Presentation by Dr Greg Botta, University of California, San Diego
At the Total Health 2023 American Society for Clinical Oncology (ASCO) review held in Denver, Colorado, Dr Greg Botta, MD, PhD, from The University of California, San Diego presented relevant updates on the topic of the non-colorectal gastrointestinal (GI) cancers, as reported at the ASCO 2023 Annual Meeting.
Biliary Tract Cancers
For cancers of the biliary tract, Dr Botta highlighted 2 studies, specifically for cancers that are human epidermal growth factor receptor 2 positive (HER2+). Dr Botta noted that HER2+ tumors constitute about 20% of biliary tract cancers (BTC), with mostly gall bladder and extra-hepatic (non-liver) cases. The first trial, SGNTUC-019, was a “basket trial” that examined the efficacy of tucatinib and trastuzumab for previously treated patients with HER2+, metastatic BTC and other cancers. In the BTC subgroup, Dr Botta highlighted a 70% reduction in tumor size with the regimen, a median 5.5-month progression-free survival (PFS), and a median overall survival (OS) of 15.5 months. He noted “these are pretty good numbers” for efficacy in a second-line setting following a gemcitabine (chemotherapy)-based regimen in BTC. The use of blood-based testing for HER2+ status was also notable in the study, as often the availability of biopsy material is limited for BTC.
The second study, HERIZON-BTC-01, was a Phase IIb study evaluating the efficacy of monotherapy with a ‘bi-specific antibody’ type drug, zanidatamab, in patients with previously treated, HER2+, BTC. Similar to SGNTUC-019, the results showed that ~70% (68.4%) of patients had a reduction in their tumor target lesions with this single-agent treatment. The median duration of response was 12.9 months, and notably, the median PFS was also similar to that seen in the SGNTUC-019 trial, at 5.5 months, whereas the OS data was not yet mature. Summarizing, Dr Botta noted the similar efficacy of these agents in pretreated HER2+ BTC patients, and their overall favorable safety profile and tolerability in this setting.
For pancreatic cancer, Dr Botta highlighted updated findings of the NAPOLI 3 trial, which examined the efficacy and safety of the NALIRIFOX drug regimen versus a nab-paclitaxel + gemcitabine regimen in previously untreated, metastatic, pancreatic ductal adenocarcinoma (PDAC). The results showed a significant benefit of the NALIRIFOX regimen over the comparator with a median OS of 11.1 versus 9.2 months, respectively (hazard ratio [HR]=0.83; P=0.04). There was also a significant improvement in PFS with the NALIRIFOX regimen (median 7.4 mo. vs. 5.6 mo.; HR=0.69; P<0.0001). In terms of toxicity, Dr Botta noted a similar incidence of hematologic toxicities such as neutropenia between the regimens, but a higher incidence of GI toxicity such as diarrhea, nausea, and vomiting, with NALIRIFOX. He also highlighted the significantly increased costs of the NALIRIFOX regimen, which will have to be weighed against the clinical benefit.
Dr Botta also highlighted NORPACT-1, a randomized, Phase II trial which compared a short course of neoadjuvant (pre-surgery) FOLFIRINOX versus upfront surgery, for patients with operable pancreatic head cancer. Findings of this trial, he noted, were somewhat surprising, as the neoadjuvant treatment group actually had lower OS (25.1 mo. vs. 38.5 mo.; P=0.096), and a lower proportion of patients were alive at 18 months (60% vs. 73%; P=0.1). Upon closer examination of the trial, however, he noted that only 50% of the patients had completed the neoadjuvant treatment as per protocol, and 73% of patients in the neoadjuvant group had received a gemcitabine-based adjuvant regimen that was also off-protocol. Other unusual observations that were inconsistent with the poor outcomes included improved resection rates and better downstaging of the tumor in the neoadjuvant group. Overall, Dr Botta views the results as indicative that there are likely some pancreatic cancer patients that can be resected upfront, but this requires discussion in a multidisciplinary tumor board setting, and he expects that forthcoming data using CA 19-9 and/or other biomarkers, might be helpful to determine which patients are the best candidates for upfront surgery.
On the topic of gastroesophageal and/or gastroesophageal junction (GEJ) cancer, Dr Botta highlighted ATTRACTION-5, a Phase III study conducted in Asia, examining the addition of an immunotherapy (nivolumab) or placebo in combination with chemotherapy as adjuvant treatment for patients with stage III gastric or GEJ cancer. The results for the primary endpoint of recurrence-free survival (RFS) showed no difference between the nivolumab + chemo or placebo + chemo arms (68.4% vs. 65.3%; P=0.4363), and there was also no significant difference in OS, suggesting no benefit of adding an immunotherapy to adjuvant chemotherapy. A caveat which Dr Botta noted was an apparent benefit of the treatment in the subgroup of patients who had high programmed death ligand 1 (PD-L1) expression (a target for nivolumab), which will need to be further investigated. As a take home message from this trial, Dr Botta suggested that use of immunotherapy is not necessarily appropriate for all gastroesophageal cancer patients, but rather necessitates stratification in order to select those patients who are most likely to respond.
Also on the topic of advanced gastric/GEJ cancers, Dr Botta described results from a prospective, open-label, Phase II trial evaluating the use of peri-operative immunotherapy (toripalimab), in combination with chemotherapy (SOX or XELOX regimen) versus chemotherapy alone, with the main goal of determining whether the addition of immunotherapy is beneficial in this setting. The overall results showed more “down-staging”, or regression of tumors, in the immunotherapy group as compared with the chemotherapy group. For example, the percentage of patients in the more favorable, pathologic ‘T0-2’ group was higher in the immunotherapy versus the chemotherapy group (46% vs. 22%), while the percentage of patients with the less favorable, pathologic ‘T3-4’ status was higher in the chemotherapy group (48% vs. 74%). Given the favorable results of the trial, Dr Botta noted the approach will be further explored in a subsequent Phase III study.
For hepatocellular cancer (HCC), Dr Botta highlighted results from the IMbrave050 trial, a Phase III trial which examined the use of an immunotherapy (atezolizumab) in combination with an anti-vascular endothelial growth factor (anti-VEGF) agent (bevacizumab) as adjuvant therapy, as compared with active surveillance, for patients with HCC who have a high risk of disease recurrence following curative treatment (i.e., either surgery or ablation therapy). The results for the primary endpoint of RFS showed a significant improvement for the active treatment (Atezo+Bev) as compared with active surveillance (12-month RFS, 78% vs. 65%), and at median 17.4 month follow up, the HR for RFS was 0.72 (P=0.012). Results for the exploratory, patient-reported endpoints assessing quality of life (QoL) outcomes (e.g., physical, social, emotional functioning) showed no significant worsening of QoL with treatment versus active surveillance.
ASCO 2023 Non-Colorectal Cancer Updates with Dr Greg Botta: Quick Summary
Biliary Tract Cancers
Gastric/Gastroesophageal Junction (GEJ) Cancers
Speaker Disclosure Information: Dr Botta reported the following disclosures for this presentation: Speaker/Advisory Board, Natera; Advisory Board, TumorGen.