Presentation by Dr Daniel Lin, MD, MSc, Sidney Kimmel Cancer Center, Jefferson Health
At the 2023 Total Health ASCO Direct Conference held in Philadelphia, Pennsylvania. Dr Daniel Lin from Sidney Kimmel Cancer Center at Jefferson Health highlighted several abstracts on the non-colorectal cancer gastrointestinal (GI) malignancies, as reported at this year’s meeting of the American Society for Clinical Oncology (ASCO).
Pancreatic Cancer: NAPOLI-3 Updated Findings
Dr Lin began by reviewing some updated findings from the NAPOLI-3 Trial, a phase III study which examined the use of the NALIRIFOX regimen (BOX 1) as compared to nab-paclitaxel with gemcitabine (Gem+Nab-P), in patients with previously untreated (treatment-naïve) metastatic pancreatic ductal adenocarcinoma (mPDAC). Dr Lin noted that FOLFIRINOX (BOX 1) and Gem+Nab-P remain the primary first line (1L) treatment options for mPDAC, as both regimens improve overall survival (OS) versus gemcitabine alone. The primary endpoint in NAPOLI-3 was OS, with secondary endpoints of progression-free survival (PFS), overall response rate (ORR), and safety profile. Results of the trial showed a significant benefit of the NALIRIFOX regimen over Gem+Nab-P in OS (median 11.2 versus 9.2 months; P=0.04), as well as PFS (median 7.4 versus 5.6 months; P<0.0001); results for OS and PFS were consistent at both the 12 month and 18 month time points. There was also higher ORR (41.8% vs. 36.2%), disease control rate (67.6% vs. 62.3%) and duration of response (DoR; 7.3 mo vs. 5.0 mo) with NALIRIFOX. Treatment-related adverse events (TRAEs) that were severe (defined as Grade 3 or higher, Gr 3+) were fairly comparable between both treatment arms. Hematologic events like anemia and thrombocytopenia were more common with Gem+Nab-P, while GI toxicity was higher with NALIRIFOX. Notably, the peripheral neuropathy rates were comparable between the treatment arms, which could be related to a lower dose of oxaliplatin used in the NALIRIFOX regimen.
Commenting on the overall results from NAPOLI-3, while acknowledging the limitations of comparing results between trials, Dr Lin noted that, although survival outcomes appear to be similar with FOLFIRINOX and NALIRIFOX based on the available data, the cost of the NALIRIFOX regimen is significantly higher, which could factor into treatment decisions. In addition, he noted that the NALIRIFOX and FOLFIRINOX regimens have not been directly compared, so the overall benefit of the NALIRIFOX regimen over FOLFIRINOX regimen may be questioned relative to its higher costs. He suggested that a 5-FU-based triplet regimen is preferred over Gem+Nab-P for fit mPDAC patients who have good performance status.
Box 1: First-Line Regimens in mPDAC
NAL-IRI = Nano-liposomal (NAL) formulation of irinotecan
Hepatocellular Carcinoma (HCC): MORPHEUS-Liver
Dr Lin then reviewed results from the MORPHEUS-Liver Study, a phase Ib/II study examining a new agent, tiragolumab, in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC). He reviewed the current treatment options for uHCC, based on the IMBrave150 and HIMALAYA studies, both of which showed an improvement in outcomes including PFS, OS, and ORR using immunotherapy in the 1L setting as compared with the previous standard of care, sorafenib. MORPHEUS-Liver was part of a larger study and examined the addition of tiragolumab, an anti-TIGI antibody, in combination with atezolizumab, another type of checkpoint inhibitor, and bevacizumab, an inhibitor of the VEGF pathway. The combination was compared with atezolizumab and bevacizumab alone (which had previously been tested in the IMBrave150 study) with the primary endpoint of ORR. The results showed an improvement in ORR with the addition of tiragolumab to the regimen, at 42.5% versus 11.1% with atezolizumab and bevacizumab alone, and PFS was also improved, at 11.1 versus 4.2 months, although Dr Lin noted that both the 11.1% ORR and the 4.2 month PFS were lower for atezolizumab and bevacizumab alone than that previously seen in the IMBrave150 study. In terms of adverse events (AEs), the tiragolumab arm had a higher incidence of lower grade toxicities, particularly dermatologic events such as rash, although the incidence of Grade 3+ AEs was fairly comparable between the treatments, and the percentage of immune-related AEs and those requiring systemic corticosteroids was also comparable. Commenting on the results of MORPHEUS-Liver overall, Dr Lin noted that despite some limitations of the study, the addition of tiragolumab improved the anti-tumor responses relative to atezolizumab/bevacizumab alone in patients with uHCC, and the triple combination treatment is now under investigation in a Phase III study (IMBrave152/SKYSCRAPER-14) to further validate the efficacy and safety of the regimen.
