thereafter. Disease burden was assessed monthly by a tumor-informed ctDNA test and bi-monthly by CT-Scan. Tumor biopsies were collected at baseline and on day 21.
About 22 pts were included, with a median age of 60 years; 59% were male and 91% had liver metastases. Treatment was well tolerated. The most frequent grade 3-4 adverse events (AEs) were neutropenia (41%), asthenia (27%), and neurotoxicity (14%). No pts discontinued study treatment due to toxicity. The objective response rate (ORR) was 50%, and the disease control rate was 95%. At a median follow-up of 8.5 months, median progression-free survival (PFS) was 7.1 months, and 1-year PFS was 32%. Seventy percent of pts had more than a 75% reduction in CA19-9.
Disease monitoring by serial analysis of ctDNA showed molecular responses in 14 of 20 pts. Patients who achieved ctDNA clearance at cycle 5 had significantly better PFS (7 vs 11.5 months; P<0.005). In 4 paired biopsies analyzed so far, researchers observed reduced hypoxia and cancer cell contents in all pts, and a reduction in CAF, Tregs, and macrophages in 1 patient.
The study concluded that the safety profile of NLM-001 + G+nP+Z is consistent with the expected G+nP regimen, with no new safety signals. Preliminary efficacy results are promising, and updated results will be presented during the congress.
The trial was sponsored by the Nelum Corp.
Source: https://cslide.ctimeetingtech.com/esmogi24hybrid/attendee/confcal/show/session/3
Clinical Trial: https://clinicaltrials.gov/study/NCT04827953
Cid R.A.P., Mercade T.M, McAndrews K, et al. (2024). “Phase Ib/IIa study to evaluate safety and efficacy of priming treatment with the hedgehog inhibitor NLM-001 prior to gemcitabine and nab-paclitaxel plus zalifrelimab as first-line treatment in patients with advanced pancreatic cancer: NUMANTIA study.” Presented at ESMO-GI 2024 (Abstract 331P).