Biliary Cancer: HERIZON-BTC-01 and ReFocus
Lastly, Dr Lin highlighted 2 studies on biliary tract cancer (BTC). The first, HERIZON-BTC-01, examined the use of a new agent, zanidatamab in previously treated BTC patients who have amplification of human epidermal growth factor receptor 2 (HER2) in their tumors. Zanidatamab is a bispecific antibody therapy that binds HER2 and causes clustering and subsequent downregulation, or decreased expression of the HER2 receptor, on tumor cells. Patients in HERIZON-BTC-01 had advanced or metastatic BTC that had progressed on a prior gemcitabine chemotherapy regimen. Most patients in this trial were Asian, had gallbladder cancers, had stage IV disease, and had received prior gemcitabine and cisplatin therapy. The results of the trial showed durable responses to zanidatamab, with an ORR of 41.3% and a DoR of 12.9 months, and the majority of patients (68.4%) had reduction in their target lesions. The safety profile was also manageable, with a low number of events leading to discontinuation, no treatment related deaths and no TRAEs of Grade 4. Infusion-related reactions (IRRs) and diarrhea were the most commonly observed toxicities with zanidatamab, but these events were predominantly low grade and manageable. Overall, Dr Lin noted that zanidatamab may be a potential treatment option in HER2-positive biliary cancers, and additional trials of zanidatamab, in combination with gemcitabine + cisplatin are ongoing in BTC and other HER2-expressing GI cancers (NCT03929666).
The second BTC abstract detailed results from the ReFocus trial, a ‘first-in-human’ study of highly selective inhibitor of the fibroblast growth factor receptor 2 (FGFR2) called RLY-4008, in cholangiocarcinoma (BTC) and other solid tumors. The agent is indicated for patients with BTC who have a mutation or fusion in the FGFR2 gene that drives the growth of their tumor (driver alteration), and who are therefore candidates for targeted treatment using FGFR inhibitors (FGFRi). The results from ReFocus, which tested escalating doses of RLY-4008, showed promising efficacy for this agent, both in patients who had never received an FGFRi (FGFRi-naïve) and in those who had resistance to FGFRi (FGFRi refractory) and in patients with different driver alterations (BOX 2).
Box 2. Efficacy Results from ReFocus at 70 mg and Higher Dose of FGFRi RLY-4008
Disease Control Rate
Duration of Response
FGFRi-naïve, FGFR2 fusion+
100% (6 month PFS, 100%)
FGFRi-refractory, FGFR fusion+
93% (6 month PFS, 43%)
FGFRi-naïve, FGFR2 mutation+
Additional pharmacokinetic (PK) and pharmacodynamic (PD) data from ReFocus showed continuous inhibition of the FGFR target of 96% or greater at the once-daily 70 mg dose, which was recommended for phase II studies (RP2D). AEs in the study were mostly “on-target” (resulting from FGFR2 inhibition), of low grade, manageable, and largely reversible. Owing to the availability of targeted treatments, Dr Lin noted the importance of performing comprehensive genomic testing in BTC patients as a means to identify potentially actionable genomic alterations. Although the results for a phase II study of this agent are pending, Dr Lin noted that the addition of this new agent could allow for more efficient sequencing of FGFRi, allowing patients to continue their targeted therapy with FGFRi, and avoid chemotherapy for a longer period of time.
Pancreatic Adenocarcinoma (NAPOLI-3):
Hepatocellular Carcinoma (MORPHEUS-Liver):
Biliary Tract Cancers
Speaker Disclosure Information: Dr Lin lists his disclosures for this presentation as follows: Consulting: Exelixis, Roche-Genentech, Bristol Meyers Squibb.